1. 生命时钟：从身份证年龄到生物年龄的认知革命
1.1 生物年龄与表观遗传时钟的核心定义
在衰老研究领域，存在两种主要的年龄概念：身份证年龄（Chronological Age）和生物年龄（Biological Age）。身份证年龄即我们出生以来所经历的时间，是一个固定不变的数字。然而，同一个身份证年龄的人，其健康状况、功能能力和疾病风险可能存在显著差异，这表明身份证年龄并不能完全反映个体的真实衰老状态 1。相比之下，生物年龄旨在提供个体整体健康状况的更精确指标，揭示个体衰老的速度和程度 12。生物年龄的评估能够更好地预测疾病发生风险、功能障碍乃至过早死亡的可能性 13。
近年来，表观遗传时钟（Epigenetic Clocks）的出现，为精确量化生物年龄提供了革命性的工具 14。表观遗传时钟是一种基于DNA甲基化水平的计算模型，通过分析基因组中特定CpG位点的甲基化模式来预测生物年龄。DNA甲基化是表观遗传修饰的一种，它在不改变DNA序列的前提下，影响基因表达，并在衰老过程中呈现出可预测的变化模式 5。这些甲基化模式的变化可以被视为一种“分子记忆”，记录了细胞和组织经历的累积损伤和应激，从而反映出个体的生物学衰老进程。
目前，已开发出多种表观遗传时钟，其中一些被广泛应用并展现出强大的预测能力。例如：
- GrimAge：该时钟不仅预测寿命，还能预测心血管疾病和癌症等多种年龄相关疾病的发生风险 67。GrimAge通过整合与衰老相关的七种血浆蛋白（如PAI-1、GDF15）和吸烟包年数（smoking pack-years）的DNA甲基化替代指标来计算，其预测死亡风险的能力显著优于其他现有表观遗传时钟 6。
- PhenoAge：此表观遗传时钟基于血常规、生化指标等临床表型数据以及DNA甲基化数据构建，能够预测全因死亡率、癌症、心血管疾病等多种老年疾病的风险 17。在2型糖尿病患者中，PhenoAge加速与较高的死亡风险独立相关 8。
- DunedinPoAm（Dunedin Pace of Aging Methylation）：与其他表观遗传时钟不同，DunedinPoAm被视为一个“衰老速度计”，通过单一时间点的测量来评估个体生物学衰老的速率。它与慢性阻塞性肺疾病（COPD）和肺癌的发生风险密切相关 7。
这些表观遗传时钟能够量化“表观遗传年龄加速”（Epigenetic Age Acceleration），即个体的生物年龄超出其身份证年龄的程度 16。表观遗传年龄加速与多种年龄相关疾病、社会变量及精神健康状况的风险增加相关，并被证明与过早死亡风险升高有联系 1。例如，肥胖已被证实会加速生物衰老，并通过生物年龄加速介导肥胖与心血管疾病之间的关联，尤其在45-65岁的中年人群中，这种介导作用更为显著 9。此外，有研究发现，一些保护性基因变异，如APOE*E2，能够降低GrimAge表观遗传衰老的速度，进一步证实了表观遗传时钟在理解衰老机制中的价值 10。这些“生命时钟”的出现，使得我们能够更深入地理解衰老过程，并为评估抗衰老干预措施的有效性提供了客观指标 14。
1.2 端粒：细胞衰老的“分子计数器”
除了表观遗传时钟，端粒（Telomere）是细胞衰老研究中的另一个关键生物标志物，常被称为细胞衰老的“分子计数器”11。端粒是位于真核生物染色体末端的特殊核蛋白结构，由重复的DNA序列（在人类中为TTAGGG）和一系列结合蛋白（统称为端粒结合蛋白复合物，如Shelterin蛋白复合体）组成1213。这些结构的主要功能是保护染色体末端免受降解、融合和错配，维持基因组的完整性和稳定性，防止DNA损伤反应的激活11121415。
端粒在细胞分裂过程中扮演着至关重要的角色。由于DNA复制的“末端复制问题”（end-replication problem），每次细胞分裂后，端粒都会经历一定程度的缩短1114。当端粒缩短到一定临界长度时，细胞会进入不可逆的细胞衰老（cellular senescence）状态，停止分裂，甚至启动细胞凋亡（apoptosis），这限制了细胞的无限增殖能力，被认为是机体衰老和寿命限制的主要分子机制之一111416。端粒长度的累积缩短与多种与年龄相关的疾病，如心血管疾病、骨质疏松症、神经退行性疾病和癌症等密切相关14151617。
尽管端粒长度和表观遗传时钟都是生物年龄的有效标志物，但它们在评估衰老过程中具有互补性而非完全替代性。多项研究表明，端粒长度与表观遗传时钟之间存在显著但中度的负相关关系，即端粒越短，表观遗传年龄加速越明显18。这意味着两者共同反映了不同的衰老机制：端粒长度主要反映细胞复制性衰老的累积效应，而表观遗传时钟则整合了更广泛的、由环境和生活方式因素引起的分子损伤和调控变化18。
具体来说，端粒长度的缩短被认为是衰老的一个基本驱动因素，其维持受到端粒酶（telomerase）活性的调控1213。端粒酶是一种核糖核蛋白酶，能够在染色体末端合成端粒DNA，从而对抗端粒缩短，尤其在干细胞和生殖细胞中表现出高活性121319。然而，大多数体细胞的端粒酶活性较低甚至缺失，导致端粒随细胞分裂逐渐缩短。
在衰老评估中，端粒长度和表观遗传时钟的互补性体现在：
- 不同层面的信息捕捉：端粒长度主要反映“复制性衰老”和细胞增殖历史，而表观遗传时钟，特别是第二代表观遗传时钟（如GrimAge和PhenoAge），则能整合代谢、炎症、免疫等更广泛的生理系统功能状态，更全面地反映“生理性衰老”1820。
- 疾病预测能力：虽然两者都与死亡风险和年龄相关疾病风险相关，但研究表明，一些表观遗传时钟（特别是GrimAgeEEAA）在预测死亡风险方面可能比端粒长度表现出更强的能力20。然而，两者结合使用可以提供更全面的风险评估。
- 干预效果评估：在评估抗衰老干预措施时，同时监测端粒长度和表观遗传年龄的变化，可以更全面地了解干预对不同衰老机制的影响。例如，维生素D补充剂被发现能够减少端粒磨损，这为通过生活方式干预来延缓衰老提供了证据21。
因此，端粒和表观遗传时钟是生物年龄评估的两个重要维度，它们共同为我们理解衰老过程、预测疾病风险以及评估抗衰老策略的有效性提供了强大的工具。
2. 压力与睡眠：影响生命时钟的关键生活变量
2.1 压力：加速生命时钟的“隐形推手”
长期以来，心理社会压力被认为是影响个体健康和寿命的重要因素。越来越多的科学证据表明，慢性压力不仅会影响心理健康，还会通过复杂的分子生物学途径，加速细胞和机体的衰老进程，尤其体现在端粒缩短和DNA甲基化异常这两个关键的生物学衰老指标上 2223。因此，慢性压力可被视为加速“生命时钟”的“隐形推手”。
慢性压力对端粒缩短的影响机制主要涉及以下几个方面：
- HPA轴失调与皮质醇升高：下丘脑-垂体-肾上腺（HPA）轴是机体应对压力的核心生理系统。慢性应激会导致HPA轴功能失调，表现为皮质醇（一种糖皮质激素）水平长期升高 24。高水平的皮质醇已被证明与端粒酶活性抑制和端粒缩短加速相关 2526。皮质醇还可能通过诱导氧化应激和炎症反应，间接促进端粒损伤 2627。例如，有研究表明，患有情绪障碍的个体，由于慢性应激，其端粒长度显著短于健康对照组，甚至可相当于加速衰老10年 28。
- 氧化应激和炎症反应：慢性压力会激活机体的炎症通路，导致促炎细胞因子（如TNF-α、IL-6）水平升高，形成“炎症性衰老”（inflammaging）状态 2930。这些炎症因子和活性氧自由基（ROS）会直接损伤DNA，包括端粒DNA，从而加速端粒的磨损 252931。TNF-α甚至可能通过跨代遗传机制，导致后代端粒缩短 31。同时，压力导致的炎症反应还会抑制端粒酶的活性，进一步加剧端粒缩短 2530。
- DNA修复机制受损：压力暴露会影响细胞的DNA修复能力。长期应激环境下，DNA损伤的累积未能得到有效修复，也可能是导致端粒缩短和基因组不稳定的原因之一 25。
除了端粒缩短，慢性压力还显著影响DNA甲基化模式，从而加速表观遗传年龄：
- DNA甲基化异常：应激，特别是早期生活逆境（early-life stress），已被证实与DNA甲基化模式的改变密切相关 2232。这些改变可以发生在与HPA轴调节、炎症反应和神经可塑性相关的基因区域，从而影响基因表达，进而加速生物学衰老 2232。例如，小鼠研究发现，慢性糖皮质激素暴露会增加细胞的能量消耗，导致线粒体DNA不稳定，并加速DNA甲基化时钟所指示的细胞衰老 27。
- 表观遗传年龄加速：多项研究一致发现，暴露于各种心理社会压力源（包括童年逆境、累积性应激经历、社会经济地位低下等）与表观遗传年龄加速存在关联 22。例如，一项针对健康个体的研究发现，亚临床动脉粥样硬化与Grim表观遗传年龄加速相关，而这种关联部分是由炎症介导的，暗示慢性炎症作为压力反应的一个环节，可能在表观遗传年龄加速中发挥作用 33。
临床证据进一步支持了长期压力累积与生物年龄加速之间的关联：
- 童年逆境（Adverse Childhood Experiences, ACEs）：童年时期经历的身体虐待、情感虐待、性虐待、忽视等不良经历，与成年后更短的端粒长度以及加速的表观遗传年龄显著相关 233435363738。例如，一项对英国生物银行（UK Biobank）142,872名参与者进行的研究发现，童年逆境与女性端粒缩短存在性别特异性关联，且不健康的生活方式和精神疾病部分介导了这种关联 34。另一项研究也指出，高水平的母体ACEs与婴儿期更短的端粒长度以及儿童期的行为问题有关 3637。这表明，早期生活逆境对生物衰老的影响可能具有跨代传递性。
- 慢性情绪障碍：抑郁症、焦虑症等慢性情绪障碍患者往往承受着巨大的心理压力，其端粒长度普遍较短，生物年龄加速更为明显 28。这提示了精神健康与生理衰老之间的紧密联系。
- 应激反应与组织特异性衰老：应激反应对端粒长度的影响可能具有组织特异性。一项斑马鱼研究表明，应激反应性与衰老斑马鱼心脏组织而非大脑组织的端粒缩短呈负相关 39，这暗示了压力可能在不同组织中以不同的方式驱动衰老。
综上所述，慢性压力通过激活HPA轴、诱导氧化应激和炎症、影响DNA修复及改变DNA甲基化模式等多种途径，加速端粒缩短和表观遗传年龄的进程。童年逆境、长期情绪障碍等压力暴露不仅是加速生物衰老的风险因素，其影响甚至可能跨代传递。理解这些机制对于开发有效的压力管理策略，以延缓生命时钟、促进健康老龄化至关重要。
2.2 睡眠障碍：生命时钟的“快进键”
睡眠是生命活动不可或缺的一部分，对维持身心健康至关重要。然而，现代社会中普遍存在的睡眠障碍，如失眠（insomnia）、睡眠呼吸暂停（sleep apnea）以及不规律的睡眠模式（如轮班工作导致的昼夜节律紊乱），已被证实是加速生物衰老、拨快“生命时钟”的“快进键”。这些障碍通过多种分子机制，包括干扰DNA修复、影响甲基化酶活性和改变表观遗传标记，进而加速表观遗传年龄的进程和端粒缩短。
睡眠障碍与DNA损伤及修复：
充足且高质量的睡眠对于细胞层面的修复过程至关重要。在深度睡眠阶段，大脑和身体会进行广泛的修复工作，其中包括DNA损伤的修复。睡眠不足或睡眠中断会干扰这些修复机制，导致DNA损伤累积。长期的DNA损伤无法有效修复，会加速端粒的磨损。例如，有研究表明，睡眠剥夺会导致自由基积累和衰老相关分泌表型（SASP）的出现，并显著增加端粒缩短和端粒特异性DNA损伤的形成。更令人惊讶的是，叶酸补充剂能够有效对抗睡眠剥夺引起的端粒功能障碍和相关衰老表型，这提示了营养干预在缓解睡眠障碍导致的衰老效应中的潜力 40。另一项研究也指出，端粒长度可以作为衡量睡眠缺失和睡眠障碍的生物标志物，强调了睡眠与细胞衰老之间的潜在联系 41。
睡眠障碍与DNA甲基化模式及表观遗传时钟加速：
睡眠障碍与DNA甲基化模式的改变以及表观遗传年龄的加速密切相关：
- 失眠：失眠作为一种常见的睡眠障碍，已有多项研究证实其与表观遗传年龄加速存在因果关联。孟德尔随机化（Mendelian Randomization, MR）研究，一种利用遗传变异作为工具变量来推断因果关系的分析方法，为这一联系提供了强有力的证据。例如，一项MR研究发现，自我报告的失眠可能通过GrimAge时钟加速衰老过程 42。另一项MR分析也支持了失眠对表观遗传衰老（特别是内在表观遗传年龄加速, IEAA）和虚弱指数的潜在因果效应 43。此外，有研究发现，失眠患者的GrimAge和SkinBloodClock表观遗传年龄加速增加，并且DNA甲基化端粒长度（DNAmTL）显著缩短。全基因组关联研究（EWAS）还揭示了失眠导致整体低甲基化模式，并富集了多种蛋白质稳态和氧化应激通路 44。这些结果提示，失眠可能通过影响这些关键的分子过程来加速生物衰老。
- 睡眠呼吸暂停：阻塞性睡眠呼吸暂停（Obstructive Sleep Apnea, OSA）是一种以反复出现上呼吸道阻塞导致间歇性缺氧和睡眠片段化为特征的睡眠障碍。多项研究表明，OSA与表观遗传年龄加速之间存在关联。一项针对工作年龄成年人的研究发现，在多种睡眠指标中，阻塞性睡眠呼吸暂停症状与表观遗传年龄加速（通过AgeDev和DunedinPACE测量）的关联最为一致 45。另一项MR研究则发现，睡眠呼吸暂停与面部衰老和虚弱指数显著相关 43。此外，研究还表明，在患有OSA的个体中，较短的白细胞端粒长度与睡眠稳定性降低有关，这可能是由于慢性睡眠片段化或呼吸化学反射激活导致的持续交感神经活动压力所致 46。
- DNA甲基化酶活性与基因表达：睡眠不足或紊乱可能会影响DNA甲基化酶（DNMTs）的活性和表达，进而改变基因组范围内的甲基化模式。有研究发现，睡眠不足与独特的DNA甲基化模式相关，其中78%的差异甲基化位点（DMPs）在睡眠不足的情况下表现出低甲基化，提示睡眠不足可能与DNA甲基化的丢失有关 47。这种低甲基化现象可能影响神经可塑性和神经退行性变相关的过程 47。
综上所述，睡眠障碍通过干扰DNA损伤修复、改变DNA甲基化模式以及加速端粒缩短，对生物衰老过程产生显著影响。失眠、睡眠呼吸暂停等问题不仅是影响生活质量的健康问题，更是加速“生命时钟”的风险因素。深入理解这些机制有助于开发针对性的干预措施，以改善睡眠健康，从而减缓生物衰老进程。
3. 压力管理：从分子修复到生物年龄逆转
鉴于慢性压力对加速生物衰老具有显著影响，有效的压力管理策略对于减缓“生命时钟”、促进健康老龄化至关重要。这些策略不仅仅是心理层面的干预，更是通过调节生理应激反应、修复分子损伤，最终实现生物年龄逆转的科学方法。
3.1 正念与认知干预：调节压力反应的神经生物学基础
正念冥想（Mindfulness Meditation）和认知行为疗法（Cognitive Behavioral Therapy, CBT）是两种被广泛研究且行之有效的心理干预方法，它们通过调节神经内分泌系统、改善基因表达和表观遗传修饰，对压力引起的生物衰老产生积极影响。
正念冥想对皮质醇水平、端粒酶活性和DNA甲基化的影响：
正念冥想是一种将注意力集中于当下，不加评判地观察思想、感受和身体感觉的练习。其在压力管理中的核心机制之一是调节下丘脑-垂体-肾上腺（HPA）轴的活性，从而降低皮质醇水平。慢性应激会导致HPA轴持续激活，皮质醇过量分泌，而冥想训练能够有效降低基线皮质醇水平和应激诱导的皮质醇反应。较低的皮质醇水平有助于减轻其对端粒酶活性的抑制作用。多项研究表明，长期正念冥想实践者，其外周血单核细胞（PBMCs）中的端粒酶活性显著高于非冥想者。端粒酶活性的提升有助于维持端粒长度，减缓端粒的缩短速率，从而延缓细胞衰老。
此外，正念冥想也被发现能够改善DNA甲基化模式。通过调节基因表达，冥想可能影响与炎症、免疫和压力反应相关的基因的甲基化状态。例如，一项针对冥想者的研究发现，正念冥想能够引起与炎症反应、免疫功能和细胞衰老相关的基因的DNA甲基化变化。这些变化有助于促进机体的适应性应激反应，减少慢性炎症，进而保护基因组的稳定性。
认知行为疗法（CBT）对生命时钟的积极作用：
认知行为疗法是一种结构化的心理治疗方法，旨在帮助个体识别并改变导致负面情绪和行为的非理性思维模式。通过教授应对技巧，CBT能够有效减轻心理压力，从而间接影响生物衰老标志物。CBT可以降低焦虑和抑郁症状，这些症状本身就与加速的生物衰老相关。例如，有研究表明，接受CBT治疗的抑郁症患者，其炎症标志物水平降低，这可能有助于减少炎症对端粒和DNA甲基化的负面影响。
更直接的证据来自对CBT与生物标志物关系的探索。虽然直接关于CBT对表观遗传时钟影响的研究相对较少，但其通过改善心理健康状况，减少慢性应激对HPA轴和免疫系统的负面影响，间接达到延缓生物衰老的效果是可预见的。CBT通过改善睡眠质量、减少吸烟和不健康饮食等行为，也能进一步减轻这些风险因素对生命时钟的加速作用。
综合来看，正念冥想和认知干预不仅是心理健康的有效工具，更是通过调节神经生物学通路，积极影响分子层面的衰老进程，从而达到延缓生物年龄的目的。
3.2 社会支持与情绪调节：压力缓冲的实证效果
良好的社会关系和有效的情绪调节策略在缓冲压力对生物衰老的负面影响方面发挥着关键作用。社会支持不仅提供情感慰藉和物质帮助，还能通过减轻个体感知到的压力，从而间接影响生物学衰老指标。
社会关系与表观遗传年龄加速：
群体研究揭示，拥有强大社会支持网络的个体，其生物年龄加速程度通常较低。社会孤立、孤独感与较高的炎症水平、HPA轴功能障碍和较短的端粒长度相关，而这些都是加速生物衰老的标志。相反，积极的社会互动可以降低皮质醇水平，增强免疫功能，这些生理变化都有助于保护细胞免受衰老损伤。例如，一项针对老年人群的纵向研究发现，社会网络规模越大，社会参与度越高，其表观遗传年龄加速越慢。这表明，社会连接不仅能改善心理健康，还能通过生物学途径延缓衰老。
积极情绪调节与表观遗传机制：
积极情绪调节，如感恩训练、乐观主义和积极应对策略，已被证明能够减少压力相关的表观遗传年龄加速。感恩是一种对他人善意或生活赐予的感激之情，它能有效提升幸福感，降低负面情绪。研究表明，高水平的感恩与较低的炎症标志物（如C反应蛋白）相关，而炎症是生物衰老的主要驱动因素之一。通过减轻炎症负担，感恩可能间接影响DNA甲基化和端粒长度。
一个具体的干预案例是“积极心理干预”（Positive Psychological Interventions, PPIs）。一些研究探索了PPIs对生物衰老标志物的影响。例如，一项小型研究发现，基于正念和积极心理学原理的干预，能够改善参与者的生活满意度，并可能对表观遗传年龄加速产生积极影响，尽管需要更大规模的研究来证实。这些干预通常通过培养积极情绪、增强应对能力和促进社会连接，来间接修复压力对分子水平的负面影响。
具体干预案例：
在社区老年人中进行的一项干预研究显示，为期数周的社交活动和认知训练结合项目，不仅提升了参与者的认知功能和生活质量，还观察到参与者在项目结束后表观遗传年龄加速的趋势有所减缓。这提示集体参与、互助支持的环境能有效对抗压力，进而对生物衰老产生积极影响。此外，一些针对慢性病患者的干预方案，如心脏康复计划，强调心理支持和社交互动，也观察到患者端粒长度缩短速度的减缓。
总而言之，通过正念冥想和认知行为疗法调节内在应激反应，以及通过强大的社会支持网络和积极情绪调节策略缓冲外部压力，个体能够从分子层面修复压力造成的损伤，有效拨慢“生命时钟”，实现生物年龄的逆转。
4. 睡眠优化：修复生命时钟的“黄金时段”
睡眠是人体进行自我修复和恢复的关键生理过程，尤其对于延缓生物衰老、修复“生命时钟”具有不可替代的作用。优质的睡眠，特别是深度睡眠阶段，被认为是维持细胞健康、修复DNA损伤、校正甲基化模式的“黄金时段”。
4.1 睡眠周期与深度睡眠：端粒维护的关键窗口
人体的睡眠并非单一状态，而是由多个不同阶段组成的循环，主要包括非快速眼动睡眠（NREM，又分为N1、N2、N3期，其中N3为深度睡眠）和快速眼动睡眠（REM）。深度睡眠（NREM N3期）在大脑和身体的修复与恢复中扮演着至关重要的角色，它不仅有助于巩固记忆、清除代谢废物，更重要的是为细胞层面的DNA损伤修复和表观遗传调控提供了关键窗口。
深度睡眠在DNA损伤修复中的作用：
在清醒状态下，细胞会不断积累DNA损伤，这些损伤可能由氧化应激、环境毒素或正常的代谢活动引起。如果这些损伤得不到及时有效的修复，将会导致基因组不稳定，加速细胞衰老。深度睡眠期间，大脑活动减缓，能量消耗降低，为细胞提供了充足的资源和时间来启动和执行DNA修复过程。研究表明，阻塞性睡眠呼吸暂停综合征（OSA）患者由于反复缺氧和睡眠片段化，其DNA修复能力受损，导致端粒缩短更为显著 48。充足的深度睡眠能够促进DNA修复酶的活性，从而更有效地清除DNA损伤，保护端粒的完整性。
甲基化模式校正与表观遗传稳定性：
DNA甲基化是表观遗传调控的关键机制，其模式的稳定对维持细胞功能和防止衰老至关重要。睡眠，特别是深度睡眠，被认为能够影响DNA甲基化酶的活性，从而校正和维持基因组的甲基化模式。多囊卵巢综合征（PCOS）患者的昼夜节律基因表达模式存在紊乱，并伴随DNA甲基化模式的异常改变 49。SIRT1是一种NAD+-依赖性去乙酰化酶，它在昼夜节律调控和端粒稳态中都发挥着积极作用。SIRT1有助于维持昼夜节律，并通过诱导端粒酶和Shelterin蛋白的表达来确保端粒稳态。SIRT1抑制会导致昼夜节律和端粒功能障碍，进而引发与年龄相关的疾病。因此，通过优化睡眠来支持SIRT1的活性，有助于维持表观遗传的稳定性和端粒健康 50。
7小时以上优质睡眠对端粒长度及表观遗传稳定性的必要性：
多项研究强调了7小时以上优质睡眠对维持端粒长度和表观遗传稳定性的必要性：
- 端粒长度与睡眠时长：研究发现，睡眠时间不足7小时的成年人，其端粒长度显著短于睡眠时间达到或超过7小时的个体 5152。一项针对健康男性的研究显示，睡眠时间少于5小时的男性，其端粒平均比睡眠超过7小时的男性短6% 53。这表明，充足的睡眠时长是保护端粒免受磨损的关键因素。在孕妇群体中，睡眠模式对新生儿端粒长度也有显著影响。研究表明，孕晚期睡眠时间≥10小时或睡眠质量差的母亲，其新生儿的端粒长度比睡眠7-9小时且睡眠质量好的母亲短9.30%至9.91% 54。
- 表观遗传年龄加速与睡眠时长：睡眠不足不仅影响端粒，还加速表观遗传年龄。一项对产后女性的研究发现，产后6个月睡眠不足（每晚少于7小时）与产后12个月时加速的内在表观遗传年龄加速（IEAA）和表型表观遗传年龄加速（PEAA）相关，并伴随DNA甲基化端粒长度的缩短 55。这提示，即使是短期内的睡眠不足，也可能对生物年龄产生持久的负面影响。
因此，为了有效修复“生命时钟”，减缓生物衰老，确保每晚7小时以上的优质睡眠至关重要。这不仅意味着足够的睡眠时长，更强调睡眠的连续性和深度，以充分发挥深度睡眠在DNA修复和表观遗传维护中的关键作用。
4.2 睡眠环境与行为调整：从失眠到逆转的实践路径
为了修复生命时钟、逆转因睡眠障碍导致的生物年龄加速，采取积极的睡眠环境与行为调整策略至关重要。这些策略旨在优化睡眠质量和时长，从而最大限度地发挥睡眠在细胞修复和表观遗传维护中的作用。
改善睡眠环境的具体策略：
- 固定作息时间：维持规律的作息是调节昼夜节律、促进良好睡眠的基石。每天在相似的时间上床睡觉和起床，包括周末，有助于训练身体的生物钟，使其在特定时间感到疲倦并保持清醒 56。
- 减少蓝光暴露：睡前数小时内应避免接触电子设备（如手机、平板电脑、电脑和电视）发出的蓝光。蓝光会抑制褪黑激素（一种促进睡眠的激素）的分泌，从而干扰入睡和睡眠质量。如果无法完全避免，可以使用蓝光过滤眼镜或设备上的夜间模式 56。
- 优化睡眠环境：
- 创造睡前放松仪式：睡前1-2小时进行放松活动，如温水浴、阅读纸质书、听轻音乐或进行温和的伸展运动，可以帮助身体和大脑逐渐放松，为入睡做好准备。
- 避免刺激性物质：睡前数小时应避免摄入咖啡因、酒精和尼古丁。这些物质会干扰睡眠结构，导致睡眠片段化和质量下降 56。
- 适度午睡：如果需要午睡，应将午睡时间控制在20-30分钟以内，并尽量在下午早些时候进行，以避免影响夜间睡眠。
产后睡眠干预研究验证效果：
产后时期是女性睡眠质量受挑战的典型阶段，婴儿的夜间喂养和照护常常导致母亲睡眠不足。一项针对产后女性的研究提供了强有力的证据，揭示了睡眠不足与生物年龄加速之间的关联以及干预的潜在价值 55。该研究发现：
- 产后睡眠不足与生物年龄加速：在产后6个月，如果母亲的睡眠时间少于7小时，那么在产后12个月时，她们的内在表观遗传年龄加速（IEAA）和表型表观遗传年龄加速（PEAA）会显著增加，同时DNA甲基化端粒长度（DNAmTL）也显著缩短 55。这意味着，即使是持续数月的睡眠不足，也可能对生物年龄产生显著且持久的负面影响，加速细胞层面的衰老进程。
- 睡眠时间的重要性：该研究强调了睡眠时长而非单纯的睡眠质量（根据匹兹堡睡眠质量指数评估）与表观遗传年龄加速的关联性 55。这提示我们，在产后等特殊时期，确保足够的睡眠时间对于减缓生物衰老至关重要。
这些发现不仅为产后女性提供了改善睡眠的强烈动机，也为其他人群提供了普遍适用的指导：通过积极调整睡眠环境和行为，确保充足且高质量的睡眠，可以有效对抗生物年龄加速，从而拨慢“生命时钟”，促进整体健康。例如，一项来自英国生物银行（UK Biobank）的大规模研究也指出，良好的睡眠质量（通过睡眠指数评估，包括打鼾、昼夜节律、白天嗜睡、睡眠时长、失眠和起床困难等六个方面）与KDM生物年龄加速和PhenoAge加速呈负相关，即睡眠质量越好，生物年龄加速越慢 59。该研究甚至通过孟德尔随机化方法，进一步证实了睡眠质量对生物年龄加速的因果效应，指出睡眠指数每增加一个单位，KDM生物年龄加速和PhenoAge加速分别减少0.104年和0.119年 59。这些研究共同强调了睡眠优化在逆转生物年龄中的关键作用。
5. 科学验证：生活方式干预逆转生命时钟的实证
尽管生物年龄加速的机制复杂，受多种因素影响，但越来越多的科学研究表明，通过积极的生活方式干预，个体有可能逆转其生物年龄，拨慢甚至部分回拨“生命时钟”。这些实证研究为我们提供了从理论走向实践的信心。
5.1 短期干预的惊喜：8周饮食睡眠计划的逆转案例
一项突破性的临床研究为生活方式干预逆转生物年龄提供了强有力的证据。该研究招募了六名女性参与者，并实施了一项为期8周的甲基化支持性饮食与生活方式干预计划，旨在探究其对DNA甲基化和生物衰老指标的影响 60。
干预方案详情：
这项为期8周的计划内容丰富，涵盖了多个生活方式维度：
- 饮食：主要以富含甲基化支持性营养素的食物为主。这包括增加蔬菜（特别是深绿色叶菜）、水果、非淀粉类碳水化合物和低脂蛋白质的摄入，同时鼓励食用鸡蛋、甜菜、核桃、鱼类等富含胆碱、甜菜碱、B族维生素（如叶酸、B6、B12）的食物，这些营养素是DNA甲基化通路中的关键辅因子。
- 睡眠：提供了睡眠指导，强调充足且高质量的睡眠，以优化细胞修复和再生过程。
- 运动：包含了适度的运动指南，以促进新陈代谢和心血管健康。
- 放松：提供了放松技巧指导，以帮助参与者管理压力，减轻慢性压力对生物衰老的负面影响。
- 补充剂：参与者还接受了益生菌和植物营养素的补充，以支持肠道健康和抗氧化防御。
- 营养指导：全程提供专业的营养教练指导，确保参与者能够有效地执行干预方案。
惊人的逆转效果：
在8周干预结束后，研究人员对参与者的血液样本进行了DNA甲基化分析，并使用Horvath DNAmAge时钟（2013年版本，通过SeSAMe流程标准化）评估了她们的生物年龄 60。结果显示，五名参与者在干预后均出现了生物年龄的显著降低，降幅介于1.22年至11.01年之间 60。
更重要的是，研究发现，所有参与者在干预后的平均生物年龄从基线时的55.83岁显著降低至51.23岁，平均生物年龄减少了4.60年（p=.039），这一结果具有统计学意义 60。考虑到参与者在项目开始时的平均身份证年龄为57.9岁，且除一名参与者外，其余参与者在干预开始时生物年龄均小于其身份证年龄，这表明生物年龄的变化并非由疾病改善引起，而是可能归因于潜在的衰老机制的积极改变 60。
饮食与睡眠的协同作用机制：
这项研究的成功，凸显了甲基化支持性饮食和睡眠优化在逆转生物年龄中的协同作用：
- B族维生素等营养素的直接影响：B族维生素（如叶酸、维生素B6、维生素B12）是DNA甲基化通路中“一碳代谢”的关键辅因子。它们通过提供甲基供体（如S-腺苷甲硫氨酸，SAM），直接影响DNA甲基化酶的活性，从而调控基因表达，校正异常的甲基化模式。富含这些营养素的饮食能够优化细胞的甲基化能力，有助于拨慢表观遗传时钟。
- 睡眠对DNA修复和甲基化稳态的维护：如前所述，优质睡眠是DNA损伤修复和维持DNA甲基化模式稳定性的关键。充足的睡眠可以促进细胞在夜间进行高效的修复工作，减少DNA损伤的积累，并支持维持正常的甲基化模式。
- 多维度干预的协同增效：这项研究的亮点在于其多维度的干预策略。饮食、睡眠、运动和放松指导的结合，共同作用于细胞和分子层面，缓解氧化应激、炎症反应，优化新陈代谢，从而全面提升机体的抗衰老能力，实现了单一干预难以达到的生物年龄逆转效果。
这项研究虽然是一个小规模的案例系列，但其结果令人鼓舞，为通过全面的生活方式干预来积极影响生物衰老进程提供了初步但有力的证据。它表明，通过有意识地调整饮食和睡眠习惯，结合压力管理和适度运动，我们有可能主动干预“生命时钟”，实现生物年龄的逆转。
5.2 长期坚持的价值：生活方式与生物年龄的动态平衡
短期干预的积极效果令人振奋，但更重要的是，长期坚持健康的生活方式对于维持生物年龄的动态平衡，实现“稳态逆转”具有不可估量的价值。队列研究（Cohort studies）通过对大量人群进行长时间跟踪，为我们揭示了健康生活习惯与DNAm年龄减速之间的长期关联。这些研究表明，持续的压力管理和睡眠优化，结合其他健康行为，能够对生命时钟产生深远而持久的影响。
健康生活方式与DNAm年龄减速的长期关联：
多项大规模队列研究已经证实，长期坚持健康的生活方式与较慢的表观遗传年龄加速（Epigenetic Age Acceleration, EAA）密切相关。这不仅仅是单一因素的影响，而是多种健康行为协同作用的结果。例如，一项研究分析了中老年中国成年人的睡眠模式与DNA甲基化年龄加速（PhenoAgeAccel, GrimAgeAccel, DunedinPACE, DNAm MS）之间的关联。结果显示，睡眠评分越高（反映了更健康的睡眠模式，综合了就寝时间、睡眠时长、睡眠质量和午睡情况），DNAm年龄加速越慢，这种关联呈剂量反应关系。每增加1分睡眠评分，PhenoAgeAccel、GrimAgeAccel、DunedinPACE和DNAm MS分别降低0.208、0.107、0.008和0.019 61。这意味着，长期维持良好的睡眠习惯，能够显著减缓生物衰老进程。
此外，体力活动也被认为是减缓表观遗传衰老的关键因素。来自“健康与退休研究”（Health and Retirement Study）的数据显示，身体活跃的参与者（每周至少进行一次剧烈运动或多次中等强度运动）的EAA显著低于不活跃的参与者。具体来说，在调整了年龄、性别、种族/民族、教育、总财富和当前吸烟状况后，活跃参与者的GrimAge加速、PhenoAge加速和DunedinPACE分别降低了1.26年、1.70年和0.05年（每实际年龄年）62。这项研究强调，无论是累积的体力活动量还是最近的体力活动水平，都是预测EAA的重要因素，凸显了长期坚持体育锻炼对于促进更健康的生物衰老的作用 62。
压力管理与睡眠优化的“稳态逆转”：
“稳态逆转”指的是通过持续性的健康干预，使生物年龄在个体生命周期中长期保持在一个相对年轻的水平，或者减缓其加速的速度，从而在整体上实现比身份证年龄更慢的衰老进程。这需要将压力管理和睡眠优化融入日常生活，形成稳定的习惯：
- 持续的压力管理：长期的慢性压力会导致应激激素水平升高，进而加速端粒缩短和DNA甲基化异常。通过长期坚持正念冥想、认知行为疗法、培养积极情绪（如感恩）以及建立强大的社会支持网络，个体能够有效缓冲压力对生物体的影响。这种持续的“压力缓冲”机制有助于维持内分泌系统的平衡，降低炎症水平，从而保护细胞和基因组免受损伤，减缓表观遗传时钟的加速 63。
- 优化的睡眠模式：持续高质量的睡眠是细胞修复、代谢平衡和表观遗传维护的基础。长期的睡眠优化（包括规律作息、充足时长、深度睡眠占比高以及良好的睡眠环境）有助于DNA损伤的及时修复，维持DNA甲基化模式的稳定，甚至可能通过调节昼夜节律相关基因的表达来影响健康的生理过程。研究表明，健康的睡眠模式与较低的DNAm年龄加速呈因果关系 61。
生活方式因素的协同效应：
值得注意的是，这些健康的生活方式因素并非孤立地发挥作用，而是相互关联、协同增效的。例如，良好的睡眠有助于情绪调节和压力管理；适度的体育锻炼可以改善睡眠质量，并降低压力水平。这种多维度的健康行为综合效应，共同构成了“稳态逆转”生命时钟的基础。因此，将这些健康行为融入日常生活的长期实践，是实现生物年龄减速，享受更长健康寿命的关键。
6. 未来展望：个体化生命时钟调控的可能性
随着衰老科学的飞速发展，我们对生物年龄的理解正从单一指标走向多维度整合。未来的目标是建立更加精准、个性化的生命时钟调控策略，以实现更有效的抗衰老干预。这需要整合前沿的生物标志物和技术，从实验室走向日常健康管理。
6.1 多维度评估：整合端粒与表观遗传时钟的精准模型
当前，端粒长度和表观遗传时钟（DNA甲基化）被认为是评估生物年龄最主要的工具。然而，单一的生物标志物往往只能反映衰老过程的某个侧面 6465。为了实现更精准的生物年龄评估和更具针对性的干预方案，未来的研究和临床实践将趋向于整合多维度数据，构建全面的生物年龄评估体系 66。
整合端粒长度与表观遗传时钟的互补优势：
尽管端粒长度和表观遗传时钟都与衰老相关，但它们反映的生物学机制有所不同。端粒长度主要反映细胞复制性衰老的累积效应和基因组稳定性，而表观遗传时钟，特别是第二代和第三代时钟（如GrimAge和PhenoAge），则能整合更广泛的生理系统功能状态，反映代谢、炎症和免疫等多个方面的衰老进程 6467。将这两种标志物结合，可以提供更全面的衰老图谱，区分不同个体的主导衰老通路。例如，一个端粒较短但表观遗传年龄正常的个体可能主要面临复制性衰老问题，而一个表观遗传年龄加速但端粒长度尚可的个体则可能受到更多环境或代谢因素的影响。这种区分对于制定个性化的干预策略至关重要 68。
多组学数据（代谢组、蛋白组等）的深度融合：
除了端粒和表观遗传数据，整合其他组学数据（omics data）将进一步提升生物年龄评估的精准度：
- 代谢组学（Metabolomics）：代谢组学通过测量生物体内的小分子代谢产物（如氨基酸、脂质、糖类等）来反映细胞和组织的实时生理状态。衰老与代谢途径的显著改变密切相关，例如线粒体功能障碍和能量代谢失衡 66。将代谢组数据纳入生物年龄模型，可以捕捉到更精细的代谢衰老特征，有助于识别与生活方式、饮食习惯紧密相关的衰老路径。例如，有研究通过整合代谢组学数据显著提高了睡眠障碍的预测能力，并揭示了潜在的生物学通路，例如LDL颗粒大小等 69。
- 蛋白质组学（Proteomics）：蛋白质组学关注细胞内蛋白质的表达、修饰和相互作用。蛋白质作为生命活动的直接执行者，其变化与衰老过程中的功能丧失和疾病发生密切相关 6566。例如，GrimAge时钟已经通过整合与衰老相关的血浆蛋白的DNA甲基化替代指标来计算生物年龄，并表现出强大的预测能力 70。直接测量血浆蛋白质水平，可以更直接地反映炎症、免疫、内分泌等系统的衰老状态。结合蛋白质组数据可以构建“蛋白质组学时钟”，提供蛋白质水平上的衰老信息，这与DNA甲基化时钟形成了互补。
- 其他组学数据：包括转录组学（Transcriptomics）、脂质组学（Lipidomics）、微生物组学（Microbiomics）等，都能从不同层次反映生物体内的衰老过程 71。例如，肠道微生物的组成和功能与宿主健康和衰老密切相关，其失衡可能加速衰老。
构建精准生物年龄评估模型的挑战与展望：
整合多维度数据构建精准模型面临多重挑战，包括数据标准化、复杂数据分析、算法开发以及生物学解释等 7273。然而，随着人工智能和机器学习技术的发展，这些挑战正逐步被克服 74。例如，通过深度学习和复杂网络分析，可以从海量的多组学数据中识别出与衰老最相关的生物标志物组合，并构建出能够更准确预测疾病风险和寿命的“多模态”生物年龄时钟 7071。这种多维度整合的模型不仅能够提供一个单一的生物年龄数值，更重要的是能够揭示个体衰老轨迹中不同器官、系统或通路的主导性衰老特征（即“年龄型”，ageotype），从而为实现真正的个性化抗衰老策略奠定基础 7475。未来的精准模型将不仅仅是预测工具，更会成为诊断工具，帮助医生和个体理解衰老的内在机制，并据此调整生活方式或接受靶向干预 6776。
6.2 技术赋能：从实验室到日常的生命时钟管理
随着科技的飞速发展，曾经深藏于实验室的生物年龄评估技术正逐步走向日常应用，通过可穿戴设备和先进的表观遗传检测技术，赋能个体进行实时的生命时钟管理。这标志着“防衰老”领域正从科研探索阶段向大众健康管理转型，使得个性化、预防性的健康干预成为可能。
可穿戴设备在生命时钟管理中的普及与应用：
可穿戴设备，如智能手表、手环、睡眠监测仪、智能服装和智能鞋垫等，已成为日常健康监测的重要工具 777879。这些设备能够连续、无创或微创地监测多项生理指标，包括心率、心率变异性、睡眠模式（睡眠时长、睡眠阶段分布、清醒次数）、活动量、体温、血氧饱和度甚至压力水平等 7779。通过集成微型传感器、物联网、人工智能和5G等先进技术，可穿戴设备的数据测量质量已可与医疗设备媲美 77。
在生命时钟管理中，可穿戴设备的作用体现在：
- 实时追踪睡眠数据：高质量的睡眠是修复“生命时钟”的关键，睡眠监测仪能够详细记录个体的睡眠周期、深度睡眠时长、醒来次数等，帮助用户了解自己的睡眠结构，发现潜在的睡眠问题。这些数据可以作为调整作息、优化睡眠环境的依据。
- 监测压力水平与活动量：许多智能穿戴设备具备心率变异性（HRV）监测功能，HRV是衡量自主神经系统活动、反映压力水平的重要指标。结合活动量数据，用户可以更全面地了解自身的生理负荷和应激反应，并据此调整日常活动和压力管理策略。
- 提供个性化反馈与建议：结合人工智能算法，可穿戴设备能够分析收集到的海量健康数据，识别个体生理模式中的异常，并提供个性化的健康建议。例如，当检测到睡眠质量下降时，设备可以建议用户调整睡前习惯；当监测到持续高压状态时，提醒用户进行放松练习或寻求专业帮助 77。
- 连接医生与患者：可穿戴设备能够追踪、存储并与医疗机构共享患者数据，从而实现远程或实时的健康评估，为精准医疗和个性化治疗提供数据支持 7780。
表观遗传检测技术的进步与普及：
过去，DNA甲基化等表观遗传检测主要局限于科研实验室。但随着技术成本的降低和检测效率的提高，表观遗传时钟的商业化检测服务正逐渐兴起，使得普通消费者也能有机会了解自己的生物年龄。
- 易于获取的生物年龄评估：通过采集唾液、血液或尿液样本，用户可以将样本送至专业实验室进行DNA甲基化分析，从而获得由GrimAge、PhenoAge等表观遗传时钟计算出的生物年龄。这种检测结果能够量化个体生物年龄与其身份证年龄的差异，直观地揭示衰老程度。
- 评估干预效果的客观指标：当个体采取生活方式干预（如改善饮食、优化睡眠、进行压力管理等）后，可以通过定期进行表观遗传检测，客观评估这些干预措施对生物年龄的影响。如果生物年龄出现“逆转”或加速减缓，将为个体提供强烈的积极反馈，激励其继续坚持健康行为。
- 指导个性化干预：结合表观遗传检测结果，可以更精准地识别个体衰老的驱动因素。例如，如果GrimAge显示加速，可能提示个体在炎症、代谢或免疫方面存在衰老风险，从而指导其采取针对性的饮食调整、炎症控制或免疫力提升策略。
从科研到大众健康管理的转型：
可穿戴设备与表观遗传检测技术的结合，正在推动“防衰老”理念从实验室的深奥研究转化为大众可及的健康管理实践。
- 提升健康素养：通过直观的生物年龄数据，人们对衰老过程有了更具象的认知，从而更容易理解健康生活方式的重要性，激发主动管理健康的意愿。
- 促进预防医学发展：实时监测和生物年龄评估能够帮助个体和医疗专业人员更早地识别衰老风险，从而在疾病发生之前采取预防措施，实现真正的“上医治未病”。
- 个体化健康方案：结合可穿戴设备提供的日常生理数据和表观遗传检测提供的深层分子信息，可以构建高度个性化的健康管理方案。例如，根据夜间睡眠得分和生物年龄评估结果，营养师和健康教练可以为用户量身定制睡眠改善计划和营养补充方案。
综上所述，技术赋能正在打破生物年龄评估的壁垒，将复杂的科学原理转化为实用的健康管理工具。可穿戴设备和表观遗传检测的普及，将极大地促进个体对生命时钟的自我管理，推动抗衰老领域从被动治疗转向主动预防，最终实现更广泛人群的健康老龄化。
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4Epigenetic ageing clocks: statistical methods and emerging computational challenges.PubMed
Andrew E Teschendorff, Steve Horvath
Nat Rev Genet. 2025 May;26(5):350-368. doi: 10.1038/s41576-024-00807-w. Epub 2025 Jan 13.
Over the past decade, epigenetic clocks have emerged as powerful machine learning tools, not only to estimate chronological and biological age but also to assess the efficacy of anti-ageing, cellular rejuvenation and disease-preventive interventions. However, many computational and statistical challenges remain that limit our understanding, interpretation and application of epigenetic clocks. Here, we review these computational challenges, focusing on interpretation, cell-type heterogeneity and emerging single-cell methods, aiming to provide guidelines for the rigorous construction of interpretable epigenetic clocks at cell-type and single-cell resolution.
5DNA Methylation Clocks in Aging: Categories, Causes, and Consequences.PubMed
Adam E Field, Neil A Robertson, Tina Wang, et al.
Mol Cell. 2018 Sep 20;71(6):882-895. doi: 10.1016/j.molcel.2018.08.008.
Age-associated changes to the mammalian DNA methylome are well documented and thought to promote diseases of aging, such as cancer. Recent studies have identified collections of individual methylation sites whose aggregate methylation status measures chronological age, referred to as the DNA methylation clock. DNA methylation may also have value as a biomarker of healthy versus unhealthy aging and disease risk; in other words, a biological clock. Here we consider the relationship between the chronological and biological clocks, their underlying mechanisms, potential consequences, and their utility as biomarkers and as targets for intervention to promote healthy aging and longevity.
6DNA methylation GrimAge strongly predicts lifespan and healthspan.PubMed
Ake T Lu, Austin Quach, James G Wilson, et al.
Aging (Albany NY). 2019 Jan 21;11(2):303-327. doi: 10.18632/aging.101684.
It was unknown whether plasma protein levels can be estimated based on DNA methylation (DNAm) levels, and if so, how the resulting surrogates can be consolidated into a powerful predictor of lifespan. We present here, seven DNAm-based estimators of plasma proteins including those of plasminogen activator inhibitor 1 (PAI-1) and growth differentiation factor 15. The resulting predictor of lifespan, DNAm GrimAge (in units of years), is a composite biomarker based on the seven DNAm surrogates and a DNAm-based estimator of smoking pack-years. Adjusting DNAm GrimAge for chronological age generated novel measure of epigenetic age acceleration, .Using large scale validation data from thousands of individuals, we demonstrate that DNAm GrimAge stands out among existing epigenetic clocks in terms of its predictive ability for time-to-death (Cox regression P=2.0E-75), time-to-coronary heart disease (Cox P=6.2E-24), time-to-cancer (P= 1.3E-12), its strong relationship with computed tomography data for fatty liver/excess visceral fat, and age-at-menopause (P=1.6E-12). AgeAccelGrim is strongly associated with a host of age-related conditions including comorbidity count (P=3.45E-17). Similarly, age-adjusted DNAm PAI-1 levels are associated with lifespan (P=5.4E-28), comorbidity count (P= 7.3E-56) and type 2 diabetes (P=2.0E-26). These DNAm-based biomarkers show the expected relationship with lifestyle factors including healthy diet and educational attainment.Overall, these epigenetic biomarkers are expected to find many applications including human anti-aging studies.
7Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden.PubMed
Robert F Hillary, Anna J Stevenson, Daniel L McCartney, et al.
Clin Epigenetics. 2020 Jul 31;12(1):115. doi: 10.1186/s13148-020-00905-6.
BACKGROUND: Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These measures include five 'epigenetic clocks' which provide an index of how much an individual's biological age differs from their chronological age at the time of measurement. The five clocks encompass methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). A sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an individual's biological ageing. This measure of ageing is termed DunedinPoAm. In this study, we test the association between these six epigenetic measures of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries (n ≤ 9537, Generation Scotland: Scottish Family Health Study). RESULTS: DNAm GrimAge predicted incidence of clinically diagnosed chronic obstructive pulmonary disease (COPD), type 2 diabetes and ischemic heart disease after 13 years of follow-up (hazard ratios = 2.22, 1.52 and 1.41, respectively). DunedinPoAm predicted the incidence of COPD and lung cancer (hazard ratios = 2.02 and 1.45, respectively). DNAm PhenoAge predicted incidence of type 2 diabetes (hazard ratio = 1.54). DNAm Telomere Length associated with the incidence of ischemic heart disease (hazard ratio = 0.80). DNAm GrimAge associated with all-cause mortality, the prevalence of COPD and spirometry measures at the study baseline. These associations were present after adjusting for possible confounding risk factors including alcohol consumption, body mass index, deprivation, education and tobacco smoking and surpassed stringent Bonferroni-corrected significance thresholds. CONCLUSIONS: Our data suggest that epigenetic measures of ageing may have utility in clinical settings to complement gold-standard methods for disease assessment and management.
8DNA Methylation-derived biological age and long-term mortality risk in subjects with type 2 diabetes.PubMed
Jacopo Sabbatinelli, Angelica Giuliani, Katarzyna Malgorzata Kwiatkowska, et al.
Cardiovasc Diabetol. 2024 Jul 13;23(1):250. doi: 10.1186/s12933-024-02351-7.
BACKGROUND: Individuals with type 2 diabetes (T2D) face an increased mortality risk, not fully captured by canonical risk factors. Biological age estimation through DNA methylation (DNAm), i.e. the epigenetic clocks, is emerging as a possible tool to improve risk stratification for multiple outcomes. However, whether these tools predict mortality independently of canonical risk factors in subjects with T2D is unknown. METHODS: Among a cohort of 568 T2D patients followed for 16.8 years, we selected a subgroup of 50 subjects, 27 survived and 23 deceased at present, passing the quality check and balanced for all risk factors after propensity score matching. We analyzed DNAm from peripheral blood leukocytes using the Infinium Human MethylationEPIC BeadChip (Illumina) to evaluate biological aging through previously validated epigenetic clocks and assess the DNAm-estimated levels of selected inflammatory proteins and blood cell counts. We tested the associations of these estimates with mortality using two-stage residual-outcome regression analysis, creating a reference model on data from the group of survived patients. RESULTS: Deceased subjects had higher median epigenetic age expressed with DNAmPhenoAge algorithm (57.49 [54.72; 60.58] years. vs. 53.40 [49.73; 56.75] years; p = 0.012), and accelerated DunedinPoAm pace of aging (1.05 [1.02; 1.11] vs. 1.02 [0.98; 1.06]; p = 0.012). DNAm PhenoAge (HR 1.16, 95% CI 1.05-1.28; p = 0.004) and DunedinPoAm (HR 3.65, 95% CI 1.43-9.35; p = 0.007) showed an association with mortality independently of canonical risk factors. The epigenetic predictors of 3 chronic inflammation-related proteins, i.e. CXCL10, CXCL11 and enRAGE, C-reactive protein methylation risk score and DNAm-based estimates of exhausted CD8 + T cell counts were higher in deceased subjects when compared to survived. CONCLUSIONS: These findings suggest that biological aging, as estimated through existing epigenetic tools, is associated with mortality risk in individuals with T2D, independently of common risk factors and that increased DNAm-surrogates of inflammatory protein levels characterize deceased T2D patients. Replication in larger cohorts is needed to assess the potential of this approach to refine mortality risk in T2D.
9How does biological age acceleration mediate the associations of obesity with cardiovascular disease? Evidence from international multi-cohort studies.PubMed
Lin Hu, Jiayuan Li, Zihuan Tang, et al.
Cardiovasc Diabetol. 2025 May 14;24(1):209. doi: 10.1186/s12933-025-02770-0.
BACKGROUND: Recent basic biological research found that obesity accelerates biological aging and increases cardiovascular disease (CVD) risk. However, there is still a lack of real-world population evidence. This study aimed to explore the potential mediation roles of biological age acceleration in the associations between different dimensions of obesity characterization and incident CVD. METHODS: This international multi-cohort study included participants aged over 45 years with 3 waves longitudinal data from China Health and Retirement Longitudinal Study (CHARLS). China Health and Nutrition Survey (CHNS) was used to develop Klemera-Doubal method-biological age (KDM-BA), and the validation analysis was performed in UK Biobank (UKB) and Hongguang Elderly Health Examination Cohort (HEHEC). Obesity indices including body mass index (BMI), waist circumference (WC), waist height ratio (WtHR), body roundness index (BRI) for body shape; Chinese visceral adiposity index (CVAI), lipid accumulation product (LAP) for visceral fat accumulation; triglyceride-glucose index (TyG) and its derivatives (TyG-BMI, TyG-WC, TyG-WtHR) for metabolic function were used to measure obesity across different dimensions. Biological age acceleration was evaluated by the classic KDM-BA acceleration (KDM-BAacc). Causal mediation analyses assessed the role of biological age acceleration in mediating obesity and incident CVD. RESULTS: In CHARLS, the median follow-up period was 9.00 years, with a baseline age of 58 (52, 65) years. Obesity, KDM-BAacc, and CVD were all significantly associated with each other. For each 1-year increase in KDM-BAacc, the risk of incident stroke, heart disease and CVD increased by 68% (OR 1.68, 95% CI 1.35-2.09), 35% (OR 1.35, 95% CI 1.15-1.59), and 44% (OR 1.44, 95% CI 1.25-1.65), respectively. KDM-BAacc mediated the associations between BMI, WC, WtHR, BRI, CVAI, LAP, TyG-BMI, TyG-WC, TyG-WtHR, with CVD, with the mediation proportions ranging from 10.03 to 25.46%. However, the mediating effect was significant mostly in middle-aged individuals aged 45-65 years. Furthermore, sex differences existed in the mediation mechanisms. Biological age acceleration strongly mediated body shape indices and incident CVD in males, whereas in females, it predominantly mediated visceral fat accumulation and metabolic function dimensions with incident CVD. Similar main results were found in UKB and HEHEC. CONCLUSIONS: Biological age acceleration partially mediates the relationship between obesity and incident CVD. This temporal evidence firstly validated the mediation pathway based on international cohorts, emphasizing the importance of addressing biological aging processes in population aged 45-65 years while providing sex-specific obesity intervention strategies to prevent CVD.
10The role of protective genetic variants in modulating epigenetic aging.PubMed
Yosra Bejaoui, Luma Srour, Abeer Qannan, et al.
Geroscience. 2025 Aug;47(4):5995-6004. doi: 10.1007/s11357-025-01548-2. Epub 2025 Feb 10.
Several progeroid syndromes' causative mutations have been linked to epigenetic age acceleration as measured via several epigenetic clocks. At the same time, several protective variants have also been discovered that can reduce the risk of developing certain age-related disorders. However, the impact of these protective variants on epigenetic aging has not been well elucidated. Our research, which involved screening over 14,669 healthy individuals enrolled in the Qatar BioBank (QBB) and sequenced by the Qatar Genome Project (QGP), identified individuals carrying protective variants against age-related disorders, including Alzheimer's disease (AD), type 2 diabetes (T2D), and atherosclerosis. In this study, we measured methylation levels in blood DNA using the EPIC v2 arrays. In addition, epigenetic age was calculated using various epigenetic clocks. Our analysis revealed that the APOE*E2 protective variant reduces the rate of GrimAge epigenetic aging when compared to individuals with the APOE4 AD risk allele. Furthermore, our differential DNA methylation analysis discovered the association of the PCSK9 protective variant with specific biological processes related to immune function and the cardiovascular system. In conclusion, APOE*E2 protective variants have a positive impact on epigenetic aging, while PCSK9 protective variants have a significant effect on DNA methylation signatures. Further studies are needed to better understand the underlying mechanisms by which protective variants influence epigenetic aging, particularly the role of APOE*E2 protective variants in biological aging. Furthermore, additional research is required to fully uncover the processes that might enable specific targeted therapies to mimic the effects of beneficial mutations, such as LOF variants in PCSK9, in reducing the risk of geriatric disorders.
11Telomere and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction.PubMed
Yukun Zhu, Xuewen Liu, Xuelu Ding, et al.
Biogerontology. 2019 Feb;20(1):1-16. doi: 10.1007/s10522-018-9769-1. Epub 2018 Sep 18.
Aging is a biological process characterized by a progressive functional decline in tissues and organs, which eventually leads to mortality. Telomeres, the repetitive DNA repeat sequences at the end of linear eukaryotic chromosomes protecting chromosome ends from degradation and illegitimate recombination, play a crucial role in cell fate and aging. Due to the mechanism of replication, telomeres shorten as cells proliferate, which consequently contributes to cellular senescence and mitochondrial dysfunction. Cells are the basic unit of organismal structure and function, and mitochondria are the powerhouse and metabolic center of cells. Therefore, cellular senescence and mitochondrial dysfunction would result in tissue or organ degeneration and dysfunction followed by somatic aging through multiple pathways. In this review, we summarized the main mechanisms of cellular senescence, mitochondrial malfunction and aging triggered by telomere attrition. Understanding the molecular mechanisms involved in the aging process may elicit new strategies for improving health and extending lifespan.
12Genetics of human telomere biology disorders.PubMed
Patrick Revy, Caroline Kannengiesser, Alison A Bertuch
Nat Rev Genet. 2023 Feb;24(2):86-108. doi: 10.1038/s41576-022-00527-z. Epub 2022 Sep 23.
Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that prevent the activation of DNA damage response and repair pathways. Numerous factors localize at telomeres to regulate their length, structure and function, to avert replicative senescence or genome instability and cell death. In humans, Mendelian defects in several of these factors can result in abnormally short or dysfunctional telomeres, causing a group of rare heterogeneous premature-ageing diseases, termed telomeropathies, short-telomere syndromes or telomere biology disorders (TBDs). Here, we review the TBD-causing genes identified so far and describe their main functions associated with telomere biology. We present molecular aspects of TBDs, including genetic anticipation, phenocopy, incomplete penetrance and somatic genetic rescue, which underlie the complexity of these diseases. We also discuss the implications of phenotypic and genetic features of TBDs on fundamental aspects related to human telomere biology, ageing and cancer, as well as on diagnostic, therapeutic and clinical approaches.
13Structural biology of telomeres and telomerase.PubMed
Eric M Smith, Devon F Pendlebury, Jayakrishnan Nandakumar
Cell Mol Life Sci. 2020 Jan;77(1):61-79. doi: 10.1007/s00018-019-03369-x. Epub 2019 Nov 14.
Telomeres are protein-DNA complexes that protect chromosome ends from illicit ligation and resection. Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric DNA to counter telomere shortening. Human telomeres are composed of complexes between telomeric DNA and a six-protein complex known as shelterin. The shelterin proteins TRF1 and TRF2 provide the binding affinity and specificity for double-stranded telomeric DNA, while the POT1-TPP1 shelterin subcomplex coats the single-stranded telomeric G-rich overhang that is characteristic of all our chromosome ends. By capping chromosome ends, shelterin protects telomeric DNA from unwanted degradation and end-to-end fusion events. Structures of the human shelterin proteins reveal a network of constitutive and context-specific interactions. The shelterin protein-DNA structures reveal the basis for both the high affinity and DNA sequence specificity of these interactions, and explain how shelterin efficiently protects chromosome ends from genome instability. Several protein-protein interactions, many provided by the shelterin component TIN2, are critical for upholding the end-protection function of shelterin. A survey of these protein-protein interfaces within shelterin reveals a series of "domain-peptide" interactions that allow for efficient binding and adaptability towards new functions. While the modular nature of shelterin has facilitated its part-by-part structural characterization, the interdependence of subunits within telomerase has made its structural solution more challenging. However, the exploitation of several homologs in combination with recent advancements in cryo-EM capabilities has led to an exponential increase in our knowledge of the structural biology underlying telomerase function. Telomerase homologs from a wide range of eukaryotes show a typical retroviral reverse transcriptase-like protein core reinforced with elements that deliver telomerase-specific functions including recruitment to telomeres and high telomere-repeat addition processivity. In addition to providing the template for reverse transcription, the RNA component of telomerase provides a scaffold for the catalytic and accessory protein subunits, defines the limits of the telomeric repeat sequence, and plays a critical role in RNP assembly, stability, and trafficking. While a high-resolution definition of the human telomerase structure is only beginning to emerge, the quick pace of technical progress forecasts imminent breakthroughs in this area. Here, we review the structural biology surrounding telomeres and telomerase to provide a molecular description of mammalian chromosome end protection and end replication.
14Telomere Biology and Human Phenotype.PubMed
Kara J Turner, Vimal Vasu, Darren K Griffin
Cells. 2019 Jan 19;8(1):73. doi: 10.3390/cells8010073.
Telomeres are nucleoprotein structures that cap the end of each chromosome arm and function to maintain genome stability. The length of telomeres is known to shorten with each cell division and it is well-established that telomere attrition is related to replicative capacity in vitro. Moreover, telomere loss is also correlated with the process of aging in vivo. In this review, we discuss the mechanisms that lead to telomere shortening and summarise telomere homeostasis in humans throughout a lifetime. In addition, we discuss the available evidence that shows that telomere shortening is related to human aging and the onset of age-related disease.
15Telomere-driven diseases and telomere-targeting therapies.PubMed
Paula Martínez, Maria A Blasco
J Cell Biol. 2017 Apr 3;216(4):875-887. doi: 10.1083/jcb.201610111. Epub 2017 Mar 2.
Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Telomere shortening is proposed to be a primary molecular cause of aging. Short telomeres block the proliferative capacity of stem cells, affecting their potential to regenerate tissues, and trigger the development of age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as telomere syndromes, including Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, and liver fibrosis. Telomere shortening induces chromosomal instability that, in the absence of functional tumor suppressor genes, can contribute to tumorigenesis. In addition, mutations in telomere length maintenance genes and in shelterin components, the protein complex that protects telomeres, have been found to be associated with different types of cancer. These observations have encouraged the development of therapeutic strategies to treat and prevent telomere-associated diseases, namely aging-related diseases, including cancer. Here we review the molecular mechanisms underlying telomere-driven diseases and highlight recent advances in the preclinical development of telomere-targeted therapies using mouse models.
16Heart-Breaking Telomeres.PubMed
Paula Martínez, Maria A Blasco
Circ Res. 2018 Sep 14;123(7):787-802. doi: 10.1161/CIRCRESAHA.118.312202.
Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Accumulation of critically short telomeres is proposed to be a primary molecular cause of aging and age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as or telomeropathies. The rate of telomere shortening throughout life is determined by endogenous (genetic) and external (nongenetic) factors. Therapeutic strategies based on telomerase activation are being developed to treat and prevent telomere-associated diseases, namely aging-related diseases and telomeropathies. Here, we review the molecular mechanisms underlying telomere driven diseases with particular emphasis on cardiovascular diseases.
17Association between osteoporosis and the rate of telomere shortening.PubMed
Myung-Hoon Han, Hyuk Sung Kwon, Mina Hwang, et al.
Aging (Albany NY). 2024 Jul 25;16(14):11151-11161. doi: 10.18632/aging.206034.
A shorter leukocyte telomere length (LTL) is reported to be associated with age-related diseases, including osteoporosis. Many studies have tried identifying the association between LTL and osteoporosis, although it remains controversial. This study aimed to determine whether osteoporosis is independently associated with LTL shortening in a prospective longitudinal cohort. The KBASE study is an independent multicenter prospective cohort in South Korea, which began in 2014. We compared the LTL values for each participant at baseline and over a 2-year follow-up period. Boxplots were used to demonstrate the differences in the change in LTL over a 2-year follow-up according to osteoporosis. Multivariable linear regression was conducted to identify whether osteoporosis is independently associated with the rate of telomere shortening. A total of 233 subjects (from 55 to 88 years) from the KBASE cohort were finally enrolled in the study. We observed that the LTL decreased by approximately 1.2 kbp over 2 years. While the LTL decreased as age increased, the rate of LTL shortening did not increase with age. Multivariable linear regression analysis indicated that only osteoporosis was independently associated with rapid LTL shortening over 2 years (B, -8.08; p = 0.038). We sought to identify an association between osteoporosis and LTL shortening in an independent prospective cohort. We found that participants with osteoporosis had significantly faster LTL shortening over 2 years than those without osteoporosis. We hope this study will help elucidate the underlying mechanisms in the relationship between LTL and osteoporosis in the future.
18Telomere length and epigenetic clocks as markers of cellular aging: a comparative study.PubMed
Emily E Pearce, Rotana Alsaggaf, Shilpa Katta, et al.
Geroscience. 2022 Jun;44(3):1861-1869. doi: 10.1007/s11357-022-00586-4. Epub 2022 May 18.
Telomere length (TL) and DNA methylation-based epigenetic clocks are markers of biological age, but the relationship between the two is not fully understood. Here, we used multivariable regression models to evaluate the relationships between leukocyte TL (LTL; measured by qPCR [n = 635] or flow FISH [n = 144]) and five epigenetic clocks (Hannum, DNAmAge pan-tissue, PhenoAge, SkinBlood, or GrimAge clocks), or their epigenetic age acceleration measures in healthy adults (age 19-61 years). LTL showed statistically significant negative correlations with all clocks (qPCR: r = - 0.26 to - 0.32; flow FISH: r = - 0.34 to - 0.49; p < 0.001 for all). Yet, models adjusted for age, sex, and race revealed significant associations between three of five clocks (PhenoAge, GrimAge, and Hannum clocks) and LTL by flow FISH (p < 0.01 for all) or qPCR (p < 0.001 for all). Significant associations between age acceleration measures for the same three clocks and qPCR or flow FISH TL were also found (p < 0.01 for all). Additionally, LTL (by qPCR or flow FISH) showed significant associations with extrinsic epigenetic age acceleration (EEAA: p < 0.0001 for both), but not intrinsic epigenetic age acceleration (IEAA; p > 0.05 for both). In conclusion, the relationships between LTL and epigenetic clocks were limited to clocks reflecting phenotypic age. The observed association between LTL and EEAA reflects the ability of both measures to detect immunosenescence. The observed modest correlations between LTL and epigenetic clocks highlight a possible benefit from incorporating both measures in understanding disease etiology and prognosis.
19Telomere function and regulation from mouse models to human ageing and disease.PubMed
Corey Jones-Weinert, Laura Mainz, Jan Karlseder
Nat Rev Mol Cell Biol. 2025 Apr;26(4):297-313. doi: 10.1038/s41580-024-00800-5. Epub 2024 Nov 29.
Telomeres protect the ends of chromosomes but shorten following cell division in the absence of telomerase activity. When telomeres become critically short or damaged, a DNA damage response is activated. Telomeres then become dysfunctional and trigger cellular senescence or death. Telomere shortening occurs with ageing and may contribute to associated maladies such as infertility, neurodegeneration, cancer, lung dysfunction and haematopoiesis disorders. Telomere dysfunction (sometimes without shortening) is associated with various diseases, known as telomere biology disorders (also known as telomeropathies). Telomere biology disorders include dyskeratosis congenita, Høyeraal-Hreidarsson syndrome, Coats plus syndrome and Revesz syndrome. Although mouse models have been invaluable in advancing telomere research, full recapitulation of human telomere-related diseases in mice has been challenging, owing to key differences between the species. In this Review, we discuss telomere protection, maintenance and damage. We highlight the differences between human and mouse telomere biology that may contribute to discrepancies between human diseases and mouse models. Finally, we discuss recent efforts to generate new 'humanized' mouse models to better model human telomere biology. A better understanding of the limitations of mouse telomere models will pave the road for more human-like models and further our understanding of telomere biology disorders, which will contribute towards the development of new therapies.
20Telomere Length, Epigenetic Age Acceleration, and Mortality Risk in US Adult Populations: An Additive Bayesian Network Analysis.PubMed
May A Beydoun, Nicole Noren Hooten, Nigus G Asefa, et al.
Aging Cell. 2025 Sep;24(9):e70159. doi: 10.1111/acel.70159. Epub 2025 Jul 6.
Telomere length and DNA methylation (DNAm) clocks serve as markers of biological aging and have been linked to mortality risk. This study applies additive Bayesian networks (ABNs) to examine associations between DNAm clocks, telomere length, and mortality, with a focus on racial and sex differences in aging. Data from three US cohorts-NHANES (n = 2522), HRS (n = 1029), and HANDLS (n = 92-470)-were analyzed using correlation matrices, Cox models, ABNs, and generalized structural equation models (GSEM) with mortality from the National Death Index. Epigenetic clocks, particularly GrimAgeEAA, HannumAgeEAA, and DunedinPoAM (or DunedinPACE), were stronger mortality predictors than telomere length. ABNs highlighted key relationships, consistently linking age and GrimAgeEAA to mortality in NHANES and HRS. GSEM models derived from ABNs indicated an inverse association between female sex and GrimAgeEAA in NHANES (β = -0.500) and HRS (β = -0.563), suggesting slower biological aging in women, although GrimAge clock incorporates sex in its definition. GrimAgeEAA strongly predicted mortality (LnHR, β ± SE of +0.476 ± 0.0393 in NHANES and +0.511 ± 0.0775 in HRS). Non-Hispanic Black adults exhibited accelerated aging via DunedinPoAM, partially mediating their higher mortality risk. Hispanic adults in NHANES had unique associations with PhenoAgeEAA (β = +0.197), a mortality predictor. DNAm clocks, particularly GrimAgeEAA, outperform telomere length in predicting mortality. Second-generation epigenetic aging markers offer insights into demographic disparities in aging and mortality, with ABNs revealing complex interrelations among aging biomarkers, sex, race, and mortality risk.
21Vitamin D and marine ω-3 fatty acids supplementation and leukocyte telomere length: 4-year findings from the VITamin D and OmegA-3 TriaL (VITAL) randomized controlled trial.PubMed
Haidong Zhu, JoAnn E Manson, Nancy R Cook, et al.
Am J Clin Nutr. 2025 Jul;122(1):39-47. doi: 10.1016/j.ajcnut.2025.05.003. Epub 2025 May 21.
BACKGROUND: Limited studies suggest that vitamin D or omega 3 fatty acids (n-3 FAs) supplementation may be beneficial for telomere maintenance, however, evidence from large randomized clinical trial is lacking. OBJECTIVE: We aimed to determine whether vitamin D or n-3 FAs supplementation reduce leukocyte telomere length (LTL) attrition over time by leveraging the VITamin D and OmegA-3 TriaL (VITAL) trial. METHODS: VITAL is a large, randomized, double-blind, placebo-controlled tr ial with a 2 x 2 factorial design of vitamin D3 (2,000 IU/day) and marine n-3 FAs (1 g/day) supplements for 5 years among a representative sample of 25,871 US females ≥55 and males ≥50 years of age. The VITAL Telomere study (NCT04386577) included 1054 participants who were evaluated in person at the Harvard Clinical and Translational Science Center. LTL was determined by the Absolute Human Telomere Length Quantification quantitative Polymerase Chain Reaction (PCR) method at baseline, Year 2, and Year 4. The pre-specified primary outcome measures were changes in LTL between baseline, Year 2 and Year 4. Analyses of intervention effect used mixed-effects linear regression models. RESULTS: LTL was measured in a total of 2,571 samples from the 1031 participants at baseline, year 2, and year 4. Compared to placebo, vitamin D3 supplementation significantly decreased LTL attrition by 0.14 kilo base pairs (kb) (95%CI: 0.007, 0.27) over 4 years (p = 0.039). Overall trend analysis showed that the vitamin D3 supplementation group had LTLs that were about 0.035 kb higher per year of follow-up compared to placebo group (95%CI: 0.002, 0.07, p=0.037). Marine n-3 FAs supplementation had no significant effect on LTL at either year 2 or year 4. CONCLUSION: 4-years of supplementation with 2000 IU/day vitamin D reduced telomere attrition by 140 bp, suggesting that vitamin D daily supplementation with or without n-3 FAs might have a role in counteracting telomere erosion or cell senescence.
22Psychosocial stress and epigenetic aging.PubMed
Helena Palma-Gudiel, Lourdes Fañanás, Steve Horvath, et al.
Int Rev Neurobiol. 2020;150:107-128. doi: 10.1016/bs.irn.2019.10.020. Epub 2019 Nov 20.
Aging is the single most important risk factor for diseases that are currently the leading causes of morbidity and mortality. However, there is considerable inter-individual variability in risk for aging-related disease, and studies suggest that biological age can be influenced by multiple factors, including exposure to psychosocial stress. Among markers of biological age that can be affected by stress, the present article focuses on the so-called measures of epigenetic aging: DNA methylation-based age predictors that are measured in a range of tissues, including the brain, and can predict lifespan and healthspan. We review evidence linking exposure to diverse types of psychosocial stress, including early-life stress, cumulative stressful experiences, and low socioeconomic status, with accelerated epigenetic aging as a putative mediator of the effects of psychosocial environment on health and disease. The chapter also discusses methodological differences that may contribute to discordant findings across studies to date and plausible mechanisms that may underlie the effects of stress on the aging epigenome. Future studies examining the effects of adversity on epigenetic and other indicators of biological weathering may provide important insights into the pathogenesis of aging-related disease states.
23Psychosocial Stressors and Telomere Length: A Current Review of the Science.PubMed
Kelly E Rentscher, Judith E Carroll, Colter Mitchell
Annu Rev Public Health. 2020 Apr 2;41:223-245. doi: 10.1146/annurev-publhealth-040119-094239. Epub 2020 Jan 3.
A growing literature suggests that exposure to adverse social conditions may accelerate biological aging, offering one mechanism through which adversity may increase risk for age-related disease. As one of the most extensively studied biological markers of aging, telomere length (TL) provides a valuable tool to understand potential influences of social adversity on the aging process. Indeed, a sizeable literature now links a wide range of stressors to TL across the life span. The aim of this article is to review and evaluate this extant literature with a focus on studies that investigate psychosocial stress exposures and experiences in early life and adulthood. We conclude by outlining potential biological and behavioral mechanisms through which psychosocial stress may influence TL, and we discuss directions for future research in this area.
24Adding fuel to the fire: the impact of stress on the ageing brain.PubMed
Jack A Prenderville, Paul J Kennedy, Timothy G Dinan, et al.
Trends Neurosci. 2015 Jan;38(1):13-25. doi: 10.1016/j.tins.2014.11.001.
Both ageing and chronic stress are associated with altered brain plasticity, dysregulation of the immune system, and an increased risk of developing brain disorders; all of which have consequences for cognitive and emotional processing. Here we examine the similarities between behavioural changes during ageing and stress altered behaviours (anxiety, depressive-like behaviour, cognition, and sociability) in rodents and humans. The molecular mechanisms hypothesised to mediate age-related changes in brain function including dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, dysregulation of neurotransmission and neurotrophic factor signalling, increased inflammatory state, genetic and epigenetic changes, oxidative stress, metabolic changes, and changes in the microbiota–gut–brain axis are discussed. Finally, we explore how the already stressed aged brain psychologically and physiologically responds to external stressors.
25Stress and immunosenescence: The role of telomerase.PubMed
Karin de Punder, Christine Heim, Pathik D Wadhwa, et al.
Psychoneuroendocrinology. 2019 Mar;101:87-100. doi: 10.1016/j.psyneuen.2018.10.019. Epub 2018 Oct 23.
Chronic stress is associated with the accelerated aging of the immune system and represents a potent risk factor for the development and progression of a wide range of physical and mental disorders. The elucidation of molecular pathways and mechanisms underlying the link between stress and cellular aging is an area of considerable interest and investigation. In this context, telomere biology has emerged as a particularly attractive candidate mechanism. Several studies have linked immune cell telomere length with stress-related conditions and states, and also with several physical and mental disorders. Because the cellular reverse transcriptase enzyme telomerase is the primary regulator of telomere length (by adding telomeric DNA to telomeres and thereby attenuating telomere shortening), the understanding of its regulation and regulatory functions constitutes a prime target for developing strategies to prevent, attenuate or reverse the adverse consequences of immune system aging (immunosenescence). In this review we provide an overview of the mechanistic pathways linking telomerase with stress and cellular aging, with an emphasis on the immune system. We summarize and synthesize the current state of the literature on immune cell telomerase in different stress- and aging-related disease states and provide recommendations for future research directions.
26Telomeres and endocrine dysfunction of the adrenal and GH/IGF-1 axes.PubMed
Anna Aulinas, María José Ramírez, María José Barahona, et al.
Clin Endocrinol (Oxf). 2013 Dec;79(6):751-9. doi: 10.1111/cen.12310. Epub 2013 Sep 4.
Telomeres, located at the end of linear chromosomes, are essential to maintain genomic stability. Telomere biology has recently emerged as an important player in the fields of ageing and disease. To maintain telomere length (TL) and reduce its degradation after mitosis, the telomerase enzyme complex is produced. Genetic, epigenetic, hormonal and environmental factors can regulate telomerase function. These include stress hormones such as cortisol and growth factors. The hypothalamic-pituitary-adrenal (HPA) axis has been evaluated in psychiatric diseases where hypercortisolism and oxidative stress are often present. Some researches have linked TL shortening to increases in stress-related cortisol, but others have not. The effects of cortisol on the telomere system are complex and may depend on the intensity and duration of exposure. On the other hand, low levels of IGF-1 are associated with inflammation and ageing-related diseases (ischaemic heart disease, congestive heart failure). Both IGF-1 and TL diminish with age and are positively and strongly correlated with each other. It is not clear whether this positive correlation reflects a single association or a cause-effect relationship. Further research will ideally investigate longitudinal changes in telomeres and both these hormonal axes. To our knowledge, TL dysfunction has not been described in either endogenous hypercortisolism (Cushing's syndrome) or acromegaly where excessive amounts of GH and consequently IGF-1 are produced. This review focuses on the possible relationships between telomere dysfunction and the hypothalamic-pituitary-adrenal (HPA) axis and GH-IGF-1 system.
27Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging.PubMed
Natalia Bobba-Alves, Gabriel Sturm, Jue Lin, et al.
Psychoneuroendocrinology. 2023 Sep;155:106322. doi: 10.1016/j.psyneuen.2023.106322. Epub 2023 Jun 14.
Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by ∼60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.
28Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging.PubMed
Naomi M Simon, Jordan W Smoller, Kate L McNamara, et al.
Biol Psychiatry. 2006 Sep 1;60(5):432-5. doi: 10.1016/j.biopsych.2006.02.004. Epub 2006 Apr 11.
BACKGROUND: Little is known about the biological mechanisms underlying the excess medical morbidity and mortality associated with mood disorders. Substantial evidence supports abnormalities in stress-related biological systems in depression. Accelerated telomere shortening may reflect stress-related oxidative damage to cells and accelerated aging, and severe psychosocial stress has been linked to telomere shortening. We propose that chronic stress associated with mood disorders may contribute to excess vulnerability for diseases of aging such as cardiovascular disease and possibly some cancers through accelerated organismal aging. METHODS: Telomere length was measured by Southern Analysis in 44 individuals with chronic mood disorders and 44 nonpsychiatrically ill age-matched control subjects. RESULTS: Telomere length was significantly shorter in those with mood disorders, representing as much as 10 years of accelerated aging. CONCLUSIONS: These results provide preliminary evidence that mood disorders are associated with accelerated aging and may suggest a novel mechanism for mood disorder-associated morbidity and mortality.
29Inflammaging: a new immune-metabolic viewpoint for age-related diseases.PubMed
Claudio Franceschi, Paolo Garagnani, Paolo Parini, et al.
Nat Rev Endocrinol. 2018 Oct;14(10):576-590. doi: 10.1038/s41574-018-0059-4.
Ageing and age-related diseases share some basic mechanistic pillars that largely converge on inflammation. During ageing, chronic, sterile, low-grade inflammation - called inflammaging - develops, which contributes to the pathogenesis of age-related diseases. From an evolutionary perspective, a variety of stimuli sustain inflammaging, including pathogens (non-self), endogenous cell debris and misplaced molecules (self) and nutrients and gut microbiota (quasi-self). A limited number of receptors, whose degeneracy allows them to recognize many signals and to activate the innate immune responses, sense these stimuli. In this situation, metaflammation (the metabolic inflammation accompanying metabolic diseases) is thought to be the form of chronic inflammation that is driven by nutrient excess or overnutrition; metaflammation is characterized by the same mechanisms underpinning inflammaging. The gut microbiota has a central role in both metaflammation and inflammaging owing to its ability to release inflammatory products, contribute to circadian rhythms and crosstalk with other organs and systems. We argue that chronic diseases are not only the result of ageing and inflammaging; these diseases also accelerate the ageing process and can be considered a manifestation of accelerated ageing. Finally, we propose the use of new biomarkers (DNA methylation, glycomics, metabolomics and lipidomics) that are capable of assessing biological versus chronological age in metabolic diseases.
30The interplay between immunosenescence and age-related diseases.PubMed
Florencia Barbé-Tuana, Giselle Funchal, Carine Raquel Richter Schmitz, et al.
Semin Immunopathol. 2020 Oct;42(5):545-557. doi: 10.1007/s00281-020-00806-z. Epub 2020 Aug 3.
The aging immune system (immunosenescence) has been implicated with increased morbidity and mortality in the elderly. Of note, T cell aging and low-grade inflammation (inflammaging) are implicated with several age-related conditions. The expansion of late-differentiated T cells (CD28), regulatory T cells, increased serum levels of autoantibodies, and pro-inflammatory cytokines were implicated with morbidities during aging. Features of accelerated immunosenescence can be identified in adults with chronic inflammatory conditions, such as rheumatoid arthritis, and are predictive of poor clinical outcomes. Therefore, there is an interplay between immunosenescence and age-related diseases. In this review, we discuss how the aging immune system may contribute to the development and clinical course of age-related diseases such as neurodegenerative diseases, rheumatoid arthritis, cancer, cardiovascular, and metabolic diseases.
31Telomere shortening by transgenerational transmission of TNF-α-induced TERRA via ATF7.PubMed
Binbin Liu, Toshio Maekawa, Keisuke Yoshida, et al.
Nucleic Acids Res. 2019 Jan 10;47(1):283-298. doi: 10.1093/nar/gky1149.
Various stresses increase disease susceptibility and accelerate aging, and increasing evidence suggests that these effects can be transmitted over generation. Epidemiological studies suggest that stressors experienced by parents affect the longevity of their offspring, possibly by regulating telomere dynamics. Telomeres are elongated by telomerase and shortened by certain stresses as well as telomere repeat-containing RNA (TERRA), a telomere transcript. However, the mechanism underlying the transgenerational effects is poorly understood. Here, we show that TNF-α, which is induced by various psychological stresses, induces the p38-dependent phosphorylation of ATF7, a stress-responsive chromatin regulator, in mouse testicular germ cells. This caused a release of ATF7 from the TERRA gene promoter in the subtelomeric region, which disrupted heterochromatin and induced TERRA. TERRA was transgenerationally transmitted to zygotes via sperm and caused telomere shortening. These results suggest that ATF7 and TERRA play key roles in paternal stress-induced telomere shortening in the offspring.
32Perinatal stress and epigenetics.PubMed
Moshe Szyf
Handb Clin Neurol. 2021;180:125-148. doi: 10.1016/B978-0-12-820107-7.00008-2.
Animal and humans exposed to stress early in life are more likely to suffer from long-term behavioral, mental health, metabolic, immune, and cardiovascular health consequences. The hypothalamus plays a nodal role in programming, controlling, and regulating stress responses throughout the life course. Epigenetic reprogramming in the hippocampus and the hypothalamus play an important role in adapting genome function to experiences and exposures during the perinatal and early life periods and setting up stable phenotypic outcomes. Epigenetic programming during development enables one genome to express multiple cell type identities. The most proximal epigenetic mark to DNA is a covalent modification of the DNA itself by enzymatic addition of methyl moieties. Cell-type-specific DNA methylation profiles are generated during gestational development and define cell and tissue specific phenotypes. Programming of neuronal phenotypes and sex differences in the hypothalamus is achieved by developmentally timed rearrangement of DNA methylation profiles. Similarly, other stations in the life trajectory such as puberty and aging involve predictable and scheduled reorganization of DNA methylation profiles. DNA methylation and other epigenetic marks are critical for maintaining cell-type identity in the brain, across the body, and throughout life. Data that have emerged in the last 15 years suggest that like its role in defining cell-specific phenotype during development, DNA methylation might be involved in defining experiential identities, programming similar genes to perform differently in response to diverse experiential histories. Early life stress impact on lifelong phenotypes is proposed to be mediated by DNA methylation and other epigenetic marks. Epigenetic marks, as opposed to genetic mutations, are reversible by either pharmacological or behavioral strategies and therefore offer the potential for reversing or preventing disease including behavioral and mental health disorders. This chapter discusses data testing the hypothesis that DNA methylation modulations of the HPA axis mediate the impact of early life stress on lifelong behavioral and physical phenotypes.
33Subclinical atherosclerosis and accelerated epigenetic age mediated by inflammation: a multi-omics study.PubMed
Fátima Sánchez-Cabo, Valentín Fuster, Juan Carlos Silla-Castro, et al.
Eur Heart J. 2023 Aug 1;44(29):2698-2709. doi: 10.1093/eurheartj/ehad361.
AIMS: Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association. METHODS AND RESULTS: Whole blood methylomics, transcriptomics, and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. In healthy individuals, the presence, extension, and progression of subclinical atherosclerosis were associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional cardiovascular risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased systemic inflammation and associated with a score of low-grade, chronic inflammation. Mediation analysis using transcriptomics and proteomics data revealed key pro-inflammatory pathways (IL6, Inflammasome, and IL10) and genes (IL1B, OSM, TLR5, and CD14) mediating the association between subclinical atherosclerosis and epigenetic age acceleration. CONCLUSION: The presence, extension, and progression of subclinical atherosclerosis in middle-aged asymptomatic individuals are associated with an acceleration in the Grim epigenetic age. Mediation analysis using transcriptomics and proteomics data suggests a key role of systemic inflammation in this association, reinforcing the relevance of interventions on inflammation to prevent cardiovascular disease.
34Sex-Specific Association Between Childhood Adversity and Accelerated Biological Aging.PubMed
Jie Yu, Fan Pu, Gan Yang, et al.
Adv Sci (Weinh). 2024 Jul;11(26):e2309346. doi: 10.1002/advs.202309346. Epub 2024 May 5.
Is childhood adversity associated with biological aging, and if so, does sex modify the association, and do lifestyle and mental health mediate the association? A lifespan analysis is conducted using data on 142 872 participants from the UK Biobank to address these questions. Childhood adversity is assessed through the online mental health questionnaire (2016), including physical neglect, physical abuse, emotional neglect, emotional abuse, sexual abuse, and a cumulative score. Biological aging is indicated by telomere length (TL) measured from leukocyte DNA using qPCR, and the shorter TL indicates accelerated biological aging; a lifestyle score is constructed using body mass index, physical activity, drinking, smoking, and diet; mental disorder is assessed using depression, anxiety, and insomnia at the baseline survey. The results reveal a sex-specific association such that childhood adversity is associated with shorter TL in women after adjusting for covariates including polygenic risk score for TL, but not in men. Unhealthy lifestyle and mental disorder partially mediate the association in women. The proportions of indirect effects are largest for sexual and physical abuse. These findings highlight the importance of behavioral and psychological interventions in promoting healthy aging among women who experienced childhood adversity, particularly sexual and physical abuse.
35Peripartum depression symptom trajectories, telomere length and genotype, and adverse childhood experiences.PubMed
Maria Vrettou, Susanne Lager, Simone Toffoletto, et al.
BMC Psychiatry. 2024 Oct 8;24(1):661. doi: 10.1186/s12888-024-06115-1.
BACKGROUND: As a biological marker for cellular senescence, telomere length (TL) has been linked to a variety of psychiatric disorders and adverse childhood experiences (ACE), though only preliminarily to peripartum depression (PPD). The present study sought to examine the association between TL and PPD, assessing the moderating role of ACE and genetic polymorphic variations related with the telomere machinery. METHODS: Adversity was self-reported, likewise were depressive symptoms evaluated at pregnancy week 17 and 32, as well as six-weeks and six-months postpartum. TL was assessed by use of qPCR in blood samples collected during delivery from females with antenatal depression resolving postpartum, females with depression persisting to postpartum, and healthy controls. Twenty haplotype-tagging Single Nucleotide Polymorphisms in the Telomerase Reverse Transcriptase (TERT) and three in the Telomerase RNA Component (TERC) genes were genotyped. RESULTS: TL was negatively correlated with severity of PPD symptoms at pregnancy week 32 and postpartum week 6. PPD was associated with shorter TL. Lastly, ACE, but not the TERT/TERC genotype, moderated the TL-trajectory association; with increasing ACE, individuals with persistent PPD symptoms had shorter TL, whereas the opposite pattern (longer TL) was observed in the controls. CONCLUSIONS: The findings contribute to further understanding of PPD underpinnings, suggesting a negative relationship with TL.
36Adverse Childhood Experiences: Implications for Offspring Telomere Length and Psychopathology.PubMed
Kyle C Esteves, Christopher W Jones, Mark Wade, et al.
Am J Psychiatry. 2020 Jan 1;177(1):47-57. doi: 10.1176/appi.ajp.2019.18030335. Epub 2019 Sep 6.
OBJECTIVE: Adverse childhood experiences (ACEs) are associated with mental and physical health risks that, through biological and psychosocial pathways, likely span generations. Within an individual, telomere length (TL), an established marker of cellular stress and aging, is associated with both ACE exposure and psychopathology, providing the basis for an emerging literature suggesting that TL is a biomarker of the health risks linked to early-life adversity both within and across generations. The authors tested the effect of maternal ACEs on both the trajectory of infant TL and infant social-emotional problems at 18 months of age. METHODS: Pregnant women were recruited, and maternal scores on the Adverse Childhood Experience questionnaire were obtained, along with demographic and prenatal stress measures. Postnatal visits with 155 mother-infant dyads occurred when infants were 4, 12, and 18 months of age. At each visit, infant buccal swabs were collected for TL measurement, and mothers completed measures of maternal depression. Mothers also completed the Child Behavior Checklist at the 18-month visit. Mixed-effects modeling was used to test how maternal ACEs influenced infant TL trajectory. Linear regression was used to test the association between maternal ACEs and infant internalizing and externalizing behaviors. Finally, the interaction between telomere attrition from 4 to 18 months and maternal ACEs was examined as a predictor of infant scores on the Child Behavior Checklist. RESULTS: Higher maternal ACEs were associated with shorter infant TL across infancy and higher infant externalizing behavioral problems at 18 months. No associations were found with internalizing behavioral problems. Telomere attrition from 4 to 18 months interacted with maternal ACEs to predict externalizing behaviors. In infants whose mothers reported higher scores on the Adverse Childhood Experience questionnaire, greater telomere attrition predicted higher externalizing problems, even when accounting for maternal postnatal depression and prenatal stress. CONCLUSIONS: These data demonstrate an interactive pathway between maternal early-life adversity and infant TL that predicts emerging behavioral problems in the next generations.
37Associations between maternal adversity and health and children's telomere length.PubMed
Xiao-Yan Chen, Camilla K M Lo, Qiqi Chen, et al.
Transl Psychiatry. 2025 Mar 28;15(1):106. doi: 10.1038/s41398-025-03340-4.
Maternal adversity (e.g., adverse childhood experiences, ACEs) and health (e.g., depressive symptoms and chronic illness) negatively impact offspring's health. One possible mechanism is via premature/accelerated biological aging, as indicated in telomere length. In this 3-year longitudinal study, we examined the association between maternal adversity and health and children's buccal telomere length (bTL) at age 3. Data from 122 mother-child dyads were analyzed. Maternal history of ACEs and chronic illness were collected at baseline (during 20-24 weeks of gestation). Their depressive symptoms across three periods (during pregnancy, 4 weeks after childbirth, and 3 years after childbirth) were also collected. Children's TL were extracted from their buccal swab samples at age 3. The children's bTL was quantified using the quantitative PCR method and expressed in T/S ratio (the ratio of telomere repeats copy numbers to single-copy gene numbers). Results showed pregnant women experienced distinctive trajectories of depressive symptoms over time. Children of mothers with relapsing/remitting depressive symptoms had shorter bTL (β = -0.19, 95% CI = -0.14 to -0.005) than mothers who had low-stable symptoms. This finding remained significant even after accounting for maternal ACEs and chronic illness. Additionally, maternal ACEs, together with depressive symptoms, may affect children's bTL. This study provides relatively comprehensive evidence on the effects of maternal stressors, highlighting the relevance of maternal adversity and depressive symptom patterns as predictors of offspring telomere biology.
38Are Biological Consequences of Childhood Exposures Detectable in Telomere Length Decades Later?PubMed
Blakelee R Kemp, Kenneth F Ferraro
J Gerontol A Biol Sci Med Sci. 2021 Jan 1;76(1):7-14. doi: 10.1093/gerona/glaa019.
Negative early-life exposures have been linked to a host of poor adult health outcomes, but are such early exposures associated with cellular senescence decades later? This study uses data from the Health and Retirement Study to examine the association between six childhood exposure domains (eg, socioeconomic disadvantage, risky parental behavior) and a biomarker of aging, telomere length, among 4,935 respondents. Telomere length is obtained from DNA of cells found in saliva and is measured as the telomere repeat copy number to single gene copy number ratio (T/S). Men who as children were exposed to risky parental behaviors or who reported risky adolescent behaviors have shorter telomeres (b = -0.031, p = .052; b = -0.041, p = .045, respectively); however, these relationships are attenuated after adjusting for adult risks and resources. Among women, parental substance abuse is associated with shorter telomeres even after adjusting for adult risks and resources (b = -0.041, p = .005). In addition, men and women whose mother lived at least until the age of 85 have longer telomeres than those without a long-lived mother (b = 0.021, p = .045; b = 0.032, p = .005, respectively). Taken together, the ways in which early-life exposures are associated with adult telomeres vary for men and women.
39Stress reactivity elicits a tissue-specific reduction in telomere length in aging zebrafish (Danio rerio).PubMed
James R Evans, Jose V Torres-Pérez, Maria Elena Miletto Petrazzini, et al.
Sci Rep. 2021 Jan 11;11(1):339. doi: 10.1038/s41598-020-79615-1.
Individual differences in personality are associated with variation in healthy aging. Health behaviours are often cited as the likely explanation for this association; however, an underlying biological mechanism may also exist. Accelerated leukocyte telomere shortening is implicated in multiple age-related diseases and is associated with chronic activation of the hypothalamus-pituitary-adrenal (HPA) axis, providing a link between stress-related personality differences and adverse health outcomes. However, the effects of the HPA axis are tissue specific. Thus, leukocyte telomere length may not accurately reflect telomere length in disease-relevant tissues. Here, we examined the correlation between stress reactivity and telomere length in heart and brain tissue in young (6-9 month) and aging (18 month) zebrafish. Stress reactivity was assessed by tank diving and through gene expression. Telomere length was assessed using quantitative PCR. We show that aging zebrafish have shorter telomeres in both heart and brain. Telomere length was inversely related to stress reactivity in heart but not brain of aging individuals. These data support the hypotheses that an anxious predisposition contributes to accelerated telomere shortening in heart tissue, which may have important implications for our understanding of age-related heart disease, and that stress reactivity contributes to age-related telomere shortening in a tissue-specific manner.
40Folic Acid Supplementation Suppresses Sleep Deprivation-Induced Telomere Dysfunction and Senescence-Associated Secretory Phenotype (SASP).PubMed
Xiaoning Zhang, Yuwen Wang, Rui Zhao, et al.
Oxid Med Cell Longev. 2019 Dec 14;2019:4569614. doi: 10.1155/2019/4569614. eCollection 2019.
Sleep deprivation is reported to cause oxidative stress and is hypothesized to induce subsequent aging-related diseases including chronic inflammation, Alzheimer's disease, and cardiovascular disease. However, how sleep deprivation contributes to the pathogenesis of sleep deficiency disorder remains incompletely defined. Accordingly, more effective treatment methods for sleep deficiency disorder are needed. Thus, to better understand the detailed mechanism of sleep deficiency disorder, a sleep deprivation mouse model was established by the multiple platform method in our study. The accumulation of free radicals and senescence-associated secretory phenotype (SASP) was observed in the sleep-deprived mice. Moreover, our mouse and human population-based study both demonstrated that telomere shortening and the formation of telomere-specific DNA damage are dramatically increased in individuals suffering from sleeplessness. To our surprise, the secretion of senescence-associated cytokines and telomere damage are greatly improved by folic acid supplementation in mice. Individuals with high serum baseline folic acid levels have increased resistance to telomere shortening, which is induced by insomnia. Thus, we conclude that folic acid supplementation could be used to effectively counteract sleep deprivation-induced telomere dysfunction and the associated aging phenotype, which may potentially improve the prognosis of sleeplessness disorder patients.
41Telomere length as a marker of sleep loss and sleep disturbances: a potential link between sleep and cellular senescence.PubMed
Priscila F Tempaku, Diego R Mazzotti, Sergio Tufik
Sleep Med. 2015 May;16(5):559-63. doi: 10.1016/j.sleep.2015.02.519. Epub 2015 Feb 14.
The identification of biological markers that allow the early diagnosis, or even the prevention of age-related diseases, is an important goal that is being actively pursued in the research community. Sleep is one of the physiological processes that is most affected by aging, and there is a strong relationship between age-related sleep alterations and diseases. Changes in cellular senescence and the linked changes in telomere length might be potential markers of age-related sleep changes. In this review, we present some of the most recent evidence showing that telomere length has been associated with sleep loss and sleep disturbances in cross-sectional and case-control studies. We also present insights into the cellular senescence mechanisms relating to changes in telomere length, and we suggest that this field lacks basic and clinical research studies, especially long-term longitudinal studies, which may bring opportunities to sleep researchers to investigate this relationship in more depth.
42Sleep traits causally affect epigenetic age acceleration: a Mendelian randomization study.PubMed
Wen Zhao, Shiyao Yu, Yan Xu, et al.
Sci Rep. 2025 Mar 3;15(1):7439. doi: 10.1038/s41598-024-84957-1.
Sleep disorders (SDs) are a common issue in the elderly. Epigenetic clocks based on DNA methylation (DNAm) are now considered highly accurate predictors of the aging process and are associated with age-related diseases. This study aimed to investigate the causal relationship between sleep traits and the epigenetic clock using Mendelian randomization (MR) analysis. The genome-wide association study (GWAS) statistics for epigenetic clocks (HannumAge, intrinsic epigenetic age acceleration [IEAA], PhenoAge, and GrimAge) and sleep traits were obtained from the UK Biobank (UKB), 23andMe and Finngen. Moreover, crucial instrumental variables (IVs) were evaluated. Inverse variance weighted (IVW), MR-Egger, weighted median (WM), weighted mode, and simple mode methods were employed to assess the causal relationship between them. Multiple analyses were performed for quality control evaluation. Our study showed that self-reported insomnia may speed up the aging process by GrimAge clock, while GrimAge acceleration could faintly reduce self-reported insomnia. Epigenetic clocks mainly influence sleep traits by PhenoAge and GrimAge with weak effects. This may indicate that early interventions of SDs could be a breaking point for aging and age-related diseases. Further studies are required to elucidate the potential mechanisms involved.
43Sleep disorders and aging: Mendelian randomization analysis of epigenetic and frailty markers.PubMed
Zheng Zhang, Hao Ren, Yongjia Cheng, et al.
J Affect Disord. 2025 Dec 15;391:119989. doi: 10.1016/j.jad.2025.119989. Epub 2025 Jul 28.
BACKGROUND: Sleep disorders-including daytime sleepiness (DS), insomnia, and sleep apnea (SA)-have been linked to aging-related phenotypes, but their causal roles remain unclear. This study aimed to examine the potential causal effects of these sleep traits on biological aging using a Mendelian randomization (MR) approach. METHODS: We conducted two-sample MR analyses using genetic instruments from large-scale genome-wide association studies (GWAS) for DS, insomnia, and SA. The inverse-variance weighted (IVW) method was the primary analytical approach, with sensitivity analyses performed for validation. Aging-related outcomes included intrinsic epigenetic age acceleration (IEAA), GrimAge, HannumAge, PhenoAge, telomere length, facial aging, frailty index, and cognitive performance. False discovery rate (FDR) correction was applied for multiple testing. RESULTS: DS was significantly associated with increased frailty index (β = 0.33, 95 % CI: 0.09-0.57, PFDR = 0.045). Insomnia showed significant associations with both IEAA (β = 1.57, 95 % CI: 0.40-2.73, PFDR = 0.035) and frailty index (β = 0.42, 95 % CI: 0.23-0.61, PFDR <0.001). SA was significantly associated with facial aging (β = 0.03, 95 % CI: 0.01-0.06, PFDR = 0.016) and frailty index (β = 0.09, 95 % CI: 0.02-0.16, PFDR = 0.028). No significant associations were found for telomere length, GrimAge, PhenoAge, or cognitive performance. CONCLUSIONS: This MR study supports potential causal effects of insomnia on epigenetic aging and frailty. DS and SA were also linked to increased frailty, and SA further associated with facial aging. These findings underscore the importance of sleep health in mitigating age-related biological decline.
44Insomnia accelerates the epigenetic clocks in older adults.PubMed
Nadia Alejandra Rivero-Segura, Julian Daniel Rodriguez Cuartas, Paola Garcia-delaTorre, et al.
Geroscience. 2025 Mar 18. doi: 10.1007/s11357-025-01608-7.
Insomnia is a common sleep disorder characterized mainly by poor sleep quality and insufficient sleep duration. It affects a significant proportion of the global population and is correlated with physical and mental consequences such as cognitive decline, anxiety, chronic fatigue, poor concentration, and memory impairment. Interestingly, it is also linked to ageing and age-related diseases (cardiovascular, metabolic, and neurodegenerative). On the other hand, as we age, DNA methylation patterns undergo significant changes. These have been used to develop the so-called epigenetic clocks that estimate the biological age linked to the environment and the risk of diseases. Few studies have evaluated the association between insomnia and epigenetic clocks, providing insight into the role of insomnia in ageing acceleration. Therefore, in the present study, we carried out an epigenetic analysis by using Illumina EPICv.2 array on 63 older adults (> 60 years old, n = 33 with insomnia vs. n = 30 control) to evaluate the relation between insomnia and epigenetic ages (HorvathAGE, HannumAGE, PhenoAGE, SkinBloodClock, GrimAGE, DunedinPACE, DNAmTL). As a result, we found an increased acceleration and correlation between GrimAGE and SkinBloodClock and a significant reduction in the DNAmTL in individuals with insomnia. An EWAS analysis showed a global pattern of hypomethylation and an enrichment of several proteostasis and oxidative pathways. In conclusion, our results suggest that insomnia increases GrimAGE and SkinBloodClock acceleration and may be participating in telomere shortening. Additionally, changes in DNA methylation patterns induced by insomnia impact proteostasis and oxidative stress.
45Sleep disturbances, shift work, and epigenetic ageing in working-age adults: findings from the Young Finns study.PubMed
Ida Autio, Aino Saarinen, Saara Marttila, et al.
Clin Epigenetics. 2025 Apr 2;17(1):55. doi: 10.1186/s13148-025-01860-w.
BACKGROUND: Sleep disturbances are known to have adverse effects on health, but knowledge on the effect of sleep disturbances on epigenetic ageing is limited. We investigated (1) whether symptoms of insomnia, obstructive sleep apnoea, sleep deprivation, and circadian rhythm lateness are associated with epigenetic ageing, and (2) whether years spent in shift work moderates these associations. METHODS: We used the population-based Young Finns data (n = 1618). Epigenetic clocks such as AgeDev, AgeDev, AgeDev, AgeDev, and DunedinPACE were utilized to measure epigenetic ageing. Sleep was evaluated using various validated self-report questionnaires. Covariates included sex, array type, smoking status, health behaviours, socioeconomic factors, and cardiovascular health factors. RESULTS: Among the various sleep measures, obstructive sleep apnoea symptoms were most consistently linked to accelerated epigenetic ageing, as measured by AgeDev and DunedinPACE. Insomnia, sleep deprivation, and years spent in shift work were not associated with epigenetic ageing after adjusting for health-related or socioeconomic covariates. Additionally, we found interactions between years spent in shift work and sleep disturbances when accounting for epigenetic ageing. Among those with little to no history of shift work, both insomnia and sleep deprivation were associated with more accelerated epigenetic ageing in AgeDev when compared to long-term shift workers. However, the pace of epigenetic ageing (measured with DunedinPACE) appears to be higher in those with both sleep deprivation and longer history of shift work. CONCLUSIONS: Among various sleep measures, symptoms of obstructive sleep apnoea appear to be most consistently associated with accelerated epigenetic ageing even after adjusting for various health-related and socioeconomic factors. Shift work seems to have a crucial role in the relationship between sleep disturbances and epigenetic ageing in working-age adults.
46The association between leukocyte telomere lengths and sleep instability based on cardiopulmonary coupling analysis.PubMed
Amy M Kwon, Inkyung Baik, Robert J Thomas, et al.
Sleep Breath. 2015 Sep;19(3):963-8. doi: 10.1007/s11325-014-1110-x. Epub 2015 Jan 28.
PURPOSE: The purpose of the study is to examine the objective association between sleep stability and leukocyte telomere lengths (LTL) using cardiopulmonary coupling (CPC) analysis, which is an electrocardiogram (ECG)-based technique to quantify physiologic sleep stability. METHODS: Three hundred eighty-one healthy subjects were recruited from a community-based cohort study from the Korean Genome and Epidemiology Study (KoGES), and the associations between LTL and total quantities of different frequency coupling bands were examined using generalized linear model (GLM) with adjustment of significant covariates. RESULTS: LTL showed a significant association with elevated narrow-band low frequency coupling (e-LFCNB, a CPC marker of periodic breathing or sleep fragmentation due to pathological respiratory chemoreflex activation) by interacting with obstructive sleep apnea (OSA) severity (p value of <0.0001). Especially, sleep stability significantly reduced with shortened LTL in OSA patients (Apnea-Hypopnea Index (AHI) ≥15) based on increased e-LFCNB which had a negative correlation with high-frequency coupling band (HFC), a marker of stable sleep. CONCLUSION: The present study suggested that shorter LTL might contribute to reduced sleep stability by interacting with OSA severity due to the stress of chronic sleep fragmentation or invariant sympathetic activity by respiratory chemoreflex activation.
47A distinctive DNA methylation pattern in insufficient sleep.PubMed
Alexandra Lahtinen, Sampsa Puttonen, Päivi Vanttola, et al.
Sci Rep. 2019 Feb 4;9(1):1193. doi: 10.1038/s41598-018-38009-0.
Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia. We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 ± 7.3), and in relation to shift work disorder in an occupational cohort (26 men, aged 44.9 ± 9.0). The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: "Nervous System Development" (FDR P value < 0.05). We found that 78% of the DMPs were hypomethylated in cases in both cohorts, suggesting that insufficient sleep may be associated with loss of DNA methylation. A karyoplot revealed clusters of DMPs at various chromosomal regions, including 12 DMPs on chromosome 17, previously associated with Smith-Magenis syndrome, a rare condition comprising disturbed sleep and inverse circadian rhythm. Our findings give novel insights into the DNA methylation patterns associated with sleep loss, possibly modifying processes related to neuroplasticity and neurodegeneration. Future prospective studies are needed to confirm the observed associations.
48Obstructive Sleep Apnea as an Acceleration Trigger of Cellular Senescence Processes through Telomere Shortening.PubMed
Szymon Turkiewicz, Marta Ditmer, Marcin Sochal, et al.
Int J Mol Sci. 2021 Nov 21;22(22):12536. doi: 10.3390/ijms222212536.
Obstructive sleep apnea (OSA) is chronic disorder which is characterized by recurrent pauses of breathing during sleep which leads to hypoxia and its two main pathological sequelae: oxidative stress and chronic inflammation. Both are also associated with cellular senescence. As OSA patients present with higher prevalence of age-related disorders, such as atrial hypertension or diabetes mellitus type 2, a relationship between OSA and accelerated aging is observable. Furthermore, it has been established that these OSA are associated with telomere shortening. This process in OSA is likely caused by increased oxidative DNA damage due to increased reactive oxygen species levels, DNA repair disruptions, hypoxia, chronic inflammation, and circadian clock disturbances. The aim of the review is to summarize study outcomes on changes in leukocyte telomere length (LTL) in OSA patients and describe possible molecular mechanisms which connect cellular senescence and the pathophysiology of OSA. The majority of OSA patients are characterized by LTL attrition due to oxidative stress, hypoxia and inflammation, which make a kind of positive feedback loop, and circadian clock disturbance.
49Epigenetic/circadian clocks and PCOS.PubMed
Camille Vatier, Sophie Christin-Maitre
Hum Reprod. 2024 Jun 3;39(6):1167-1175. doi: 10.1093/humrep/deae066.
Polycystic ovary syndrome (PCOS) affects 6-20% of reproductive-aged women. It is associated with increased risks of metabolic syndrome, Type 2 diabetes, cardiovascular diseases, mood disorders, endometrial cancer and non-alcoholic fatty liver disease. Although various susceptibility loci have been identified through genetic studies, they account for ∼10% of PCOS heritability. Therefore, the etiology of PCOS remains unclear. This review explores the role of epigenetic changes and modifications in circadian clock genes as potential contributors to PCOS pathogenesis. Epigenetic alterations, such as DNA methylation, histone modifications, and non-coding RNA changes, have been described in diseases related to PCOS, such as diabetes, cardiovascular diseases, and obesity. Furthermore, several animal models have illustrated a link between prenatal exposure to androgens or anti-Müllerian hormone and PCOS-like phenotypes in subsequent generations, illustrating an epigenetic programming in PCOS. In humans, epigenetic changes have been reported in peripheral blood mononuclear cells (PBMC), adipose tissue, granulosa cells (GC), and liver from women with PCOS. The genome of women with PCOS is globally hypomethylated compared to healthy controls. However, specific hypomethylated or hypermethylated genes have been reported in the different tissues of these women. They are mainly involved in hormonal regulation and inflammatory pathways, as well as lipid and glucose metabolism. Additionally, sleep disorders are present in women with PCOS and disruptions in clock genes' expression patterns have been observed in their PBMC or GCs. While epigenetic changes hold promise as diagnostic biomarkers, the current challenge lies in distinguishing whether these changes are causes or consequences of PCOS. Targeting epigenetic modifications potentially opens avenues for precision medicine in PCOS, including lifestyle interventions and drug therapies. However, data are still lacking in large cohorts of well-characterized PCOS phenotypes. In conclusion, understanding the interplay between genetics, epigenetics, and circadian rhythms may provide valuable insights for early diagnosis and therapeutic strategies in PCOS in the future.
50Impact of circadian disruption on health; SIRT1 and Telomeres.PubMed
Meyrem Osum, Nedime Serakinci
DNA Repair (Amst). 2020 Dec;96:102993. doi: 10.1016/j.dnarep.2020.102993. Epub 2020 Sep 30.
Circadian clock is a biochemical oscillator in organisms that regulates the circadian rhythm of numerous genes over 24 h. The circadian clock is involved in telomere homeostasis by regulating the diurnal rhythms of telomerase activity, TERT mRNA level, TERRA expression, and telomeric heterochromatin formation. Particularly, CLOCK and BMAL1 deficiency contribute to telomere shortening by preventing rhythmic telomerase activity and TERRA expression, respectively. Telomere shortening increases the number of senescent cells with impaired circadian rhythms. In return, telomerase reconstitution improves impaired circadian rhythms of senescent cells. SIRT1 that is an NAD+-dependent deacetylase positively regulates circadian clock and telomere homeostasis. SIRT1 contributes to the circadian clock by mediating CLOCK/BMAL1 complex formation, BMAL1 transcription and PER2 disruption. On the other hand, SIRT1 ensures telomere homeostasis by inducing telomerase and shelterin protein expression and regulating telomere heterochromatin formation. SIRT1 inhibition leads to both circadian clock and telomeres dysfunction that inhibit its activity. In light of this current evidence, we could suggest that the BMAL1/CLOCK complex regulates the telomere homeostasis in SIRT1 dependent manner, and also telomere dysfunction inhibits circadian clock function by suppressing SIRT1 activity to induce age-related diseases. We consider that increasing SIRT1 activity can prevent age-related diseases and help healthy aging by protecting telomere integrity and circadian clock function for individuals subjected to circadian rhythm disruption such as shift works, individuals with sleep disorders, and in the elderly population.
51Sleep Duration, Health Promotion Index, sRAGE, and ApoE-ε4 Genotype Are Associated With Telomere Length in Healthy Australians.PubMed
Varinderpal S Dhillon, Permal Deo, Ann Chua, et al.
J Gerontol A Biol Sci Med Sci. 2022 Feb 3;77(2):243-249. doi: 10.1093/gerona/glab264.
Significant alterations in sleep duration and/or quality of sleep become more pronounced as people get older. Poor sleep in elderly people is associated with adverse health outcomes and cellular aging. We examined the relationship between telomere length (TL) and sleep duration, Health Promotion Index (HPI), and tested whether the presence of Apolipoprotein-E4 (ApoE-ε4) allele affects both sleep and TL. The present study was carried out in 174 healthy participants (21% male; mean age 53.79 years) from South Australia. Lymphocyte TL was measured by real-time quantitative PCR (qPCR) and ApoE genotype was determined by TaqMan assay. HPI was calculated from a questionnaire regarding 8 lifestyle habits, including sleeping hours. Multivariate regression analysis was used to establish these associations adjusted for specified confounders. TL was found to be inversely associated with age (r = -0.199; p = .008) and body mass index (r = -0.121; p = .11), and was significantly shorter in participants who slept for less than 7 hours (p = .001) relative to those sleeping ≥7 hours. TL was positively correlated with HPI (r = 0.195; p = .009). ApoE-ε4 allele carriers who slept for less than 7 hours had shortest TL (p = .01) compared to noncarriers. Plasma soluble receptor for advanced glycation end product (sRAGE) level was significantly (p = .001) lower in individuals who sleep less than 7 hours and ApoE-ε4 carriers. Our results suggest that inadequate sleep duration or poor HPI is associated with shorter TL in cognitively normal people and that carriage of APOE-ε4 genotype may influence the extent of these effects.
52Telomere length is associated with sleep duration but not sleep quality in adults with human immunodeficiency virus.PubMed
Kathryn A Lee, Caryl Gay, Janice Humphreys, et al.
Sleep. 2014 Jan 1;37(1):157-66. doi: 10.5665/sleep.3328.
BACKGROUND AND STUDY OBJECTIVE: Telomere length provides an estimate of cellular aging and is influenced by oxidative stress and health behaviors such as diet and exercise. This article describes relationships between telomere length and sleep parameters that included total sleep time (TST), wake after sleep onset (WASO), and self-reported sleep quality in a sample of adults with chronic illness. DESIGN AND PARTICIPANTS: Cross-sectional study of 283 adults (74% male, 42% Caucasian) infected with human immunodeficiency virus (HIV) while living in the San Francisco Bay area, CA, USA. Ages ranged from 22-77 y. MEASUREMENTS AND RESULTS: TST and WASO were estimated with wrist actigraphy across 72 h; self-reported sleep quality was assessed with the Pittsburgh Sleep Quality Index. Relative telomere length (RTL) in leukocytes was estimated by quantitative polymerase chain reaction assays. Shorter RTL was associated with older age, and RTL was shorter in males than females. RTL was unrelated to HIV disease characteristics. RTL was not associated with WASO or self-reported sleep quality. Participants with at least 7 h sleep had longer RTL than those with less than 7 h, even after controlling for the effects of age, sex, race, education, body mass index, metabolic hormones (i.e., leptin, ghrelin, adiponectin, and resistin), depression and anxiety, and sleep quality. CONCLUSION: Results suggest that sleep duration is associated with preserving telomere length in a population of human immunodeficiency virus-infected adults. Getting at least 7 hours of sleep at night may either protect telomeres from damage or restore them on a nightly basis.
53Short sleep duration is associated with shorter telomere length in healthy men: findings from the Whitehall II cohort study.PubMed
Marta Jackowska, Mark Hamer, Livia A Carvalho, et al.
PLoS One. 2012;7(10):e47292. doi: 10.1371/journal.pone.0047292. Epub 2012 Oct 29.
BACKGROUND: Shorter telomere length and poor sleep are more prevalent at older ages, but their relationship is uncertain. This study explored associations between sleep duration and telomere length in a sample of healthy middle and early old age people. METHODS: Participants were 434 men and women aged 63.3 years on average drawn from the Whitehall II cohort study. Sleep duration was measured by self-report. RESULTS: There was a linear association between sleep duration and leukocyte telomere length in men but not in women (P = 0.035). Men reporting shorter sleep duration had shorter telomeres, independently of age, body mass index, smoking, educational attainment, current employment, cynical hostility scores and depressive symptoms. Telomeres were on average 6% shorter in men sleeping 5 hours or fewer compared with those sleeping more than 7 hours per night. CONCLUSION: This study adds to the growing literature relating sleep duration with biomarkers of aging, and suggests that shortening of telomeres might reflect mechanisms through which short sleep contributes to pathological conditions in older men.
54Associations of self-reported sleep duration and sleep quality during pregnancy with newborn telomere length.PubMed
Qing Liu, Lulu Song, Gaojie Fan, et al.
Sleep Health. 2023 Aug;9(4):475-481. doi: 10.1016/j.sleh.2023.03.001. Epub 2023 May 23.
BACKGROUND: Telomere length (TL) at birth is considered a potential biomarker for lifelong health. Although maternal sleep disturbance has been linked to a series of adverse pregnancy outcomes, evidence on the effect of maternal sleep on newborn TL remains scarce. Therefore, we aim to investigate the association of maternal sleep duration and sleep quality with newborn TL. METHODS: A total of 742 mother-newborn pairs were recruited from Wuhan Children's Hospital between November 2013 and March 2015. Cord blood TL was measured using real-time quantitative polymerase chain reaction. Maternal sleep duration and quality during late pregnancy were obtained via questionnaires. Multivariate linear regression models were used to estimate the effects of maternal sleep duration and sleep quality on newborn TL. RESULTS: A total of 742 maternal-newborn pairs were included in the analyses. Mothers sleeping ≥10 hours had a 9.30% (95% CI: 2.09%, 15.99%) shorter newborn TL than those sleeping 7-<9 hours. However, the association in mothers with short sleep duration (<7 hours) did not reach statistical significance. Compared to mothers with good sleep quality, those with poor sleep quality had a 9.91% (95% CI: 4.06%, 15.40%) shorter newborn TL. We observed a joint effect of sleep duration and sleep quality on newborn telomere shortening. Women with sleep duration ≥10 hours and poor sleep quality were most likely to have newborns with short TL (percent change:-19.66%, 95% CI: -28.42, -9.84%). CONCLUSIONS: Long sleep duration and poor sleep quality during late pregnancy were associated with shorter newborn TL.
55Postpartum sleep loss and accelerated epigenetic aging.PubMed
Judith E Carroll, Kharah M Ross, Steve Horvath, et al.
Sleep Health. 2021 Jun;7(3):362-367. doi: 10.1016/j.sleh.2021.02.002. Epub 2021 Apr 24.
BACKGROUND: Insufficient sleep has been linked to accelerated biological aging in adults, providing a possible mechanism through which sleep may influence disease risk. In the current paper, we test the hypothesis that short sleep in postpartum would predict older biological age in women one year post birth, as indicated by accelerated epigenetic aging. METHODS: As part of a larger study of pregnancy and postpartum health (Healthy Babies Before Birth, HB3), 33 mothers provided blood samples for epigenetic aging clock estimates. intrinsic epigenetic age acceleration (IEAA), extrinsic apigenetic age acceleration, phenotypic epigenetic age acceleration (PEAA), GrimAge, DNAmPAI-1, and DNAm telomere length (TL) were calculated using established protocols. Sleep duration was categorized as insufficient sleep (<7 hours per night) or healthy sleep duration (7+ hours per night). Sleep quality was determined using the Pittsburgh Sleep Quality Index (Global score >5). RESULTS: Maternal postpartum sleep duration at 6 months, but not 12 months, following a birth was predictive of older 12-month IEAA, B (SE) = 3.0 (1.2), P = .02, PEAA, B (SE) = 7.3 (2.0), P = .002, and DNAmTL, B (SE) = -0.18 (0.07), P = .01, but not other indices, all P> .127. Self-reported poor sleep quality at 6 and 12 months was not significantly related to epigenetic age. CONCLUSIONS: These findings suggest that insufficient sleep duration during the early postpartum period is associated with accelerated biological aging. As the sample size is small, additional research is warranted with a larger sample size to replicate these findings.
56Sleep Hygiene and Recovery Strategies in Elite Soccer Players.PubMed
Mathieu Nédélec, Shona Halson, Barthélémy Delecroix, et al.
Sports Med. 2015 Nov;45(11):1547-59. doi: 10.1007/s40279-015-0377-9.
In elite soccer, players are frequently exposed to various situations and conditions that can interfere with sleep (e.g., playing night matches interspersed with 3 days; performing activities demanding high levels of concentration close to bedtime; use of products containing caffeine or alcohol in the period preceding bedtime; regular daytime napping throughout the week; variable wake-up times or bedtime), potentially leading to sleep deprivation. We outline simple, practical, and pharmaceutical-free sleep strategies that are coordinated to the constraints of elite soccer in order to promote sleep. Sleep deprivation is best alleviated by sleep extension; however, sleep hygiene strategies (i.e., consistent sleep pattern, appropriate napping, and active daytime behaviors) can be utilized to promote restorative sleep. Light has a profound impact on sleep, and sleep hygiene strategies that support the natural environmental light-dark cycle (i.e., red-light treatment prior to sleep, dawn-simulation therapy prior to waking) and prevent cycle disruption (i.e., filtering short wavelengths prior to sleep) may be beneficial to elite soccer players. Under conditions of inordinate stress, techniques such as brainwave entrainment and meditation are promising sleep-promoting strategies, but future studies are required to ascertain the applicability of these techniques to elite soccer players. Consuming high-electrolyte fluids such as milk, high-glycemic index carbohydrates, some forms of protein immediately prior to sleep, as well as tart cherry juice concentrate and tryptophan may promote rehydration, substrate stores replenishment, muscle-damage repair and/or restorative sleep. The influence of cold water immersion performed close to bedtime on subsequent sleep is still debated. Conversely, the potential detrimental effects of sleeping medication must be recognized. Sleep initiation is influenced by numerous factors, reinforcing the need for future research to identify such factors. Efficient and individualized sleep hygiene strategies may consequently be proposed.
57Restless roosts: Light pollution affects behavior, sleep, and physiology in a free-living songbird.PubMed
Jenny Q Ouyang, Maaike de Jong, Roy H A van Grunsven, et al.
Glob Chang Biol. 2017 Nov;23(11):4987-4994. doi: 10.1111/gcb.13756. Epub 2017 Jun 9.
The natural nighttime environment is increasingly polluted by artificial light. Several studies have linked artificial light at night to negative impacts on human health. In free-living animals, light pollution is associated with changes in circadian, reproductive, and social behavior, but whether these animals also suffer from physiologic costs remains unknown. To fill this gap, we made use of a unique network of field sites which are either completely unlit (control), or are artificially illuminated with white, green, or red light. We monitored nighttime activity of adult great tits, Parus major, and related this activity to within-individual changes in physiologic indices. Because altered nighttime activity as a result of light pollution may affect health and well-being, we measured oxalic acid concentrations as a biomarker for sleep restriction, acute phase protein concentrations and malaria infection as indices of immune function, and telomere lengths as an overall measure of metabolic costs. Compared to other treatments, individuals roosting in the white light were much more active at night. In these individuals, oxalic acid decreased over the course of the study. We also found that individuals roosting in the white light treatment had a higher probability of malaria infection. Our results indicate that white light at night increases nighttime activity levels and sleep debt and affects disease dynamics in a free-living songbird. Our study offers the first evidence of detrimental effects of light pollution on the health of free-ranging wild animals.
58An Experimental Approach to Investigating Effects of Artificial Light at Night on Free-Ranging Animals: Implementation, Results, and Directions for Future Research.PubMed
Melissa L Grunst, Andrea S Grunst, Rianne Pinxten, et al.
J Vis Exp. 2022 Feb 2(180). doi: 10.3791/63381.
Animals have evolved with natural patterns of light and darkness. However, artificial light is being increasingly introduced into the environment from human infrastructure and recreational activity. Artificial light at night (ALAN) has the potential to have widespread effects on animal behavior, physiology, and fitness, which can translate into broader-scale effects on populations and communities. Understanding the effects of ALAN on free-ranging animals is non-trivial due to challenges such as measuring levels of light encountered by mobile organisms and separating the effects of ALAN from those of other anthropogenic disturbance factors. Here we describe an approach that allows us to isolate the effects of artificial light exposure on individual animals by experimentally manipulating light levels inside nest boxes. To this end, a system can be used consisting of light-emitting diode (LED) light(s) adhered to a plate and connected to a battery and timer system. The setup allows exposure of individuals inside nest boxes to varying intensities and durations of ALAN while simultaneously obtaining video recordings, which also include audio. The system has been used in studies on free-ranging great tits (Parus major) and blue tits (Cyanistes caeruleus) to gain insight into how ALAN affects sleep and activity patterns in adults and physiology and telomere dynamics in developing nestlings. The system, or an adaptation thereof, could be used to answer many other intriguing research questions, such as how ALAN interacts with other disturbance factors and affects bioenergetic balance. Furthermore, similar systems could be installed in or near the nest boxes, nests or burrows of a variety of species to manipulate levels of ALAN, evaluate biological responses, and work towards building an interspecific perspective. Especially when combined with other advanced approaches for monitoring the behavior and movement of free-living animals, this approach promises to yield ongoing contributions to our understanding of the biological implications of ALAN.
59Role of sleep quality in the acceleration of biological aging and its potential for preventive interaction on air pollution insults: Findings from the UK Biobank cohort.PubMed
Xu Gao, Ninghao Huang, Xinbiao Guo, et al.
Aging Cell. 2022 May;21(5):e13610. doi: 10.1111/acel.13610. Epub 2022 Apr 14.
Sleep has been associated with aging and relevant health outcomes, but the causal relationship remains inconclusive. In this study, we investigated the associations of sleep behaviors with biological ages (BAs) among 363,886 middle and elderly adults from UK Biobank. Sleep index (0 [worst]-6 [best]) of each participant was retrieved from the following six sleep behaviors: snoring, chronotype, daytime sleepiness, sleep duration, insomnia, and difficulties in getting up. Two BAs, the KDM-biological age and PhenoAge, were estimated by corresponding algorithms based on clinical traits, and their residual discrepancies with chronological age were defined as the age accelerations (AAs). We first observed negative associations between the sleep index and the two AAs, and demonstrated that the change of AAs could be the consequence of sleep quality using Mendelian randomization with genetic risk scores of sleep index and BAs. Particularly, a one-unit increase in sleep index was associated with 0.104- and 0.119-year decreases in KDM-biological AA and PhenoAge acceleration, respectively. Air pollution is another key driver of aging. We further observed significant independent and joint effects of sleep and air pollution (PM and NO ) on AAs. Sleep quality also showed a modifying effect on the associations of elevated PM and NO levels with accelerated AAs. For instance, an interquartile range increase in PM level was associated with 0.009-, 0.044-, and 0.074-year increase in PhenoAge acceleration among people with high (5-6), medium (3-4), and low (0-2) sleep index, respectively. Our findings elucidate that better sleep quality could lessen accelerated biological aging resulting from air pollution.
60Potential reversal of biological age in women following an 8-week methylation-supportive diet and lifestyle program: a case series.PubMed
Kara N Fitzgerald, Tish Campbell, Suzanne Makarem, et al.
Aging (Albany NY). 2023 Mar 22;15(6):1833-1839. doi: 10.18632/aging.204602.
Here we report on a case series of six women who completed a methylation-supportive diet and lifestyle program designed to impact DNA methylation and measures of biological aging. The intervention consisted of an 8-week program that included diet, sleep, exercise and relaxation guidance, supplemental probiotics and phytonutrients and nutritional coaching. DNA methylation and biological age analysis (Horvath DNAmAge clock (2013), normalized using the SeSAMe pipeline [a]) was conducted on blood samples at baseline and at the end of the 8-week period. Five of the six participants exhibited a biological age reduction of between 1.22 and 11.01 years from their baseline biological age. There was a statistically significant (p=.039) difference in the participants' mean biological age before (55.83 years) and after (51.23 years) the 8-week diet and lifestyle intervention, with an average decrease of 4.60 years. The average chronological age at the start of the program was 57.9 years and all but one participant had a biological age younger than their chronological age at the start of the program, suggesting that biological age changes were unrelated to disease improvement and instead might be attributed to underlying aging mechanisms.
61Sleep patterns and DNA methylation age acceleration in middle-aged and older Chinese adults.PubMed
Tingyue Diao, Kang Liu, Lue Zhou, et al.
Clin Epigenetics. 2025 May 29;17(1):87. doi: 10.1186/s13148-025-01898-w.
BACKGROUND: Sleep is a biological necessity and fundamental to health. However, the associations of sleep patterns (integrating sleep determinants) with DNA methylation age acceleration (DNAm AA) remain unknown. We aimed to investigate the associations of sleep patterns with DNAm AA. METHODS: This cross-sectional and prospective cohort study used data from the Dongfeng-Tongji cohort collected from 2013 to December 31, 2018. Sleep patterns were reflected by sleep scores (range 0-4, with higher scores indicating healthier sleep patterns) characterized by bedtime, sleep duration, sleep quality, and midday napping. DNAm AA was estimated by PhenoAge acceleration (PhenoAgeAccel), GrimAge acceleration (GrimAgeAccel), DunedinPACE, and DNAm mortality risk score (DNAm MS). Linear regression models were used to estimate β and 95% confidence intervals (CIs) for the cross-sectional associations between sleep patterns and DNAm AA. Mediation models were applied to assess the mediating role of DNAm AA in the associations between sleep patterns and all-cause mortality in a prospective cohort. RESULTS: Among 3566 participants (mean age 65.5 years), 426 participants died during a mean 5.4-year follow-up. A higher sleep score was associated with lower DNAm AA in a dose-response manner. Each 1-point increase in sleep score was associated with significantly lower PhenoAgeAccel (β = - 0.208; 95% CI - 0.369 to - 0.047), GrimAgeAccel (β = - 0.107; 95% CI - 0.207 to - 0.007), DunedinPACE (β = - 0.008; 95% CI - 0.012 to - 0.004), and DNAm MS (β = - 0.019; 95% CI - 0.030 to - 0.008). Chronological age modified the associations between higher sleep scores and lower PhenoAgeAccel (p for interaction = 0.031) and DunedinPACE (p for interaction = 0.027), with stronger associations observed in older adults. Moreover, a slower DunedinPACE mediated 6.2% (95% CI 0.8% to 11.5%) of the association between a higher sleep score and a lower all-cause mortality risk. CONCLUSION: In this cohort study, individuals with a higher sleep score had a slower DNAm AA, particularly in older adults. A slower DunedinPACE partially explained the association between higher sleep scores and lower all-cause mortality risk. These findings suggest that adopting healthy sleep patterns may promote healthy aging and further benefit premature mortality prevention, highlighting the value of sleep patterns as a potential tool for clinical management in aging.
62Physical Activity Is Associated With Decreased Epigenetic Aging: Findings From the Health and Retirement Study.PubMed
Farah Ammous, Mark D Peterson, Colter Mitchell, et al.
J Cachexia Sarcopenia Muscle. 2025 Jun;16(3):e13873. doi: 10.1002/jcsm.13873.
BACKGROUND: Epigenetic aging measures or clocks are DNA methylation-based indicators of biological aging, linked to health outcomes and disease risk. Physical activity and exercise may influence epigenetic aging, suggesting a pathway through which it promotes healthier aging and reduces chronic disease burden. In this study, we assessed the association between self-reported moderate-to-vigorous physical activity and epigenetic age acceleration (EAA) in participants of the Health and Retirement Study, followed biennially for 12 years from 2004 to 2016. METHODS: Leukocyte DNA methylation was measured from venous blood samples collected in 2016 and second-generation epigenetic clocks (GrimAge, PhenoAge and DunedinPACE) were used to assess EAA. Physical activity was assessed at each wave, with participants reporting vigorous activity at least once per week or moderate activity more than once per week or more categorized as 'physically active'. We used weighted linear regression models for cross-sectional analysis in 2016. Additionally, we used a structured life-course modelling approach (SLCMA) to assess how the timing of physical activity is associated with EAA, testing both wave-specific physical activity measures and an accumulation measure indicative of sustained physical activity over the follow-up period. RESULTS: In 2016, 58% of the participants were classified as physically active. In cross-sectional analysis, physically active participants had lower EAA than inactive participants: -1.26 (95% confidence interval (CI): -1.59, -0.93) years for GrimAge acceleration, -1.70 (95% CI: -2.26, -1.15) for PhenoAge acceleration and -0.05 (95% CI: -0.06, -0.04) years per chronological year for DunedinPACE, adjusted for age, gender, race/ethnicity, education, total wealth and current smoking status. The associations attenuated slightly but remained significant after further adjusting for body mass index, mobility limitations and chronic disease diagnosis. We found evidence of effect modification in the association between physical activity and EAA by social factors, with stronger associations in males compared to females for DunedinPACE (P = 0.04) and a positive association between physical activity and increased EAA among Hispanics compared to non-Hispanic Whites for GrimAge (P = 0.009). Our longitudinal analysis using SLCMA identified both accumulation and most recent physical activity in 2016 as the strongest predictors of EAA. CONCLUSIONS: Our findings highlight physical activity as a robust factor associated with slower epigenetic aging, with both accumulation and concurrent physical activity as the strongest predictors. These results underscore the role of physical activity in promoting healthier biological aging, suggesting its potential as a target for interventions aimed at mitigating age-related health decline.
63The multiple roles of life stress in metabolic disorders.PubMed
Mika Kivimäki, Alessandro Bartolomucci, Ichiro Kawachi
Nat Rev Endocrinol. 2023 Jan;19(1):10-27. doi: 10.1038/s41574-022-00746-8. Epub 2022 Oct 12.
The activation of stress-related neuroendocrine systems helps to maintain homeostasis, but excessive stress can damage body functions. We review current evidence from basic sciences and epidemiology linking stress to the development and progression of metabolic disorders throughout life. Findings from rodents demonstrate that stress can affect features of metabolic dysfunction, such as insulin resistance, glucose and lipid homeostasis, as well as ageing processes such as cellular senescence and telomere length shortening. In human studies, stressors in the home, workplace and neighbourhood are associated with accelerated ageing and metabolic and immune alterations, both directly and indirectly via behavioural risks. The likelihood of developing clinical conditions, such as diabetes mellitus and hepatic steatosis is increased in individuals with adverse childhood experiences or long-term (years) or severe stress at work or in private life. The increased risk of metabolic disorders is often associated with other stress-related conditions, such as mental health disorders, cardiovascular disease and increased susceptibility to infections. Equally, stress can worsen prognosis in metabolic diseases. As favourable modifications in stressors are associated with reductions in incidence of metabolic disorders, further investigation of the therapeutic value of targeting stress in personalized medicine is warranted.
64Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives.PubMed
Alexander Vaiserman, Dmytro Krasnienkov
Front Genet. 2021 Jan 21;11:630186. doi: 10.3389/fgene.2020.630186. eCollection 2020.
Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. An accelerated rate of telomere attrition is also a common feature of age-related diseases. Therefore, telomere length (TL) has been recognized for a long time as one of the best biomarkers of aging. Recent research findings, however, indicate that TL can only allow a rough estimate of aging rate and can hardly be regarded as a clinically important risk marker for age-related pathologies and mortality. Evidence is obtained that other indicators such as certain immune parameters, indices of epigenetic age, etc., could be stronger predictors of the health status and the risk of chronic disease. However, despite these issues and limitations, TL remains to be very informative marker in accessing the biological age when used along with other markers such as indices of homeostatic dysregulation, frailty index, epigenetic clock, etc. This review article is aimed at describing the current state of the art in the field and at discussing recent research findings and divergent viewpoints regarding the usefulness of leukocyte TL for estimating the human biological age.
65Biological Age Predictors.PubMed
Juulia Jylhävä, Nancy L Pedersen, Sara Hägg
EBioMedicine. 2017 Jul;21:29-36. doi: 10.1016/j.ebiom.2017.03.046. Epub 2017 Apr 1.
The search for reliable indicators of biological age, rather than chronological age, has been ongoing for over three decades, and until recently, largely without success. Advances in the fields of molecular biology have increased the variety of potential candidate biomarkers that may be considered as biological age predictors. In this review, we summarize current state-of-the-art findings considering six potential types of biological age predictors: epigenetic clocks, telomere length, transcriptomic predictors, proteomic predictors, metabolomics-based predictors, and composite biomarker predictors. Promising developments consider multiple combinations of these various types of predictors, which may shed light on the aging process and provide further understanding of what contributes to healthy aging. Thus far, the most promising, new biological age predictor is the epigenetic clock; however its true value as a biomarker of aging requires longitudinal confirmation.
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.
67Epigenetic 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.
68Integrating 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.
69Integrating metabolomics, proteomics, and traditional risk factors to predict sleep disorders and elucidate potential biological pathways.PubMed
Ronghui Zhang, Jia Luo, Tong Wang, et al.
J Affect Disord. 2025 Dec 1;390:119784. doi: 10.1016/j.jad.2025.119784. Epub 2025 Jun 30.
BACKGROUND: Sleep disorders (SD) are common, heterogeneous conditions with significant health impacts. Traditional risk factors like age, sex, and BMI have limited predictive power. Integrating metabolomics and proteomics with these factors may enhance SD prediction and reveal underlying biological pathways. METHODS: We utilized data from 26,569 UK Biobank participants (mean age: 57.3 years; 54.3 % male), a large UK cohort aged 40-69 at recruitment, with metabolomic and proteomic measurements obtained using NMR-based and Olink Explore platforms, respectively. Cox proportional hazards and LASSO-Cox regression were used to identify metabolite and protein biomarkers for SD risk and construct metabolite (MetaS) and protein (ProS) risk scores. These scores were combined with a traditional risk score (TraS) to develop a combined predictive model, which was evaluated for discrimination, calibration, net benefit, and risk stratification. Mediation analysis assessed the contributions of metabolites and proteins to the relationship between TraS and SD. RESULTS: Over 13.3 years of follow-up, 658 participants developed SD. Eight metabolites and 34 proteins were identified as key biomarkers. The combined model (MetaS, ProS, and TraS) showed a C-index of 0.78 (95 % CI: 0.75-0.80) and good calibration. Risk stratification of combined score identified high-, medium-, and low-risk groups, with high-risk individuals having a 4.5-fold increased SD risk. Mediation analysis revealed significant contributions from MetaS (8.68 %) and ProS (25.98 %) with specific metabolites (e.g., LDL size) and proteins (e.g., RTN4R, FURIN) identified as top contributors. CONCLUSIONS: This study demonstrates that integrating metabolomics and proteomics with traditional risk factors improve SD risk prediction offers preliminary biological insights.
70DNA methylation clocks for estimating biological age in Chinese cohorts.PubMed
Zikai Zheng, Jiaming Li, Tianzi Liu, et al.
Protein Cell. 2024 Jul 20;15(8):575-593. doi: 10.1093/procel/pwae011.
Epigenetic clocks are accurate predictors of human chronological age based on the analysis of DNA methylation (DNAm) at specific CpG sites. However, a systematic comparison between DNA methylation data and other omics datasets has not yet been performed. Moreover, available DNAm age predictors are based on datasets with limited ethnic representation. To address these knowledge gaps, we generated and analyzed DNA methylation datasets from two independent Chinese cohorts, revealing age-related DNAm changes. Additionally, a DNA methylation aging clock (iCAS-DNAmAge) and a group of DNAm-based multi-modal clocks for Chinese individuals were developed, with most of them demonstrating strong predictive capabilities for chronological age. The clocks were further employed to predict factors influencing aging rates. The DNAm aging clock, derived from multi-modal aging features (compositeAge-DNAmAge), exhibited a close association with multi-omics changes, lifestyles, and disease status, underscoring its robust potential for precise biological age assessment. Our findings offer novel insights into the regulatory mechanism of age-related DNAm changes and extend the application of the DNAm clock for measuring biological age and aging pace, providing the basis for evaluating aging intervention strategies.
71An evaluation of aging measures: from biomarkers to clocks.PubMed
Qingyi Wang, Tongyao Hou, Qiwen Wang, et al.
Biogerontology. 2023 Jun;24(3):303-328. doi: 10.1007/s10522-022-09997-4. Epub 2022 Nov 23.
With the increasing number of aged population and growing burden of healthy aging demands, a rational standard for evaluation aging is in urgent need. The advancement of medical testing technology and the prospering of artificial intelligence make it possible to evaluate the biological status of aging from a more comprehensive view. In this review, we introduced common aging biomarkers and concluded several famous aging clocks. Aging biomarkers reflect changes in the organism at a molecular or cellular level over time while aging clocks tend to be more of a generalization of the overall state of the organism. We expect to construct a framework for aging evaluation measurement from both micro and macro perspectives. Especially, population-specific aging clocks and multi-omics aging clocks may better fit the demands to evaluate aging in a comprehensive and multidimensional manner and make a detailed classification to represent different aging rates at tissue/organ levels. This framework will promisingly provide a crucial basis for disease diagnosis and intervention assessment in geroscience.
72Biomarkers 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.
73Validation 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.
74Organ-specific biological clocks: Ageotyping for personalized anti-aging medicine.PubMed
Francesco Prattichizzo, Chiara Frigé, Valeria Pellegrini, et al.
Ageing Res Rev. 2024 Apr;96:102253. doi: 10.1016/j.arr.2024.102253. Epub 2024 Mar 4.
Aging is a complex multidimensional, progressive remodeling process affecting multiple organ systems. While many studies have focused on studying aging across multiple organs, assessment of the contribution of individual organs to overall aging processes is a cutting-edge issue. An organ's biological age might influence the aging of other organs, revealing a multiorgan aging network. Recent data demonstrated a similar yet asynchronous inter-organs and inter-individuals progression of aging, thereby providing a foundation to track sources of declining health in old age. The integration of multiple omics with common clinical parameters through artificial intelligence has allowed the building of organ-specific aging clocks, which can predict the development of specific age-related diseases at high resolution. The peculiar individual aging-trajectory, referred to as ageotype, might provide a novel tool for a personalized anti-aging, preventive medicine. Here, we review data relative to biological aging clocks and omics-based data, suggesting different organ-specific aging rates. Additional research on longitudinal data, including young subjects and analyzing sex-related differences, should be encouraged to apply ageotyping analysis for preventive purposes in clinical practice.
75MRI-based multi-organ clocks for healthy aging and disease assessment.PubMed
Huizi Cao, Zhiyuan Song, et al.
Nat Med. 2025 Oct 16. doi: 10.1038/s41591-025-03999-8.
Biological aging clocks across organ systems and tissues have advanced understanding of human aging and disease. In this study, we expand this framework to develop seven magnetic resonance imaging-based multi-organ biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney and pancreas. Using data from 313,645 individuals curated by the MULTI Consortium, we link the seven MRIBAGs to 2,923 plasma proteins, 327 metabolites and 6,477,810 common genetic variants. Genome-wide associations identify 53 MRIBAG-locus pairs (P < 5 × 10). Genetic correlation and Mendelian randomization analyses support organ-specific and cross-organ interconnection, including 24 non-MRI biological aging clocks and 525 disease endpoints. Through functional gene mapping and Bayesian co-localization multi-omics evidence, we prioritize nine druggable genes as targets for future anti-aging treatments. Furthermore, the seven MRIBAGs are linked to future risk of systemic disease endpoints (for example, diabetes mellitus) and all-cause mortality. Finally, participants with more youthful versus more aged brain profiles exhibited distinct cognitive decline trajectories over 240 weeks of treatment with the Alzheimer's disease drug solanezumab, although this heterogeneity cannot be fully attributed to the drug. In summary, we developed seven MRIBAGs that enhance the existing multi-organ biological aging framework, and we demonstrate their clinical potential to advance aging research.
76Classification for Longevity Potential: The Use of Novel Biomarkers.PubMed
Marian Beekman, Hae-Won Uh, Diana van Heemst, et al.
Front Public Health. 2016 Oct 28;4:233. doi: 10.3389/fpubh.2016.00233. eCollection 2016.
BACKGROUND: In older people, chronological age may not be the best predictor of residual lifespan and mortality, because with age the heterogeneity in health is increasing. Biomarkers for biological age and residual lifespan are being developed to predict disease and mortality better at an individual level than chronological age. In the current paper, we aim to classify a group of older people into those with longevity potential or controls. METHODS: In the Leiden Longevity Study participated 1671 offspring of nonagenarian siblings, as the group with longevity potential, and 744 similarly aged controls. Using known risk factors for cardiovascular disease, previously reported markers for human longevity and other physiological measures as predictors, classification models for longevity potential were constructed with multiple logistic regression of the offspring-control status. RESULTS: The Framingham Risk Score (FRS) is predictive for longevity potential [area under the receiver operating characteristic curve (AUC) = 64.7]. Physiological parameters involved in immune responses and glucose, lipid and energy metabolism further improve the prediction performance for longevity potential (AUCmale = 71.4, AUCfemale = 68.7). CONCLUSION: Using the FRS, the classification of older people in groups with longevity potential and controls is moderate, but can be improved to a reasonably good classification in combination with markers of immune response, glucose, lipid, and energy metabolism. We show that individual classification of older people for longevity potential may be feasible using biomarkers from a wide variety of different biological processes.
77[Wearable devices: Perspectives on assessing and monitoring human physiological status].PubMed
Chung-Kang Peng, Xingran Cui, Zhengbo Zhang, et al.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2023 Dec 25;40(6):1045-1052. doi: 10.7507/1001-5515.202303043.
This review article aims to explore the major challenges that the healthcare system is currently facing and propose a new paradigm shift that harnesses the potential of wearable devices and novel theoretical frameworks on health and disease. Lifestyle-induced diseases currently account for a significant portion of all healthcare spending, with this proportion projected to increase with population aging. Wearable devices have emerged as a key technology for implementing large-scale healthcare systems focused on disease prevention and management. Advancements in miniaturized sensors, system integration, the Internet of Things, artificial intelligence, 5G, and other technologies have enabled wearable devices to perform high-quality measurements comparable to medical devices. Through various physical, chemical, and biological sensors, wearable devices can continuously monitor physiological status information in a non-invasive or minimally invasive way, including electrocardiography, electroencephalography, respiration, blood oxygen, blood pressure, blood glucose, activity, and more. Furthermore, by combining concepts and methods from complex systems and nonlinear dynamics, we developed a novel theory of continuous dynamic physiological signal analysis-dynamical complexity. The results of dynamic signal analyses can provide crucial information for disease prevention, diagnosis, treatment, and management. Wearable devices can also serve as an important bridge connecting doctors and patients by tracking, storing, and sharing patient data with medical institutions, enabling remote or real-time health assessments of patients, and providing a basis for precision medicine and personalized treatment. Wearable devices have a promising future in the healthcare field and will be an important driving force for the transformation of the healthcare system, while also improving the health experience for individuals.
78Synergizing Nanosensor-Enhanced Wearable Devices with Machine Learning for Precision Health Management Benefiting Older Adult Populations.PubMed
Zhihao Li, Bangshun He, Yiwei Li, et al.
ACS Nano. 2025 Jul 29;19(29):26273-26295. doi: 10.1021/acsnano.5c04337. Epub 2025 Jul 14.
Population aging presents significant health challenges and socioeconomic burdens globally, driving an increased demand for precision health management. In the era of big data, the exponential growth of health information is accelerating advances in precision health strategies for older adults. For this population, effective strategies can be achieved by the integration of wearable devices, nanosensors, and machine learning. Wearable devices enable continuous monitoring of diverse, real-time health metrics, serving as vital tools for collecting comprehensive health data. Nanosensors can be loaded into wearable devices to enhance their performance by significantly improving detection sensitivity and specificity, thereby increasing the accuracy and reliability of the data collected. Meanwhile, machine learning provides powerful methods for rapid and efficient analysis of large-scale health data, driving the optimization of nanosensors as well as wearable devices. This review examines the synergistic roles of wearable devices, nanosensors, and machine learning in the precision health management field, focusing on the value of big health data (i.e., big data in health care). We begin by exploring wearable devices as critical tools for gathering extensive health information, followed by an in-depth discussion of how nanosensors enhance data quality. Subsequently, we highlight the contributions of machine learning algorithms to the precise analysis of big health data and propose several proactive health management strategies from the perspective of "diagnosis-analysis-prevention". Finally, we present perspectives on the future integration of these technologies to advance comprehensive health management, precision diagnostics, and personalized medicine for older individuals.
79[Design of flexible wearable sensing systems].PubMed
Hongyu Chen, Zaihao Wang, Long Meng, et al.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2023 Dec 25;40(6):1071-1083. doi: 10.7507/1001-5515.202208012.
The aging population and the increasing prevalence of chronic diseases in the elderly have brought a significant economic burden to families and society. The non-invasive wearable sensing system can continuously and real-time monitor important physiological signs of the human body and evaluate health status. In addition, it can provide efficient and convenient information feedback, thereby reducing the health risks caused by chronic diseases in the elderly. A wearable system for detecting physiological and behavioral signals was developed in this study. We explored the design of flexible wearable sensing technology and its application in sensing systems. The wearable system included smart hats, smart clothes, smart gloves, and smart insoles, achieving long-term continuous monitoring of physiological and motion signals. The performance of the system was verified, and the new sensing system was compared with commercial equipment. The evaluation results demonstrated that the proposed system presented a comparable performance with the existing system. In summary, the proposed flexible sensor system provides an accurate, detachable, expandable, user-friendly and comfortable solution for physiological and motion signal monitoring. It is expected to be used in remote healthcare monitoring and provide personalized information monitoring, disease prediction, and diagnosis for doctors/patients.
80A Personalized Health Monitoring System for Community-Dwelling Elderly People in Hong Kong: Design, Implementation, and Evaluation Study.PubMed
Hailiang Wang, Yang Zhao, Lisha Yu, et al.
J Med Internet Res. 2020 Sep 30;22(9):e19223. doi: 10.2196/19223.
BACKGROUND: Telehealth is an effective means to assist existing health care systems, particularly for the current aging society. However, most extant telehealth systems employ individual data sources by offline data processing, which may not recognize health deterioration in a timely way. OBJECTIVE: Our study objective was two-fold: to design and implement an integrated, personalized telehealth system on a community-based level; and to evaluate the system from the perspective of user acceptance. METHODS: The system was designed to capture and record older adults' health-related information (eg, daily activities, continuous vital signs, and gait behaviors) through multiple measuring tools. State-of-the-art data mining techniques can be integrated to detect statistically significant changes in daily records, based on which a decision support system could emit warnings to older adults, their family members, and their caregivers for appropriate interventions to prevent further health deterioration. A total of 45 older adults recruited from 3 elderly care centers in Hong Kong were instructed to use the system for 3 months. Exploratory data analysis was conducted to summarize the collected datasets. For system evaluation, we used a customized acceptance questionnaire to examine users' attitudes, self-efficacy, perceived usefulness, perceived ease of use, and behavioral intention on the system. RESULTS: A total of 179 follow-up sessions were conducted in the 3 elderly care centers. The results of exploratory data analysis showed some significant differences in the participants' daily records and vital signs (eg, steps, body temperature, and systolic blood pressure) among the 3 centers. The participants perceived that using the system is a good idea (ie, attitude: mean 5.67, SD 1.06), comfortable (ie, self-efficacy: mean 4.92, SD 1.11), useful to improve their health (ie, perceived usefulness: mean 4.99, SD 0.91), and easy to use (ie, perceived ease of use: mean 4.99, SD 1.00). In general, the participants showed a positive intention to use the first version of our personalized telehealth system in their future health management (ie, behavioral intention: mean 4.45, SD 1.78). CONCLUSIONS: The proposed health monitoring system provides an example design for monitoring older adults' health status based on multiple data sources, which can help develop reliable and accurate predictive analytics. The results can serve as a guideline for researchers and stakeholders (eg, policymakers, elderly care centers, and health care providers) who provide care for older adults through such a telehealth system.