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  5. 人类寿命上限的生物学基础与影响因素研究综述

人类寿命上限的生物学基础与影响因素研究综述

深度研究匿名用户发表于 2025年11月26日 22:470阅读
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1. 人类寿命的生物学基础与理论上限探讨

1.1 传统寿命理论与极限值争议

人类寿命的生物学上限是一个长期存在争议的科学问题。传统上，有多种理论试图解释衰老的机制以及个体寿命的限制。其中，Hayflick极限和自由基理论是两个最具影响力的经典衰老理论。

Hayflick极限理论指出，正常人体细胞在体外培养中，其分裂次数是有限的，达到一定次数后便会停止分裂并进入衰老状态，这一现象被称为“复制性衰老” 12。莱纳德·海弗利克（Leonard Hayflick）在50年前发现，人类二倍体成纤维细胞在培养中的寿命是有限的 3。这一极限被认为是物种寿命的内在限制因素之一，因为它反映了细胞维持遗传完整性和功能的极限 1。端粒（Telomere）在其中扮演了关键角色。端粒是染色体末端的特殊异染色质结构，由富含G的重复DNA序列和特定蛋白质组成，对维持遗传完整性和功能至关重要 1。每次细胞分裂时，端粒会缩短。当端粒达到一定长度时，细胞就会停止分裂，触发细胞周期停滞，即Hayflick极限 14。虽然端粒酶可以延长端粒，但在大多数人体细胞中，端粒酶水平不足以阻止端粒DNA的丢失 5。因此，Hayflick极限为人类寿命设定了一个潜在的细胞层面的上限 2。

自由基理论则认为，衰老是由体内活性氧自由基（oxyradicals）的累积性损伤造成的 67。这些自由基是正常新陈代谢过程的副产物，它们会攻击细胞中的DNA、蛋白质和脂质等大分子，导致细胞损伤和功能障碍 6。随着时间的推移，这些损伤逐渐累积，最终导致组织和器官功能的衰退，进而影响整体寿命 7。研究发现，特定抗氧化剂（如超氧化物歧化酶、类胡萝卜素、α-生育酚和尿酸）的组织浓度与哺乳动物的寿命呈正相关，这支持了自由基在衰老过程中的作用 6。该理论在后来的发展中演变为线粒体衰老理论，强调线粒体作为自由基主要来源在衰老中的核心作用 7。

尽管这些理论为理解衰老提供了重要的生物学基础，但人类的实际寿命是否真的存在一个绝对的生物学上限，仍存在争议。从历史数据来看，人类的最高寿命一直在不断刷新。自19世纪初以来，人类的最高年龄增长了约20年 8。法国女性珍妮·卡尔芒（Jeanne Calment）活到122岁，是迄今为止有记录的最长寿个体 89。她的案例以及其他十多位达到115岁或更高年龄的个体，引发了关于人类寿命是否存在“天花板”的讨论 810。一些研究认为，尽管存在生物学限制，但人类死亡率的“高原现象”（plateau of human mortality）表明，在极端长寿的年龄段，死亡风险趋于平稳，这使得突破122岁的记录成为可能 10。然而，这并不意味着没有生物学上的限制。有观点认为，即便如此，寿命的延长仍可能伴随着疾病和共病的高发，因为超长寿个体并非总是健康状况良好 8。因此，这些经典理论虽然解释了衰老的部分机制，但对于人类寿命的最终极限，特别是能否突破现有记录，仍然存在持续的科学争议。

1.2 衰老的分子机制与非线性特征

衰老是一个复杂且多层面的生物学过程，其特征在于身体功能逐步下降，并与多种慢性疾病的风险增加密切相关。近年来，随着多组学技术的发展，我们对衰老过程中分子层面的变化有了更深入的理解，并揭示了这些变化的非线性特征 11。

一项针对18-95岁人群血浆蛋白质组的纵向分析研究，测量了4263名个体血浆中2925种蛋白质的水平，揭示了人类血浆蛋白质组随着年龄增长呈现出显著的非线性变化 11。该研究发现，在生命周期的第四、第七和第八个十年（大约44岁、60岁和80岁左右）会出现“变化波”（waves of changes）。这些关键年龄节点上的蛋白质组变化反映了不同的生物学通路重塑，并与年龄相关的疾病及表型特征在基因组和蛋白质组层面显示出差异关联 11。例如，在44岁左右，代谢和免疫通路可能发生显著的重塑，提示中年时期是衰老进程中的一个关键转折点。同样，60岁和80岁左右的波峰则可能与更广泛的系统性衰退和疾病易感性增加相关。这些非线性变化表明，衰老并非一个简单的线性过程，而是在特定年龄阶段存在加速或减速的关键节点，为理解衰老机制和寻找干预靶点提供了新的视角 1112。

除了蛋白质组的非线性变化，多种分子机制在衰老过程中扮演着核心角色，并对寿命构成限制。

端粒缩短：端粒是染色体末端的保护性结构，每次细胞分裂时都会缩短。当端粒达到临界短度时，细胞会进入不可逆的复制性衰老状态，停止分裂并丧失功能 1。端粒的缩短被认为是细胞衰老和寿命限制的关键因素之一 1。研究表明，慢性压力也会加速端粒缩短，这进一步强调了环境因素在细胞衰老中的作用 13。维持端粒长度的两种主要机制是端粒酶（Telomerase）和端粒替代延长（Alternative Lengthening of Telomeres, ALT）机制 14。虽然端粒酶能够延长端粒，但在大多数体细胞中其活性受到严格限制，导致端粒随年龄增长而缩短 1。有趣的是，某些与长端粒相关的基因突变（如POT1基因突变）可能导致端粒异常延长，但同时也增加了某些癌症和克隆性造血的风险，表明端粒长度的异常可能带来复杂的影响 15。

线粒体功能障碍：线粒体作为细胞的能量工厂，其功能衰退是衰老的另一个标志性特征 16。随着年龄增长，线粒体DNA损伤、活性氧（ROS）产生增加、线粒体动力学失衡以及清除受损线粒体的线粒体自噬（mitophagy）效率下降等问题日益突出 16。线粒体功能障碍会导致细胞能量供应不足、氧化应激加剧以及细胞凋亡增加，进而损害组织和器官功能 16。例如，神经元线粒体功能障碍已被证明与衰老相关的神经退行性疾病（如阿尔茨海默病）和认知功能下降密切相关 1718。此外，线粒体功能障碍在骨骼肌衰减症（sarcopenia）和衰弱（frailty）等老年综合征中也扮演着关键角色 1920。对线粒体质量控制（Mitochondrial Quality Control, MQC）机制的深入理解有望为延缓衰老和延长寿命提供干预策略，但过度激活或抑制任何一种MQC机制都可能加速异常能量代谢和线粒体功能障碍引起的衰老 16。

表观遗传学改变：衰老还伴随着DNA甲基化、组蛋白修饰和非编码RNA表达等表观遗传学模式的改变 21。这些变化不涉及DNA序列的改变，但会影响基因的表达，导致细胞功能失调 21。例如，Sirtuins是一类NAD+依赖性酶，在细胞代谢中发挥作用，并能调节DNA修复、炎症反应、细胞周期和细胞凋亡等多种细胞功能 21。Sirtuins的表达与衰老过程之间存在密切联系，被认为是潜在的抗衰老靶点 21。

细胞衰老：除了复制性衰老，细胞衰老还表现为应激诱导的衰老（stress-induced senescence），即细胞在面对各种损伤（如DNA损伤、氧化应激、炎症等）时，会停止分裂并分泌促炎因子，被称为衰老相关分泌表型（SASP） 17。衰老细胞的积累被认为是衰老和多种年龄相关疾病（如动脉粥样硬化、骨关节炎、糖尿病等）发生发展的重要驱动因素 17。在果蝇大脑中，衰老胶质细胞的形成与神经元线粒体功能障碍相关，并会促进非衰老胶质细胞中脂质的积累，表明衰老细胞在组织衰老中的复杂作用 17。

这些分子机制相互交织，共同构成了衰老的复杂网络，对人类寿命上限构成深远的限制。对这些机制的深入研究，特别是其非线性特征的揭示，为开发靶向性抗衰老策略提供了新的理论基础。

1.3 基因与遗传因素的作用

人类寿命的长度和健康衰老的进程受到多种因素的影响，其中遗传因素扮演着不可或缺的角色。对寿命和健康衰老的研究已揭示，遗传力在成年后的死亡年龄中约为25% 22。在极长寿个体中，这种遗传力的作用更为显著，这表明基因在决定超长寿命方面具有更大的影响力 22。随着基因组学技术的飞速发展，我们能够更深入地探索基因型与寿命之间的复杂关联。

可操作基因型与寿命影响

某些基因变异被明确认定为具有临床可操作性，即通过医学干预可以改善其引起的健康风险。例如，美国医学遗传学和基因组学学会（ACMG）推荐了73个基因，这些基因的致病性变异与一系列疾病风险增加相关。虽然ACMG推荐的基因列表主要关注疾病风险，但这些疾病与寿命长短之间存在直接关联。例如，APOE基因的ε4等位基因是阿尔茨海默病的主要遗传风险因子，而阿尔茨海默病是影响老年人健康和寿命的重要疾病之一。携带致病性变异可能导致寿命缩短，而通过早期诊断和干预，可以潜在地减轻这些基因对寿命的负面影响。

冰岛人群的研究为我们提供了基因与寿命关联的独特见解。一项研究发现，在淀粉样蛋白前体蛋白（APP）基因中的A673T（rs63750847）编码变异体与冰岛人群的晚发性阿尔茨海默病具有保护性关联，并且与长寿相关 23。这个变异体在北欧人群中相对常见，但在非北欧人群中极为罕见 23。尽管丹麦人群中该变异体的频率显著低于其他北欧国家，限制了其在丹麦人口中与长寿关联的评估 23，但这一发现强调了特定基因变异对长寿的潜在贡献，以及不同人群之间遗传背景的差异可能导致寿命相关基因变异分布的差异。

长寿基因及其潜在机制

除了致病性变异外，还存在一些“长寿基因”或与寿命相关的基因位点，它们通过延缓衰老进程来促进健康长寿。大规模全基因组关联研究（GWAS）已经识别出许多影响关键人类衰老性状（包括寿命）的基因座 24。例如，FOXO3A基因的变异已被发现与长寿显著相关 22。FOXO3A参与细胞应激反应、代谢调节和细胞凋亡等过程，被认为是衰老和寿命的关键调控因子。此外，APOE基因，除了其在阿尔茨海默病中的作用，也被发现与寿命存在关联，尽管其影响可能更为复杂，需要考虑基因-环境相互作用 22。

一项针对中国老年人群的20年队列研究构建了一个基于11个寿命相关位点的遗传风险评分。研究发现，健康的生活方式（如不吸烟、不饮酒、规律运动和健康饮食）与较低的全因死亡风险和更长的预期寿命相关，尤其是在具有高遗传风险的个体中，健康生活方式的寿命延长效果更为显著 25。这意味着，即使个体携带有不利的遗传背景，健康的生活方式也能起到缓冲作用，从而延长寿命 25。

总的来说，长寿基因通常通过以下机制发挥作用：

  • 维持基因组稳定性：修复DNA损伤，防止突变积累，从而减少细胞功能障碍和疾病风险 2426。
  • 调节代谢途径：影响能量代谢、营养感知等，如通过调节胰岛素/IGF-1信号通路等，这些通路在模式生物的寿命调控中发挥关键作用 2627。
  • 增强细胞应激抵抗：提高细胞对抗氧化应激、炎症和其他环境压力的能力，保护细胞免受损伤 26。
  • 优化免疫功能：维持免疫系统的稳态，降低慢性炎症水平，从而减少感染和自身免疫疾病的风险 26。
  • 促进蛋白质稳态：确保蛋白质的正确折叠、降解和清除，防止有毒蛋白质聚集，这对于神经系统健康尤为重要 26。

随着对这些“长寿基因”及其作用机制理解的加深，未来有可能开发出基于个体遗传特征的精准干预策略，以延缓衰老，促进健康长寿 28。

2. 环境与生活方式对寿命上限的调节作用

2.1 环境风险因素的全球负担

环境因素和生活方式在人类寿命上限的调节中扮演着至关重要的角色。全球疾病负担（Global Burden of Disease, GBD）研究提供了大量数据，揭示了环境风险因素对全球疾病负担和寿命的深远影响。环境和职业风险因素在2021年导致了全球18.9%（1280万）的死亡和14.4%的伤残调整生命年（DALYs），其中空气污染是主要驱动因素29。

空气污染的影响

细颗粒物（PM2.5）是全球最主要的室外空气污染物之一，也是导致全球疾病负担的主要环境风险因素。2021年，环境PM空气污染导致470万死亡和4.2%的DALYs，而使用固体燃料烹饪造成的家庭空气污染导致310万死亡和3.9%的DALYs29。PM2.5与年龄特异性死亡风险之间存在显著关联，且这种关联在不同年龄组中存在差异，在成人和老年人中更为显著30。

以中国为例，2021年PM污染导致约230万死亡和4670万DALYs，分别占总死亡的19.4%和总DALYs的11.6%31。其中，环境PM暴露导致190万死亡和3780万DALYs，而家庭固体燃料使用导致40万死亡和890万DALYs31。中风、缺血性心脏病和慢性阻塞性肺病是PM污染导致疾病负担的前三大原因31。值得注意的是，疾病负担在0-4岁儿童和70岁及以上人群中呈现两个高峰31。这表明，虽然空气污染对所有年龄段的人群都有影响，但老年人和婴幼儿是尤其脆弱的群体。环境PM的疾病负担在男性中更高，而家庭PM的疾病负担在女性中更高31。

从1990年到2021年，尽管中国总PM污染导致年龄标化死亡率下降了66.0%，家庭PM导致的死亡率下降了92.2%31，但环境PM导致的疾病负担持续增加，直到最近十年才开始下降31。这强调了持续加强环境空气污染控制的紧迫性，特别是在北方和西北地区。

代谢风险因素的影响

除了空气污染，代谢风险因素对寿命的影响也日益显著。GBD 2021研究指出，高收缩压、高空腹血糖、高BMI和高低密度脂蛋白胆固醇等代谢风险在老年人群中造成更大的健康影响32。从2000年到2021年，代谢风险导致的DALYs增加了49.4%，这反映了全球人口老龄化和生活方式的改变32。高BMI和高空腹血糖的年龄标化DALY率在此期间显著上升，分别增长了15.7%和7.9%32。

例如，缺血性心脏病（IHD）是全球主要的死亡原因，环境暴露对其负担有显著贡献33。1990年至2021年间，全球环境IHD死亡率下降了31.13%，DALY率下降了29.85%33。然而，高社会人口指数（SDI）地区IHD死亡率大幅下降了70.39%，而低SDI地区仅下降了3.13%33。颗粒物污染仍然是最大的环境贡献因素，在南亚、中东和北非地区的负担最高33。

不同年龄组风险因素的差异

GBD 2021研究强调了风险因素对不同年龄组影响的差异。对于0-4岁和5-14岁的年轻群体，低出生体重、早产以及不安全的饮用水、环境卫生和手部卫生（WaSH）是主要的风险因素32。而对于老年群体，高收缩压、高BMI、高空腹血糖和高LDL胆固醇等代谢风险的影响更大32。这些差异性表明，公共卫生干预措施需要根据特定年龄段的风险特征进行定制化设计。

环境改善对延长群体寿命的贡献

环境风险因素对寿命的负面影响是巨大的。例如，气候变化加剧了热浪、空气污染、病媒传播疾病、风暴和洪水等多种环境危害，导致疾病负担增加29。因此，通过改善环境质量来降低这些风险，能够显著延长群体寿命。减少环境PM空气污染和家庭空气污染，以及控制代谢风险因素，将是未来提高全球人口健康寿命的关键策略。通过实施旨在改善空气质量的公平公共政策，可以有效增加预期寿命30。在低SDI地区，将环境健康纳入发展战略至关重要，而在高污染负担地区，应加强空气质量监测和排放控制33。气候敏感地区需要实施适应气候变化的温度规划，而历史工业化地区则应加强铅暴露监测并确保男性职业保护33。

2.2 生活方式干预的实证效果

生活方式的选择对人类的寿命上限具有显著的调节作用，多项研究已证实通过饮食管理、规律运动和健康行为可以有效延长寿命并改善健康状况。

饮食限制与热量限制

热量限制（Calorie Restriction, CR）作为一种非遗传性干预手段，已被证实能可靠地延长多种物种的寿命，包括酵母、线虫、果蝇，甚至犬类等 34。一项长达20年的犬类寿命限制研究发现，对拉布拉多猎犬实施25%的热量限制，能使其中位寿命延长1.8年，并延缓了晚年疾病（特别是骨关节炎）的发生 3536。研究显示，与对照组相比，热量限制组的犬只体内脂肪量更少，胰岛素抵抗风险降低。高脂肪量和体脂率超过25%与胰岛素抵抗增加相关，而胰岛素抵抗则独立预测了寿命和慢性疾病的发生 35。热量限制的效果被认为与沉默信息调节因子2（Sir2）组蛋白去乙酰化酶及其哺乳动物同源物Sirt1的水平增加和活化密切相关 34。

间歇性禁食

间歇性禁食（Intermittent Fasting, IF），作为一种周期性地限制能量摄入的饮食模式，近年来受到广泛关注。多项研究表明，间歇性禁食能够带来诸多健康益处，包括延长寿命、减轻体重，并能对抗多种疾病状况 373839。这些益处部分是通过优化能量利用、促进细胞自噬（autophagy）和细胞更新来实现的 3839。自噬是细胞自我清理和回收受损细胞器及蛋白质的过程，对维持细胞健康和延缓衰老至关重要 38。有证据表明，间歇性禁食能激活多种生物学通路，诱导自噬，阻止癌细胞增殖和扩散，并延缓衰老 38。例如，精胺（spermidine）被发现是禁食介导的自噬和长寿所必需的，在酵母、线虫、小鼠和人体志愿者中，禁食或热量限制都能增加精胺水平，并通过自噬诱导和eIF5A的次黄嘌呤化介导其对寿命和健康的益处 40。动物模型和人体研究均表明，间歇性禁食能改善生理功能，提高运动表现，并减缓衰老和疾病进程 39。

健康心血管行为

心血管健康（Cardiovascular Health, CVH）水平与预期寿命密切相关。美国心脏协会（American Heart Association, AHA）提出的“生命必需8项”（Life's Essential 8, LE8）评分系统，评估了饮食、体育活动、烟草/尼古丁暴露、睡眠时间、体重指数（BMI）、非高密度脂蛋白胆固醇、血糖和血压等8个关键指标，用于衡量个体的整体心血管健康水平。

一项针对美国成年人的研究发现，在50岁时，高心血管健康（LE8评分≥80）的参与者比低心血管健康（LE8评分<50）的参与者平均预期寿命延长8.9年（95% CI, 6.2-11.5）41。在男性和女性中均观察到相似的显著关联 41。高心血管健康带来的寿命延长，其中42.6%可归因于心血管疾病死亡率的降低 41。

另一项针对英国成年人的队列研究也证实了高心血管健康水平与更长的无主要慢性病（包括心血管疾病、糖尿病、癌症和痴呆）的预期寿命相关 42。在50岁时，与低心血管健康水平的男性相比，高心血管健康水平的男性平均多活6.9年而无慢性疾病；女性则多活9.4年 42。研究还指出，高心血管健康水平可能有助于缩小社会经济健康不平等 42。这表明，采纳健康的生活方式，并不仅仅是延长生命，更是延长“健康生命”的关键。

晚年健康生活方式对延长寿命的作用

即使在老年阶段，保持健康的生活方式也对延长寿命和促进健康老龄化至关重要。一项对中国80岁及以上老年人进行的队列研究（中国长寿健康调查）评估了健康生活方式评分（HLS-100，包括吸烟、运动和饮食多样性）与成为百岁老人可能性之间的关系 43。研究结果显示，即使在非常高龄的人群中，坚持健康的生活方式也能显著提高成为百岁老人的几率 43。与最低HLS-100评分组（0-2分）相比，最高HLS-100评分组（5-6分）成为百岁老人的调整优势比为1.61（95% CI, 1.32-1.96; P < .001）43。这意味着，即使在生命后期，戒烟、保持规律运动和多样化饮食等健康习惯仍能为长寿带来益处。

具体而言，非吸烟、规律运动和限制饮酒等健康行为在老年人群中具有重要的寿命延长作用 44454647。世界卫生组织建议成年人每周进行150-300分钟中等强度活动或75-150分钟高强度活动 44。体育锻炼能显著促进睾酮生成，改善老年男性的身体功能、力量、蛋白质合成、骨密度和认知功能 44。戒烟和限制酒精摄入即使在老年阶段也具有健康益处 454647。此外，避免头部损伤、减少空气污染暴露和增加社交联系也被认为是预防认知功能下降的有效干预措施 48。

综上所述，通过热量限制、间歇性禁食、保持良好的心血管健康以及在生命各个阶段（包括晚年）坚持健康的生活方式，能够显著调节人类的寿命上限，并提高健康寿命的质量。

2.3 社会经济与代际因素

人类的寿命上限不仅受到生物学和个体生活方式的影响，还深刻地根植于复杂的社会经济和代际结构之中。教育水平、医疗资源可及性以及社会不平等作为核心的社会决定因素（Social Determinants of Health, SDH），通过多重机制调节着个体的健康行为、疾病累积风险以及最终的寿命长度，甚至影响到一个社会整体的寿命上限 49。

教育水平与寿命

教育水平是衡量社会经济地位的重要指标，与寿命长短呈正相关。通常而言，教育程度越高，个体获得优质工作的机会越大，收入水平也更高，从而能负担更好的生活条件、营养饮食和医疗保健服务。一项针对美国人群的研究发现，收入与预期寿命之间存在显著关联，收入最高的1%人群与收入最低的1%人群之间的预期寿命差距，男性为14.6年，女性为10.1年 50。虽然这项研究主要关注收入，但收入与教育水平往往高度相关。

父母的教育水平也被发现对子女的寿命产生深远影响。例如，历史研究表明，在18世纪至20世纪的美国，虽然寿命不平等现象在下降，但父母与子女寿命之间的关联并未减弱，甚至有所增强，这暗示了教育等代际传递的社会经济因素在寿命决定中的持续作用 51。教育还通过影响健康知识、健康行为（如吸烟、饮食和运动习惯）以及对医疗信息的理解和利用能力，间接调节寿命。

医疗资源可及性

医疗资源的可及性是影响寿命的另一个关键社会经济因素。即使在拥有普遍医疗保障体系的国家，医疗服务的质量和可及性也可能存在差异，从而影响特定人群的寿命。例如，瑞典拥有高预期寿命和低可避免死亡率，其医疗系统提供全民可及服务，且具有促进社会公平的悠久传统，公共支出占总医疗支出的86%以上，国民未满足的医疗需求水平较低 52。然而，其初级保健资源相对不足，并且存在劳动力短缺和医疗碎片化的问题，尤其是在护理协调方面。

与此形成对比的是，在一些低收入或社会经济地位较低的社区，医疗资源的可及性往往较差，这导致诊断延误、治疗不足，进而加剧健康不平等和寿命差距 5354。例如，马来西亚低收入人群面临着非传染性疾病、心理健康问题以及营养不良和身体功能受损等多重健康挑战，亟需可持续的干预模式来解决这些问题 55。在拉丁美洲，许多国家通过卫生系统改革，旨在扩大全民医疗保障，特别关注贫困公民，以减少医疗可及性方面的不平等 56。

社会不平等与累积健康差异

社会不平等是导致寿命差距的核心驱动因素。收入、教育、职业、居住地以及种族/民族等社会经济地位的差异，共同构成了复杂的社会不平等网络，并通过影响健康行为和累积健康差异来影响寿命 57。在美国，低收入个体的预期寿命在不同地区之间存在显著差异，这种差异与吸烟等健康行为高度相关，但与医疗可及性、物理环境因素、收入不平等或劳动力市场条件的相关性不显著 50。这表明，社会经济地位通过塑造个体的生活方式和健康选择，而非仅仅通过医疗服务，来影响寿命。

一项在英国和美国进行的全国性队列研究表明，对于患有2型糖尿病的成年人，不利的社会决定因素组合与更短的预期寿命和更高的未来不良健康结局风险相关 58。与社会决定因素良好组相比，社会决定因素不利组的45岁个体平均预期寿命在英国缩短4.4年，在美国缩短3.0年。这些关联在不同的社会背景下相似，并且在不同的人口统计学、生活方式和临床特征人群中基本一致，突显了社会决定因素在疾病管理和寿命预测中的重要性 58。

此外，代际支持和社区服务在缓解老年人抑郁症状方面发挥着重要作用。一项针对中国老年人的研究发现，代际支持、社区服务支持以及智能健康设备的使用均与较低的抑郁症状评分独立相关 59。这表明，社会支持网络和技术干预可以共同作用，改善老年人的心理健康，从而间接影响其健康寿命和整体寿命。

总体而言，社会经济和代际因素对人类寿命上限的调节作用是全面且深远的。解决教育不平等、提升医疗资源可及性以及缩小社会经济差距，不仅能够改善个体的健康状况，也是提升全社会整体寿命上限和健康寿命的关键。

3. 医疗技术与干预对寿命上限的突破潜力

3.1 抗衰老药物与生物制剂

随着对衰老分子机制理解的深入，开发针对性的抗衰老药物和生物制剂已成为延长人类健康寿命的重要方向。这些干预措施旨在调节关键的衰老通路、修复细胞损伤，从而延缓与年龄相关的疾病的发生和发展。

天然化合物的抗衰老机制

许多天然化合物因其在延缓衰老过程中的潜在作用而受到广泛关注，其中姜黄素和肌酸是两个典型的例子。

姜黄素 (Curcumin)：姜黄素是从姜黄（Curcuma longa）中提取的一种多酚类化合物，因其广泛的药理活性而备受瞩目，包括抗氧化、抗炎、抗癌和神经保护作用等 60。在抗衰老研究中，姜黄素被发现能够通过多种分子机制延长多种模式生物（如秀丽隐杆线虫、果蝇、酵母和小鼠）的平均寿命 60。

  • 抗氧化作用：姜黄素能够增强超氧化物歧化酶（SOD）等内源性抗氧化酶的活性，并降低丙二醛（MDA）和脂褐素水平，从而减少氧化应激对细胞的损伤 60。氧化应激是衰老和多种年龄相关疾病的重要驱动因素。
  • 调节信号通路：姜黄素能够调节多个与长寿相关的关键信号通路，包括胰岛素/胰岛素样生长因子-1信号通路（IIS）、mTOR通路、PKA通路和FOXO信号通路 60。这些通路在能量代谢、细胞生长、细胞自噬和应激反应中发挥核心作用，其调控失衡是衰老的重要特征。
  • 抗炎作用：慢性炎症被认为是“炎症衰老”（inflammaging）的关键组成部分，是衰老和年龄相关疾病的共同特征 61。姜黄素通过抑制促炎细胞因子和信号通路，发挥抗炎作用，从而有助于延缓衰老进程 60。
  • 改善脑能量代谢：姜黄素还被发现对认知功能和神经退行性疾病具有潜在的保护作用，部分机制可能涉及改善脑能量代谢和减少神经炎症 62。一项系统评价指出，姜黄素在认知功能、神经退行性疾病和肌肉健康方面可能具有改善作用，但仍需要更多的临床试验来验证其疗效和最佳剂量 62。

肌酸 (Creatine)：肌酸是一种天然存在于脊椎动物体内的氨基酸衍生物，主要储存于肌肉中，在能量代谢中扮演关键角色。虽然其抗衰老机制不如姜黄素研究广泛，但一些研究表明肌酸可能通过改善细胞能量稳态和抗氧化能力，对健康衰老产生积极影响。肌酸能够提高三磷酸腺苷（ATP）的再生速率，这对于维持高能量需求的细胞（如神经元和肌肉细胞）的正常功能至关重要。衰老过程中线粒体功能障碍和能量产生效率下降是普遍现象，肌酸的补充可能有助于缓解这些问题。

新型疗法：IL-11信号抑制

除了天然化合物，靶向特定信号通路的生物制剂也展现出巨大的抗衰老潜力。白细胞介素-11（IL-11）是一种IL-6家族的促炎细胞因子，近年来被认为是影响健康寿命和寿命的关键负面调节因子 6163。

  • IL-11在衰老中的作用：研究发现，随着小鼠年龄增长，IL-11在各种细胞类型和组织中的表达水平会升高，并通过调节ERK-AMPK-mTORC1轴来影响细胞、组织和整体水平的衰老病理学 6163。这意味着IL-11的过度激活可能加速衰老进程，导致代谢功能下降、多重共病和衰弱。
  • 抑制IL-11信号的益处：对小鼠的研究表明，敲除Il11基因或其受体Il11ra1基因，能够有效抵抗老年期的代谢衰退、多重共病和衰弱 6163。更令人振奋的是，对75周龄小鼠施用抗IL-11抗体25周，能够显著改善其代谢和肌肉功能，降低衰老生物标志物，并减少两性小鼠的衰弱程度 63。
  • 寿命延长效果：在寿命研究中，基因敲除Il11能够使两性小鼠的平均寿命延长24.9% 63。从75周龄开始施用抗IL-11抗体直至死亡，能使雄性小鼠的中位寿命延长22.5%，雌性小鼠延长25% 63。这些结果明确表明，IL-11是一种促炎因子，在哺乳动物的健康寿命和寿命中发挥负面作用 6163。
  • 临床转化潜力：鉴于抗IL-11疗法目前正处于针对纤维化肺病的早期临床试验阶段，这为评估IL-11抑制对老年人衰老病理学的效果提供了潜在的临床转化机会 63。

这些研究进展不仅揭示了抗衰老药物和生物制剂的多样性，也为未来开发更有效、更精准的干预策略以延长人类健康寿命指明了方向。通过靶向关键的衰老通路，我们有望在分子层面实现对衰老进程的调控，从而突破人类寿命的传统上限。

3.2 生物标志物与精准干预

随着衰老生物学研究的飞速发展，生物标志物已成为评估衰老进程、预测疾病风险和监测干预效果的关键工具。这些“衰老生物标志物”通过量化生物学年龄来捕捉个体间衰老轨迹的差异，从而为实现精准医疗和个性化抗衰老干预奠定基础 646566。

衰老生物标志物的验证标准与临床应用价值

一个理想的衰老生物标志物应具备以下特性：能够准确反映衰老过程中的生理变化、可重复测量、与年龄相关疾病和死亡率高度相关，并能响应抗衰老干预措施 6467。目前，DNA甲基化（DNAm）衍生的“表观遗传时钟”（epigenetic clocks）因其对生物学年龄的强大预测能力而备受关注。

  • 表观遗传时钟（Epigenetic Clocks）：这是一类基于DNA甲基化模式的模型，能够估算个体的生物学年龄 6869。它们比实际的年龄（chronological age）更能反映个体的健康状况和疾病风险。
    • Horvath’s clock 和 Hannum’s clock：这些是最早开发的表观遗传时钟，利用全基因组范围内的CpG位点甲基化数据来预测生物学年龄 69。
    • PhenoAge：这是一个基于1000多个CpG位点和七个临床生化指标（如白蛋白、肌酐、血糖等）开发的表观遗传时钟。它被证明与全因死亡率、心血管疾病、癌症、认知衰退等多种年龄相关结局的风险密切相关，并且优于单纯的实足年龄 6869。PhenoAge能够识别出那些“加速衰老”的个体，为早期干预提供了依据。
    • GrimAge：作为另一个重要的表观遗传时钟，GrimAge通过将DNA甲基化数据与血浆蛋白水平、吸烟状态等临床指标相结合，能更准确地预测全因死亡率，甚至能预测癌症和心血管疾病的发生风险 6869。
    • DunedinPACE：这个时钟衡量的是衰老的速度（pace of aging），而非简单的生物学年龄，可以捕捉衰老过程的动态变化，对于评估干预措施的效果尤为重要 6568。
    • DamAge 和 AdaptAge：一些最新的表观遗传时钟尝试引入因果信息。例如，DamAge和AdaptAge分别追踪有害性和适应性的甲基化变化。DamAge与不良健康结局（包括死亡率）相关，而AdaptAge则与有益的适应性变化相关。这些因果强化的时钟对短期干预措施表现出敏感性，有助于评估衰老相关的变化是否可逆 70。

这些表观遗传时钟的临床应用价值体现在：

  1. 风险分层：通过估算个体的生物学年龄，可以识别出高风险人群，对他们在年龄相关疾病方面进行更精细的风险分层 6568。
  2. 早期干预：在特定疾病发生之前，生物学年龄加速可以作为早期预警信号，为实施预防性干预提供“干预窗口” 65。
  3. 疗效评估：在抗衰老临床试验中，表观遗传时钟可以作为替代终点，快速评估药物或生活方式干预对衰老进程的影响 646769。

除了表观遗传时钟，其他“组学”（omics）技术也为衰老生物标志物的发现和应用提供了丰富的数据 28。例如，基于核磁共振（NMR）的代谢组学分析能够识别与年龄相关的代谢物特征。一项针对英国生物银行25万多人的研究，分析了325个NMR生物标志物，识别出54个与全因死亡率相关的代表性衰老相关生物标志物，并开发了一个代谢衰老评分，该评分在预测短期死亡风险方面优于其他衰老指标 71。

然而，目前衰老生物标志物的转化仍面临挑战，包括缺乏统一的验证标准、个体变异性大以及测量技术标准化等问题 646772。未来需要更多纵向研究来建立稳健的生物标志物。

多组学衰老时钟指导个性化干预

多组学整合（Multi-omics integration）是未来精准干预的关键。通过结合基因组学、转录组学、蛋白质组学、代谢组学和表观遗传组学数据，可以构建更全面的“衰老时钟”，更准确地描绘个体的衰老状态和潜在风险通路 65。这些多组学数据能够揭示衰老过程中分子网络的复杂变化，从而指导个性化的抗衰老策略。

  • 营养基因组学（Nutrigenomics）：该领域研究个体基因型如何影响其对饮食成分的反应，以及饮食如何影响基因表达。通过结合表观遗传时钟和营养基因组学，可以为个体设计最适合的饮食方案，以延缓衰老进程。例如，某些营养素（如抗氧化剂、omega-3脂肪酸、多酚和B族维生素）已被证明能够调节端粒长度和表观遗传状态，从而影响生物学年龄 7273。精准营养策略，特别是那些富含特定氮化合物的饮食，通过调节基因表达、细胞信号传导和代谢途径，对健康衰老产生深远影响 7274。
  • 靶向代谢通路调节：多组学分析可以识别在个体衰老过程中失调的关键代谢通路。例如，AMPK和Sirtuins的激活，以及mTOR信号通路的抑制，是热量限制和间歇性禁食等干预措施的核心机制，能改善胰岛素敏感性、脂质代谢和炎症 75。基于个体代谢组学特征，可以精准地选择能够调节这些通路的药物或营养补充剂。例如，对于APOE基因型不同的个体，对益生元菊粉的代谢反应也存在差异，这提示了营养基因组学在调节系统代谢和神经保护中的潜力 76。
  • 整合数字健康技术：将生物标志物与数字健康技术（如可穿戴设备监测的生理指标）相结合，可以实现对衰老进程的实时监控和个性化反馈，从而更好地指导生活方式干预和药物调整 2875。

总而言之，衰老生物标志物，特别是多组学衍生的衰老时钟，正在成为精准医学时代抗衰老策略的核心。通过对个体生物学年龄的精确评估，并结合多组学数据，未来将能实现高度个性化的干预，从而最大化地延长健康寿命。

3.3 再生医学与基因编辑

再生医学和基因编辑技术代表了突破人类寿命上限的未来方向，它们通过修复受损组织、逆转细胞衰老进程，甚至直接修改基因以增强长寿潜力。

端粒酶激活与衰老逆转

端粒是染色体末端的保护帽，在每次细胞分裂时会缩短，最终导致细胞衰老和功能丧失，这是细胞衰老的标志之一 7778。端粒酶是一种核糖核蛋白酶，能够通过合成端粒重复序列来维持端粒长度，从而延长细胞的复制寿命。在大多数体细胞中，端粒酶活性较低，导致端粒随年龄增长而缩短 77。

激活端粒酶被认为是延缓衰老和年龄相关病理的潜在策略。最近的研究发现了一种端粒酶逆转录酶（TERT）激活剂化合物（TAC），它通过MEK/ERK/AP-1信号通路提高TERT转录水平。在原代人类细胞和自然衰老的小鼠中，TAC诱导的TERT水平升高能够促进端粒合成，减少细胞衰老和炎症细胞因子，并抑制p16表达。在小鼠大脑中，TAC还能减轻神经炎症，增加神经营养因子，刺激成年神经发生，并在没有明显毒性（包括癌症风险）的情况下保留认知功能 79。这些发现强调了TERT在衰老过程中的关键作用，并为通过生理性TERT激活来减轻多种衰老标志和相关病理提供了概念验证 79。然而，需要注意的是，端粒过度激活也可能带来癌症风险，因为癌细胞常常依赖高活性的端粒酶来无限增殖。因此，开发安全有效的端粒酶激活策略仍需深入研究。

干细胞移植与组织修复

干细胞因其自我更新和多向分化潜力，在再生医学领域展现出巨大潜力，有望通过替代或修复受损组织来逆转衰老和延长寿命 80。随着人类预期寿命的增加，衰老导致的组织结构退化和功能下降日益突出，而干细胞疗法可能提供解决方案 80。

  • 干细胞在组织修复中的作用：干细胞能够分化成多种细胞类型，修复受损或退化的组织和器官。例如，间充质干细胞（Mesenchymal Stem Cells, MSCs）因其多能性、免疫调节和旁分泌效应，在治疗多种衰老相关疾病中显示出潜力。它们可以应用于心血管疾病、神经退行性疾病和骨关节炎等领域。
  • 衰老逆转的潜力：干细胞疗法能够通过多种机制延缓或逆转衰老进程，包括：
    • 替代衰老细胞：通过移植年轻、健康的干细胞，替换体内衰老或功能低下的细胞，从而恢复组织功能。
    • 分泌营养因子和生长因子：干细胞能够分泌多种生物活性分子，促进内源性细胞的生长、分化和存活，改善局部微环境，从而支持组织修复和再生 80。
    • 调节免疫反应：干细胞具有免疫调节特性，可以减轻慢性炎症，而慢性炎症是衰老的重要驱动因素。
  • 临床应用进展：在视网膜神经节细胞再生、子宫内膜修复等领域，干细胞疗法已取得显著进展 8182。然而，干细胞疗法的临床转化仍面临挑战，例如，为了将这些疗法转化为实际的医疗解决方案，需要解决确保安全性、优化递送机制、克服监管障碍以及解决高成本等关键问题 83。

基因编辑（CRISPR）与寿命延长

基因编辑技术，特别是CRISPR/Cas9系统，为精确修改基因组提供了前所未有的工具，这为靶向与衰老相关的基因并延长寿命带来了革命性的可能性 7884。CRISPR/Cas9系统能够特异性地切割DNA，从而实现基因敲除、基因修复或基因插入，为治疗遗传性疾病和延缓衰老提供了新的途径 84。

  • 靶向衰老相关基因：
    • 端粒维持：CRISPR/Cas9可用于调控端粒酶基因的表达，从而影响端粒长度。例如，可以通过基因编辑激活或增强端粒酶活性，以延缓端粒缩短，对抗细胞衰老 78。
    • DNA修复机制：衰老的一个重要特征是DNA损伤的积累。CRISPR/Cas9可以用于修复或增强DNA修复相关基因的功能，从而减少基因组不稳定性，延缓衰老进程 78。
    • 细胞代谢调控：CRISPR/Cas9可用于调控参与细胞代谢的基因，如mTOR、AMPK和Sirtuin通路相关的基因，这些通路与寿命调控密切相关。通过精确编辑这些基因，有望优化细胞能量代谢，从而延缓衰老。
    • 清除衰老细胞：衰老细胞在组织中积累是衰老和年龄相关疾病的重要驱动因素。CRISPR/Cas9可以通过特异性靶向衰老细胞的基因，诱导其凋亡或清除，从而减轻衰老细胞对组织的负面影响。例如，有研究探索利用CRISPR技术去除表达特定衰老标记物的细胞 78。
  • 动物模型中的寿命延长实验：在模式生物中，通过基因编辑技术延长寿命的实验已取得初步成功。将这些成果转化到人类仍面临巨大挑战，包括安全性、脱靶效应、递送效率以及伦理问题。
  • 人类应用中的挑战与伦理考量：尽管CRISPR技术前景广阔，但在人类应用中仍存在诸多挑战：
    • 安全性与脱靶效应：虽然基因编辑工具的改进旨在提高精确性，但基因编辑的安全性以及潜在的脱靶效应，即在非预期位置进行基因编辑，仍是需要关注的问题。确保基因编辑的精确性，避免不必要的基因组改变和潜在的副作用至关重要。
    • 递送效率：如何将CRISPR系统高效且特异性地递送到靶细胞或组织是实现临床应用的关键瓶颈。
    • 伦理与社会公平：基因编辑技术可能引发深刻的伦理问题，例如“设计婴儿”的争议，以及延长寿命技术可能加剧社会不平等的风险 8385。确保这些技术的可及性和公平性，避免其成为少数富人的特权，是亟需解决的伦理挑战。

综上所述，再生医学和基因编辑为突破人类寿命上限提供了强大的工具和前所未有的机遇。通过端粒酶激活、干细胞移植和精确的基因编辑，我们有望在分子和细胞层面逆转衰老，修复损伤，从而延长人类的健康寿命。然而，这些前沿技术在带来巨大希望的同时，也伴随着科学、技术和伦理层面的复杂挑战，需要审慎推进。

4. 全球寿命趋势与未来预测

4.1 不同地区的寿命差异与收敛趋势

全球人口的预期寿命在过去几十年中取得了显著进步，但不同地区之间的寿命水平和增长速度存在明显差异。全球疾病负担（GBD）研究持续追踪并预测这些趋势，为理解全球健康格局提供了关键洞察 86。

高收入国家与低收入国家的寿命差距

根据GBD 2021及2024年的预测数据，全球和超区域的预期寿命从2022年到2050年都将增加，但这种改善的速度将比COVID-19大流行前三十年要慢 86。未来预期寿命的增长预计主要发生在预期寿命相对较低的超区域，例如撒哈拉以南非洲，而高收入超区域的增长速度会较慢 86。这种趋势将导致各地区之间预期寿命的趋同，即低寿命地区的人口寿命增长速度快于高寿命地区，从而缩小全球范围内的寿命差距 86。例如，在参考情景预测下，撒哈拉以南非洲的预期寿命将有显著增长，而高收入国家（如北欧部分地区）虽然整体寿命水平较高，但增长空间相对有限 86。

然而，即使存在趋同趋势，高收入国家与低收入国家之间的寿命差距仍将持续。例如，在某些高收入国家和地区，如澳大利亚，其2019年的出生预期寿命为82.9岁，年龄标准化死亡率也显著降低 87。相比之下，撒哈拉以南非洲等低收入地区，尽管预期寿命有所改善，但仍面临更高的疾病负担和过早死亡率 86。这些地区在传染病、孕产妇和新生儿疾病以及营养不良相关疾病（CMNNs）方面仍然承受着巨大的DALY（伤残调整生命年）负担，尽管预测显示到2050年，这些地区的疾病负担将从CMNNs转向非传染性疾病（NCDs） 86。

人口老龄化对全球疾病负担的影响

全球人口老龄化是一个不可逆转的趋势，它对全球疾病负担产生了深远影响，并且在未来几十年内将持续加剧。随着预期寿命的延长，老年人口的比例不断增加，这意味着与年龄相关的慢性疾病，如心血管病、痴呆、糖尿病和癌症等，将成为主要的健康挑战。

  • 心血管疾病：缺血性心脏病（IHD）仍然是全球主要的死亡原因。虽然从1990年到2021年，全球年龄标准化IHD死亡率有所下降，但在低社会人口指数（SDI）地区下降幅度微小，而在高SDI地区则大幅下降 88。到2050年，缺血性心脏病预计仍将是全球DALYs的前四大主要原因之一 86。心力衰竭作为IHD的主要并发症，其病例数在2021年已超过1916万，到2045年预计仍将增加，特别是在较低SDI的国家，负担加剧 88。
  • 痴呆与神经退行性疾病：随着年龄的增长，神经退行性疾病如阿尔茨海默病和帕金森病的发病率显著上升。帕金森病预计到2050年将在全球范围内影响2520万人，比2021年增加112% 89。人口老龄化将是导致帕金森病病例增长的主要因素，贡献了约89%的增长 89。尤其是在东亚和撒哈拉以南非洲西部地区，帕金inson病病例将呈现显著增长 89。
  • 糖尿病：2型糖尿病的流行率在全球范围内呈上升趋势，2017年全球约有4.62亿人患有2型糖尿病，预计到2030年这一数字将继续上升 90。糖尿病是心血管疾病、肾病和失明等多种并发症的驱动因素，对老年人口的健康和寿命构成严重威胁。
  • 慢性肾病：人口增长和老龄化也是慢性肾病（CKD）负担增加的主要驱动因素 91。从1990年到2016年，全球CKD的患病率和死亡率均显著增加，其中63%的负担集中在低收入和中低收入国家 91。
  • 中风：中风是全球第二大死因，尤其是在低收入和中等收入国家，中风的发病率和疾病负担在1990年至2010年间有所增加 92。即使在75岁以下人群中，中风的负担也占了大部分 92。

2050年不同地区的寿命变化趋势预测

GBD 2021的预测显示，到2050年，全球所有年龄标准化DALYs（残疾调整生命年）的负担都将减少，这意味着整体健康状况将有所改善 86。然而，由于人口增长和老龄化，总的DALY负担（以数量计）在每个超区域都将增加 86。疾病负担的构成也将继续从CMNNs转向NCDs，特别是在撒哈拉以南非洲和南亚等地区，NCDs将占据更大的比例 86。

例如，在2050年，缺血性心脏病、中风、糖尿病和慢性阻塞性肺病将成为全球前四大DALYs原因，取代了2022年的新生儿疾病和下呼吸道感染等CMNNs 86。此外，从2022年到2050年，由YLDs（伤残致死年）引起的DALYs在全球范围内的比例将从33.8%增加到41.1%，这表明整体疾病负担将更多地转向发病率而非过早死亡，尤其是在撒哈拉以南非洲，YLDs导致的DALYs比例将大幅增加 86。

这些预测强调了公共卫生政策需要适应人口老龄化和疾病谱的转变。未来需要重点投资于非传染性疾病的预防和管理，特别是在低收入和中等收入国家，以应对不断增长的疾病负担，同时不能忽视CMNNs的持续预防和治疗 86。

4.2 健康寿命与寿命的平衡挑战

随着全球预期寿命的普遍延长，人类社会正面临一个日益严峻的挑战：如何确保延长的寿命同时伴随着健康和高质量的生活，而非仅仅是生命长度的增加。 “寿命延长但健康寿命未同步增长”的现象日益凸显，促使研究者和政策制定者将关注点从单纯的“寿命（lifespan）”转向“健康寿命（healthspan）”93。健康寿命是指个体在没有重大疾病或功能障碍的情况下，保持活跃和独立生活的时间。

“寿命延长但健康寿命未同步增长”的现状

尽管医学进步和公共卫生改善显著提高了预期寿命，但老年人普遍面临多重共病（multimorbidity）的困扰。多重共病通常定义为个体同时患有两种或两种以上慢性疾病94，其患病率随年龄增长而显著升高95。例如，糖尿病患者的寿命延长，但老年糖尿病患者往往伴有多重共病，如心血管疾病、肾病、认知障碍和衰弱等，这严重影响了其生活质量96。一项系统性综述和荟萃分析发现，多重共病与生活质量（Quality of Life, QoL）或健康相关生活质量（Health-Related Quality of Life, HRQoL）的显著下降有关94。每增加一种疾病，HRQoL的心理成分摘要得分平均下降1.55%，世卫组织生活质量简表（WHOQoL-BREF）身体健康领域得分平均下降4.37%94。这意味着，许多老年人尽管活得更久，却不得不忍受更多的疾病痛苦和功能受限，这与高质量的衰老目标背道而驰97。

老年多重共病对寿命质量的影响

多重共病对老年人的生活质量构成巨大挑战。它不仅增加了医疗负担，降低了身体功能，还影响了心理健康和社会参与98。

  • 风湿性关节炎加速衰老：类风湿关节炎（RA）是一种慢性自身免疫性疾病，其患者的预期寿命通常会缩短99100。研究表明，加速的生物学衰老（通过KDMAge和PhenoAge等生物标志物衡量）与类风湿关节炎的风险增加以及患者寿命的缩短密切相关99。即使在具有高遗传风险的人群中，加速的生物学衰老也会进一步增加类风湿关节炎的发生风险。对于45岁的类风湿关节炎患者，加速的生物学衰老会进一步减少其预期寿命99。这表明，类风湿关节炎不仅是一种慢性病，更可能通过加速生物学衰老进程，对患者的健康寿命和整体寿命产生双重打击。
  • 其他共病链条：中国的一项针对中老年人群的慢性病轨迹网络分析显示，高血压是最普遍的慢性病，并且与消化系统疾病、心脏病、血脂异常等处于疾病网络的核心位置，而关节炎被发现是许多其他疾病的起点101。这意味着，许多慢性病并非孤立存在，而是相互关联，形成复杂的共病链条，加剧了老年人的健康负担。例如，糖尿病、高血压和慢性肾病常常并存，共同导致心血管事件和死亡风险的增加102。
  • 衰弱与功能下降：多重共病常导致衰弱（frailty），表现为身体储备能力下降，对压力源的抵抗力减弱，从而增加跌倒、住院和死亡的风险。例如，糖尿病与衰弱、功能下降和认知障碍密切相关96。这种功能下降不仅限制了老年人的日常活动，也极大地损害了他们的生活质量。

健康寿命优先的干预策略

为了应对“寿命延长但健康寿命未同步增长”的挑战，公共卫生和医疗实践需要转向以“健康寿命优先”的干预策略93。

  • 整合性护理模式：传统的“单病种”管理模式难以有效应对多重共病患者的复杂需求。需要发展整合性的护理模式，以患者为中心，协调多学科医疗团队，制定个性化的治疗方案，平衡不同疾病的治疗目标，避免不必要的药物相互作用和过度医疗9596。
  • 预防性干预和健康生活方式：强调从生命早期开始，通过健康饮食、规律运动（如步行，可降低心血管疾病、糖尿病、痴呆等风险103）、戒烟限酒、充足睡眠等健康生活方式，预防慢性病的发生。即使在老年阶段，积极的生活方式干预也能有效改善健康状况，延长健康寿命104。例如，适度的体育活动可以显著改善老年人的身体功能、力量和认知功能103104。
  • 生物标志物指导的精准医疗：利用生物标志物（如衰老时钟）来评估个体的生物学年龄和衰老速度，识别高风险人群，并根据个体的遗传和生理特征，实施精准化的抗衰老干预67105。这包括个性化的营养干预、靶向衰老相关通路（如Sirtuins和mTOR通路）的药物，以及监测肠道微生物群等，因为肠道微生物群的健康与长寿息息相关106。
  • 社会支持与环境改善：加强社会支持系统，包括家庭支持、社区服务以及老年友好型环境的建设，可以帮助老年人更好地应对疾病和功能限制，维持心理健康和社交参与93101。例如，代际支持和社区服务可以有效缓解老年人的抑郁症状101。
  • 关注弱势群体：需要采取协调的公共卫生方法，以促进健康老龄化，并减轻人口老龄化带来的经济和社会影响93。

综上所述，实现健康寿命与寿命的平衡是未来人类寿命研究和公共卫生政策的核心目标。通过多方面的、整合性的干预策略，我们有望不仅延长人类的生命长度，更重要的是，提高其生命质量，实现真正意义上的健康长寿。

5. 寿命上限的争议与伦理思考

5.1 绝对上限的科学争议

人类寿命是否存在一个不可逾越的绝对上限，一直是科学界争论的焦点。尽管过去一个世纪以来，全球预期寿命持续增长，且有少数个体突破了120岁的界限，但关于是否存在“寿命天花板”的讨论从未停止。

“寿命天花板”理论的支持证据

支持“寿命天花板”理论的观点认为，人类寿命存在一个生物学上的固有极限，即便是医疗技术再进步，也无法无限延长。这种观点主要基于以下几点：

  • 记录个体寿命的停滞：尽管平均预期寿命持续增长，但人类最长寿个体的寿命记录在珍妮·卡尔芒（Jeanne Calment）于1997年去世后（122岁零164天）并未被显著超越。一些研究人员指出，在超过一定年龄后，死亡率的降低速度趋于平稳，甚至在极高龄时可能出现死亡率高原期（mortality plateaus）。然而，一项研究认为，这种高原现象很可能是由人口统计学误差造成的，而非生物学事实。该研究指出，即使是低于万分之一的年龄估算和队列混合误差，也足以导致晚年死亡率减速和高原现象的出现 107。这意味着，衰老过程在极高龄阶段并未放缓或停止，人类寿命仍存在有限的上限 107。
  • 衰老的基本生物学机制：衰老被认为是生物体“活性机制失调”的结果，而非简单的磨损。这意味着存在一些内在的调节机制，在特定阶段诱导生物体的功能下降，从而限制寿命 108。虽然这些机制并非不可干预，但它们在物种进化过程中形成，可能设定了生物体的基本寿命范围。
  • 生物体维护的进化限制：从进化的角度看，衰老并非由积极的基因编程引起，而是由于体细胞维护方面的进化限制，导致损伤的累积 109。不同物种的寿命差异反映了在生长、繁殖和体细胞生存之间投资权衡的结果。这种内在的维护限制暗示了寿命的上限。
  • 健康寿命与总寿命的脱节：即使平均寿命得以延长，健康寿命（healthspan）却没有同等幅度的增长 110。这意味着许多老年人虽然活得更久，但却伴随着更多的疾病和功能障碍，这暗示着生物体在维持健康功能方面存在一个极限。

“寿命天花板”理论的反对证据

另一些研究者则认为，人类寿命可能没有一个固定的上限，或者说现有的“天花板”是可以被突破的。他们的论据包括：

  • 死亡率的持续下降：历史数据显示，最高年龄的死亡率仍在持续下降，并未达到平台期。这意味着在未来几年内，人类最高寿命记录仍有可能被刷新。
  • 衰老的可塑性：对衰老生物学机制的深入研究表明，衰老过程并非一成不变，而是具有高度可塑性。基因变异、环境因素和医疗干预都可以显著影响衰老速度和寿命长度 111。例如，在模式生物中，通过基因干预可以显著延长寿命，这表明在分子层面对衰老机制的调控有很大的潜力。
  • 生物医学技术的进步：随着抗衰老药物、再生医学和基因编辑等领域的快速发展，未来我们可能拥有更多强大的工具来延缓衰老进程，甚至逆转一些衰老相关的损伤。例如，对Sirtuins的研究显示，它们在调节寿命方面发挥重要作用，通过干预Sirtuin通路可能实现寿命延长 112。

“寿命均等化”趋势对群体寿命上限的影响

“寿命均等化”趋势是指不同个体之间的死亡年龄趋于一致，即死亡年龄的方差减小，个体死亡年龄的分布变得更加集中。这一现象在某些人口中被观察到，反映了人类在达到一定年龄后，死亡风险的个体差异在减小。

  • 死亡年龄的收敛：如果存在一个固定的生物学上限，那么当人类接近这个上限时，死亡年龄的分布会变得越来越窄，意味着大多数人将在接近这个极限的年龄去世。这种收敛现象可能被解读为生物学极限存在的证据。
  • 对群体寿命上限的解读：从群体层面看，“寿命均等化”趋势可能意味着，随着医疗和社会条件的改善，那些原本因早期疾病或环境因素而早逝的人得以活到更长年龄，从而使得群体寿命的整体分布向高龄移动并趋于集中。这并不一定意味着个体寿命的绝对上限被突破，而是更多人能够达到其生物学潜力的上限。
  • 与生物学误差的关联：正如前文所述，Newman的研究指出，晚年死亡率的减速和高原现象可能源于人口统计学误差，这提示我们对“寿命均等化”的解读需要更加谨慎 107。如果这些误差被修正，可能会发现衰老过程在晚年并未停止，人类寿命仍然存在一个有限的生物学极限 107。

总而言之，人类寿命上限的争议是生物学、统计学和哲学等多学科交叉的问题。虽然有观点认为人类寿命存在一个不可突破的“天花板”，但也有证据表明衰老的可塑性和生物医学技术的进步可能使我们突破现有的极限。对“寿命均等化”趋势的深入理解，需要结合更精确的人口统计学数据和对衰老分子机制的持续研究，才能更准确地评估人类寿命的最终潜力。

5.2 技术干预的伦理边界

随着人类对衰老机制理解的深入以及基因编辑、抗衰老药物等前沿技术的飞速发展，人类寿命的延长不再是遥不可及的梦想。然而，这些强大的技术在带来突破性潜力的同时，也引发了深刻的伦理、社会和经济思考。如何确保这些技术能够造福全人类，而非加剧现有不平等，以及如何平衡“延长寿命”与“提高生命质量”之间的关系，是当前社会亟需面对和解决的伦理挑战。

基因编辑、抗衰老药物等技术的公平可及性问题

基因编辑（如CRISPR技术）和新兴的抗衰老药物（如靶向IL-11信号通路的生物制剂）无疑具有延长健康寿命、治疗年龄相关疾病的巨大潜力 7883。然而，这些高度复杂的生物医学技术往往研发成本高昂，生产过程复杂，其初始价格可能远超普通民众的支付能力。这将直接导致一个严重的公平性问题：

  • 加剧健康不平等：如果这些先进的延寿技术仅限于少数富裕人群可及，那么它将进一步拉大富人与穷人之间的“健康鸿沟”，形成“健康精英阶层”。这不仅违背了医疗公平的原则，也可能在社会中制造新的阶级分化，导致社会张力加剧。
  • 资源分配的困境：有限的医疗资源如何在疾病治疗和寿命延长之间进行分配，是一个复杂的伦理难题。如果大量资源投入到少数人的寿命延长上，可能会挤占用于基础医疗、疾病预防和贫困地区健康改善的资源，从而损害更广泛人群的健康福祉。例如，阿尔茨海默病等慢性病的治疗成本已经非常高昂，这将对全球医疗系统构成巨大压力 113。
  • “设计婴儿”的担忧：基因编辑技术在人类胚胎或生殖细胞上的应用，引发了“设计婴儿”的伦理担忧。虽然其初衷可能是为了消除遗传性疾病，但若被用于增强非医学特征（如智力、外貌），将可能导致遗传上的社会不平等，并模糊治疗与增强之间的界限。

“延长寿命”与“提高生命质量”的优先级

在追求寿命延长的过程中，社会必须反思一个核心问题：我们追求的是单纯的生命长度，还是健康且有尊严的生命质量？许多研究和临床实践表明，延长寿命若不伴随生命质量的提升，可能会带来更大的痛苦和负担 114115。

  • “不健康的长寿”的风险：如果技术仅仅是延长了生命，却无法有效改善与衰老相关的疾病和功能障碍，那么个体可能会面临长期卧床、慢性疼痛、认知障碍、多重共病以及对他人高度依赖的困境。例如，乳腺癌、帕金森病、神经系统疾病等在全球范围内的负担日益加重，即便延长了寿命，如果这些疾病无法得到有效管理，生活质量也难以保障 116117118。这不仅对个体是巨大的痛苦，也会对家庭和社会造成沉重负担。
  • 患者意愿的考量：在面临疾病晚期或高度依赖时，许多患者及其家属会优先考虑生活质量而非单纯的生命延长。例如，在儿科姑息治疗中，父母最看重的是孩子的生命质量（QOL），而非生命延长，并且随着时间的推移，对生命质量的重视程度会进一步提高，而对生命延长的重视程度则会下降 114。这表明，在生命终末期，维持患者的尊严、舒适和心理健康，可能比机械地延长生命更为重要。
  • 姑息治疗的重要性：姑息治疗（palliative care）旨在改善面临危及生命疾病的患者及其家属的生活质量，它关注症状管理、疼痛缓解和心理支持，而非单纯的疾病治愈或寿命延长 119。在杜氏肌营养不良症等复杂疾病的终末期护理中，虽然有生命延长技术，但也要充分考虑患者偏好、生活质量和伦理问题，因为有些患者可能认为其生活质量低于预期而不愿继续延长生命 120。这提示我们，任何延寿技术都应与高质量的姑息和支持性护理相结合。

如何避免“不健康的长寿”对社会医疗系统的冲击

“不健康的长寿”将给本已紧张的全球医疗系统带来巨大冲击。随着老年人口的增加和多重共病发病率的上升，医疗需求将爆炸式增长，对医疗资源、护理人员和财政投入都构成严峻考验。为了避免这种冲击，需要采取多方面的策略：

  • 发展预防性医学和健康管理：将重心从疾病治疗转向健康促进和疾病预防，鼓励健康的生活方式，早期筛查和干预，从而降低慢性病发病率，延长健康寿命。
  • 投资于健康寿命而非仅仅是寿命：研发和推广能够真正提升健康寿命、减少疾病负担的抗衰老技术，而非仅仅是延长生命长度却不改善生命质量的技术。这意味着需要更多关注那些能延缓衰老进程、预防多种年龄相关疾病的综合性干预措施。
  • 建立健全的社会保障和长期护理体系：随着老年人口的增多，对长期护理服务的需求将急剧上升。政府和社会应共同投入，建立健全的居家养老、社区养老和机构养老体系，提供多层次、高质量的护理服务，减轻家庭负担。
  • 制定合理的政策和监管框架：政府和国际组织应积极参与，制定科学、公正的伦理指南和监管政策，确保延寿技术的研发和应用符合伦理原则，促进公平可及，并避免滥用。
  • 公众教育和对话：加强公众对衰老、寿命延长和生命质量之间关系的理解，促进社会对这些复杂伦理问题的公开讨论，形成广泛共识，引导技术向有益于社会的方向发展。

总之，技术干预在延长人类寿命方面具有无限前景，但其伦理边界必须被严格审视和划定。确保公平可及性，优先考虑健康寿命，并为“不健康的长寿”可能带来的社会冲击做好准备，是我们在追求长寿梦想时不可回避的责任 83。

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参考文献

1Roles of Telomere Biology in Cell Senescence, Replicative and Chronological Ageing.PubMed

Jun Liu, Lihui Wang, Zhiguo Wang, et al.
Cells. 2019 Jan 15;8(1):54. doi: 10.3390/cells8010054.
Telomeres with G-rich repetitive DNA and particular proteins as special heterochromatin structures at the termini of eukaryotic chromosomes are tightly maintained to safeguard genetic integrity and functionality. Telomerase as a specialized reverse transcriptase uses its intrinsic RNA template to lengthen telomeric G-rich strand in yeast and human cells. Cells sense telomere length shortening and respond with cell cycle arrest at a certain size of telomeres referring to the "Hayflick limit." In addition to regulating the cell replicative senescence, telomere biology plays a fundamental role in regulating the chronological post-mitotic cell ageing. In this review, we summarize the current understandings of telomere regulation of cell replicative and chronological ageing in the pioneer model system and provide an overview on telomere regulation of animal lifespans. We focus on the mechanisms of survivals by telomere elongation, DNA damage response and environmental factors in the absence of telomerase maintenance of telomeres in the yeast and mammals.

2Cellular aging (the Hayflick limit) and species longevity: a unification model based on clonal succession.PubMed

D A Juckett
Mech Ageing Dev. 1987 Mar;38(1):49-71. doi: 10.1016/0047-6374(87)90110-2.
A model is presented which proposes a specific cause-and-effect relationship between a limited cell division potential and the maximum lifespan of humans and other mammals. It is based on the clonal succession hypothesis of Kay which states that continually replicating cell beds (e.g. bone marrow, intestinal crypts, epidermis) could be composed of cells with short, well-defined division potentials. In this model, the cells of these beds are proposed to exist in an ordered hierarchy which establishes a specific sequence for cell divisions throughout the organism's lifespan. The depletion of division potential at all hierarchical levels leads to a loss of bed function and sets an intrinsic limit to species longevity. A specific hierarchy for cell proliferation is defined which allows the calculation of time to bed depletion and, ultimately, to organism mortality. The model allows the existence of a small number (n) of critical cell beds within the organism and defines organism death as the inability of any one of these beds to produce cells. The model is consistent with all major observations related to cellular and organismic aging. In particular, it links the PDLs (population doubling limit) observed for various species to their mean lifespan; it explains the slow decline in PDL as a function of age of the donor; it establishes a thermodynamically stable maximum lifespan for a disease-free population; and it can explain why tissue transplants outlive donors or hosts.

3The commitment of human cells to senescence.PubMed

Robin Holliday
Interdiscip Top Gerontol. 2014;39:1-7. doi: 10.1159/000358896. Epub 2014 May 13.
Fifty years ago, it was demonstrated by Leonard Hayflick that human diploid fibroblasts grown in culture have a finite lifespan. Since that time, innumerable experiments have been published to discover the mechanism(s) that are responsible for this 'Hayflick limit' to continuous growth. Much new information has been gained, but there are certain features of this experimental system which have not been fully understood. One is the fact that different populations of the foetal lung strains WI-38 and MRC-5 have a range in division potential of at least a millionfold. The commitment theory of cellular aging, published more than 30 years ago, is able to explain this, but it has been consistently ignored. The theory predicts that bottlenecks, which are transient reductions in population size, can significantly reduce lifespan, or increase variability of lifespans. Computer simulations specify the effects of bottlenecks on longevity, and these were confirmed in two series of experiments. Commitment to senescence may be the loss of telomerase, which leads to the erosion of telomeres and the inability to grow indefinitely. Many experiments have been done with skin fibroblasts from human donors of different age, and it was originally thought that in vitro lifespan was inversely correlated with donor age. In these experiments, a single skin biopsy produces a population of cells that are grown to senescence. However, there is no reason to believe that skin fibroblasts are less variable in their in vitro lifespan than foetal lung strains, in which case the data points with skin cells are so variable that they may completely obscure any inverse correlation between culture lifespans and donor age.

4Endless quest.PubMed

R Holliday
Bioessays. 1996 Jan;18(1):3-5. doi: 10.1002/bies.950180103.
The replication of linear chromosome DNA by DNA polymerase leads to the loss of terminal sequences, in the absence of a special mechanism to maintain ends or telomeres. This mechanism is known to consist of short terminal repeats and the enzyme telomerase, which contains RNA complementary to the DNA repeats. There is evidence that telomeric DNA continually decreases in size in the absence of telomerase, and this is followed by cellular senescence. Immortalisation of somatic cells is accompanied, at least in some cases, by acquisition of telomerase activity. The cloning of DNA coding for the RNA component of telomerase has opened up some new experimental approaches, including the study of telomerases with mutant RNA. The telomere theory of cellular senescence appears to provide a molecular basis for the 'Hayflick limit' to human fibroblast growth. However the telomeres and behaviour of primary mouse cells are anomolous, and many immortalised human cell lines lack normal telomerase activity. These exceptions are not easily accommodated in the telomere theory.

5Sex differences in telomere length, lifespan, and embryonic dyskerin levels.PubMed

Peter M Lansdorp
Aging Cell. 2022 May;21(5):e13614. doi: 10.1111/acel.13614. Epub 2022 Apr 20.
Telomerase levels in most human cells are insufficient to prevent loss of telomeric DNA with each replication cycle. The resulting "Hayflick" limit may have allowed lifespan to increase by suppressing the development of tumors early in life be it at the expense of compromised cellular responses late in life. At any given age, the average telomere length in leukocytes shows considerably variation between individuals with females having, on average, longer telomeres than males. Sex differences in average telomere length are already present at birth and correspond to reported differences in the average life expectancy between the sexes. Levels of telomerase RNA and dyskerin, encoded by DKC1, are known to limit telomerase activity in embryonic stem cells. X-linked DKC1 is expressed from both alleles in female embryo cells and higher levels of dyskerin and telomerase could elongate telomeres prior to embryo implantation. The hypothesis that embryonic telomerase levels set the stage for the sex differences in telomere length and lifespan deserves further study.

6Antioxidants and aging.PubMed

R G Cutler
Am J Clin Nutr. 1991 Jan;53(1 Suppl):373S-379S. doi: 10.1093/ajcn/53.1.373S.
Aging in mammalian species appears to be the result of normal developmental and metabolic processes. In spite of the vast complexity of aging processes, relatively less complex processes such as longevity determinant genes (LDGs) may exist governing aging rate. Much experimental data exists indicating a causative role of oxyradicals in aging processes. In testing the hypothesis that antioxidants may represent LDGs, a positive correlation in the tissue concentration of specific antioxidants with life span of mammals was found. These antioxidants include superoxide dismutase, carotenoids, alpha-tocopherol, and uric acid. We also found that the resistance of tissues to spontaneous autoxidation and the amount of oxidative damage to DNA correlates inversely with life span of mammals. These results suggest a role of oxyradicals in causing aging and that the antioxidant status of an individual could be important in determining frequency of age-dependent diseases and duration of general health maintenance.

7Theories of ageing.PubMed

Jose Viña, Consuelo Borrás, Jaime Miquel
IUBMB Life. 2007 Apr-May;59(4-5):249-54. doi: 10.1080/15216540601178067.
Ageing is a universal, intrinsic, progressive and deleterious process. Understanding it is of major interest to scientist, physicians as well as to the general population. Critical to this understanding is to formulate comprehensive theories of aging with high predictive and explanatory power. More than 300 theories have been postulated and are reviewed here. The free radical theory of ageing is one of the most prominent and well studied. It was further developed by one of us (JM) in what has become known as the mitochondrial theory of ageing. These theories provide new experimental approaches to further develop our understanding of the phenomenon of ageing.

8Living longer--but better?PubMed

Bernard Jeune
Aging Clin Exp Res. 2002 Apr;14(2):72-93. doi: 10.1007/BF03324421.
The highest attained age has increased by about 20 years since the beginning of the 19th century. In the course of the 1990s, more than ten individuals reached 115 years or more, including Jeanne Calment who attained the age of 122 years. In low-mortality countries, the number of centenarians has doubled every decade since 1950. This dramatic increase was mainly due to periodical effects related to the drastic fall in mortality among the elderly. The fact that centenarians are survivors does not mean that they are healthy. A high prevalence of comorbidity is found, and many centenarians have survived major diseases thanks to medical treatment and surgery. It is, however, possible that the comorbidity is less serious than in younger elderly. Certain personality traits may also be important in surviving health-threatening conditions. Furthermore, a number of biological and cognitive functions seem to be well-preserved in several centenarians. The influence of the apoE-gene and other genes involved in fundamental mechanisms illustrates that with advancing age and increasing mortality even small risks may have a substantial effect on survival to 100 years. A small proportion of long-livers may be considered as relatively autonomous, and this proportion will probably increase in the future. We are living longer and seem to postpone the terminal dependent phase to higher ages. Longevity may thus be perceived as part of our postmodern condition with its mix of pleasure and suffering.

9[The present and future of antiaging].PubMed

Takahiko Shimizu, Takuji Shirasawa
Gan To Kagaku Ryoho. 2008 Jan;35(1):1-5.
When we discuss advances in longevity research during lectures and seminars, the question of the deciding factor for longevity often comes up. Even without looking at examples of research in molecular biology research, it is obvious to most that genetics play a major factor in longevity. The longest-lived human recorded was a French woman named Jeanne Calment, who died at age 122. All her family was long-lived. The quest for the identification of longevity genes by studying centenarian families has been explored for a decade, but no bona-fide longevity gene was identified. The environmental factors influencing the lifespan of human beings, such as nutrition, physical exercise, and mental relaxation play an important role in the determination of an individual lifespan. The mortality rates of lifestyle-related diseases such as heart disease, stroke, and cancer becoming getting higher and higher in Japan as well as in western countries where much of the population is graying. The preventive measures for lifestyle-related diseases such as nutritional intervention or regular physical exercise should be introduced for further extension of the healthy lifespan. Caloric restriction in experimental animals has been shown to extend the lifespan of animals with the decreased frequency of age-related diseases. Regular physical exercise stimulates the adipose tissues to secrete beneficial adipose hormones, such as adiponectin that suppress the progression of atherosclerosis and insulin resistance in type II DM and metabolic syndrome.

10Response to Comment on "The plateau of human mortality: Demography of longevity pioneers".PubMed

Elisabetta Barbi, Francesco Lagona, Marco Marsili, et al.
Science. 2018 Oct 19;362(6412). doi: 10.1126/science.aav3229.
Beltrán-Sánchez based their comment on misleading calculations of the maximum survival age. With realistic numbers of people attaining age 105 and the estimated plateau, the Jeanne Calment record is indeed plausible.

11Undulating changes in human plasma proteome profiles across the lifespan.PubMed

Benoit Lehallier, David Gate, Nicholas Schaum, et al.
Nat Med. 2019 Dec;25(12):1843-1850. doi: 10.1038/s41591-019-0673-2. Epub 2019 Dec 5.
Aging is a predominant risk factor for several chronic diseases that limit healthspan. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases.

12The 'middle-aging' brain.PubMed

Sebastian Dohm-Hansen, Jane A English, Aonghus Lavelle, et al.
Trends Neurosci. 2024 Apr;47(4):259-272. doi: 10.1016/j.tins.2024.02.001. Epub 2024 Mar 19.
Middle age has historically been an understudied period of life compared to older age, when cognitive and brain health decline are most pronounced, but the scope for intervention may be limited. However, recent research suggests that middle age could mark a shift in brain aging. We review emerging evidence on multiple levels of analysis indicating that midlife is a period defined by unique central and peripheral processes that shape future cognitive trajectories and brain health. Informed by recent developments in aging research and lifespan studies in humans and animal models, we highlight the utility of modeling non-linear changes in study samples with wide subject age ranges to distinguish life stage-specific processes from those acting linearly throughout the lifespan.

13Accelerated telomere shortening in response to life stress.PubMed

Elissa S Epel, Elizabeth H Blackburn, Jue Lin, et al.
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17312-5. doi: 10.1073/pnas.0407162101. Epub 2004 Dec 1.
Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets "under the skin" remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress--both perceived stress and chronicity of stress--is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases.

14Telomere dynamic in humans and animals: Review and perspectives in environmental toxicology.PubMed

Maxime Louzon, Michael Coeurdassier, Frédéric Gimbert, et al.
Environ Int. 2019 Oct;131:105025. doi: 10.1016/j.envint.2019.105025. Epub 2019 Jul 25.
Telomeres (TLs) play major roles in stabilizing the genome and are usually shortened with ageing. The maintenance of TLs is ensured by two mechanisms involving telomerase (TA) enzyme and alternative lengthening telomeres (ALT). TL shortening and/or TA inhibition have been related to health effects on organisms (leading to reduced reproductive lifespan and survival), suggesting that they could be key processes in toxicity mechanisms (at molecular and cellular levels) and relevant as an early warning of exposure and effect of chemicals on human health and animal population dynamics. Consequently, a critical analysis of knowledge about relationships between TL dynamic and environmental pollution is essential to highlight the relevance of TL measurement in environmental toxicology. The first objective of this review is to provide a survey on the basic knowledge about TL structure, roles, maintenance mechanisms and causes of shortening in both vertebrates (including humans) and invertebrates. Overall, TL length decreases with ageing but some unexpected exceptions are reported (e.g., in species with different lifespans, such as the nematode Caenorhabditis elegans or the crustacean Homarus americanus). Inconsistent results reported in various biological groups or even between species of the same genus (e.g., the microcrustacean Daphnia sp.) indicate that the relation usually proposed between TL shortening and a decrease in TA activity cannot be generalized and depends on the species, stage of development or lifespan. Although the scientific literature provides evidence of the effect of ageing on TL shortening, much less information on the relationships between shortening, maintenance of TLs, influence of other endogenous and environmental drivers, including exposure to chemical pollutants, is available, especially in invertebrates. The second objective of this review is to connect knowledge on TL dynamic and exposure to contaminants. Most of the studies published on humans rely on correlative epidemiological approaches and few in vitro experiments. They have shown TL attrition when exposed to contaminants, such as polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB), pesticides and metallic elements (ME). In other vertebrates, the studies we found deals mainly with birds and, overall, report a disturbance of TL dynamic consecutively to exposure to chemicals, including metals and organic compounds. In invertebrates, no data are available and the potential of TL dynamic in environmental risk assessment remains to be explored. On the basis of the main gaps identified some research perspectives (e.g., impact of endogenous and environmental drivers, dose response effects, link between TL length, TA activity, longevity and ageing) are proposed to better understand the potential of TL and TA measurements in humans and animals in environmental toxicology.

15Familial Clonal Hematopoiesis in a Long Telomere Syndrome.PubMed

Emily A DeBoy, Michael G Tassia, Kristen E Schratz, et al.
N Engl J Med. 2023 Jun 29;388(26):2422-2433. doi: 10.1056/NEJMoa2300503. Epub 2023 May 4.
BACKGROUND: Telomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is advantageous is poorly understood. METHODS: We examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene and noncarrier relatives. RESULTS: A total of 17 mutation carriers and 21 noncarrier relatives were initially included in the study, and a validation cohort of 6 additional mutation carriers was subsequently recruited. A majority of the mutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile). mutation carriers had a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues in addition to B- and T-cell lymphoma and myeloid cancers. Five of 18 mutation carriers (28%) had T-cell clonality, and 8 of 12 (67%) had clonal hematopoiesis of indeterminate potential. A predisposition to clonal hematopoiesis had an autosomal dominant pattern of inheritance, as well as penetrance that increased with age; somatic and hotspot mutations were common. These and other somatic driver mutations probably arose in the first decades of life, and their lineages secondarily accumulated a higher mutation burden characterized by a clocklike signature. Successive generations showed genetic anticipation (i.e., an increasingly early onset of disease). In contrast to noncarrier relatives, who had the typical telomere shortening with age, mutation carriers maintained telomere length over the course of 2 years. CONCLUSIONS: mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.).

16Mitochondrial dysfunction in aging.PubMed

Ying Guo, Teng Guan, Kashfia Shafiq, et al.
Ageing Res Rev. 2023 Jul;88:101955. doi: 10.1016/j.arr.2023.101955. Epub 2023 May 15.
Aging is a complex process that features a functional decline in many organelles. Although mitochondrial dysfunction is suggested as one of the determining factors of aging, the role of mitochondrial quality control (MQC) in aging is still poorly understood. A growing body of evidence points out that reactive oxygen species (ROS) stimulates mitochondrial dynamic changes and accelerates the accumulation of oxidized by-products through mitochondrial proteases and mitochondrial unfolded protein response (UPR). Mitochondrial-derived vesicles (MDVs) are the frontline of MQC to dispose of oxidized derivatives. Besides, mitophagy helps remove partially damaged mitochondria to ensure that mitochondria are healthy and functional. Although abundant interventions on MQC have been explored, over-activation or inhibition of any type of MQC may even accelerate abnormal energy metabolism and mitochondrial dysfunction-induced senescence. This review summarizes mechanisms essential for maintaining mitochondrial homeostasis and emphasizes that imbalanced MQC may accelerate cellular senescence and aging. Thus, appropriate interventions on MQC may delay the aging process and extend lifespan.

17Senescent glia link mitochondrial dysfunction and lipid accumulation.PubMed

China N Byrns, Alexandra E Perlegos, Karl N Miller, et al.
Nature. 2024 Jun;630(8016):475-483. doi: 10.1038/s41586-024-07516-8. Epub 2024 Jun 5.
Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species. Acutely, senescent cells promote wound healing and prevent tumour formation; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.

18Emerging roles of oxidative stress in brain aging and Alzheimer's disease.PubMed

Andra Ionescu-Tucker, Carl W Cotman
Neurobiol Aging. 2021 Nov;107:86-95. doi: 10.1016/j.neurobiolaging.2021.07.014. Epub 2021 Jul 25.
Reactive oxygen species (ROS) are metabolic byproducts that are necessary for physiological function but can be toxic at high levels. Levels of these oxidative stressors increase gradually throughout the lifespan, impairing mitochondrial function and damaging all parts of the body, particularly the central nervous system. Emerging evidence suggests that accumulated oxidative stress may be one of the key mechanisms causing cognitive aging and neurodegenerative diseases such as Alzheimer's disease (AD). Here, we synthesize the current literature on the effect of neuronal oxidative stress on mitochondrial dysfunction, DNA damage and epigenetic changes related to cognitive aging and AD. We further describe how oxidative stress therapeutics such as antioxidants, caloric restriction and physical activity can reduce oxidation and prevent cognitive decline in brain aging and AD. Of the currently available therapeutics, we propose that long term physical activity is the most promising avenue for improving cognitive health by reducing ROS while promoting the low levels required for optimal function.

19Management of Type 2 Diabetes Mellitus in Elderly Patients with Frailty and/or Sarcopenia.PubMed

Jaime Sanz-Cánovas, Almudena López-Sampalo, Lidia Cobos-Palacios, et al.
Int J Environ Res Public Health. 2022 Jul 16;19(14):8677. doi: 10.3390/ijerph19148677.
The life expectancy of the population is increasing worldwide due to improvements in the prevention, diagnosis, and treatment of diseases. This favors a higher prevalence of type 2 diabetes mellitus (T2DM) in the elderly. Sarcopenia and frailty are also frequently present in aging. These three entities share common mechanisms such as insulin resistance, chronic inflammation, and mitochondrial dysfunction. The coexistence of these situations worsens the prognosis of elderly patients. In this paper, we review the main measures for the prevention and management of sarcopenia and/or frailty in elderly patients with T2DM.

20Biological basis and treatment of frailty and sarcopenia.PubMed

Ryosuke Sato, Mirela Vatic, Guilherme Wesley Peixoto da Fonseca, et al.
Cardiovasc Res. 2024 Jul 31;120(9):982-998. doi: 10.1093/cvr/cvae073.
In an ageing society, the importance of maintaining healthy life expectancy has been emphasized. As a result of age-related decline in functional reserve, frailty is a state of increased vulnerability and susceptibility to adverse health outcomes with a serious impact on healthy life expectancy. The decline in skeletal muscle mass and function, also known as sarcopenia, is key in the development of physical frailty. Both frailty and sarcopenia are highly prevalent in patients not only with advanced age but also in patients with illnesses that exacerbate their progression like heart failure (HF), cancer, or dementia, with the prevalence of frailty and sarcopenia in HF patients reaching up to 50-75% and 19.5-47.3%, respectively, resulting in 1.5-3 times higher 1-year mortality. The biological mechanisms of frailty and sarcopenia are multifactorial, complex, and not yet fully elucidated, ranging from DNA damage, proteostasis impairment, and epigenetic changes to mitochondrial dysfunction, cellular senescence, and environmental factors, many of which are further linked to cardiac disease. Currently, there is no gold standard for the treatment of frailty and sarcopenia, however, growing evidence supports that a combination of exercise training and nutritional supplement improves skeletal muscle function and frailty, with a variety of other therapies being devised based on the underlying pathophysiology. In this review, we address the involvement of frailty and sarcopenia in cardiac disease and describe the latest insights into their biological mechanisms as well as the potential for intervention through exercise, diet, and specific therapies.

21Sirtuins, epigenetics and longevity.PubMed

Mateusz Wątroba, Ilona Dudek, Marta Skoda, et al.
Ageing Res Rev. 2017 Nov;40:11-19. doi: 10.1016/j.arr.2017.08.001. Epub 2017 Aug 5.
Aging of organisms begins from a single cell at the molecular level. It includes changes related to telomere shortening, cell senescence and epigenetic modifications. These processes accumulate over the lifespan. Research studies show that epigenetic signaling contributes to human disease, tumorigenesis and aging. Epigenetic DNA modifications involve changes in the gene activity but not in the DNA sequence. An epigenome consists of chemical modifications to the DNA and histone proteins without the changes in the DNA sequence. These modifications strongly depend on the environment, could be reversible and are potentially transmittable to daughter cells. Epigenetics includes DNA methylation, noncoding RNA interference, and modifications of histone proteins. Sirtuins, a family of nicotine adenine dinucleotide (NAD+)-dependent enzymes, are involved in the cell metabolism and can regulate many cellular functions including DNA repair, inflammatory response, cell cycle or apoptosis. Literature shows the strong interconnection between sirtuin expression and aging processes. However, the direct relationship is still unknown. Here, we would like to summarize the existing knowledge about epigenetic processes in aging, especially those related to sirtuin expression. Another objective is to explain why some negative correlations between sirtuin activity and the rate of aging can be assumed.

22Genetics of healthy aging and longevity.PubMed

Angela R Brooks-Wilson
Hum Genet. 2013 Dec;132(12):1323-38. doi: 10.1007/s00439-013-1342-z. Epub 2013 Aug 8.
Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may 'buffer' the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.

23The APP A673T frequency differs between Nordic countries.PubMed

Jonas Mengel-From, Bernard Jeune, Tienari Pentti, et al.
Neurobiol Aging. 2015 Oct;36(10):2909.e1-4. doi: 10.1016/j.neurobiolaging.2015.07.011. Epub 2015 Jul 11.
A coding gene variant A673T (rs63750847) in the APP gene has recently been recognized as a protective variant of late-onset Alzheimer's Disease in a large Icelandic population and has been observed recurrently in populations from Nordic countries. The variant also was related to longevity in the Icelandic population. However, because of the extreme rarity of A673T in non-Nordic populations, the association with Alzheimer's disease has not yet been formally replicated. Because the variant has not been reported among the Danes, we aimed to study its frequency among healthy middle-age twins and oldest-old singletons and explore the possible effects on longevity and cognitive abilities. Surprisingly, only 1 of 3487 unrelated Danes carried the A673T variant, (0.014% [95% CI 0.000-0.080]), which was significantly lower than in the other Nordic countries averaging to 0.43% (95% CI 0.40-0.46). In conclusion, the A673T variant is rarer in Danes than other Nordic countries, thus precluding assessment of association with longevity or cognitive functioning.

24The genetics of human ageing.PubMed

David Melzer, Luke C Pilling, Luigi Ferrucci
Nat Rev Genet. 2020 Feb;21(2):88-101. doi: 10.1038/s41576-019-0183-6. Epub 2019 Nov 5.
The past two centuries have witnessed an unprecedented rise in human life expectancy. Sustaining longer lives with reduced periods of disability will require an understanding of the underlying mechanisms of ageing, and genetics is a powerful tool for identifying these mechanisms. Large-scale genome-wide association studies have recently identified many loci that influence key human ageing traits, including lifespan. Multi-trait loci have been linked with several age-related diseases, suggesting shared ageing influences. Mutations that drive accelerated ageing in prototypical progeria syndromes in humans point to an important role for genome maintenance and stability. Together, these different strands of genetic research are highlighting pathways for the discovery of anti-ageing interventions that may be applicable in humans.

25Healthy lifestyle in late-life, longevity genes, and life expectancy among older adults: a 20-year, population-based, prospective cohort study.PubMed

Jun Wang, Chen Chen, Jinhui Zhou, et al.
Lancet Healthy Longev. 2023 Oct;4(10):e535-e543. doi: 10.1016/S2666-7568(23)00140-X.
BACKGROUND: Lifestyle and longevity genes have different and important roles in the human lifespan; however, the association between a healthy lifestyle in late-life and life expectancy mediated by genetic risk is yet to be elucidated. We aimed to investigate the associations of healthy lifestyle in late-life and genetic risk with life expectancy among older adults. METHODS: A weighted healthy lifestyle score was constructed from the following variables: current non-smoking, non-harmful alcohol consumption, regular physical activity, and a healthy diet. Participants were recruited from the Chinese Longitudinal Healthy Longevity Survey, a prospective community-based cohort study that took place between 1998 and 2018. Eligible participants were aged 65 years and older with available information on lifestyle factors at baseline, and then were categorised into unhealthy (bottom tertile of the weighted healthy lifestyle score), intermediate (middle tertile), and healthy (top tertile) lifestyle groups. A genetic risk score was constructed based on 11 lifespan loci among 9633 participants, divided by the median and classified into low and high genetic risk groups. Stratified Cox proportional hazard regression was used to estimate the interaction between genetic and lifestyle factors on all-cause mortality risk. FINDINGS: Between Jan 13, 1998, and Dec 31, 2018, 36 164 adults aged 65 years and older were recruited, among whom a total of 27 462 deaths were documented during a median follow-up of 3·12 years (IQR 1·62-5·94) and included in the lifestyle association analysis. Compared with the unhealthy lifestyle category, participants in the healthy lifestyle group had a lower all-cause mortality risk (hazard ratio [HR] 0·56 [95% CI 0·54-0·57]; p<0·0001). The highest mortality risk was observed in individuals in the high genetic risk and unhealthy lifestyle group (HR 1·80 [95% CI 1·63-1·98]; p<0·0001). The absolute risk reduction was greater for participants in the high genetic risk group. A healthy lifestyle was associated with a gain of 3·84 years (95% CI 3·05-4·64) at the age of 65 years in the low genetic risk group, and 4·35 years (3·70-5·06) in the high genetic risk group. INTERPRETATION: A healthy lifestyle, even in late-life, was associated with lower mortality risk and longer life expectancy among Chinese older adults, highlighting the importance of a healthy lifestyle in extending the lifespan, especially for individuals with high genetic risk. FUNDING: National Natural Science Foundation of China. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

26Molecular mechanisms of aging and anti-aging strategies.PubMed

Yumeng Li, Xutong Tian, Juyue Luo, et al.
Cell Commun Signal. 2024 May 24;22(1):285. doi: 10.1186/s12964-024-01663-1.
Aging is a complex and multifaceted process involving a variety of interrelated molecular mechanisms and cellular systems. Phenotypically, the biological aging process is accompanied by a gradual loss of cellular function and the systemic deterioration of multiple tissues, resulting in susceptibility to aging-related diseases. Emerging evidence suggests that aging is closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient sensing, altered intercellular communication, and dysbiosis. These age-related changes may be alleviated by intervention strategies, such as calorie restriction, improved sleep quality, enhanced physical activity, and targeted longevity genes. In this review, we summarise the key historical progress in the exploration of important causes of aging and anti-aging strategies in recent decades, which provides a basis for further understanding of the reversibility of aging phenotypes, the application prospect of synthetic biotechnology in anti-aging therapy is also prospected.

27Longevity: Lesson from Model Organisms.PubMed

Giusi Taormina, Federica Ferrante, Salvatore Vieni, et al.
Genes (Basel). 2019 Jul 9;10(7):518. doi: 10.3390/genes10070518.
Research on longevity and healthy aging promises to increase our lifespan and decrease the burden of degenerative diseases with important social and economic effects. Many aging theories have been proposed, and important aging pathways have been discovered. Model organisms have had a crucial role in this process because of their short lifespan, cheap maintenance, and manipulation possibilities. Yeasts, worms, fruit flies, or mammalian models such as mice, monkeys, and recently, dogs, have helped shed light on aging processes. Genes and molecular mechanisms that were found to be critical in simple eukaryotic cells and species have been confirmed in humans mainly by the functional analysis of mammalian orthologues. Here, we review conserved aging mechanisms discovered in different model systems that are implicated in human longevity as well and that could be the target of anti-aging interventions in human.

28From geroscience to precision geromedicine: Understanding and managing aging.PubMed

Guido Kroemer, Andrea B Maier, Ana Maria Cuervo, et al.
Cell. 2025 Apr 17;188(8):2043-2062. doi: 10.1016/j.cell.2025.03.011.
Major progress has been made in elucidating the molecular, cellular, and supracellular mechanisms underlying aging. This has spurred the birth of geroscience, which aims to identify actionable hallmarks of aging. Aging can be viewed as a process that is promoted by overactivation of gerogenes, i.e., genes and molecular pathways that favor biological aging, and alternatively slowed down by gerosuppressors, much as cancers are caused by the activation of oncogenes and prevented by tumor suppressors. Such gerogenes and gerosuppressors are often associated with age-related diseases in human population studies but also offer targets for modeling age-related diseases in animal models and treating or preventing such diseases in humans. Gerogenes and gerosuppressors interact with environmental, behavioral, and psychological risk factors to determine the heterogeneous trajectory of biological aging and disease manifestation. New molecular profiling technologies enable the characterization of gerogenic and gerosuppressive pathways, which serve as biomarkers of aging, hence inaugurating the era of precision geromedicine. It is anticipated that, pending results from randomized clinical trials and regulatory approval, gerotherapeutics will be tailored to each person based on their genetic profile, high-dimensional omics-based biomarkers of aging, clinical and digital biomarkers of aging, psychosocial profile, and past or present exposures.

29Global Burden of Disease from Environmental Factors.PubMed

Sierra N Clark, Susan C Anenberg, Michael Brauer
Annu Rev Public Health. 2025 Apr;46(1):233-251. doi: 10.1146/annurev-publhealth-071823-105338. Epub 2024 Dec 17.
Estimation of the disease burden attributable to environmental factors is a powerful tool for prioritizing environmental and pollution management and public health actions around the world. The World Health Organization (WHO) began estimating the environmental disease burden in 2000, which has formed the basis for the modern estimation approach conducted in the Global Burden of Disease, Injuries, and Risk Factor (GBD) study. In 2021, environmental and occupational risk factors in the GBD were responsible for 18.9% (12.8 million) of global deaths and 14.4% of all disability-adjusted life years (DALYs), led by ambient PM air pollution (4.2% DALYs, 4.7 million deaths) and household air pollution from the use of solid fuels for cooking (3.9% DALYs, 3.1 million deaths). Climate change exacerbates many environmental hazards, leading to increased disease burdens from heat, air pollution, vector-borne diseases, storms, and flooding. Other environmental risk factors not included in the GBD, such as poor indoor air quality, various chemical exposures, and environmental noise pollution, also significantly contribute to disease burden in many countries, though more efforts are needed to generate and integrate data resources for inclusion in global estimations.

30Air Pollution, Socioeconomic Status, and Age-Specific Mortality Risk in the United States.PubMed

Antonio Fernando Boing, Priyanka deSouza, Alexandra Crispim Boing, et al.
JAMA Netw Open. 2022 May 2;5(5):e2213540. doi: 10.1001/jamanetworkopen.2022.13540.
IMPORTANCE: Prior studies on the association between fine particulate matter with diameters 2.5 μm or smaller (PM2.5) and probability of death have not applied multilevel analysis disaggregating data for US census tract, states, and counties, nor tested its interaction by socioeconomic status (SES). Such an approach could provide a more refined identification and targeting of populations exposed to increased risk from PM2.5. OBJECTIVE: To assess the association between PM2.5 and age-specific mortality risk (ASMR) using disaggregated data at the census tract level and evaluate such association according to census tract SES. DESIGN, SETTING, AND PARTICIPANTS: This nationwide cross-sectional study used a linkage of 3 different data sets. ASMR for the period of 2010 to 2015 was obtained from the National Center for Health Statistic, SES data covering a period from 2006 to 2016 came from the American Community Survey, and mean PM2.5 exposure levels from 2010 to 2015 were derived from well-validated atmospheric chemistry and machine learning models. Data were analyzed in April 2021. EXPOSURES: The main exploratory variable was mean census tract-level long-term exposure to PM2.5 from 2010 to 2015. MAIN OUTCOMES AND MEASURES: The primary outcome was census tract-level ASMR. Multilevel models were used to quantify the geographic variation in ASMR at levels of census tract, county, and state. Additional analysis explored the interaction of SES in the association of ASMR with PM2.5 exposure. RESULTS: Data from 67 148 census tracts nested in 3087 counties and 50 states were analyzed. The association between exposure to PM2.5 and ASMR varied substantially across census tracts. The magnitude of such association also varied across age groups, being higher among adults and older adults. Census tracts accounted for most of the total geographic variation in mortality risk (range, 77.0%-94.2%). ASMR was higher in deciles with greater PM2.5 concentration. For example, ASMR for age 75 to 84 years was 54.6 per 1000 population higher in the decile with the second-highest PM2.5 concentration than in the decile with the lowest PM2.5 concentration. The ASMR, PM2.5 concentrations, and magnitude of the association between both were higher in the census tracts with the lowest SES. CONCLUSIONS AND RELEVANCE: This cross-sectional study found that census tracts with lower SES presented higher PM2.5 concentrations. ASMR and air pollution varied substantially across census tracts. There was an association between air pollution and ASMR across all age groups in the United States. These findings suggest that equitable public policies aimed at improving air quality are needed and important to increase life expectancy.

31National and provincial burden of disease attributable to fine particulate matter air pollution in China, 1990-2021: an analysis of data from the Global Burden of Disease Study 2021.PubMed

Tanchun Yu, Yixuan Jiang, Renjie Chen, et al.
Lancet Planet Health. 2025 Mar;9(3):e174-e185. doi: 10.1016/S2542-5196(25)00024-5.
BACKGROUND: Fine particulate matter (PM) is the leading environmental risk factor for mortality and disability worldwide. We aimed to evaluate the temporal trend in, and spatial distribution of, the disease burden attributable to PM in China from 1990 to 2021. METHODS: Based on the methodology framework and general analytical strategies applied in the Global Burden of Diseases, Injuries, and Risk Factors Study 2021, we calculated the numbers, age-standardised rates, and percentage of deaths and disability-adjusted life-years (DALYs) attributable to PM air pollution from 1990 to 2021 at the national and provincial level in China, by disease, sex, and age groups. Exposure to PM, including ambient PM pollution and household PM pollution from solid fuels, was evaluated across 33 provincial administrative units in China. FINDINGS: In 2021, 2·3 million (95% uncertainty interval [UI] 1·8-2·9) deaths and 46·7 million (36·6-59·7) DALYs could be attributable to PM pollution in China, accounting for 19·4% (16·0-23·6) of total deaths and 11·6% (9·4-14·1) of total DALYs. Of these, 1·9 million (95% UI 1·3-2·3) deaths and 37·8 million (26·3-46·5) DALYs resulted from ambient exposure, while 0·4 million (0·1-1·3) deaths and 8·9 million (1·5-27·8) DALYs were due to household exposure from solid fuel use. Stroke, ischaemic heart disease, and chronic obstructive pulmonary disease were the leading three causes. Two peaks in the burden were observed: in children aged younger than 5 years, and in people aged 70 years and older. The percentage of deaths and DALYs due to ambient PM was higher in men, while that due to household PM was higher in women. Geographically, the disease burden from ambient PM was higher in north and northwest China, while that from household PM was higher in southwest China. From 1990 to 2021, age-standardised death rates attributable to total PM decreased by 66·0% (95% UI 57·7-73·1) and those attributable to household PM decreased by 92·2% (76·6-98·7), with larger reductions observed in east and south China. By contrast, the disease burden related to ambient PM continued to increase and only began to decline in the past decade. INTERPRETATION: Despite the decline in the disease burden attributable to total PM in China during 1990-2021, ambient PM remains a major contributor to mortality and disability. This study highlights considerable spatial heterogeneity across different provinces and provides valuable insights for developing geographically tailored strategies for PM control and public health promotion in China. Stricter control of ambient air pollution is needed in northern and northwestern regions, while promoting clean cooking energy is more urgently warranted in southwestern areas. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program of China, Shanghai Municipal Science and Technology Major Project, China Postdoctoral Science Foundation.

32Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.PubMed

Lancet. 2024 May 18;403(10440):2162-2203. doi: 10.1016/S0140-6736(24)00933-4.
BACKGROUND: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. METHODS: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk-outcome pairs. Pairs were included on the basis of data-driven determination of a risk-outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk-outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk-outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. FINDINGS: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7-9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4-9·2]), smoking (5·7% [4·7-6·8]), low birthweight and short gestation (5·6% [4·8-6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8-6·0]). For younger demographics (ie, those aged 0-4 years and 5-14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9-27·7]) and environmental and occupational risks (decrease of 22·0% [15·5-28·8]), coupled with a 49·4% (42·3-56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9-21·7] for high BMI and 7·9% [3·3-12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6-1·9) for high BMI and 1·3% (1·1-1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4-78·8) for child growth failure and 66·3% (60·2-72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). INTERPRETATION: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions. FUNDING: Bill & Melinda Gates Foundation.

33Global ischemic heart disease burden attributable to environmental risk factors, 1990-2021: an Age-Period-Cohort analysis.PubMed

Rui Su, Wangchu Ze, Ruiyu Huang, et al.
Front Public Health. 2025 Aug 1;13:1622108. doi: 10.3389/fpubh.2025.1622108. eCollection 2025.
BACKGROUND: Ischemic heart disease (IHD) is the leading cause of global deaths. Environmental exposures contribute substantially to IHD burden, yet their combined effects across socio-demographic strata remain poorly characterized. OBJECTIVE: This study aimed to systematically evaluate the global burden of IHD attributable to environmental factors, analyzing its temporal trends, geographical patterns, and Age-Period-Cohort (APC) effects across different socio-demographic index regions from 1990 to 2021. METHODS: Data for this study were obtained from the Global Burden of Disease 2021 (GBD 2021) public dataset to investigate age-standardized deaths rates and disability-adjusted life years (DALYs) rates of IHD attributable to environmental factors from 1990 to 2021. Environmental factors included particulate matter pollution, non-optimal temperature, and lead exposure. Countries were categorized into five socio-demographic index (SDI) levels. The APC analysis model was employed to disentangle age, period, and cohort effects. Data processing and visualization were conducted using R version 4.4.3. RESULTS: Between 1990 and 2021, global environmental IHD deaths rates decreased by 31.13% and DALYs rates by 29.85%. High SDI regions achieved 70.39% reduction in deaths rates, while low SDI regions showed only 3.13% decrease. Particulate matter pollution remained the predominant environmental contributor with the highest burdens in South Asia, the Middle East, and North Africa. APC analysis revealed that environmental-related IHD burden increased exponentially with age, with earlier birth cohorts showing substantially higher Risk Ratios (RR). Males consistently demonstrated higher burden than females across all environmental factors. CONCLUSION: IHD burden attributable to environmental factors shows a declining trend globally but with notable regional and gender disparities. Policymakers in low SDI regions should integrate environmental health into development strategies, high-pollution burden regions should strengthen air quality monitoring and emission control, climate-sensitive regions need to implement temperature adaptation planning, and historically industrialized regions should enhance lead exposure monitoring while ensuring occupational protection for males and environmental health safeguards for the older adults.

34Dietary activators of Sirt1.PubMed

Joanne S Allard, Evelyn Perez, Sige Zou, et al.
Mol Cell Endocrinol. 2009 Feb 5;299(1):58-63. doi: 10.1016/j.mce.2008.10.018. Epub 2008 Nov 1.
Calorie restriction (CR) is a non-genetic manipulation that reliably results in extended lifespan of several species ranging from yeast to dogs. The lifespan extension effect of CR has been strongly associated with an increased level and activation of the silent information regulator 2 (Sir2) histone deacetylase and its mammalian ortholog Sirt1. This association led to the search for potential Sirt1-activating, life-extending molecules. This review briefly outlines the experimental findings on resveratrol and other dietary activators of Sirt1.

35Diet restriction and ageing in the dog: major observations over two decades.PubMed

Dennis F Lawler, Brian T Larson, Joan M Ballam, et al.
Br J Nutr. 2008 Apr;99(4):793-805. doi: 10.1017/S0007114507871686. Epub 2007 Dec 6.
This report reviews decade two of the lifetime diet restriction study of the dog. Labrador retrievers (n 48) were paired at age 6 weeks by sex and weight within each of seven litters, and assigned randomly within the pair to control-feeding (CF) or 25 % diet restriction (DR). Feeding began at age 8 weeks. The same diet was fed to all dogs; only the quantity differed. Major lifetime observations included 1.8 years longer median lifespan among diet-restricted dogs, with delayed onset of late life diseases, especially osteoarthritis. Long-term DR did not negatively affect skeletal maturation, structure or metabolism. Among all dogs, high static fat mass and declining lean body mass predicted death, most strongly at 1 year prior. Fat mass above 25 % was associated with increasing insulin resistance, which independently predicted lifespan and chronic diseases. Metabolizable energy requirement/lean body mass most accurately explained energy metabolism due to diet restriction; diet-restricted dogs required 17 % less energy to maintain each lean kilogram. Metabonomics-based urine metabolite trajectories reflected DR-related differences, suggesting that signals from gut microbiota may be involved in the DR longevity and health responses. Independent of feeding group, increased hazard of earlier death was associated with lower lymphoproliferative responses to phytohaemagglutinin, concanavalin A, and pokeweed mitogen; lower total lymphocytes, T-cells, CD4 and CD8 cells; lower CD8 percentages and higher B-cell percentages. When diet group was taken into account, PWM responses and cell counts and percentages remained predictive of earlier death.

36Conference on "Multidisciplinary approaches to nutritional problems". Symposium on "Nutrition and health". Nutritional therapies to improve health: lessons from companion animals.PubMed

Richard C Hill
Proc Nutr Soc. 2009 Feb;68(1):98-102. doi: 10.1017/S0029665108008835. Epub 2008 Dec 1.
Companion animals represent an under-utilised resource. The present paper is designed to encourage collaborative studies. Dogs and cats are out-bred animals that are willing to consume a consistent diet for long periods, so are ideal candidates for prospective studies of naturally-occurring disease. In some studies the effect of diet on survival has been substantial. Food restriction, for example, slows the development of osteoarthritis and increases the lifespan of Labrador retrievers by 2 years, protein and P restriction more than doubles the median survival time of dogs and cats with chronic kidney disease and adding n-3 fats and arginine to the diet of dogs with stage 3 lymphoma improves median survival time by one-quarter. Obesity is also very common in both dogs and cats and is also associated with disease as in human subjects. When interpreting these results, however, it is essential to take into account pathophysiological differences among species. Dogs and cats do not display all the characteristics of metabolic disease in human subjects, they metabolise fat well and atherosclerosis and cardiac infarction are uncommon. Such differences should not, however, preclude further study because differences among species often clarify knowledge. Monitoring of disease in companion animals may also provide a surveillance system for the safety of the food supply, as illustrated by recent outbreaks of acute renal failure and liver failure in cats and dogs in the USA caused respectively by melamine and mycotoxin contamination of pet foods.

37Health Benefits of Intermittent Fasting.PubMed

B Lakshmi Reddy, Vamsee S Reddy, Milton H Saier
Microb Physiol. 2024;34(1):142-152. doi: 10.1159/000540068. Epub 2024 Jul 2.
We propose that intermittent fasting (time-restricted eating), in agreement with the conclusions of other biologists, as revealed in recent publications, promotes the achievement of numerous health benefits including the extension of human and animal lifespans. Background: There is evidence, obtained both with animal model systems and with humans, that intermittent fasting has health benefits. These benefits include extended longevity, weight loss, and counteracting various disease conditions. Such procedures positively influence the benefits of human tissue-specific microbiomes and minimize the consequences of organellar apoptosis. Key Messages: In this review, we attempt to summarize the predominant evidence, published in the scientific literature, relevant to the conclusions that in general, and in many specific instances, intermittent fasting has long-term benefits to animals, including humans, with respect to overall and specific organismal health and longevity.

38The Health-Promoting Effects and the Mechanism of Intermittent Fasting.PubMed

Simin Liu, Min Zeng, Weixi Wan, et al.
J Diabetes Res. 2023 Mar 3;2023:4038546. doi: 10.1155/2023/4038546. eCollection 2023.
Intermittent fasting (IF) is an eating pattern in which individuals go extended periods with little or no energy intake after consuming regular food in intervening periods. IF has several health-promoting effects. It can effectively reduce weight, fasting insulin levels, and blood glucose levels. It can also increase the antitumor activity of medicines and cause improvement in the case of neurological diseases, such as memory deficit, to achieve enhanced metabolic function and prolonged longevity. Additionally, IF activates several biological pathways to induce autophagy, encourages cell renewal, prevents cancer cells from multiplying and spreading, and delays senescence. However, IF has specific adverse effects and limitations when it comes to people of a particular age and gender. Hence, a more systematic study on the health-promoting effects and safety of IF is needed. This article reviewed the research on the health-promoting effects of IF, providing a theoretical basis, direction for subsequent basic research, and information related to the clinical application of IF.

39Intermittent fasting and longevity: From animal models to implication for humans.PubMed

Olha Strilbytska, Svitlana Klishch, Kenneth B Storey, et al.
Ageing Res Rev. 2024 Apr;96:102274. doi: 10.1016/j.arr.2024.102274. Epub 2024 Mar 17.
In recent years, intermittent fasting (IF) and its numerous modifications have been increasingly suggested as a promising therapy for age-related problems and a non-pharmacological strategy to extend lifespan. Despite the great variability in feeding schedules that we describe in the current work, underlying physiological processes are the same and include a periodic switch from glucose metabolism (generated by glycogenolysis) to fatty acids and fatty acid-derived ketones. Many of the beneficial effects of IF appear to be mediated by optimization of energy utilization. Findings to date from both human and animal experiments indicate that fasting improves physiological function, enhances performance, and slows aging and disease processes. In this review, we discuss some of the remarkable discoveries about the beneficial effects of IF on metabolism, endocrine and cardiovascular systems, cancer prevention, brain health, neurodegeneration and aging. Experimental studies on rodent models and human investigations are summarized to compare the outcomes and underlying mechanisms of IF. Metabolic and cellular responses triggered by IF could help to achieve the aim of preventing disease, and maximizing healthspan and longevity with minimal side effects.

40Spermidine is essential for fasting-mediated autophagy and longevity.PubMed

Sebastian J Hofer, Ioanna Daskalaki, Martina Bergmann, et al.
Nat Cell Biol. 2024 Sep;26(9):1571-1584. doi: 10.1038/s41556-024-01468-x. Epub 2024 Aug 8.
Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine-hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity.

41Cardiovascular Health and Life Expectancy Among Adults in the United States.PubMed

Hao Ma, Xuan Wang, Qiaochu Xue, et al.
Circulation. 2023 Apr 11;147(15):1137-1146. doi: 10.1161/CIRCULATIONAHA.122.062457. Epub 2023 Apr 10.
BACKGROUND: Cardiovascular disease may be the main reason for stagnant growth in life expectancy in the United States since 2010. The American Heart Association recently released an updated algorithm for evaluating cardiovascular health (CVH)-Life's Essential 8 (LE8) score. We aimed to quantify the associations of CVH levels, estimated by the LE8 score, with life expectancy in a nationally representative sample of US adults. METHODS: We included 23 003 nonpregnant, noninstitutionalized participants aged 20 to 79 years who participated in the National Health and Nutrition Examination Survey from 2005 to 2018 and whose mortality was identified through linkage to the National Death Index through December 31, 2019. The overall CVH was evaluated by the LE8 score (range, 0-100), as well as the score for each component of diet, physical activity, tobacco/nicotine exposure, sleep duration, body mass index, non-high-density lipoprotein cholesterol, blood glucose, and blood pressure. Life table method was used to estimate life expectancy by levels of the CVH. RESULTS: During a median of 7.8 years of follow-up, 1359 total deaths occurred. The estimated life expectancy at age 50 years was 27.3 years (95% CI, 26.1-28.4), 32.9 years (95% CI, 32.3-33.4), and 36.2 years (95% CI, 34.2-38.2) in participants with low (LE8 score <50), moderate (50≤ LE8 score <80), and high (LE8 score ≥80) CVH, respectively. Equivalently, participants with high CVH had an average 8.9 (95% CI, 6.2-11.5) more years of life expectancy at age 50 years compared with those with low CVH. On average, 42.6% of the gained life expectancy at age 50 years from adhering to high CVH was attributable to reduced cardiovascular disease death. Similarly significant associations of CVH with life expectancy were observed in men and women, respectively. Similarly significant associations of CVH with life expectancy were observed in White participants and Black participants but not in Mexican participants. CONCLUSIONS: Adhering to a high CVH, defined as the LE8 score, is related to a considerably increased life expectancy in US adults, but more research needs to be done in other races and ethnicities (eg, Hispanic and Asian).

42Association of Cardiovascular Health With Life Expectancy Free of Cardiovascular Disease, Diabetes, Cancer, and Dementia in UK Adults.PubMed

Xuan Wang, Hao Ma, Xiang Li, et al.
JAMA Intern Med. 2023 Apr 1;183(4):340-349. doi: 10.1001/jamainternmed.2023.0015.
IMPORTANCE: The average life expectancy has increased substantially in the past few decades in most industrialized countries; however, not all of the increased life expectancy is being spent in optimal health, especially among individuals with low socioeconomic status. OBJECTIVE: To quantify the associations between levels of cardiovascular health (CVH), estimated by the American Heart Association's Life's Essential 8 (LE8) metrics, with life expectancy free of major chronic disease, including cardiovascular disease (CVD), diabetes, cancer, and dementia, in UK adults. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 135 199 adults in the UK Biobank study who were initially free of major chronic disease and had complete data on LE8 metrics. Data analyses were performed in August 2022. EXPOSURES: Cardiovascular health levels, as estimated by LE8 score. The LE8 score, which consists of 8 components: (1) diet, (2) physical activity, (3) tobacco/nicotine exposure, (4) sleep, (5) body mass index, (6) non-high-density lipoprotein cholesterol, (7) blood glucose, and (8) blood pressure. The CVH level was evaluated at baseline and categorized into low (LE8 score <50), moderate (LE8 score ≥50 but <80), and high (LE8 score ≥80) levels. MAIN OUTCOMES AND MEASURES: The primary outcome was the life expectancy free of 4 major chronic diseases (CVD, diabetes, cancer, and dementia). RESULTS: Of the 135 199 adults (44.7% men; mean [SD] age, 55.4 [7.9] years) included in the study, a total of 4712, 48 955, and 6748 men had low, moderate, and high CVH levels, respectively, and the corresponding numbers for women were 3661, 52 192, and 18 931. At age 50 years, the estimated disease-free years were 21.5 (95% CI, 21.0-22.0), 25.5 (95% CI, 25.4-25.6), and 28.4 (95% CI, 27.8-29.0) for men with low, moderate, and high CVH levels, respectively; the corresponding estimated disease-free years at age 50 years for women were 24.2 (95% CI, 23.5-24.8), 30.5 (95% CI, 30.4-30.6), and 33.6 (95% CI, 33.1-34.0). Equivalently, men with moderate or high CVH levels lived on average 4.0 (95% CI, 3.4-4.5) or 6.9 (95% CI, 6.1-7.7) longer years free of chronic disease, respectively, at age 50 years, compared with men with low CVH levels. The corresponding longer years lived free of disease for women were 6.3 (95% CI, 5.6-7.0) or 9.4 (95% CI, 8.5-10.2). For participants with high CVH level, there was not a statistically significant difference in disease-free life expectancy between participants with low and other socioeconomic status. CONCLUSIONS AND RELEVANCE: In this cohort study, a high level of CVH, evaluated using the LE8 metrics, was associated with longer life expectancy free of major chronic diseases and may contribute to narrowing socioeconomic health inequalities in both men and women.

43Healthy Lifestyle and the Likelihood of Becoming a Centenarian.PubMed

Yaqi Li, Kaiyue Wang, Guliyeerke Jigeer, et al.
JAMA Netw Open. 2024 Jun 3;7(6):e2417931. doi: 10.1001/jamanetworkopen.2024.17931.
IMPORTANCE: Previous studies have reported that lifestyle factors were associated with life expectancy and/or mortality, but most of them studied the middle-aged or older age groups (aged ≥60 years), and few focused on people aged 80 years or older. OBJECTIVES: To examine healthy lifestyle and the likelihood of becoming centenarians among people aged 80 years or older in China. DESIGN, SETTINGS, AND PARTICIPANTS: Using data from the Chinese Longitudinal Healthy Longevity Survey, a nationally representative and one of the largest prospective cohorts targeting people aged 80 years or older established in 1998, a community-based, prospective nested case-control study was performed. Data were analyzed from December 1, 2022, to April 15, 2024. EXPOSURES: A healthy lifestyle score for 100 (HLS-100, ranging from 0 to 6), including smoking, exercise, and dietary diversity, was constructed, with higher scores indicating potentially better health outcomes. MAIN OUTCOMES AND MEASURES: The primary outcome was survivorship to becoming a centenarian by 2018 (the end of follow-up). Information on sociodemographic characteristics, lifestyle factors, and other covariates was collected. RESULTS: The sample comprised 5222 individuals (61.7% women, mean [SD] age, 94.3 [3.3] years), including 1454 identified centenarians and 3768 controls (died before becoming centenarians) matched by age, sex, and year of entry. During a median follow-up of 5 (IQR, 3-7) years, 373 of 1486 individuals among the lowest HLS-100 (0-2) group and 276 of 851 individuals among the highest HLS-100 (5-6) group became centenarians. The adjusted odds ratio (AOR) comparing the highest vs the lowest HLS-100 groups was 1.61 (95% CI, 1.32-1.96; P < .001 for trend). An association was noted when we further treated centenarians with relatively healthy status as the outcome, as evaluated by self-reported chronic conditions, physical and cognitive function, and mental wellness (AOR, 1.54; 95% CI, 1.05-2.26). Similar results were observed in other sensitivity analyses. CONCLUSIONS AND RELEVANCE: In this case-control study of Chinese older adults, adhering to a healthy lifestyle appears to be important even at late ages, suggesting that constructing strategic plans to improve lifestyle behaviors among all older adults may play a key role in promoting healthy aging and longevity.

44Testosterone in long-term sedentary aging males: Effect of antiaging strategies.PubMed

Khaled A Abdel-Sater
Physiol Int. 2025 Feb 6;112(1):1-11. doi: 10.1556/2060.2024.00486. Print 2025 Mar 27.
Physical activity can provide health benefits if done regularly and of sufficient duration and intensity. The World Health Organization recommends adults do 150-300 min of moderate-intensity activity per week, 75-150 min of vigorous-intensity activity, or an equivalent combination.Physical inactivity is the fourth leading cause of early death globally, with 31% of the world's population not getting enough physical activity. Aging is defined by rapid decline in physical activity, loss of mobility, and premature morbidity.Low testosterone levels in men decline from 30 to 40 years of age, and this continues until death. Antiaging strategies, such as caloric restriction, balanced diet, regular exercise, weight management, diabetes control, and smoking cessation can prevent and treat aging-related diseases. Exercise significantly boosts testosterone production, with levels varying based on type, frequency, volume, intensity, and duration. It increases muscle steroidogenesis, total testosterone, and free testosterone in the elderly. Testosterone replacement therapy in elderly men improves physical function, strength, protein synthesis, cholesterol, bone density, sexual desire, erectile function, and overall cognition. However, some studies suggest dehydroepiandrosterone supplementation may provide health improvements without negative effects, potentially reversing arterial aging and reducing the risk of cardiovascular diseases. Senolytic therapeutics focus on cellular senescence, and stem cell transplantation investigates the therapeutic potential of older stem cells.

45Issues in Geriatric Care: Maintaining Health and Vigor.PubMed

Richard J Ackermann
FP Essent. 2018 May;468:11-17.
Medicare covers annual wellness visits that are scheduled separately from regular medical appointments. These visits focus on prevention and health maintenance to help patients achieve successful aging, which is defined as living to old age without disability while also maintaining high physical and psychological levels of functioning and social engagement. To achieve these goals, most adults should perform at least 150 min/week of moderate-intensity exercise and maintain an optimal body mass index (ie, 23 to 32 kg/m). Healthy diets for most older adults include 1 to 1.2 g/kg/day of protein, with more for individuals with serious acute or chronic conditions. A varied vitamin-rich diet should be consumed. In the absence of deficiencies, vitamin supplements are unnecessary. Neither testosterone nor growth hormone supplementation is recommended. When patients have difficulty sleeping, physicians should assess for conditions affecting sleep and promote good sleep hygiene rather than prescribe hypnotics. Screening for depression and assessing driving safety are important. Smoking cessation and limiting alcohol ingestion to small amounts have benefits even in older age. Cancer screening should be offered only to patients with life expectancy of at least 10 years and who understand the risks and benefits.

46Cancer in the elderly: is it preventable?PubMed

Ramzi R Hajjar
Clin Geriatr Med. 2004 May;20(2):293-316. doi: 10.1016/j.cger.2004.03.002.
It is the goal of the American Cancer Society to decrease the mortality from cancer by 50% and the incidence of cancer by 25% by the year 2015 in the United States. Achieving this goal requires intervention at the primary (incidence) and secondary (mortality) prevention stages, and will involve a concerted effort of the individual practitioner, governmental agencies, local, state, and national interest groups, and the population at large. Primary care practitioners must increase their level of enthusiasm for cancer prevention, and actively counsel patients about cancer risks and preventive measures. Practitioners should encourage inclined patients by providing support and specialty resources, such as dieticians, exercise therapists, and smoking and alcohol cessation programs. The greatest effort lies in the general population, who must adopt a healthier lifestyle, including appropriate diet, smoking cessation, control of obesity, and daily exercise. None of these lifestyle changes are easy to embrace, but once educated about lifestyle and risk of cancer, people have a powerful incentive to change. Continued public awareness campaigns and encouragement from health care providers are essential for the success of such programs. The success in smoking cessation shows that achieving societal lifestyle changes on a large scale is possible. The elderly are especially prone to benefit from primary and secondary prevention techniques, and it must not be assumed that only the young will realize the benefits of prevention and screening. The association of age and cancer risk will always be present, but need not be as consequential as it is now. Although cancer prevention may have a limited role in antiaging per se, the feasibility of cancer risk reduction has a definite role in aging successfully.

47Diagnosis and management of osteoporosis in the older senior.PubMed

Sheryl F Vondracek, Sunny A Linnebur
Clin Interv Aging. 2009;4:121-36. doi: 10.2147/cia.s4965. Epub 2009 May 14.
The older senior is at high risk for osteoporosis. It is important for healthcare providers to be fully aware of the potential risks and benefits of diagnosing and treating osteoporosis in the older senior population. Data indicate that bone mineral density testing is under-utilized and drug therapy is often not initiated when indicated in this population. Bone mineral density testing with central dual energy x-ray absorptiometry is essential and cost-effective in this population. All older seniors should be educated on a bone-healthy lifestyle including age-appropriate weight-bearing exercise and smoking cessation if necessary. It is important to remember that falls play a very important role in the risk for osteoporotic fractures, especially in the older senior. All older seniors should be evaluated annually for falls and strategies should be implemented to reduce fall risk in this population. The risk for vitamin D insufficiency and deficiency is high in the older senior and can contribute to falls and fractures. Adequate intakes of calcium and vitamin D are important and deficiencies need to be treated. Data on osteoporosis drug therapy in the older senior are lacking. Based on data from subgroup analyses of large osteoporosis trials in postmenopausal women, current osteoporosis therapies appear safe and efficacious in the older senior and most will live long enough to derive a benefit from these therapies. Further studies are needed in older seniors, especially men, to better understand the risks and benefits of pharmacologic therapy for the management of osteoporosis.

48Evidence-based strategies to prevent cognitive decline in older people.PubMed

Leon Flicker
Maturitas. 2024 Sep;187:108062. doi: 10.1016/j.maturitas.2024.108062. Epub 2024 Jun 27.
A helpful method to understand cognitive decline in older people is to consider this entity as increasing cognitive frailty caused by a number of interacting pathological processes. Over the last 20 years, multiple lifestyle, environmental and constitutional factors have been linked to the development of cognitive decline. For two interventions based on these factors, increasing physical activity and the control of hypertension, there is class 1 evidence for benefit. Other interventions based on these factors do not have the support of high-level evidence for the alteration of cognitive decline, but their other benefits would argue for their implementation. These interventions include increasing education, smoking cessation, avoiding head injuries, decreasing exposure to air pollution and increased social connections. As cognitive decline is experienced almost universally with ageing, and serious cognitive decline is experienced by substantial numbers of low-risk individuals, whole-of-population intervention strategies are the most effective and efficient. For other interventions to help prevent cognitive decline there is not sufficient evidence for their implementation to be recommended. These include alteration of alcohol ingestion, correction of hearing loss, treatment of depression, dietary interventions, menopausal hormone treatment and monoclonal antibodies directed against amyloid-β.

49The health gap: the challenge of an unequal world.PubMed

Michael Marmot
Lancet. 2015 Dec 12;386(10011):2442-4. doi: 10.1016/S0140-6736(15)00150-6. Epub 2015 Sep 9.

50The Association Between Income and Life Expectancy in the United States, 2001-2014.PubMed

Raj Chetty, Michael Stepner, Sarah Abraham, et al.
JAMA. 2016 Apr 26;315(16):1750-66. doi: 10.1001/jama.2016.4226.
IMPORTANCE: The relationship between income and life expectancy is well established but remains poorly understood. OBJECTIVES: To measure the level, time trend, and geographic variability in the association between income and life expectancy and to identify factors related to small area variation. DESIGN AND SETTING: Income data for the US population were obtained from 1.4 billion deidentified tax records between 1999 and 2014. Mortality data were obtained from Social Security Administration death records. These data were used to estimate race- and ethnicity-adjusted life expectancy at 40 years of age by household income percentile, sex, and geographic area, and to evaluate factors associated with differences in life expectancy. EXPOSURE: Pretax household earnings as a measure of income. MAIN OUTCOMES AND MEASURES: Relationship between income and life expectancy; trends in life expectancy by income group; geographic variation in life expectancy levels and trends by income group; and factors associated with differences in life expectancy across areas. RESULTS: The sample consisted of 1,408,287,218 person-year observations for individuals aged 40 to 76 years (mean age, 53.0 years; median household earnings among working individuals, $61,175 per year). There were 4,114,380 deaths among men (mortality rate, 596.3 per 100,000) and 2,694,808 deaths among women (mortality rate, 375.1 per 100,000). The analysis yielded 4 results. First, higher income was associated with greater longevity throughout the income distribution. The gap in life expectancy between the richest 1% and poorest 1% of individuals was 14.6 years (95% CI, 14.4 to 14.8 years) for men and 10.1 years (95% CI, 9.9 to 10.3 years) for women. Second, inequality in life expectancy increased over time. Between 2001 and 2014, life expectancy increased by 2.34 years for men and 2.91 years for women in the top 5% of the income distribution, but by only 0.32 years for men and 0.04 years for women in the bottom 5% (P < .001 for the differences for both sexes). Third, life expectancy for low-income individuals varied substantially across local areas. In the bottom income quartile, life expectancy differed by approximately 4.5 years between areas with the highest and lowest longevity. Changes in life expectancy between 2001 and 2014 ranged from gains of more than 4 years to losses of more than 2 years across areas. Fourth, geographic differences in life expectancy for individuals in the lowest income quartile were significantly correlated with health behaviors such as smoking (r = -0.69, P < .001), but were not significantly correlated with access to medical care, physical environmental factors, income inequality, or labor market conditions. Life expectancy for low-income individuals was positively correlated with the local area fraction of immigrants (r = 0.72, P < .001), fraction of college graduates (r = 0.42, P < .001), and government expenditures (r = 0.57, P < .001). CONCLUSIONS AND RELEVANCE: In the United States between 2001 and 2014, higher income was associated with greater longevity, and differences in life expectancy across income groups increased over time. However, the association between life expectancy and income varied substantially across areas; differences in longevity across income groups decreased in some areas and increased in others. The differences in life expectancy were correlated with health behaviors and local area characteristics.

51Historical Patterns in the Intergenerational Transmission of Lifespan and Longevity: A Research Note on U.S. Cohorts Born Between 1700 and 1900.PubMed

Saverio Minardi, Giulia Corti, Nicola Barban
Demography. 2024 Aug 1;61(4):979-994. doi: 10.1215/00703370-11458359.
This research note examines historical trends in lifespan inequality and the intergenerational transmission of lifespan and longevity in the United States over the eighteenth, nineteenth, and twentieth centuries. We contribute to the literature by expanding the estimates of the familial component beyond parent-child associations to include multigenerational and horizontal classes of relatives of different sexes. We also examine how lifespan inequality and the role of the family in lifespan and longevity changed over time. We address the challenge of studying extended family networks in historical times by leveraging recent online crowdsourced genealogical data. Results confirm the presence of a familial component for all classes of relatives considered and highlight a stronger association for horizontal than for vertical relationships. Despite decreasing lifespan inequality, we find no evidence of decreased familial lifespan stratification throughout history. If anything, the results suggest a strengthening of the parent-child association. Finally, the results contribute to the debate on the representativeness and usability of crowdsourced genealogical data by emphasizing the importance of sample selection based on the quality of the information collected.

52The healthcare system in Sweden.PubMed

Jonas F Ludvigsson, David Bergman, Catharina Ihre Lundgren, et al.
Eur J Epidemiol. 2025 May;40(5):563-579. doi: 10.1007/s10654-025-01226-9. Epub 2025 May 19.
The Swedish population is characterized by high life expectancy and low avoidable mortality rates. This review outlines the Swedish healthcare system, which offers universal access to all residents and has a long tradition of reforms for social equity. Responsibility for healthcare is shared between the state, the regions, and the municipalities. The Ministry of Health and Social Affairs provides the overall healthcare framework; additionally, several governmental agencies are directly involved in healthcare and public health initiatives. The 21 regions organize, finance, and provide most primary, secondary, and tertiary care, as well as health information channels. Resources for primary care are less plentiful than in many other countries. The 290 municipalities deliver care to elderly people and those with functional impairment. The Swedish healthcare system is primarily tax-funded, with 86% of total healthcare expenditures from public expenses and < 1% from voluntary health insurance. The gross domestic product (GDP) share of healthcare expenditures, 10.5% in 2022, is above the EU average. The level of unmet needs in the population is low, due to universal coverage and caps on user charges except for dental care. Sweden's healthcare system performs well on care quality and patient satisfaction, but suffers from workforce shortage and care fragmentation. Limitations in care coordination can be attributed to a siloed digital infrastructure and care governance, a low number of hospital beds per capita, and a compensation system that often does not incentivize coordination. Despite these challenges, life expectancy is high and avoidable mortality rates are low in Sweden.

53Longevity, Metabolic Disease, and Community Health.PubMed

Stephen J Spann, Mary Ann Ottinger
Prog Mol Biol Transl Sci. 2018;155:1-9. doi: 10.1016/bs.pmbts.2017.11.015. Epub 2018 Feb 6.
In the United States, the average lifespan has increased despite the dramatic increase in obesity, diabetes, and other conditions that worsen during aging. As the longevity of US population increases, it is critical to understand the factors that impact aging populations especially as age-related disease and declining health becomes more prevalent. Diabetes related to obesity has become much more prevalent throughout the United States and globally. Further, the prevalence of age-related health problems accelerate in lower income communities with less access to health care. All these factors become critical as individuals age. Furthermore, in communities with less availability to health care, diagnosis may be delayed and treatments are initiated at a much later stage in disease. As such, the costs of medical care skyrocket leading to higher costs both to the community and to taxpayers. This chapter reviews some key health problems and issues in community health and healthy aging, recognizing the importance of organizations and programs that provide education and support to the aging population. Finally, cultural differences in approaches to healthy aging provide important insights and lessons for optimizing quality of life during aging.

54Mortality inequality, spatial differences and health care access.PubMed

Kadir Atalay, Rebecca Edwards, Fiona Georgiakakis
Health Econ. 2023 Nov;32(11):2632-2654. doi: 10.1002/hec.4746. Epub 2023 Jul 28.
Although Australia maintains relatively high standards of health and healthcare, there exists disparity in health outcomes and longevity among different segments of the population. Internationally, there is growing evidence that life expectancy gains are not being shared equally among the rich and the poor. In this paper we examine the evolution of mortality inequality in Australia between 2001 and 2018. Using a spatial inequality model and combining data from several administrative data sources, we document significant mortality inequality between the rich and the poor in Australia. For most age groups, mortality inequality has remained unchanged over the last 20 years. However, mortality inequality is increasing for middle-aged men and women. In part, this can be explained by improvements in longevity which favor urban over rural Australians. Another contributing factor we identify is differential access to healthcare in rich and poor regions. Although Australia's socioeconomic gradient of mortality is flatter than in the US, due to universal health coverage, the fact that mortality inequality is increasing for some groups accentuates the importance of safeguarding health care accessibility.

55Health, access and nutritional issues among low-income population in Malaysia: introductory note.PubMed

Suzana Shahar, Huijin Lau, Sharifa Ezat Wan Puteh, et al.
BMC Public Health. 2019 Jun 13;19(Suppl 4):552. doi: 10.1186/s12889-019-6852-8.
The current issue of BMC Public Health presents work by the Consortium of Low Income Population Research (CB40R), highlighting a comprehensive aspect of health, i.e., physical health, mental health, health behaviour and health financing; and also nutrition involving all stages of lifespan of the socioeconomic deprived group in Malaysia.Consortium of B40 Research (CB40R) reposited and harmonised shared, non-identifiable data from epidemiological studies involving low income population (B40) in Malaysia. CB40R also performed joint or mega-analyses using combined, harmonised data sets that yield collated results with enhanced statistical power, more variabilities (study population, geographical regions, ethnicities and sociocultural groups) to better understand the needs, characteristics and issues of B40 groups in Malaysia. It also aimed to develope a system/framework of minimum/standard variables to be collected in research involving B40 in future. For this special issues, members of the consortium have been invited to contribute an original article involving analysis of the health aspects, access to health and nutritional issues of the B40 samples.All the papers in this special issue have successfully highlighted the health and nutritional issues (i.e., non-communicable disease (NCD), inflammatory bowel disease (IBD), knowledge towards sexually transmitted disease (STD), low birth weight, Motoric Cognitive Risk (MCR) syndrome, urinary incontinence), mental health, oral health and inequalities among the low-income group in Malaysia, including the rural population and also the urban poor. The low-income population in Malaysia is also at risk of both under- and over nutrition, of which specific cost effective strategies are indeed needed to improve their quality of life.The low income population in Malaysia is facing various health challenges, particularly related to NCD and poor mental health, nutritional and physical function. There is a need for a sustainable intervention model to tackle the issues. It is also important to highlight that reducing SES disparities in health will require policy initiatives addressing the components of socioeconomic status (income, education, and occupation) as well as the pathways by which these affect health.

56Health-system reform and universal health coverage in Latin America.PubMed

Rifat Atun, Luiz Odorico Monteiro de Andrade, Gisele Almeida, et al.
Lancet. 2015 Mar 28;385(9974):1230-47. doi: 10.1016/S0140-6736(14)61646-9. Epub 2014 Oct 15.
Starting in the late 1980s, many Latin American countries began social sector reforms to alleviate poverty, reduce socioeconomic inequalities, improve health outcomes, and provide financial risk protection. In particular, starting in the 1990s, reforms aimed at strengthening health systems to reduce inequalities in health access and outcomes focused on expansion of universal health coverage, especially for poor citizens. In Latin America, health-system reforms have produced a distinct approach to universal health coverage, underpinned by the principles of equity, solidarity, and collective action to overcome social inequalities. In most of the countries studied, government financing enabled the introduction of supply-side interventions to expand insurance coverage for uninsured citizens--with defined and enlarged benefits packages--and to scale up delivery of health services. Countries such as Brazil and Cuba introduced tax-financed universal health systems. These changes were combined with demand-side interventions aimed at alleviating poverty (targeting many social determinants of health) and improving access of the most disadvantaged populations. Hence, the distinguishing features of health-system strengthening for universal health coverage and lessons from the Latin American experience are relevant for countries advancing universal health coverage.

57WHO European review of social determinants of health and the health divide.PubMed

Michael Marmot, Jessica Allen, Ruth Bell, et al.
Lancet. 2012 Sep 15;380(9846):1011-29. doi: 10.1016/S0140-6736(12)61228-8. Epub 2012 Sep 8.
The European region has seen remarkable heath gains in those populations that have experienced progressive improvements in the conditions in which people are born, grow, live, and work. However, inequities, both between and within countries, persist. The review reported here, of inequities in health between and within countries across the 53 Member States of the WHO European region, was commissioned to support the development of the new health policy framework for Europe: Health 2020. Much more is understood now about the extent, and social causes, of these inequities, particularly since the publication in 2008 of the report of the Commission on Social Determinants of Health. The European review builds on the global evidence and recommends policies to ensure that progress can be made in reducing health inequities and the health divide across all countries, including those with low incomes. Action is needed--on the social determinants of health, across the life course, and in wider social and economic spheres--to achieve greater health equity and protect future generations.

58Associations of social determinants of health with life expectancy and future health risks among individuals with type 2 diabetes: two nationwide cohort studies in the UK and USA.PubMed

Jiale Zhong, Yanbo Zhang, Kai Zhu, et al.
Lancet Healthy Longev. 2024 Aug;5(8):e542-e551. doi: 10.1016/S2666-7568(24)00116-8. Epub 2024 Aug 5.
BACKGROUND: Social determinants of health (SDHs) are the primary drivers of preventable health inequities, and the associations between SDHs and health outcomes among individuals with type 2 diabetes remain unclear. This study aimed to estimate the associations of combined SDHs with life expectancy and future health risks among adults with type 2 diabetes from the UK and USA. METHODS: In an analysis of two nationwide cohort studies, adults with type 2 diabetes were identified from the UK Biobank from March 13, 2006, to Oct 1, 2010 (adults aged 37-73 years) and the US National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 (adults aged ≥20 years). Participants with type 2 diabetes at baseline were included in our analysis. Participants without information on SDHs or follow-up were excluded. The UK Biobank assessed 17 SDHs and the US NHANES assessed ten SDHs, with each SDH dichotomised into advantaged and disadvantaged levels. The combined score of SDHs were calculated as the sum of the weighted scores for each SDH. Participants were then categorised into tertiles (favourable, medium, and unfavourable SDH groups). Primary outcomes were life expectancy and mortality in both cohorts, and incidences of cardiovascular disease, diabetes-related microvascular disease, dementia, and cancer in the UK Biobank. Outcomes were obtained from disease registries up until Dec 31, 2021, in the UK Biobank and Dec 31, 2019, in the US NHANES cohorts. FINDINGS: We included 17 321 participants from the UK Biobank cohort (median age 61·0 years [IQR 56·0-65·0]; 6028 [34·8%] women and 11 293 [65·2%] men) and 7885 participants from the NHANES cohort (mean age 59·2 years [95% CI 58·7-59·6]; 3835 [49·1%, weighted] women and 4050 [50·9%, weighted] men) in our analysis. In the UK Biobank, 3235 deaths (median follow-up 12·3 years [IQR 11·5-13·2]), 3010 incident cardiovascular disease (12·1 years [10·8-13·0]), 1997 diabetes-related microvascular disease (8·0 years [7·1-8·9]), 773 dementia (12·6 years [11·8-13·5]), and 2259 cancer cases (11·3 years [10·4-12·2]) were documented; and the US NHANES documented 2278 deaths during a median follow-up of 7·0 years (3·7-11·2). After multivariable adjustment, compared with the favourable SDH group, the hazard ratio was 1·33 (95% CI 1·21-1·46) in the medium SDH group and 1·89 (1·72-2·07) in the unfavourable SDH group in the UK Biobank cohort; 1·51 (1·34-1·70) in the medium SDH group and 2·02 (1·75-2·33) in the unfavourable SDH group in the US NHANES cohort for all-cause mortality; 1·13 (1·04-1·24) in the medium SDH group and 1·40 (1·27-1·53) in the unfavourable SDH group for incident cardiovascular disease; 1·13 (1·01-1·27) in the medium SDH group and 1·41 (1·26-1·59) in the unfavourable SDH group for incident diabetes-related microvascular disease; 1·35 (1·11-1·64) in the medium SDH group and 1·76 (1·46-2·13) in the unfavourable SDH group for incident dementia; and 1·02 (0·92-1·13) in the medium SDH group and 1·17 (1·05-1·30) in the unfavourable SDH group for incident cancer in the UK Biobank cohort (p<0·010 for each category). At the age of 45 years, the mean life expectancy of participants was 1·6 years (0·6-2·3) shorter in the medium SDH group and 4·4 years (3·3-5·4) shorter in the unfavourable SDH group than in the favourable SDH group in the UK Biobank. In the US NHAHES cohort, the life expectancy was 1·7 years (0·6-2·7) shorter in the medium SDH group and 3·0 years (1·8-4·3) shorter in the unfavourable SDH group, compared with the favourable group. INTERPRETATION: Combined unfavourable SDHs were associated with a greater loss of life expectancy and higher risks of developing future adverse health outcomes among adults with type 2 diabetes. These associations were similar across two nationwide cohorts from varied social contexts, and were largely consistent across populations with different demographic, lifestyle, and clinical features. Thus, assessing the combined SDHs of individuals with type 2 diabetes might be a promising approach to incorporate into diabetes care to identify socially vulnerable groups and reduce disease burden. FUNDING: The National Natural Science Foundation of China, the National Key R&D Program of China, and the Fundamental Research Funds for the Central Universities.

59Intergenerational support and depressive symptoms: Moderating effects of community services and smart health devices.PubMed

Yuexuan Mu, Peng Lu, Qingshuai Liu
J Affect Disord. 2025 Nov 1;388:119602. doi: 10.1016/j.jad.2025.119602. Epub 2025 Jun 4.
OBJECTIVE: Prior research suggests that intergenerational support can buffer depressive symptoms among older adults, yet the roles of community services and digital health technologies remain under-explored. We examined whether community service support and use of smart-health devices moderate the association between intergenerational support and depressive symptoms among Chinese older adults. METHODS: We analyzed two waves (2018, 2020) of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), including 4054 older adults. A multilevel mixed-effects model was employed to account for both community-level clustering and unobserved time-invariant confounders. Intergenerational support was the primary predictor, community service support and smart health device use were specified as moderating variables, and depressive symptoms was the outcome. RESULTS: In the fully adjusted model, intergenerational support, community service support, and smart health device use were each independently associated with lower depressive symptom scores. A significant two-way interaction between intergenerational support and smart health device use indicated that the protective association of intergenerational support with depressive symptoms was attenuated among users of smart devices. Moreover, the three-way interaction involving intergenerational support, community service support, and smart device use was also significant, suggesting a synergistic effect of "family+community+technology" in mitigating depressive symptoms among older adults. CONCLUSION: Rather than implying causality, these findings demonstrate that intergenerational support, community services, and smart health devices jointly shape mental health-especially when all three resources coexist. Policies aiming to reduce late-life depression should foster integrated interventions that combine familial, community, and technological supports.

60The role of curcumin in aging and senescence: Molecular mechanisms.PubMed

Aliabbas Zia, Tahereh Farkhondeh, Ali Mohammad Pourbagher-Shahri, et al.
Biomed Pharmacother. 2021 Feb;134:111119. doi: 10.1016/j.biopha.2020.111119. Epub 2020 Dec 24.
Healthy aging and human longevity are intricate phenotypes affected by environmental factors such as physical exercise, diet, health habits, and psychosocial situations as well as genetic factors. Diet and caloric restriction have a crucial role in healthy aging. Curcumin, a polyphenolic compound isolated from the Curcuma longa, has been shown to exert anti-aging characteristics. Recently, investigations on curcumin with regard to aging and age-associated disease in model organisms has described that curcumin and its metabolites, prolong the mean lifespan of some aging model organisms such as C. elegans, D. melanogaster, yeast, and mouse. It has been proposed to have several biological activities, such as antioxidative, anti-inflammatory, anticancer, chemopreventive, and anti-neurodegenerative characteristics. In several studies on various model organisms it has been shown that the lifespan extension via curcumin treatment was connected with enhanced superoxide dismutase (SOD) activity, and also declined malondialdehyde (MDA) and lipofuscin levels. As well as the pivotal role of curcumin on the modulating of major signaling pathways that influence longevity of organisms like IIS, mTOR, PKA, and FOXO signaling pathways. This review defines the use of curcumin in traditional and modern medicine, its biochemistry and biological functions, such as curcumin's anti-aging, anti-cancer, anti-microbial, anti-inflammatory, and anti-oxidant characteristics. Also, the review further describes the role of curcumin in a pharmacological context and new insights on its therapeutic capacity and restrictions. Particularly, the review emphasizes in-depth on the efficiency of curcumin and its mechanism of action as an anti-aging compound and also treating age-related disease.

61The inflammaging clock strikes IL-11!PubMed

Saad Khan, Veronica Chang, Daniel A Winer
Immunity. 2024 Sep 10;57(9):2010-2012. doi: 10.1016/j.immuni.2024.08.010.
Chronic inflammation is considered a hallmark of aging. In a recent issue of Nature, Widjaja et al. examined genetic and pharmacologic inhibition of interleukin (IL)-11 on aging pathology and found that inhibiting IL-11 signaling increases lifespan and healthspan in mice.

62Curcumin: A Golden Approach to Healthy Aging: A Systematic Review of the Evidence.PubMed

Yandra Cervelim Nunes, Nathalia M Mendes, Enzo Pereira de Lima, et al.
Nutrients. 2024 Aug 15;16(16):2721. doi: 10.3390/nu16162721.
Aging-related disorders pose significant challenges due to their complex interplay of physiological and metabolic factors, including inflammation, oxidative stress, and mitochondrial dysfunction. Curcumin, a natural compound with potent antioxidant and anti-inflammatory properties, has emerged as a promising candidate for mitigating these age-related processes. However, gaps in understanding the precise mechanisms of curcumin's effects and the optimal dosages for different conditions necessitate further investigation. This systematic review synthesizes current evidence on curcumin's potential in addressing age-related disorders, emphasizing its impact on cognitive function, neurodegeneration, and muscle health in older adults. By evaluating the safety, efficacy, and mechanisms of action of curcumin supplementation, this review aims to provide insights into its therapeutic potential for promoting healthy aging. A systematic search across three databases using specific keywords yielded 2256 documents, leading to the selection of 15 clinical trials for synthesis. Here, we highlight the promising potential of curcumin as a multifaceted therapeutic agent in combating age-related disorders. The findings of this review suggest that curcumin could offer a natural and effective approach to enhancing the quality of life of aging individuals. Further research and well-designed clinical trials are essential to validate these findings and optimize the use of curcumin in personalized medicine approaches for age-related conditions.

63Inhibition of IL-11 signalling extends mammalian healthspan and lifespan.PubMed

Anissa A Widjaja, Wei-Wen Lim, Sivakumar Viswanathan, et al.
Nature. 2024 Aug;632(8023):157-165. doi: 10.1038/s41586-024-07701-9. Epub 2024 Jul 17.
For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.

64Biomarkers of aging for the identification and evaluation of longevity interventions.PubMed

Mahdi Moqri, Chiara Herzog, Jesse R Poganik, et al.
Cell. 2023 Aug 31;186(18):3758-3775. doi: 10.1016/j.cell.2023.08.003.
With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice.

65Towards Healthy Longevity: Comprehensive Insights from Molecular Targets and Biomarkers to Biological Clocks.PubMed

Khalishah Yusri, Sanjay Kumar, Sheng Fong, et al.
Int J Mol Sci. 2024 Jun 20;25(12):6793. doi: 10.3390/ijms25126793.
Aging is a complex and time-dependent decline in physiological function that affects most organisms, leading to increased risk of age-related diseases. Investigating the molecular underpinnings of aging is crucial to identify geroprotectors, precisely quantify biological age, and propose healthy longevity approaches. This review explores pathways that are currently being investigated as intervention targets and aging biomarkers spanning molecular, cellular, and systemic dimensions. Interventions that target these hallmarks may ameliorate the aging process, with some progressing to clinical trials. Biomarkers of these hallmarks are used to estimate biological aging and risk of aging-associated disease. Utilizing aging biomarkers, biological aging clocks can be constructed that predict a state of abnormal aging, age-related diseases, and increased mortality. Biological age estimation can therefore provide the basis for a fine-grained risk stratification by predicting all-cause mortality well ahead of the onset of specific diseases, thus offering a window for intervention. Yet, despite technological advancements, challenges persist due to individual variability and the dynamic nature of these biomarkers. Addressing this requires longitudinal studies for robust biomarker identification. Overall, utilizing the hallmarks of aging to discover new drug targets and develop new biomarkers opens new frontiers in medicine. Prospects involve multi-omics integration, machine learning, and personalized approaches for targeted interventions, promising a healthier aging population.

66Biomarkers of aging.PubMed

Hainan Bao, Jiani Cao, et al.
Sci China Life Sci. 2023 May;66(5):893-1066. doi: 10.1007/s11427-023-2305-0. Epub 2023 Apr 11.
Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant.

67Validation of biomarkers of aging.PubMed

Mahdi Moqri, Chiara Herzog, Jesse R Poganik, et al.
Nat Med. 2024 Feb;30(2):360-372. doi: 10.1038/s41591-023-02784-9. Epub 2024 Feb 14.
The search for biomarkers that quantify biological aging (particularly 'omic'-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve as surrogate endpoints for the evaluation of interventions promoting healthy aging and longevity. However, no consensus exists on how biomarkers of aging should be validated before their translation to the clinic. Here, we review current efforts to evaluate the predictive validity of omic biomarkers of aging in population studies, discuss challenges in comparability and generalizability and provide recommendations to facilitate future validation of biomarkers of aging. Finally, we discuss how systematic validation can accelerate clinical translation of biomarkers of aging and their use in gerotherapeutic clinical trials.

68Epigenetic Clocks and EpiScore for Preventive Medicine: Risk Stratification and Intervention Models for Age-Related Diseases.PubMed

Hidekazu Yamada
J Clin Med. 2025 May 21;14(10):3604. doi: 10.3390/jcm14103604.
Aging is the primary risk factor for chronic diseases such as cardiovascular disease, cancer, and dementia. However, chronological age alone fails to capture individual variability in aging trajectories and disease susceptibility. Recent advances in epigenetic clocks-DNA methylation-based models that estimate biological age-have opened new possibilities for personalized and preventive medicine. This review explores the clinical potential of epigenetic clocks and EpiScores, composite biomarkers that predict health risks and physiological status. We present a comparative evaluation of widely used epigenetic clocks, including Horvath, GrimAge, PhenoAge, and DunedinPACE, and summarize their predictive performance for mortality, cognitive decline, and cardiovascular outcomes. EpiScores linked to inflammation, glycemic control, and immunosenescence are highlighted as tools for stratified risk assessment. When integrated with multi-omics data and electronic health records, these measures enhance the precision of population health management. Special emphasis is placed on applications in longevity clinics and anti-aging clinics, community-based care, and national health checkup systems. We also explore global standardization efforts and ethical considerations, as well as Japan's unique initiatives-including the "Aging Measurement" project at the Osaka-Kansai Expo 2025. Furthermore, we propose the development of a Global Health and Aging Index that integrates the biological, functional, and subjective dimensions of aging, aligned with the WHO concept of Intrinsic Capacity. In conclusion, epigenetic clocks and EpiScores represent transformative tools for shifting from reactive treatment to proactive health optimization, and from chronological to biological metrics in aging science and public health policy.

69Epigenetic clock: A promising biomarker and practical tool in aging.PubMed

Ran Duan, Qiaoyu Fu, Yu Sun, et al.
Ageing Res Rev. 2022 Nov;81:101743. doi: 10.1016/j.arr.2022.101743. Epub 2022 Oct 4.
As a complicated process, aging is characterized by various changes at the cellular, subcellular and nuclear levels, one of which is epigenetic aging. With increasing awareness of the critical role that epigenetic alternations play in aging, DNA methylation patterns have been employed as a measure of biological age, currently referred to as the epigenetic clock. This review provides a comprehensive overview of the epigenetic clock as a biomarker of aging and a useful tool to manage healthy aging. In this burgeoning scientific field, various kinds of epigenetic clocks continue to emerge, including Horvath's clock, Hannum's clock, DNA PhenoAge, and DNA GrimAge. We hereby present the most classic epigenetic clocks, as well as their differences. Correlations of epigenetic age with morbidity, mortality and other factors suggest the potential of epigenetic clocks for risk prediction and identification in the context of aging. In particular, we summarize studies on promising age-reversing interventions, with epigenetic clocks employed as a practical tool in the efficacy evaluation. We also discuss how the lack of higher-quality information poses a major challenge, and offer some suggestions to address existing obstacles. Hopefully, our review will help provide an appropriate understanding of the epigenetic clocks, thereby enabling novel insights into the aging process and how it can be manipulated to promote healthy aging.

70Causality-enriched epigenetic age uncouples damage and adaptation.PubMed

Kejun Ying, Hanna Liu, Andrei E Tarkhov, et al.
Nat Aging. 2024 Feb;4(2):231-246. doi: 10.1038/s43587-023-00557-0. Epub 2024 Jan 19.
Machine learning models based on DNA methylation data can predict biological age but often lack causal insights. By harnessing large-scale genetic data through epigenome-wide Mendelian randomization, we identified CpG sites potentially causal for aging-related traits. Neither the existing epigenetic clocks nor age-related differential DNA methylation are enriched in these sites. These CpGs include sites that contribute to aging and protect against it, yet their combined contribution negatively affects age-related traits. We established a new framework to introduce causal information into epigenetic clocks, resulting in DamAge and AdaptAge-clocks that track detrimental and adaptive methylation changes, respectively. DamAge correlates with adverse outcomes, including mortality, while AdaptAge is associated with beneficial adaptations. These causality-enriched clocks exhibit sensitivity to short-term interventions. Our findings provide a detailed landscape of CpG sites with putative causal links to lifespan and healthspan, facilitating the development of aging biomarkers, assessing interventions, and studying reversibility of age-associated changes.

71A metabolomic profile of biological aging in 250,341 individuals from the UK Biobank.PubMed

Shiyu Zhang, Zheng Wang, Yijing Wang, et al.
Nat Commun. 2024 Sep 15;15(1):8081. doi: 10.1038/s41467-024-52310-9.
The metabolomic profile of aging is complex. Here, we analyse 325 nuclear magnetic resonance (NMR) biomarkers from 250,341 UK Biobank participants, identifying 54 representative aging-related biomarkers associated with all-cause mortality. We conduct genome-wide association studies (GWAS) for these 325 biomarkers using whole-genome sequencing (WGS) data from 95,372 individuals and perform multivariable Mendelian randomization (MVMR) analyses, discovering 439 candidate "biomarker - disease" causal pairs at the nominal significance level. We develop a metabolomic aging score that outperforms other aging metrics in predicting short-term mortality risk and exhibits strong potential for discriminating aging-accelerated populations and improving disease risk prediction. A longitudinal analysis of 13,263 individuals enables us to calculate a metabolomic aging rate which provides more refined aging assessments and to identify candidate anti-aging and pro-aging NMR biomarkers. Taken together, our study has presented a comprehensive aging-related metabolomic profile and highlighted its potential for personalized aging monitoring and early disease intervention.

72Integrating biological age, epigenetic clocks, and telomere length in precision nutrition strategies for chronic disease management: Potential frameworks and ongoing challenges.PubMed

Beatriz G Carvalho, Amanda A Ribeiro, Jhulia C N L da Mota, et al.
Nutr Res. 2025 Aug;140:135-160. doi: 10.1016/j.nutres.2025.06.010. Epub 2025 Jun 29.
Precision nutrition is emerging as a transformative strategy for optimizing health, particularly in the context of biological aging and chronic disease prevention. This review aims to examine how biological age markers-specifically telomere length and epigenetic clocks-can be integrated into precision nutrition frameworks to personalize interventions, enhance chronic disease management, and support healthy aging. Telomere length is a widely studied biomarker of aging and chronic disease risk, while epigenetic clocks, based on DNA methylation patterns, offer complementary insights into biological age, gene expression, and disease susceptibility. Nutritional interventions rich in antioxidants, omega-3 fatty acids, polyphenols, B vitamins, and anti-inflammatory compounds have shown potential to modulate these biomarkers, supporting cellular health and delaying aging processes. In addition, lifestyle factors such as physical activity, stress management, and adequate sleep play critical roles in maintaining telomere integrity and epigenetic stability. However, challenges remain in translating these biomarkers into clinical practice. Importantly, variability is not the only barrier; most of these biomarkers still lack clinical validation, and there is no consensus on standardized protocols or reference values that would support their routine application in healthcare. Current guidelines recommend combining telomere length and epigenetic age with other molecular markers, such as multi-omics data, within integrative biological age assessment approaches. Nevertheless, translating this approach into clinical practice will require overcoming significant limitations, including the validation of biomarkers, standardization of measurement techniques, cost-effectiveness, and the development of clear clinical guidelines. Continued research is essential to confirm their predictive value and practical utility in precision nutrition strategies aimed at promoting healthy aging and preventing chronic diseases.

73Bioactive Nutrients and Nutrigenomics in Age-Related Diseases.PubMed

Tania Rescigno, Luigina Micolucci, Mario F Tecce, et al.
Molecules. 2017 Jan 8;22(1):105. doi: 10.3390/molecules22010105.
The increased life expectancy and the expansion of the elderly population are stimulating research into aging. Aging may be viewed as a multifactorial process that results from the interaction of genetic and environmental factors, which include lifestyle. Human molecular processes are influenced by physiological pathways as well as exogenous factors, which include the diet. Dietary components have substantive effects on metabolic health; for instance, bioactive molecules capable of selectively modulating specific metabolic pathways affect the development/progression of cardiovascular and neoplastic disease. As bioactive nutrients are increasingly identified, their clinical and molecular chemopreventive effects are being characterized and systematic analyses encompassing the "omics" technologies (transcriptomics, proteomics and metabolomics) are being conducted to explore their action. The evolving field of molecular pathological epidemiology has unique strength to investigate the effects of dietary and lifestyle exposure on clinical outcomes. The mounting body of knowledge regarding diet-related health status and disease risk is expected to lead in the near future to the development of improved diagnostic procedures and therapeutic strategies targeting processes relevant to nutrition. The state of the art of aging and nutrigenomics research and the molecular mechanisms underlying the beneficial effects of bioactive nutrients on the main aging-related disorders are reviewed herein.

74Decoding aging through nitrogen containing compounds: A nutrigenomic insight.PubMed

Spandana Rajendra Kopalli, Nitu L Wankhede, Sushruta Koppula, et al.
Mol Cell Neurosci. 2025 Nov 13;135:104055. doi: 10.1016/j.mcn.2025.104055.
Nitrogen compounds are increasingly recognized as key modulators in nutrigenomics, with profound implications for understanding and influencing the aging process. Traditionally central to human nutrition, these compounds are now understood to play critical roles in regulating gene expression, cellular signalling, and metabolic pathways that are essential for maintaining health during aging. Nitrogen-containing molecules, such as amino acids, polyamines, and nitric oxide, contribute to vital processes including protein synthesis, mitochondrial function, and oxidative stress management. These mechanisms are crucial for cellular homeostasis but become increasingly vulnerable to disruption during aging, leading to tissue degeneration and heightened susceptibility to age-related diseases. Disruptions in nitrogen metabolism can impair proteostasis, mitochondrial bioenergetics, and antioxidant defences, accelerating cellular decline. Recent research has expanded our understanding of how nitrogen compounds interact with nutrient-sensing pathways such as mTOR and AMPK, as well as epigenetic regulators that influence DNA repair, autophagy, and inflammation. These findings highlight the therapeutic potential of optimizing nitrogen metabolism to enhance health span and mitigate the effects of aging. The emerging field of nitrogen nutrigenomics offers promising opportunities for developing targeted nutritional strategies aimed at improving quality of life and delaying age-related decline. By integrating historical perspectives with contemporary discoveries, this review underscores the complex interplay between nitrogen compounds and aging while inspiring future research into innovative interventions that harness their benefits for longevity and well-being. Ultimately, optimizing nitrogen metabolism could pave the way for new approaches to extending health span and addressing age-related health challenges.

75Dietary and Pharmacological Modulation of Aging-Related Metabolic Pathways: Molecular Insights, Clinical Evidence, and a Translational Model.PubMed

Antonio Fernando Murillo-Cancho, David Lozano-Paniagua, Bruno José Nievas-Soriano
Int J Mol Sci. 2025 Oct 2;26(19):9643. doi: 10.3390/ijms26199643.
Advances in geroscience suggest that aging is modulated by molecular pathways that are amenable to dietary and pharmacological intervention. We conducted an integrative critical review of caloric restriction (CR), intermittent fasting (IF), and caloric restriction mimetics (CR-mimetics) to compare shared mechanisms, clinical evidence, limitations, and translational potential. Across modalities, CR and IF consistently activate AMP-activated protein kinase and sirtuins, inhibit mTOR (mechanistic target of rapamycin) signaling, and enhance autophagy, aligning with improvements in insulin sensitivity, lipid profile, low-grade inflammation, and selected epigenetic aging measures in humans. CR-mimetics, such as metformin, resveratrol, rapamycin, and spermidine, partially reproduce these effects; however, long-term safety and efficacy in healthy populations remain incompletely defined. Methodological constraints-short trial duration, selective samples, intermediate (nonclinical) endpoints, and limited adherence monitoring-impede definitive conclusions on hard outcomes (frailty, disability, hospitalization, mortality). We propose the Active Management of Aging and Longevity (AMAL) model, a three-level biomarker-guided framework that integrates personalized diet, chrono-nutrition, exercise, and the selective use of CR-mimetics, along with digital monitoring and decision support. AMAL emphasizes epigenetic clocks, multi-omics profiling, inflammatory and microbiome metrics, and adaptive protocols to enhance adherence and clinical relevance. Overall, CR, IF, and CR mimetics constitute promising, complementary strategies to modulate biological aging; rigorous long-term trials with standardized biomarkers and clinically meaningful endpoints are needed to enable their scalable implementation.

76Apolipoprotein E genotype-dependent nutrigenetic effects to prebiotic inulin for modulating systemic metabolism and neuroprotection in mice via gut-brain axis.PubMed

Lucille M Yanckello, Jared D Hoffman, Ya-Hsuan Chang, et al.
Nutr Neurosci. 2022 Aug;25(8):1669-1679. doi: 10.1080/1028415X.2021.1889452. Epub 2021 Mar 5.
OBJECTIVE: The goal of the study was to identify the potential nutrigenetic effects to inulin, a prebiotic fiber, in mice with different human apolipoprotein E (APOE) genetic variants. Specifically, we compared responses to inulin for the potential modulation of the systemic metabolism and neuroprotection via gut-brain axis in mice with human ϵ3 and ϵ4 alleles. METHOD: We performed experiments with young mice expressing the human (FAD mice and gene (FAD mice). We fed mice with either inulin or control diet for 16 weeks starting from 3 months of age. We determined gut microbiome diversity and composition using16s rRNA sequencing, systemic metabolism using MRI and metabolomics, and blood-brain barrier (BBB) tight junction expression using Western blot. RESULTS: In both FAD and FAD mice, inulin altered the alpha and beta diversity of the gut microbiome, increased beneficial taxa of bacteria and elevated cecal short chain fatty acid and hippocampal scyllo-inositol. FAD mice had altered metabolism related to tryptophan and tyrosine, while FAD mice had changes in the tricarboxylic acid cycle, pentose phosphate pathway, and bile acids. Differences were found in levels of brain metabolites related to oxidative stress, and levels of Claudin-1 and Claudin-5 BBB tight junction expression. DISCUSSION: We found that inulin had many similar beneficial effects in the gut and brain for both FAD and FAD mice, which may be protective for brain functions and reduce risk for neurodegeneration. . FAD and FAD mice also had distinct responses in several metabolic pathways, suggesting an APOE-dependent nutrigenetic effects in modulating systemic metabolism and neuroprotection.

77Telomerase-Mediated Anti-Ageing Interventions.PubMed

Phoebe L Dunn, Dhenugen Logeswaran, Julian J-L Chen
Subcell Biochem. 2024;107:1-20. doi: 10.1007/978-3-031-66768-8_1.
The ageing process involves a gradual decline of chromosome integrity throughout an organism's lifespan. Telomeres are protective DNA-protein complexes that cap the ends of linear chromosomes in eukaryotic organisms. Telomeric DNA consists of long stretches of short "TTAGGG" repeats that are conserved across most eukaryotes including humans. Telomeres shorten progressively with each round of DNA replication due to the inability of conventional DNA polymerase to completely replicate the chromosome ends, known as the "end-replication problem". The telomerase enzyme counteracts the telomeric DNA loss by de novo addition of telomeric repeats onto chromosomal ends. Germline and stem cells maintain significant levels of telomerase activity to maintain telomere length and can divide almost indefinitely. However, the differentiation of stem cells accompanies the inactivation of telomerase gene expression, resulting in the progressive shortening of telomeres in somatic cells over successive divisions. Critically short telomeres elicit and sustain a persistent DNA damage response leading to permanent growth arrest of cells known as cellular senescence, a hallmark of cellular ageing. The accumulation of senescent cells in tissues and organs contributes to organismal ageing. Thus, the prevention of telomere shortening is a promising means to delay or even reverse cellular ageing. In this chapter, we summarize potential anti-ageing interventions that mitigate telomere shortening through increasing telomerase level or activity and discuss these strategies' risks, benefits, and future outlooks.

78Applications of CRISPR-Cas9 in mitigating cellular senescence and age-related disease progression.PubMed

Alireza Azani, Malihe Sharafi, Reyhaneh Doachi, et al.
Clin Exp Med. 2025 Jul 8;25(1):237. doi: 10.1007/s10238-025-01771-3.
Aging is a multifaceted process influenced by many elements. During cell division, the repetitive DNA sequences at the ends of chromosomes called telomeres protect them from degradation. Telomeres shorten alongside each cell division, eventually contributing to cellular senescence and aging. Telomerase as an enzyme has a role in the maintenance of telomere length. Reduced function of telomerase is linked to acceleration of aging and age-related diseases. By affecting cellular function, mutations in particular genes can cause aging. Genes involved in DNA repair, cellular metabolism, and inflammation play the key roles in this process. Accumulated mutations result in cellular dysfunction and age-related diseases over time. Epigenetic changes are the modifications that impact gene expression without altering the DNA sequence. Lifestyle factors (diet, exercise, stress) and environmental influences (toxins, trauma) can cause epigenetic alterations. DNA methylation as well as histone modifications are examples of epigenetic alterations. They influence how cells work and are essential to the aging process. Understanding these molecular mechanisms is essential for developing interventions to promote healthy aging and prevent age-related diseases. This paper explores the potential of CRISPR/Cas9 as a gene-editing tool to target these mechanisms and mitigate age-related conditions, ultimately enhancing longevity and quality of life.

79TERT activation targets DNA methylation and multiple aging hallmarks.PubMed

Hong Seok Shim, Jonathan Iaconelli, Xiaoying Shang, et al.
Cell. 2024 Jul 25;187(15):4030-4042.e13. doi: 10.1016/j.cell.2024.05.048. Epub 2024 Jun 21.
Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16 expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.

80Stem cells to reverse aging.PubMed

Le Chang, Weiwen Fan, Xinghua Pan, et al.
Chin Med J (Engl). 2022 Apr 20;135(8):901-910. doi: 10.1097/CM9.0000000000001984.
As human life expectancy continues to increase and the birth rate continues to decline, the phenomenon of aging is becoming more prominent worldwide. Therefore, addressing the problems associated with global aging has become a current research focus. The main manifestations of human aging are structural degeneration and functional decline of aging tissues and organs, quality of life decline, decreased ability to resist diseases, and high incidence rates of a variety of senile degenerative diseases. Thus far, no ideal treatments have been found. Stem cell (SC) therapies have broad application prospects in the field of regenerative medicine due to the inherent biological characteristics of SCs, such as their plasticity, self-renewal, and multidirectional differentiation potential. Thus, SCs could delay or even reverse aging. This manuscript reviews the causes of human aging, the biological characteristics of SCs, and research progress on age reversal.

81Adult stem cells in endometrial regeneration: Molecular insights and clinical applications.PubMed

Qiaoying Lv, Lulu Wang, Xuezhen Luo, et al.
Mol Reprod Dev. 2021 Jun;88(6):379-394. doi: 10.1002/mrd.23476. Epub 2021 May 20.
Endometrial damage is an important cause of female reproductive problems, manifested as menstrual abnormalities, infertility, recurrent pregnancy loss, and other complications. These conditions are collectively termed "Asherman syndrome" (AS) and are typically associated with recurrent induced pregnancy terminations, repeated diagnostic curettage and intrauterine infections. Cancer treatment also has unexpected detrimental side effects on endometrial function in survivors independently of ovarian effects. Endometrial stem cells act in the regeneration of the endometrium and in repair through direct differentiation or paracrine effects. Nonendometrial adult stem cells, such as bone marrow-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells, with autologous and allogenic applications, can also repair injured endometrial tissue in animal models of AS and in human studies. However, there remains a lack of research on the repair of the damaged endometrium after the reversal of tumors, especially endometrial cancers. Here, we review the biological mechanisms of endometrial regeneration, and research progress and challenges for adult stem cell therapy for damaged endometrium, and discuss the potential applications of their use for endometrial repair after cancer remission, especially in endometrial cancers. Successful application of such cells will improve reproductive parameters in patients with AS or cancer. Significance: The endometrium is the fertile ground for embryos, but damage to the endometrium will greatly impair female fertility. Adult stem cells combined with tissue engineering scaffold materials or not have made great progress in repairing the injured endometrium due to benign lesions. However, due to the lack of research on the repair of the damaged endometrium caused by malignant tumors or tumor therapies, the safety and effectiveness of such stem cell-based therapies need to be further explored. This review focuses on the molecular insights and clinical application potential of adult stem cells in endometrial regeneration and discusses the possible challenges or difficulties that need to be overcome in stem cell-based therapies for tumor survivors. The development of adult stem cell-related new programs will help repair damaged endometrium safely and effectively and meet fertility needs in tumor survivors.

82Stem Cell-Based Regeneration and Restoration for Retinal Ganglion Cell: Recent Advancements and Current Challenges.PubMed

Jingxue Zhang, Shen Wu, Zi-Bing Jin, et al.
Biomolecules. 2021 Jul 5;11(7):987. doi: 10.3390/biom11070987.
Glaucoma is a group of irreversible blinding eye diseases characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. Currently, there is no effective method to fundamentally resolve the issue of RGC degeneration. Recent advances have revealed that visual function recovery could be achieved with stem cell-based therapy by replacing damaged RGCs with cell transplantation, providing nutritional factors for damaged RGCs, and supplying healthy mitochondria and other cellular components to exert neuroprotective effects and mediate transdifferentiation of autologous retinal stem cells to accomplish endogenous regeneration of RGC. This article reviews the recent research progress in the above-mentioned fields, including the breakthroughs in the fields of in vivo transdifferentiation of retinal endogenous stem cells and reversal of the RGC aging phenotype, and discusses the obstacles in the clinical translation of the stem cell therapy.

83Age reprogramming: Innovations and ethical considerations for prolonged longevity (Review).PubMed

Timur Saliev, Prim B Singh
Biomed Rep. 2025 Apr 10;22(6):96. doi: 10.3892/br.2025.1974. eCollection 2025 Jun.
Age reprogramming and cellular rejuvenation therapies are revolutionizing the approach to aging and age-related diseases. These ground-breaking interventions target fundamental biological processes, including genomic instability, telomere attrition, and mitochondrial dysfunction, to restore cellular function and delay the onset of degenerative conditions. Emerging strategies such as epigenetic reprogramming, gene editing, stem cell therapy, and senolytic drugs show immense promise in extending health spans and potentially reversing aspects of aging. Despite marked progress in preclinical studies and early-stage clinical trials, translating these therapies into practical healthcare solutions presents significant challenges. Key issues include ensuring safety, optimizing delivery mechanisms, overcoming regulatory barriers, and addressing high costs. Moreover, ethical and economic considerations, such as equitable access and societal impacts, must be carefully addressed to prevent widening health disparities. The present review examines the current state of cellular rejuvenation research, highlighting both scientific advancements and the complex challenges associated with these therapies. With interdisciplinary collaboration, robust ethical frameworks, and scalable technological innovations, these therapies have the potential to transform healthcare. By shifting the focus from disease management to proactive health preservation, they offer a future where aging becomes a manageable and equitable process.

84Use of CRISPR/Cas9 to model brain diseases.PubMed

Sen Yan, Zhuchi Tu, Shihua Li, et al.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Feb 2;81:488-492. doi: 10.1016/j.pnpbp.2017.04.003. Epub 2017 Apr 6.
Aging-related brain diseases consist of a number of important neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, all of which have become more prevalent as the life expectancy of humans is prolonged. Age-dependent brain disorders are associated with both environmental insults and genetic mutations. For those brain disorders that are inherited, gene editing is an important tool for establishing animal models to investigate the pathogenesis of disease and identify effective treatments. Here we focus on the tools for gene editing, especially CRISPR/Cas9, and discuss their application for generating animal models that can recapitulate the brain pathology seen in human diseases. We also highlight the advantages and disadvantages of establishing genetically modified animal models. Finally, we discuss recent findings to resolve technical issues related to the use of CRISPR/Cas9 for generating animal models of brain diseases.

85Ethical concerns in aging research: perspectives of global frontline researchers.PubMed

Yaojin Peng, Lulu Ding, Zhenyu Xiao, et al.
Sci China Life Sci. 2024 Oct;67(10):2149-2156. doi: 10.1007/s11427-024-2650-y. Epub 2024 Jul 19.
This study investigated the ethical landscape of aging research amid the increasing global focus on extending the human lifespan and health span. Our global survey of 180 researchers across 38 jurisdictions revealed divergent perceptions of aging, a consensus regarding the feasibility of delaying aging, and multiple perspectives regarding lifespan extension. The present findings underscore a paradigm shift toward inclusive and ethically sound research, emphasizing the need for an approach that strikes a balance between basic and clinical research. In addition, this study highlighted key ethical concerns in aging research, including the effects of misleading advertising, potential inequality in access to aging interventions, and risks pertaining to the extrapolation of research findings from lower-model organisms to humans. The insights presented in this paper call for an integrated approach for overcoming the complex ethical and societal challenges in aging research to ensure responsible and equitable advancements in this burgeoning field.

86Burden of disease scenarios for 204 countries and territories, 2022-2050: a forecasting analysis for the Global Burden of Disease Study 2021.PubMed

Lancet. 2024 May 18;403(10440):2204-2256. doi: 10.1016/S0140-6736(24)00685-8.
BACKGROUND: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. METHODS: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. FINDINGS: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8-63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0-45·0] in 2050) and south Asia (31·7% [29·2-34·1] to 15·5% [13·7-17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4-40·3) to 41·1% (33·9-48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6-25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5-43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5-17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7-11·3) in the high-income super-region to 23·9% (20·7-27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5-6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2-26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [-0·6 to 3·6]). INTERPRETATION: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions. FUNDING: Bill & Melinda Gates Foundation.

87The burden and trend of diseases and their risk factors in Australia, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.PubMed

Lancet Public Health. 2023 Aug;8(8):e585-e599. doi: 10.1016/S2468-2667(23)00123-8.
BACKGROUND: A comprehensive understanding of temporal trends in the disease burden in Australia is lacking, and these trends are required to inform health service planning and improve population health. We explored the burden and trends of diseases and their risk factors in Australia from 1990 to 2019 through a comprehensive analysis of the Global Burden of Disease Study (GBD) 2019. METHODS: In this systematic analysis for GBD 2019, we estimated all-cause mortality using the standardised GBD methodology. Data sources included primarily vital registration systems with additional data from sample registrations, censuses, surveys, surveillance, registries, and verbal autopsies. A composite measure of health loss caused by fatal and non-fatal disease burden (disability-adjusted life-years [DALYs]) was calculated as the sum of years of life lost (YLLs) and years of life lived with disability (YLDs). Comparisons between Australia and 14 other high-income countries were made. FINDINGS: Life expectancy at birth in Australia improved from 77·0 years (95% uncertainty interval [UI] 76·9-77·1) in 1990 to 82·9 years (82·7-83·1) in 2019. Between 1990 and 2019, the age-standardised death rate decreased from 637·7 deaths (95% UI 634·1-641·3) to 389·2 deaths (381·4-397·6) per 100 000 population. In 2019, non-communicable diseases remained the major cause of mortality in Australia, accounting for 90·9% (95% UI 90·4-91·9) of total deaths, followed by injuries (5·7%, 5·3-6·1) and communicable, maternal, neonatal, and nutritional diseases (3·3%, 2·9-3·7). Ischaemic heart disease, self-harm, tracheal, bronchus, and lung cancer, stroke, and colorectal cancer were the leading causes of YLLs. The leading causes of YLDs were low back pain, depressive disorders, other musculoskeletal diseases, falls, and anxiety disorders. The leading risk factors for DALYs were high BMI, smoking, high blood pressure, high fasting plasma glucose, and drug use. Between 1990 and 2019, all-cause DALYs decreased by 24·6% (95% UI 21·5-28·1). Relative to similar countries, Australia's ranking improved for age-standardised death rates and life expectancy at birth but not for YLDs and YLLs between 1990 and 2019. INTERPRETATION: An important challenge for Australia is to address the health needs of people with non-communicable diseases. The health systems must be prepared to address the increasing demands of non-communicable diseases and ageing. FUNDING: Bill & Melinda Gates Foundation.

88The burden and trends of heart failure caused by ischaemic heart disease at the global, regional, and national levels from 1990 to 2021.PubMed

Hongwei Zhang, Xiaoyu Zheng, Pingping Huang, et al.
Eur Heart J Qual Care Clin Outcomes. 2025 Mar 3;11(2):186-196. doi: 10.1093/ehjqcco/qcae094.
BACKGROUND: Ischaemic heart disease (IHD) is a major cause of heart failure (HF), a condition expected to increasingly affect global health and economics. This study evaluates the global burden, trends, and disparities of HF linked to IHD, aiming to inform health policy development. METHODS AND RESULTS: Data from the Global Burden of Disease Study 2021 (GBD2021) are analysed using joinpoint regression, decomposition analysis, and Bayesian age-period-cohort analysis (BAPC). Health disparities are assessed through the Socio-demographic Index (SDI) via the Slope Index of Inequality and the Concentration Index, with future trends projected from 2022 to 2045. In 2021, global HF cases due to IHD were over 19.16 million, with an age-standardized prevalence rate (ASPR) of 228.31 per 100 000 [95% Uncertainty Interval (UI), 188.18-279.55] and age-standardized years lived with disability (ASYLDs) rate of 20.43 per 100 000 [95% UI, 13.55-28.7]. In 2021, there was a 2.87% increase in ASPR and ASYLDs compared with 1990, primarily driven by population growth and aging. Significant reductions in global ASPR and ASYLDs disparities are observed, though the disease burden has intensified in countries with lower SDI levels. Projections indicate that by 2045, while the prevalence and years lived with disability for HF caused by IHD will increase, the ASPR and ASYLDs are expected to decrease. CONCLUSION: The global burden of HF due to IHD remains a significant concern. Urgent improvements in the allocation of medical resources and the implementation of effective prevention and management strategies are necessary to address this issue.

89Projections for prevalence of Parkinson's disease and its driving factors in 195 countries and territories to 2050: modelling study of Global Burden of Disease Study 2021.PubMed

Dongning Su, Yusha Cui, Chengzhang He, et al.
BMJ. 2025 Mar 5;388:e080952. doi: 10.1136/bmj-2024-080952.
OBJECTIVE: To predict the global, regional, and national prevalence of Parkinson's disease by age, sex, year, and Socio-demographic Index to 2050 and quantify the factors driving changes in Parkinson's disease cases. DESIGN: Modelling study. DATA SOURCE: Global Burden of Disease Study 2021. MAIN OUTCOME MEASURES: Prevalent number, all age prevalence and age standardised prevalence of Parkinson's disease in 2050, and average annual percentage change of prevalence from 2021 to 2050; contribution of population ageing, population growth, and changes in prevalence to the growth in Parkinson's disease cases; population attributable fractions for modifiable factors. RESULTS: 25.2 (95% uncertainty interval 21.7 to 30.1) million people were projected to be living with Parkinson's disease worldwide in 2050, representing a 112% (95% uncertainty interval 71% to 152%) increase from 2021. Population ageing (89%) was predicted to be the primary contributor to the growth in cases from 2021 to 2050, followed by population growth (20%) and changes in prevalence (3%). The prevalence of Parkinson's disease was forecasted to be 267 (230 to 320) cases per 100 000 in 2050, indicating a significant increase of 76% (56% to 125%) from 2021, whereas the age standardised prevalence was predicted to be 216 (168 to 281) per 100 000, with an increase of 55% (50% to 60%) from 2021. Countries in the middle fifth of Socio-demographic Index were projected to have the highest percentage increase in the all age prevalence (144%, 87% to 183%) and age standardised prevalence (91%, 82% to 101%) of Parkinson's disease between 2021 and 2050. Among Global Burden of Disease regions, East Asia (10.9 (9.0 to 13.3) million) was projected to have the highest number of Parkinson's disease cases in 2050, with western Sub-Saharan Africa (292%, 266% to 362%) experiencing the most significant increase from 2021. The ≥80 years age group was projected to have the greatest increase in the number of Parkinson's disease cases (196%, 143% to 235%) from 2021 to 2050. The male-to-female ratios of age standardised prevalence of Parkinson's disease were projected to increase from 1.46 in 2021 to 1.64 in 2050 globally. CONCLUSIONS: By 2050 Parkinson's disease will have become a greater public health challenge for patients, their families, care givers, communities, and society. The upward trend is expected to be more pronounced among countries with middle Socio-demographic Index, in the Global Burden of Disease East Asia region, and among men. This projection could serve as an aid in promoting health research, informing policy decisions, and allocating resources.

90Epidemiology of Type 2 Diabetes - Global Burden of Disease and Forecasted Trends.PubMed

Moien Abdul Basith Khan, Muhammad Jawad Hashim, Jeffrey Kwan King, et al.
J Epidemiol Glob Health. 2020 Mar;10(1):107-111. doi: 10.2991/jegh.k.191028.001.
The rising burden of type 2 diabetes is a major concern in healthcare worldwide. This research aimed to analyze the global epidemiology of type 2 diabetes. We analyzed the incidence, prevalence, and burden of suffering of diabetes mellitus based on epidemiological data from the Global Burden of Disease (GBD) current dataset from the Institute of Health Metrics, Seattle. Global and regional trends from 1990 to 2017 of type 2 diabetes for all ages were compiled. Forecast estimates were obtained using the SPSS Time Series Modeler. In 2017, approximately 462 million individuals were affected by type 2 diabetes corresponding to 6.28% of the world's population (4.4% of those aged 15-49 years, 15% of those aged 50-69, and 22% of those aged 70+), or a prevalence rate of 6059 cases per 100,000. Over 1 million deaths per year can be attributed to diabetes alone, making it the ninth leading cause of mortality. The burden of diabetes mellitus is rising globally, and at a much faster rate in developed regions, such as Western Europe. The gender distribution is equal, and the incidence peaks at around 55 years of age. Global prevalence of type 2 diabetes is projected to increase to 7079 individuals per 100,000 by 2030, reflecting a continued rise across all regions of the world. There are concerning trends of rising prevalence in lower-income countries. Urgent public health and clinical preventive measures are warranted.

91Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016.PubMed

Yan Xie, Benjamin Bowe, Ali H Mokdad, et al.
Kidney Int. 2018 Sep;94(3):567-581. doi: 10.1016/j.kint.2018.04.011. Epub 2018 Aug 3.
The last quarter century witnessed significant population growth, aging, and major changes in epidemiologic trends, which may have shaped the state of chronic kidney disease (CKD) epidemiology. Here, we used the Global Burden of Disease study data and methodologies to describe the change in burden of CKD from 1990 to 2016 involving incidence, prevalence, death, and disability-adjusted-life-years (DALYs). Globally, the incidence of CKD increased by 89% to 21,328,972 (uncertainty interval 19,100,079- 23,599,380), prevalence increased by 87% to 275,929,799 (uncertainty interval 252,442,316-300,414,224), death due to CKD increased by 98% to 1,186,561 (uncertainty interval 1,150,743-1,236,564), and DALYs increased by 62% to 35,032,384 (uncertainty interval 32,622,073-37,954,350). Measures of burden varied substantially by level of development and geography. Decomposition analyses showed that the increase in CKD DALYs was driven by population growth and aging. Globally and in most Global Burden of Disease study regions, age-standardized DALY rates decreased, except in High-income North America, Central Latin America, Oceania, Southern Sub-Saharan Africa, and Central Asia, where the increased burden of CKD due to diabetes and to a lesser extent CKD due to hypertension and other causes outpaced burden expected by demographic expansion. More of the CKD burden (63%) was in low and lower-middle-income countries. There was an inverse relationship between age-standardized CKD DALY rate and health care access and quality of care. Frontier analyses showed significant opportunities for improvement at all levels of the development spectrum. Thus, the global toll of CKD is significant, rising, and unevenly distributed; it is primarily driven by demographic expansion and in some regions a significant tide of diabetes. Opportunities exist to reduce CKD burden at all levels of development.

92Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010.PubMed

Valery L Feigin, Mohammad H Forouzanfar, Rita Krishnamurthi, et al.
Lancet. 2014 Jan 18;383(9913):245-54. doi: 10.1016/s0140-6736(13)61953-4.
BACKGROUND: Although stroke is the second leading cause of death worldwide, no comprehensive and comparable assessment of incidence, prevalence, mortality, disability, and epidemiological trends has been estimated for most regions. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to estimate the global and regional burden of stroke during 1990-2010. METHODS: We searched Medline, Embase, LILACS, Scopus, PubMed, Science Direct, Global Health Database, the WHO library, and WHO regional databases from 1990 to 2012 to identify relevant studies published between 1990 and 2010.We applied the GBD 2010 analytical technique (DisMod-MR), based on disease-specific, pre-specified associations between incidence, prevalence, and mortality, to calculate regional and country-specific estimates of stroke incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) lost by age group (<75 years, ≥ 75 years, and in total)and country income level (high-income, and low-income and middle-income) for 1990, 2005, and 2010. FINDINGS: We included 119 studies (58 from high-income countries and 61 from low-income and middle-income countries). From 1990 to 2010, the age-standardised incidence of stroke significantly decreased by 12% (95% CI 6-17)in high-income countries, and increased by 12% (-3 to 22) in low-income and middle-income countries, albeit nonsignificantly. Mortality rates decreased significantly in both high income (37%, 31-41) and low-income and middle income countries (20%, 15-30). In 2010, the absolute numbers of people with fi rst stroke (16・9 million), stroke survivors (33 million), stroke-related deaths (5・9 million), and DALYs lost (102 million) were high and had significantly increased since 1990 (68%, 84%, 26%, and 12% increase, respectively), with most of the burden (68・6% incident strokes, 52・2% prevalent strokes, 70・9% stroke deaths, and 77・7% DALYs lost) in low-income and middle-income countries. In 2010, 5・2 million (31%) strokes were in children (aged <20 years old) and young and middle-aged adults(20-64 years), to which children and young and middle-aged adults from low-income and middle-income countries contributed almost 74 000 (89%) and 4・0 million (78%), respectively, of the burden. Additionally, we noted significant geographical differences of between three and ten times in stroke burden between GBD regions and countries. More than 62% of new strokes, 69・8% of prevalent strokes, 45・5% of deaths from stroke, and 71・7% of DALYs lost because of stroke were in people younger than 75 years. INTERPRETATION: Although age-standardised rates of stroke mortality have decreased worldwide in the past two decades,the absolute number of people who have a stroke every year, stroke survivors, related deaths, and the overall global burden of stroke (DALYs lost) are great and increasing. Further study is needed to improve understanding of stroke determinants and burden worldwide, and to establish causes of disparities and changes in trends in stroke burden between countries of different income levels. FUNDING: Bill & Melinda Gates Foundation.

93Aging, longevity, and healthy aging: the public health approach.PubMed

Vincenza Gianfredi, Daniele Nucci, Flavia Pennisi, et al.
Aging Clin Exp Res. 2025 Apr 17;37(1):125. doi: 10.1007/s40520-025-03021-8.
BACKGROUND: Population aging is one of the most significant global demographic changes of the 21st century, driven by increased life expectancy and declining fertility rates. This phenomenon presents both achievements and challenges for public health systems worldwide. AIMS: On the one hand, advances in healthcare and socio-economic conditions have contributed to longer lives and improved quality of life for older adults. On the other hand, aging populations are increasingly affected by chronic diseases, greriatric syndromes, and multimorbidity, leading to greater healthcare demands and higher associated costs. METHODS: This manuscript explores evidence on regards of the impact of aging on healthcare and economic systems, emphasizing the need for a paradigm shift toward healthy aging. RESULTS: Healthy aging, as defined by the World Health Organization, focuses on the maintenance of intrinsic capacity, physical, mental, and social well-being throughout life. It highlights the importance of preventive healthcare, proper nutrition, and regular physical activity in delaying the onset of chronic conditions and maintaining functional independence. Furthermore, the manuscript addresses the challenges faced by healthcare infrastructures and pension systems as they adapt to aging populations, with particular attention to the strain caused by workforce shortages and the rising need for long-term care. DISCUSSION: A coordinated public health approach is essential to promote healthy aging and mitigate the economic and societal impacts of population aging. CONCLUSIONS: This paper underscores the need for integrated health policies and multidisciplinary care models to ensure that longer life expectancy is accompanied by better quality of life for older individuals.

94Multimorbidity and quality of life: Systematic literature review and meta-analysis.PubMed

Tatjana T Makovski, Susanne Schmitz, Maurice P Zeegers, et al.
Ageing Res Rev. 2019 Aug;53:100903. doi: 10.1016/j.arr.2019.04.005. Epub 2019 Apr 30.
Multimorbidity is typically defined as the co-existence of two or more chronic diseases within an individual. Its prevalence is highest among the elderly, with poor quality of life (QoL) being one of the major consequences. This study aims to: (1) understand the relationship between multimorbidity and QoL or health-related quality of life (HRQoL) through systematic literature review; (2) explore the strength of this association by conducting the first meta-analysis on the subject. Following PRISMA, Medline/PubMed, Embase, CINAHL and PsycINFO were searched for studies published through September 1st, 2018. Original studies with clear operationalization of multimorbidity and validated QoL (or HRQoL) measurement were retained. For random-effect meta-analysis, a minimum of three studies with the same multimorbidity tool (e.g. number of diseases or equal comorbidity index) and the same QoL tool were required. Number of diseases was most common and the only measure on which meta-analysis was carried out. The outcome of interest was the linear regression slope between increasing number of diseases and QoL. Heterogeneity was explored with meta-regression. Out of 25,890 studies initially identified, 74 studies were retained for systematic review (total of 2,500,772 participants), of which 39 were included in the meta-analysis. The mean decrease in HRQoL per each added disease, depending on the scale, ranged from: -1.55% (95%CI: -2.97%, -0.13%) for the mental component summary score of pooled SF-36, -12 and -8 scales to -4.37% (95%CI: -7.13%, -1.61%) for WHOQoL-BREF physical health domain. Additional studies considering severity, duration and patterns of diseases are required to further clarify this association.

95Multimorbidity in Older Adults With Cardiovascular Disease.PubMed

Daniel E Forman, Mathew S Maurer, Cynthia Boyd, et al.
J Am Coll Cardiol. 2018 May 15;71(19):2149-2161. doi: 10.1016/j.jacc.2018.03.022.
Multimorbidity occurs in adults of all ages, but the number and complexity of comorbid conditions commonly increase with advancing age such that cardiovascular disease (CVD) in older adults typically occurs in a context of multimorbidity. Current clinical practice and research mainly target single disease-specific care that does not embrace the complexities imposed by concurrent conditions. In this paper, emerging concepts regarding CVD in combination with multimorbidity are reviewed, including recommendations for incorporating multimorbidity into clinical decision making, critical knowledge gaps, and research priorities to optimize care of complex older patients.

96Management of older adults with diabetes mellitus: Perspective from geriatric medicine.PubMed

Hiroyuki Umegaki
J Diabetes Investig. 2024 Oct;15(10):1347-1354. doi: 10.1111/jdi.14283. Epub 2024 Aug 8.
Advances in diabetes medication and population aging are lengthening the lifespans of people with diabetes mellitus (DM). Older patients with diabetes mellitus often have multimorbidity and tend to have polypharmacy. In addition, diabetes mellitus is associated with frailty, functional decline, cognitive impairment, and geriatric syndrome. Although the numbers of patients with frailty, dementia, disability, and/or multimorbidity are increasing worldwide, the accumulated evidence on the safe and effective treatment of these populations remains insufficient. Older patients, especially those older than 75 years old, are often underrepresented in randomized controlled trials of various treatment effects, resulting in limited clinical evidence for this population. Therefore, a deeper understanding of the characteristics of older patients is essential to tailor management strategies to their needs. The clinical guidelines of several academic societies have begun to recognize the importance of relaxing glycemic control targets to prevent severe hypoglycemia and to maintain quality of life. However, glycemic control levels are thus far based on expert consensus rather than on robust clinical evidence. There is an urgent need for the personalized management of older adults with diabetes mellitus that considers their multimorbidity and function and strives to maintain a high quality of life through safe and effective medical treatment. Older adults with diabetes mellitus accompanied by frailty, functional decline, cognitive impairment, and multimorbidity require special management considerations and liaison with both carers and social resources.

97Unlocking the biochemical secrets of longevity: balancing healthspan and lifespan.PubMed

Jose Viña, Consuelo Borrás
FEBS Lett. 2024 Sep;598(17):2135-2144. doi: 10.1002/1873-3468.14963. Epub 2024 Jul 2.
In an era of rising global life expectancies, research focuses on enhancing the quality of extended years. This review examines the link between mitochondrial function and aging, highlighting the importance of healthspan alongside lifespan. This involves significant human and economic challenges, with longer lifespans often accompanied by reduced well-being. Addressing mitochondrial decline, exploring targeted interventions, and understanding the complexities of research models are vital for advancing our knowledge in this field. Additionally, promoting physical exercise and adopting personalized supplementation strategies based on individual needs can contribute to healthy aging. The insights from this Perspective article offer a hopeful outlook for future advances in extending both lifespan and healthspan, aiming to improve the overall quality of life in aging populations.

98Editorial: quality of life in multimorbidity.PubMed

Mike Martin, Edouard Battegay, Christina Röcke
Gerontology. 2014;60(3):247-8. doi: 10.1159/000358797. Epub 2014 Feb 28.

99Associations between biological ageing and the risk of, genetic susceptibility to, and life expectancy associated with rheumatoid arthritis: a secondary analysis of two observational studies.PubMed

Li Chen, Bangfu Wu, Li Mo, et al.
Lancet Healthy Longev. 2024 Jan;5(1):e45-e55. doi: 10.1016/S2666-7568(23)00220-9. Epub 2023 Dec 8.
BACKGROUND: Rheumatoid arthritis is a chronic autoimmune disorder that affects life expectancy. Accelerated biological ageing is thought to be a major risk factor for age-related diseases, but its role in rheumatoid arthritis remains uncertain. We aimed to assess the associations between biological ageing and risk of rheumatoid arthritis and genetic susceptibility to the disease. We also aimed to assess the effect of biological ageing on the life expectancy of people with rheumatoid arthritis. METHODS: We calculated the chronological age-adjusted biological age-by both the Klemera-Doubal method (KDMAge) and phenotypic age (PhenoAge)-as a surrogate measure for biological ageing in participants from the US National Health and Nutrition Examination Survey (NHANES) and UK Biobank study. KDMAge or PhenoAge acceleration was defined as the residual of the regression of KDMAge or PhenoAge based on chronological age. Participants with accelerated biological ageing had KDMAge or PhenoAge acceleration values greater than 0, whereas those without accelerated ageing had values less than or equal to 0. We did cross-sectional analyses to assess the association between biological ageing and prevalent rheumatoid arthritis in both cohorts and prospective analyses to assess the association between biological ageing and incident rheumatoid arthritis in the UK Biobank. Logistic regression and Cox proportional hazards models were used to analyse these associations. Polygenic risk scores were used to establish genetic susceptibility to rheumatoid arthritis and to analyse the interaction between biological ageing and genetic risk. We also assessed the association between life expectancy and biological ageing status in people with rheumatoid arthritis. FINDINGS: In the cross-sectional analyses, each 1-year increase in age-adjusted biological age was associated with an increase in the risk of rheumatoid arthritis of between 1% and 10%. In the NHANES, individuals with accelerated ageing had a higher risk of rheumatoid arthritis than non-accelerated ageing individuals, with odds ratios of 1·21 (95% CI 1·03-1·42; p=0·018) for KDMAge acceleration and 1·46 (1·26-1·69; p<0·0001) for PhenoAge acceleration. Similarly, in the UK Biobank, the risk of rheumatoid arthritis was increased in individuals with accelerated ageing compared with individuals with no accelerated ageing (KDMAge odds ratio 1·96 [95% CI 1·71-2·24]; PhenoAge 2·71 [2·51-2·92]). In the prospective analyses of the UK Biobank population, accelerated biological ageing was associated with an increased risk of incident rheumatoid arthritis as measured by both KDMAge (hazard ratio 1·27 [95% CI 1·03-1·55]) and PhenoAge (1·70 [1·52-1·92]). Among participants with high genetic predisposition to rheumatoid arthritis, accelerated biological ageing was associated with an increased risk of incident disease, and we noted significant additive interactions between accelerated biological ageing and genetic risk. At age 45 years, people with rheumatoid arthritis had reduced life expectancy compared with those without rheumatoid arthritis. Among people with rheumatoid arthritis, accelerated biological ageing was associated with reduced life expectancy compared with not having accelerated biological ageing. INTERPRETATION: Accelerated biological ageing could increase the risk of rheumatoid arthritis, especially among people with high genetic risk, and could reduce the life expectancy of people with rheumatoid arthritis. The identification of populations with accelerated biological ageing has important implications for reducing the risk of rheumatoid arthritis and of lowered life expectancy. FUNDING: National Natural Science Foundation of China.

100Trends in rheumatoid arthritis burden in China and globally, 1990-2021: A longitudinal study based on the GBD database.PubMed

Zhengpeng Li, Hao Zeng, Bo Jin, et al.
PLoS One. 2025 May 21;20(5):e0323372. doi: 10.1371/journal.pone.0323372. eCollection 2025.
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that imposes significant health and economic burdens worldwide, particularly in developing countries such as China. METHOD: In this study, the Global Burden of Disease, The GBD database system stratified the incidence,prevalence,death and disability-adjusted life years (DALYs) of RA in China and the world from 1990 to 2021 by age, sex and period. Joinpoint Regression Program 5.1.0 was then used to calculate average annual percent change (AAPC) and 95% confidence interval (95% confidence interval). CI) to identify trends in disease burden. In addition, data collation using WPS allows for the comparison of RA burdens across different age groups, genders and time points in China and globally, and the data is rigorously screened and processed to ensure accuracy and comparability. RESULTS: From 1990 to 2021, ASIR of RA in China increased by 0.54%, while the global ASIR rose by 0.41%.The number of RA cases in China increased cumulatively by 133%, compared to a global increase of 125.21%.Simultaneously, ASPR in China and globally increased by 17% and 14.44%, respectively.Regarding mortality, although the number of RA-related deaths increased in both China and globally, ASMR decreased by 26.23% in China and 22.86% globally.The trend in ASDR was consistent with ASMR, with declines of 0.40% in China and 1.46% globally.Furthermore, the study revealed significant gender disparities in RA both in China and globally, with women experiencing higher incidence, prevalence, mortality, and DALYs than men.The burden of RA increased significantly with age, particularly among middle-aged and older adults aged 45 and above. CONCLUSION: Over the past 30 years, the burden of RA in China and globally has undergone significant changes.The study found that while RA related mortality and DALYs have slightly decreased in China and globally, the incidence and prevalence rates have continued to rise, particularly among women and middle-aged to elderly populations.Population aging and changes in lifestyle are key drivers of the increasing RA burden, with women showing higher susceptibility and burden due to their unique physiological characteristics and societal roles.The study highlights the need to strengthen early screening and intervention, optimize personalized treatment plans, and pay special attention to the unique needs of elderly and female populations.Additionally, promoting healthy lifestyles, improving primary healthcare services, and implementing supportive policies can effectively alleviate the health and socioeconomic burden of RA, ensuring a better quality of life for patients.

101Trajectories network analysis of chronic diseases among middle-aged and older adults: evidence from the China Health and Retirement Longitudinal Study (CHARLS).PubMed

Jiade Chen, Fan Zhang, Yuan Zhang, et al.
BMC Public Health. 2024 Feb 22;24(1):559. doi: 10.1186/s12889-024-17890-7.
BACKGROUND: Given the increased risk of chronic diseases and comorbidity among middle-aged and older adults in China, it is pivotal to identify the disease trajectory of developing chronic multimorbidity and address the temporal correlation among chronic diseases. METHOD: The data of 15895 participants from the China Health and Retirement Longitudinal Study (CHARLS 2011 - 2018) were analyzed in the current study. Binomial tests and the conditional logistic regression model were conducted to estimate the associations among 14 chronic diseases, and the disease trajectory network analysis was adopted to visualize the relationships. RESULTS: The analysis showed that hypertension is the most prevalent disease among the 14 chronic conditions, with the highest cumulative incidence among all chronic diseases. In the disease trajectory network, arthritis was found to be the starting point, and digestive diseases, hypertension, heart diseases, and dyslipidemia were at the center, while memory-related disease (MRD), stroke, and diabetes were at the periphery of the network. CONCLUSIONS: With the chronic disease trajectory network analysis, we found that arthritis was prone to the occurrence and development of various other diseases. In addition, patients of heart diseases/hypertension/digestive disease/dyslipidemia were under higher risk of developing other chronic conditions. For patients with multimorbidity, early prevention can preclude them from developing into poorer conditions, such as stroke, MRD, and diabetes. By identifying the trajectory network of chronic disease, the results provided critical insights for developing early prevention and individualized support services to reduce disease burden and improve patients' quality of life.

102Frailty, Multimorbidity, and Polypharmacy: Exploratory Analyses of the Effects of Empagliflozin from the EMPA-KIDNEY Trial.PubMed

Kaitlin J Mayne, Rebecca J Sardell, Natalie Staplin, et al.
Clin J Am Soc Nephrol. 2024 Sep 1;19(9):1119-1129. doi: 10.2215/CJN.0000000000000498. Epub 2024 Jun 27.
BACKGROUND: Sodium-glucose cotransporter-2 inhibitors are recommended treatment for adults with CKD, but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk–benefit profile in a post hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. METHODS: The EMPA-KIDNEY trial randomized 6609 patients with CKD (eGFR ≥20 to <45 ml/min per 1.73 m2, or ≥45 to <90 ml/min per 1.73 m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed them for 2 years (median). Additional characteristics analyzed in subgroups were multimorbidity, polypharmacy, and health-related quality of life at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. RESULTS: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility, and diabetes and then eGFR and other comorbidities. Empagliflozin was generally well tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio, 0.72; 95% confidence interval, 0.64 to 0.82) and all-cause hospitalization by 14% (hazard ratio, 0.86; 95% confidence interval, 0.78 to 0.95), with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy, or health-related quality of life. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. CONCLUSIONS: These findings support the use of sodium-glucose cotransporter-2 inhibitors in CKD, irrespective of frailty, multimorbidity, or polypharmacy.

103The multifaceted benefits of walking for healthy aging: from Blue Zones to molecular mechanisms.PubMed

Zoltan Ungvari, Vince Fazekas-Pongor, Anna Csiszar, et al.
Geroscience. 2023 Dec;45(6):3211-3239. doi: 10.1007/s11357-023-00873-8. Epub 2023 Jul 26.
Physical activity, including walking, has numerous health benefits in older adults, supported by a plethora of observational and interventional studies. Walking decreases the risk or severity of various health outcomes such as cardiovascular and cerebrovascular diseases, type 2 diabetes mellitus, cognitive impairment and dementia, while also improving mental well-being, sleep, and longevity. Dose-response relationships for walking duration and intensity are established for adverse cardiovascular outcomes. Walking's favorable effects on cardiovascular risk factors are attributed to its impact on circulatory, cardiopulmonary, and immune function. Meeting current physical activity guidelines by walking briskly for 30 min per day for 5 days can reduce the risk of several age-associated diseases. Additionally, low-intensity physical exercise, including walking, exerts anti-aging effects and helps prevent age-related diseases, making it a powerful tool for promoting healthy aging. This is exemplified by the lifestyles of individuals in Blue Zones, regions of the world with the highest concentration of centenarians. Walking and other low-intensity physical activities contribute significantly to the longevity of individuals in these regions, with walking being an integral part of their daily lives. Thus, incorporating walking into daily routines and encouraging walking-based physical activity interventions can be an effective strategy for promoting healthy aging and improving health outcomes in all populations. The goal of this review is to provide an overview of the vast and consistent evidence supporting the health benefits of physical activity, with a specific focus on walking, and to discuss the impact of walking on various health outcomes, including the prevention of age-related diseases. Furthermore, this review will delve into the evidence on the impact of walking and low-intensity physical activity on specific molecular and cellular mechanisms of aging, providing insights into the underlying biological mechanisms through which walking exerts its beneficial anti-aging effects.

104Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR).PubMed

Mikel Izquierdo, Philipe de Souto Barreto, Hidenori Arai, et al.
J Nutr Health Aging. 2025 Jan;29(1):100401. doi: 10.1016/j.jnha.2024.100401. Epub 2025 Jan 1.
Aging, a universal and inevitable process, is characterized by a progressive accumulation of physiological alterations and functional decline over time, leading to increased vulnerability to diseases and ultimately mortality as age advances. Lifestyle factors, notably physical activity (PA) and exercise, significantly modulate aging phenotypes. Physical activity and exercise can prevent or ameliorate lifestyle-related diseases, extend health span, enhance physical function, and reduce the burden of non-communicable chronic diseases including cardiometabolic disease, cancer, musculoskeletal and neurological conditions, and chronic respiratory diseases as well as premature mortality. Physical activity influences the cellular and molecular drivers of biological aging, slowing aging rates-a foundational aspect of geroscience. Thus, PA serves both as preventive medicine and therapeutic agent in pathological states. Sub-optimal PA levels correlate with increased disease prevalence in aging populations. Structured exercise prescriptions should therefore be customized and monitored like any other medical treatment, considering the dose-response relationships and specific adaptations necessary for intended outcomes. Current guidelines recommend a multifaceted exercise regimen that includes aerobic, resistance, balance, and flexibility training through structured and incidental (integrated lifestyle) activities. Tailored exercise programs have proven effective in helping older adults maintain their functional capacities, extending their health span, and enhancing their quality of life. Particularly important are anabolic exercises, such as Progressive resistance training (PRT), which are indispensable for maintaining or improving functional capacity in older adults, particularly those with frailty, sarcopenia or osteoporosis, or those hospitalized or in residential aged care. Multicomponent exercise interventions that include cognitive tasks significantly enhance the hallmarks of frailty (low body mass, strength, mobility, PA level, and energy) and cognitive function, thus preventing falls and optimizing functional capacity during aging. Importantly, PA/exercise displays dose-response characteristics and varies between individuals, necessitating personalized modalities tailored to specific medical conditions. Precision in exercise prescriptions remains a significant area of further research, given the global impact of aging and broad effects of PA. Economic analyses underscore the cost benefits of exercise programs, justifying broader integration into health care for older adults. However, despite these benefits, exercise is far from fully integrated into medical practice for older people. Many healthcare professionals, including geriatricians, need more training to incorporate exercise directly into patient care, whether in settings including hospitals, outpatient clinics, or residential care. Education about the use of exercise as isolated or adjunctive treatment for geriatric syndromes and chronic diseases would do much to ease the problems of polypharmacy and widespread prescription of potentially inappropriate medications. This intersection of prescriptive practices and PA/exercise offers a promising approach to enhance the well-being of older adults. An integrated strategy that combines exercise prescriptions with pharmacotherapy would optimize the vitality and functional independence of older people whilst minimizing adverse drug reactions. This consensus provides the rationale for the integration of PA into health promotion, disease prevention, and management strategies for older adults. Guidelines are included for specific modalities and dosages of exercise with proven efficacy in randomized controlled trials. Descriptions of the beneficial physiological changes, attenuation of aging phenotypes, and role of exercise in chronic disease and disability management in older adults are provided. The use of exercise in cardiometabolic disease, cancer, musculoskeletal conditions, frailty, sarcopenia, and neuropsychological health is emphasized. Recommendations to bridge existing knowledge and implementation gaps and fully integrate PA into the mainstream of geriatric care are provided. Particular attention is paid to the need for personalized medicine as it applies to exercise and geroscience, given the inter-individual variability in adaptation to exercise demonstrated in older adult cohorts. Overall, this consensus provides a foundation for applying and extending the current knowledge base of exercise as medicine for an aging population to optimize health span and quality of life.

105Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity.PubMed

Yu-Xuan Lyu, Qiang Fu, Dominika Wilczok, et al.
Aging (Albany NY). 2024 Oct 16;16(20):12955-12976. doi: 10.18632/aging.206135.
The recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan.

106The human gut microbiome and aging.PubMed

Evan Bradley, John Haran
Gut Microbes. 2024 Jan-Dec;16(1):2359677. doi: 10.1080/19490976.2024.2359677. Epub 2024 Jun 3.
The composition of the human gut microbiome has been observed to change over the course of an individual's life. From birth, it is shaped by mode of delivery, diet, environmental exposures, geographic location, exposures to medications, and by aging itself. Here, we present a narrative review of the gut microbiome across the lifespan with a focus on its impacts on aging and age-related diseases in humans. We will describe how it is shaped, and features of the gut microbiome that have been associated with diseases at different phases of life and how this can adversely affect healthy aging. Across the lifespan, and especially in old age, a diverse microbiome that includes organisms suspected to produce anti-inflammatory metabolites such as short-chain fatty acids, has been reported to be associated with healthy aging. These findings have been remarkably consistent across geographic regions of the world suggesting that they could be universal features of healthy aging across all cultures and genetic backgrounds. Exactly how these features of the microbiome affect biologic processes associated with aging thus promoting healthy aging will be crucial to targeting the gut microbiome for interventions that will support health and longevity.

107Errors as a primary cause of late-life mortality deceleration and plateaus.PubMed

Saul Justin Newman
PLoS Biol. 2018 Dec 20;16(12):e2006776. doi: 10.1371/journal.pbio.2006776. eCollection 2018 Dec.
Several organisms, including humans, display a deceleration in mortality rates at advanced ages. This mortality deceleration is sufficiently rapid to allow late-life mortality to plateau in old age in several species, causing the apparent cessation of biological ageing. Here, it is shown that late-life mortality deceleration (LLMD) and late-life plateaus are caused by common demographic errors. Age estimation and cohort blending errors introduced at rates below 1 in 10,000 are sufficient to cause LLMD and plateaus. In humans, observed error rates of birth and death registration predict the magnitude of LLMD. Correction for these sources of demographic error using a mixed linear model eliminates LLMD and late-life mortality plateaus (LLMPs) without recourse to biological or evolutionary models. These results suggest models developed to explain LLMD have been fitted to an error distribution, that ageing does not slow or stop during old age in humans, and that there is a finite limit to human longevity.

108[Active mechanisms of dysfunction in the process of aging].PubMed

G M Butenko
Vestn Akad Med Nauk SSSR. 1990(1):20-3.
Current views on the causes and mechanisms of aging are discussed. Evidence for active mechanisms which are regulatory in their origin and operate at the body and its systemic levels is presented. These mechanisms are believed to be capable of inducing changes in the organism thus bringing its functioning to the level which is characteristic of old age. Such phenomena have been observed in the immune and reproductive systems, connective tissue, skin, and liver. Examination of heterochronic parabionts revealed that these mechanisms affect the general viability of a young organism paired to an old one causing a marked reduction of the young parabiont's life-span up to the life limit of his old partner. This suggests a possible role played by aging in a species' adaptation to the environmental conditions.

109Understanding the odd science of aging.PubMed

Thomas B L Kirkwood
Cell. 2005 Feb 25;120(4):437-47. doi: 10.1016/j.cell.2005.01.027.
Evolutionary considerations suggest aging is caused not by active gene programming but by evolved limitations in somatic maintenance, resulting in a build-up of damage. Ecological factors such as hazard rates and food availability influence the trade-offs between investing in growth, reproduction, and somatic survival, explaining why species evolved different life spans and why aging rate can sometimes be altered, for example, by dietary restriction. To understand the cell and molecular basis of aging is to unravel the multiplicity of mechanisms causing damage to accumulate and the complex array of systems working to keep damage at bay.

110Breaking the Glass Ceiling.PubMed

Ghadeer Falah, Abram Giller, Danielle Gutman, et al.
Gerontology. 2020;66(4):309-314. doi: 10.1159/000505995. Epub 2020 Feb 26.
Over the past century, the life expectancy in industrialized countries has rapidly risen by over 30 years due to improvements in standards of medical care, sanitation, and lifestyle. Estimation of life expectancy has traditionally been viewed through a lens of epidemiology and public health. However, this data, while considered the "gold standard" of measuring healthy life expectancy, may soon find itself redundant in the face of advancing medical technology. Even as average life expectancy has increased, there has not been an equivalent increase in healthy life expectancy, or "healthspan"; furthermore, there is a current trend of stagnation in life expectancy, as the supposed increases are estimated to be drastically slowing down, in part due to exhaustion of our current ability to extend the human lifespan. In this viewpoint, we will examine the developing fields of medicine and life sciences which will reshape our current approach to life expectancy prediction.

111From discoveries in ageing research to therapeutics for healthy ageing.PubMed

Judith Campisi, Pankaj Kapahi, Gordon J Lithgow, et al.
Nature. 2019 Jul;571(7764):183-192. doi: 10.1038/s41586-019-1365-2. Epub 2019 Jul 10.
For several decades, understanding ageing and the processes that limit lifespan have challenged biologists. Thirty years ago, the biology of ageing gained unprecedented scientific credibility through the identification of gene variants that extend the lifespan of multicellular model organisms. Here we summarize the milestones that mark this scientific triumph, discuss different ageing pathways and processes, and suggest that ageing research is entering a new era that has unique medical, commercial and societal implications. We argue that this era marks an inflection point, not only in ageing research but also for all biological research that affects the human healthspan.

112The contentious history of sirtuin debates.PubMed

Shoshana Naiman, Haim Y Cohen
Rambam Maimonides Med J. 2012 Oct 31;3(4):e0022. doi: 10.5041/RMMJ.10093. Print 2012 Oct.
The sirtuins are highly conserved enzyme homologues of the yeast Sir2, with activities of NAD+ dependent deacetylase and/or mono ADP ribosyltransferase. A long line of evidence has implicated sirtuins in regulating the aging process of yeast, worms, flies, and rodents. Moreover, much work has been published on the important role of sirtuins in several age-related diseases such as diabetes type II, cancer, cardiovascular diseases, and dyslipidemia. However, despite the many publications supporting a pro-longevity role for sirtuins, there has been emerging debate about the direct role of Caenorhabditis elegans and Drosophila melanogaster sirtuins in aging and in lifespan extension in response to dietary restriction. In addition, until recently, the role of the seven mammalian sirtuins, SIRT1 to SIRT7, in regulating lifespan was unclear. Here, we review the history of the scientific debate on the role of sirtuins in regulating lifespan, especially in light of a recent publication showing a direct regulation of mammalian lifespan by a sirtuin family member, SIRT6.

113Assessing the societal impact of acetylcholinesterase inhibitor therapies.PubMed

B Winblad, A Wimo
Alzheimer Dis Assoc Disord. 1999 Nov;13 Suppl 2:S9-19.
The symptomatology of Alzheimer disease (AD), its longevity, and associated cost make it an extremely challenging disease for individuals, their families, health care, and social support systems. Moreover, the expanding aging population worldwide means that strategies to contain costs are an urgent priority. As the largest component of the direct costs of AD is due to the cost of institutionalization, cost-containment strategies have focused on ways to maintain the AD patient in the community for as long as possible. Disease severity is a strong predictor of institutionalization, and patients' cognitive function (in the form of their Mini-Mental State Examination score) is frequently used as a prognostication of their living environment, and thus the overall cost of their care. Strategies to maintain patients at home are directed at either the patient's symptoms or the caregiver's ability to cope with those symptoms and the responsibilities of caregiving. Examples of strategies directed at the caregiver include education and support programs. Drug treatments, notably acetylcholinesterase inhibitors, present the best option for improving patient function, thereby preserving patient autonomy. A number of preliminary studies, whose results are summarized here, have demonstrated that the use of the acetylcholinesterase inhibitors tacrine, metrifonate and donepezil, and the glial cell modulator, propentofylline, results in reductions in the overall costs of care. Most health economic studies have focused only on comparison of the costs associated with paying for administering a treatment and the savings produced by postponed institutionalization. However, there is a growing realization that some measures of the quality of life or well-being of both patient and caregiver should also be incorporated. Thus, the health economics of dementia is an extremely complex area of study that is rapidly growing, due to the likelihood that cost-effectiveness will form the basis for future reimbursement decisions.

114Goals of Care Among Parents of Children Receiving Palliative Care.PubMed

Chris Feudtner, Leah J Beight, Jackelyn Y Boyden, et al.
JAMA Pediatr. 2023 Aug 1;177(8):800-807. doi: 10.1001/jamapediatrics.2023.1602.
IMPORTANCE: While knowing the goals of care (GOCs) for children receiving pediatric palliative care (PPC) are crucial for guiding the care they receive, how parents prioritize these goals and how their priorities may change over time is not known. OBJECTIVE: To determine parental prioritization of GOCs and patterns of change over time for parents of children receiving palliative care. DESIGN, SETTING, AND PARTICIPANTS: A Pediatric Palliative Care Research Network's Shared Data and Research cohort study with data collected at 0, 2, 6, 12, 18, and 24 months in hospital, outpatient, or home settings from April 10, 2017, to February 15, 2022, at 7 PPC programs based at children's hospitals across the US. Participants included parents of patients, birth to 30 years of age, who received PPC services. EXPOSURES: Analyses were adjusted for demographic characteristics, number of complex chronic conditions, and time enrolled in PPC. MAIN OUTCOMES: Parents' importance scores, as measured using a discrete choice experiment, of 5 preselected GOCs: seeking quality of life (QOL), health, comfort, disease modification, or life extension. Importance scores for the 5 GOCs summed to 100. RESULTS: A total of 680 parents of 603 patients reported on GOCs. Median patient age was 4.4 (IQR, 0.8-13.2) years and 320 patients were male (53.1%). At baseline, parents scored QOL as the most important goal (mean score, 31.5 [SD, 8.4]), followed by health (26.3 [SD, 7.5]), comfort (22.4 [SD, 11.7]), disease modification (10.9 [SD, 9.2]), and life extension (8.9 [SD, 9.9]). Importantly, parents varied substantially in their baseline scores for each goal (IQRs more than 9.4), but across patients in different complex chronic conditions categories, the mean scores varied only slightly (means differ 8.7 or less). For each additional study month since PPC initiation, QOL was scored higher by 0.06 (95% CI, 0.04-0.08) and comfort scored higher by 0.3 (95% CI, 0-0.06), while the importance score for life extension decreased by 0.07 (95% CI, 0.04-0.09) and disease modification by 0.02 (95% CI, 0-0.04); health scores did not significantly differ from PPC initiation. CONCLUSIONS AND RELEVANCE: Parents of children receiving PPC placed the highest value on QOL, but with considerable individual-level variation and substantial change over time. These findings emphasize the importance of reassessing GOCs with parents to guide appropriate clinical intervention.

115Death or dialysis: the value of burdensome life-extending treatments for the cognitively impairedPubMed

Jordan A. Parsons
All medical treatments carry with them some level of burden for the patient, though this is usually outweighed by the benefits. Some long-term, life-extending treatments, however, are highly burdensome and the benefits are not always clearly greater. When a patient lacks decision-making capacity, there is a risk of undue harm if the decision is made on their behalf to initiate that treatment. In this chapter, I question the prioritisation of life-extension over quality of life in such circumstances, arguing that the latter ought sometimes to be prioritised. I suggest that in appealing to the principle of equal treatment of the cognitively impaired (which is endorsed in the majority of countries and is often the very purpose of legislation which governs treatment decisions for this population) we ought to accept that the very fact some patients with decision-making capacity choose to forego a medical intervention entails that sometimes cognitively impaired patients in similar situations ought also to forego that medical intervention. In doing so, maintenance dialysis is employed as a case study. Kidney failure is a reality for millions of individuals globally. Due to the shortage of organs for transplantation, patients with or approaching kidney failure are usually started on maintenance dialysis. This is often considered the default, with the alternative of conservative kidney management – which, incidentally, some studies have suggested may provide a similar survival benefit in some patients – thought of as giving up. Dialysis is a hugely burdensome treatment, often proving both physically and mentally exhausting and thereby negatively impacting on quality of life. Depending on treatment modality it may also require thrice weekly visits to an outpatient unit for the procedure to be performed. With the increasing age of the dialysis population, for patients to have several comorbidities is common and may compromise quality of life further. Given the significance of these burdens, it is not uncommon for patients – particularly those who are older and with several comorbidities – to forego dialysis in favour of conservative kidney management. Many of the burdens associated with dialysis may be exacerbated in cognitively impaired patients; they may not understand why they are being put through the treatment, and dialysis clinics may not be suitable environments depending on the nature of the patient's impairment. Not only are the burdens high for cognitively impaired patients, but these patients may be subjected to them for an extended period of time. The organ shortage, as well as many older cognitively impaired patients not being suitable candidates for transplantation, mean that dialysis is not always a bridge therapy. Rather, it is something that will be a part of the rest of these patients’ lives. This raises the question of dialysis withdrawal, which I frame in terms of the equivalence thesis and the possible omission bias of clinicians. I conclude that given some patients choose themselves to forego dialysis, patients who lack decision-making capacity ought sometimes also to forego dialysis in favour of conservative kidney management. This discussion is applicable to other highly burdensome treatments for cognitively impaired patients, and indeed is also useful in considering decisions concerning dialysis more broadly. Nonetheless, I also call for further research in this area to better explore the issues raised.

116Understanding breast cancer as a global health concern.PubMed

Louise Wilkinson, Toral Gathani
Br J Radiol. 2022 Feb 1;95(1130):20211033. doi: 10.1259/bjr.20211033. Epub 2021 Dec 14.
Breast cancer is now the most commonly diagnosed cancer in the world. The most recent global cancer burden figures estimate that there were 2.26 million incident breast cancer cases in 2020 and the disease is the leading cause of cancer mortality in women worldwide. The incidence is strongly correlated with human development, with a large rise in cases anticipated in regions of the world that are currently undergoing economic transformation. Survival, however, is far less favourable in less developed regions. There are a multitude of factors behind disparities in the global survival rates, including delays in diagnosis and lack of access to effective treatment. The World Health Organization's new Global Breast Cancer Initiative was launched this year to address this urgent global health challenge. It aims to improve survival across the world through three pillars: health promotion, timely diagnosis, and comprehensive treatment and supportive care. In this article, we discuss the key challenges of breast cancer care and control in a global context.

117Global trends and forecasts of breast cancer incidence and deaths.PubMed

Yuyan Xu, Maoyuan Gong, Yue Wang, et al.
Sci Data. 2023 May 27;10(1):334. doi: 10.1038/s41597-023-02253-5.
Breast cancer (BC) is one of the major public health challenges worldwide. Studies that address the new evidence on trends of BC are of great importance for preventing and controlling the occurrence and development of diseases and improving health. The aim of this study was to analyze the outcomes for the global burden of disease (GBD), incidence, deaths, and risk factors for BC from 1990 to 2019, and predict the GBD of BC until 2050 to inform global BC control planning efforts. In this study, the results show that the regions with low levels of socio-demographic index (SDI) will have the largest disease burden of BC in the future. The leading global risk factor for death attributable to BC in 2019 was metabolic risks, followed by behavioral risks. This study supports the worldwide urgent need for comprehensive cancer prevention and control strategies to reduce exposure, early screening, and improve treatment to effectively reduce the GBD of BC.

118The global burden of neurological disorders: translating evidence into policy.PubMed

Valery L Feigin, Theo Vos, Emma Nichols, et al.
Lancet Neurol. 2020 Mar;19(3):255-265. doi: 10.1016/S1474-4422(19)30411-9. Epub 2019 Dec 5.
Neurological disorders are the leading cause of disability and the second leading cause of death worldwide. In the past 30 years, the absolute numbers of deaths and people with disabilities owing to neurological diseases have risen substantially, particularly in low-income and middle-income countries, and further increases are expected globally as a result of population growth and ageing. This rise in absolute numbers of people affected suggests that advances in prevention and management of major neurological disorders are not sufficiently effective to counter global demographic changes. Urgent measures to reduce this burden are therefore needed. Because resources for health care and research are already overstretched, priorities need to be set to guide policy makers, governments, and funding organisations to develop and implement action plans for prevention, health care, and research to tackle the growing challenge of neurological disorders.

119Completing the continuum of cancer care: integrating life-prolongation and palliation.PubMed

I Byock
CA Cancer J Clin. 2000 Mar-Apr;50(2):123-32. doi: 10.3322/canjclin.50.2.123.
Cancer care extends from diagnosis through the late stages of advanced illness as patients confront dying and their families cope with caregiving and grief. Palliative care is a rapidly developing area of clinical focus that offers valuable services to patients in terms of symptom management and adjustment to illness, including issues of life completion and life closure. It is often appropriate to offer certain elements of palliative care early in the course of illness. As disease progresses, physical comfort and enhancing quality of life increasingly become primary goals of cancer care. Specialized palliative care programs, epitomized by hospice, are invaluable resources for patients with far-advanced illness and their families. Current regulations and prevailing payment structures limit access to and the scope of hospice services and highlight the need for innovative models of delivering and financing palliative care.

120End of life care in Duchenne muscular dystrophy.PubMed

T Hilton, R D Orr, R M Perkin, et al.
Pediatr Neurol. 1993 May-Jun;9(3):165-77. doi: 10.1016/0887-8994(93)90080-v.
End of life care for patients with Duchenne muscular dystrophy (DMD) has become increasingly complex because of new technologies, changes in medical personnel over periods of time, emergence of home health care systems, and increasing patient and family autonomy in decision-making. In this review, we discuss the medical problems, particularly respiratory and cardiac failure, faced by DMD patients. Current concepts concerning the evaluation and options for treatment of these problems are presented as well as the ethical issues involved in the care of the DMD patient. These issues include the medical indications for treatment, patient preferences, quality-of-life issues, and contextual features related to legal, institutional, religious, geographic, cultural, social, and financial factors. We also present our experience at Loma Linda University Medical Center over the past 10 years in the development of a home mechanical ventilation program for DMD patients and an algorithm for the evaluation of these patients. Many patients with DMD do well on long-term ventilation, but some find that their quality of life is less than desirable and choose to discontinue this method of life-prolongation. Many of these new options are very expensive, making the decision to use them a difficult one. Ultimately, these are societal issues that require clear reflection on matters of resource allocation that should be performed by health care professionals, citizens, and health planners.