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二甲双胍与长寿的相关性研究，最新的、最权威的研究
结论：二甲双胍（Metformin）目前是抗衰老领域最受瞩目、证据最充分的“明星候选药物”，但它更多被证实能“延长健康寿命（Healthspan）”，即让人在老去时少生病，而非单纯地“延长绝对寿命（Lifespan）”。
最新的权威研究表明，二甲双胍不仅能控制血糖，还能像一位“细胞管家”一样，通过激活能量感应器（AMPK）、清理“僵尸细胞”和抑制慢性炎症来延缓衰老进程 。虽然在英国生物银行（UK Biobank）的大数据分析中，二甲双胍使用者显示出更年轻的“生物学年龄” ，但在健康人群中是否真能长寿仍有争议，且有研究警示在特定肾脏损伤情况下可能存在风险 。
以下是基于最新科学证据的详细解读：
1. 二甲双胍究竟是如何“抗衰老”的？（核心机制）
要理解二甲双胍的神奇之处，我们得先了解它在微观世界里做了什么。最新的研究揭示了它有三把“抗衰老金钥匙”：
- 钥匙一：唤醒“能量指挥官”AMPK
我们的细胞里有一个叫 AMPK（腺苷酸活化蛋白激酶） 的东西。
- 通俗解释：你可以把AMPK想象成细胞里的“节约能源指挥官”。当我们年轻或运动时，它很活跃；当我们老了，它就偷懒了。
- 二甲双胍的作用：它能强行把这个指挥官叫醒。一旦AMPK被激活，它就会命令细胞：“现在能量紧缺，别忙着生长分裂了，赶紧清理垃圾、修复受损的零件！”这能增强细胞的自噬功能（相当于细胞的自我清洁），让细胞焕然一新 。
- 钥匙二：安抚“发炎”的身体 衰老往往伴随着一种慢性的、低度的炎症，科学家称之为“炎性衰老（Inflammaging）”。二甲双胍能像灭火器一样，通过特定的信号通路（如Nrf2），降低身体里的炎症水平，保护血管和器官不被这种“慢火”烤坏 。
- 钥匙三：清除大脑中的“僵尸”
2024年发表在《神经炎症杂志》上的一项重要研究发现，二甲双胍能保护我们的大脑。
- 背景：大脑里有一类叫“星形胶质细胞”的支持细胞，老了之后会变成“衰老细胞”（俗称僵尸细胞），不仅不干活，还释放毒素伤害周围神经。
- 新发现：二甲双胍通过调节线粒体（细胞的电池），阻止了一种名为 Mfn2-cGAS 的信号通路被错误激活。简单说，就是它阻止了电池漏液引发的报警，从而延缓了这些脑细胞的衰老，这对于预防帕金森病等老年痴呆症具有巨大潜力 。
2. 权威数据怎么说？（最新证据）
并不是空口无凭，科学家们用实实在在的数据支撑了这些观点：
- 让人“生理上”变年轻：
2023年发表在《柳叶刀·健康长寿》上的一项研究，分析了庞大的英国生物银行数据库。结果发现，那些因为基因变异导致类似“二甲双胍起效”效果（即糖化血红蛋白较低）的人，他们的 “表型年龄（Phenotypic Age）” 显著更年轻 。
- 术语解释：表型年龄 不是你身份证上的年龄，而是根据你血液里的各种生化指标算出来的“身体真实年龄”。这项研究暗示，二甲双胍可能通过模拟这种代谢状态，让人体内部更年轻。
- 保护心脏，减少死亡： 二甲双胍不仅仅是降糖药。回顾性研究发现，使用二甲双胍的糖尿病患者，其全因死亡风险（不管什么原因导致的死亡）降低了，心力衰竭和心肌梗死的发生率也更低 。对于一种使用了60多年的老药来说，这是非常了不起的“副作用”。
- 多管齐下的潜力： 2025年即将发表在《JAMA》的一篇综述指出，二甲双胍被列为最有希望的“老年保护剂”之一，因为它针对的是衰老的生物学根源，而不仅仅是治疗单一疾病 。
3. 需要警惕的“阴暗面”（风险提示）
虽然二甲双胍被捧上神坛，但最新的科学研究也泼了一盆必要的冷水，这一点对于老年人尤为重要。
- 肾脏受损时的“反噬”：
2023年发表在《Cell Discovery》上的一项颠覆性研究发现，在小鼠模型中，如果本来就有急性肾损伤，使用二甲双胍反而会加重病情，甚至增加死亡率 。
- 机制解释：这是因为二甲双胍在这种特定情况下，会引发一种叫 “铁死亡（Ferroptosis）” 的细胞死亡方式。简单说，就是细胞因为铁代谢紊乱而“生锈”死掉了，并且引来免疫细胞疯狂攻击肾脏。
- 建议：这意味着肾功能不全的患者，或者正处于急性疾病期间的老人，使用二甲双胍必须非常谨慎，听从医生建议。
- 并非人人都能“长寿”： 尽管对病人有效，但在完全健康、没有疾病的人身上，二甲双胍是否能延长寿命还存在争议 。有些研究甚至发现，它可能会抑制剧烈运动带来的部分好处（比如线粒体的适应性增加）。
4. 未来展望：我们在等什么？
目前科学界最期待的是一项名为 TAME (Targeting Aging with Metformin) 的大型临床试验。这项试验旨在直接验证：二甲双胍是否能让健康或亚健康的老年人，晚几年得心脏病、癌症或认知障碍 。
总结建议： 如果您或家里的长辈患有2型糖尿病，二甲双胍无疑是“一石二鸟”的优选，既降糖又可能抗衰老。但如果您身体完全健康，想把它当作“长生不老药”来吃，目前的科学证据并不支持这么做，特别是在考虑到潜在的肾脏风险和个体差异时。最好的抗衰老良药，目前依然是均衡饮食和适度运动（或者配合类似轻断食的策略，如部分研究显示的那样 ）。
References
1Human trials exploring anti-aging medicines.PubMed
Leonard Guarente, David A Sinclair, Guido Kroemer
Cell Metab. 2024 Feb 6;36(2):354-376. doi: 10.1016/j.cmet.2023.12.007. Epub 2024 Jan 4.
Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic: metformin, NAD precursors, glucagon-like peptide-1 receptor agonists, TORC1 inhibitors, spermidine, senolytics, probiotics, and anti-inflammatories. Multiple clinical trials have commenced to evaluate the efficacy of such agents against age-associated diseases including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases. There are reasonable expectations that drugs able to decelerate or reverse aging processes will also exert broad disease-preventing or -attenuating effects. Hence, the outcome of past, ongoing, and future disease-specific trials may pave the way to the development of new anti-aging medicines. Drugs approved for specific disease indications may subsequently be repurposed for the treatment of organism-wide aging consequences.
2Metformin: Is it a drug for all reasons and diseases?PubMed
Chris R Triggle, Ibrahim Mohammed, Khalifa Bshesh, et al.
Metabolism. 2022 Aug;133:155223. doi: 10.1016/j.metabol.2022.155223. Epub 2022 May 29.
Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people. An accumulation of positive pre-clinical and clinical data has stimulated interest in re-purposing metformin to treat a variety of diseases including COVID-19. In polycystic ovary syndrome metformin improves insulin sensitivity. In type 1 diabetes metformin may help reduce the insulin dose. Meta-analysis and data from pre-clinical and clinical studies link metformin to a reduction in the incidence of cancer. Clinical trials, including MILES (Metformin In Longevity Study), and TAME (Targeting Aging with Metformin), have been designed to determine if metformin can offset aging and extend lifespan. Pre-clinical and clinical data suggest that metformin, via suppression of pro-inflammatory pathways, protection of mitochondria and vascular function, and direct actions on neuronal stem cells, may protect against neurodegenerative diseases. Metformin has also been studied for its anti-bacterial, -viral, -malaria efficacy. Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an anti-hyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct anti-viral actions. Clarification is also sought as to whether data from ex vivo studies based on the use of high concentrations of metformin can be translated into clinical benefits, or whether they reflect a 'Paracelsus' effect. The environmental impact of metformin, a drug with no known metabolites, is another emerging issue that has been linked to endocrine disruption in fish, and extensive use in T2D has also raised concerns over effects on human reproduction. The objectives for this review are to: 1) evaluate the putative mechanism(s) of action of metformin; 2) analyze the controversial evidence for metformin's effectiveness in the treatment of diseases other than type 2 diabetes; 3) assess the reproducibility of the data, and finally 4) reach an informed conclusion as to whether metformin is a drug for all diseases and reasons. We conclude that the primary clinical benefits of metformin result from its insulin-sensitizing and antihyperglycaemic effects that secondarily contribute to a reduced risk of a number of diseases and thereby enhancing healthspan. However, benefits like improving vascular endothelial function that are independent of effects on glucose homeostasis add to metformin's therapeutic actions.
3Aging and age-related diseases: from mechanisms to therapeutic strategies.PubMed
Zhe Li, Zhenkun Zhang, Yikun Ren, et al.
Biogerontology. 2021 Apr;22(2):165-187. doi: 10.1007/s10522-021-09910-5. Epub 2021 Jan 27.
Aging is a physiological process mediated by numerous biological and genetic pathways, which are directly linked to lifespan and are a driving force for all age-related diseases. Human life expectancy has greatly increased in the past few decades, but this has not been accompanied by a similar increase in their healthspan. At present, research on aging biology has focused on elucidating the biochemical and genetic pathways that contribute to aging over time. Several aging mechanisms have been identified, primarily including genomic instability, telomere shortening, and cellular senescence. Aging is a driving factor of various age-related diseases, including neurodegenerative diseases, cardiovascular diseases, cancer, immune system disorders, and musculoskeletal disorders. Efforts to find drugs that improve the healthspan by targeting the pathogenesis of aging have now become a hot topic in this field. In the present review, the status of aging research and the development of potential drugs for aging-related diseases, such as metformin, rapamycin, resveratrol, senolytics, as well as caloric restriction, are summarized. The feasibility, side effects, and future potential of these treatments are also discussed, which will provide a basis to develop novel anti-aging therapeutics for improving the healthspan and preventing aging-related diseases.
4Human age reversal: Fact or fiction?PubMed
Adiv A Johnson, Bradley W English, Maxim N Shokhirev, et al.
Aging Cell. 2022 Aug;21(8):e13664. doi: 10.1111/acel.13664. Epub 2022 Jul 2.
Although chronological age correlates with various age-related diseases and conditions, it does not adequately reflect an individual's functional capacity, well-being, or mortality risk. In contrast, biological age provides information about overall health and indicates how rapidly or slowly a person is aging. Estimates of biological age are thought to be provided by aging clocks, which are computational models (e.g., elastic net) that use a set of inputs (e.g., DNA methylation sites) to make a prediction. In the past decade, aging clock studies have shown that several age-related diseases, social variables, and mental health conditions associate with an increase in predicted biological age relative to chronological age. This phenomenon of age acceleration is linked to a higher risk of premature mortality. More recent research has demonstrated that predicted biological age is sensitive to specific interventions. Human trials have reported that caloric restriction, a plant-based diet, lifestyle changes involving exercise, a drug regime including metformin, and vitamin D3 supplementation are all capable of slowing down or reversing an aging clock. Non-interventional studies have connected high-quality sleep, physical activity, a healthy diet, and other factors to age deceleration. Specific molecules have been associated with the reduction or reversal of predicted biological age, such as the antihypertensive drug doxazosin or the metabolite alpha-ketoglutarate. Although rigorous clinical trials are needed to validate these initial findings, existing data suggest that aging clocks are malleable in humans. Additional research is warranted to better understand these computational models and the clinical significance of lowering or reversing their outputs.
5A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan.PubMed
Ibrahim Mohammed, Morley D Hollenberg, Hong Ding, et al.
Front Endocrinol (Lausanne). 2021 Aug 5;12:718942. doi: 10.3389/fendo.2021.718942. eCollection 2021.
The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug. Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts either its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin. We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.
6Metformin: From diabetes to cancer to prolongation of life.PubMed
Cesare R Sirtori, Sofia Castiglione, Chiara Pavanello
Pharmacol Res. 2024 Oct;208:107367. doi: 10.1016/j.phrs.2024.107367. Epub 2024 Aug 25.
The metformin molecule dates back to over a century, but its clinical use started in the '50s. Since then, its use in diabetics has grown constantly, with over 150 million users today. The therapeutic profile also expanded, with improved understanding of novel mechanisms. Metformin has a major activity on insulin resistance, by acting on the insulin receptors and mitochondria, most likely by activation of the adenosine monophosphate-activated kinase. These and associated mechanisms lead to significant lipid lowering and body weight loss. An anti-cancer action has come up in recent years, with mechanisms partly dependent on the mitochondrial activity and also on phosphatidylinositol 3-kinase resistance occurring in some malignant tumors. The potential of metformin to raise life-length is the object of large ongoing studies and of several basic and clinical investigations. The present review article will attempt to investigate the basic mechanisms behind these diverse activities and the potential clinical benefits. Metformin may act on transcriptional activity by histone modification, DNA methylation and miRNAs. An activity on age-associated inflammation (inflammaging) may occur via activation of the nuclear factor erythroid 2 related factor and changes in gut microbiota. A senolytic activity, leading to reduction of cells with the senescent associated secretory phenotype, may be crucial in lifespan prolongation as well as in ancillary properties in age-associated diseases, such as Parkinson's disease. Telomere prolongation may be related to the activity on mitochondrial respiratory factor 1 and on peroxisome gamma proliferator coactivator 1-alpha. Very recent observations on the potential to act on the most severe neurological disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, have raised considerable hope.
7Geroscience: A Translational Review.PubMed
Stephen B Kritchevsky, Steven R Cummings
JAMA. 2025 Sep 23;334(12):1094-1102. doi: 10.1001/jama.2025.11289.
IMPORTANCE: The incidence of stroke, heart failure, dementia, many cancers, coronary artery disease, and physical disability rise exponentially with age. Geroscience is a relatively new discipline that aims to define and modify aging-related biologic pathways, slow age-related disability, prevent age-related diseases, and increase disability-free survival. OBSERVATIONS: Medical therapies typically alter biologic pathways to treat or prevent specific diseases. For example, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are cholesterol-lowering medications used to prevent development and progression of atherosclerosis. However, disease-focused treatments do not alter aging's effects on disease and declining function (eg, statins do not significantly reduce noncardiovascular mortality or cancer). In animal models, treatments can alter aging's effect on disease. For example, in mice, caloric restriction increases mean lifespan from 10% to 40% compared with mice fed ad libitum and favorably affects multiple cellular pathways implicated in aging including nutrient sensing, protein synthesis, autophagy, and inflammation. In adults with obesity and diabetes, compared with non-caloric restriction intervention groups, randomization to receive caloric restriction was associated with a 15% reduction in all-cause mortality and a lower incidence of weight-related chronic diseases. Rapamycin, a drug approved to suppress posttransplant organ rejection, increased mouse median lifespan by 249 days in females and 154 days in males. A rapamycin analogue, everolimus, improved antibody titers to influenza vaccine in older adults. In humans, senescent cells increase in abundance with age and are characterized by growth arrest, apoptosis resistance, and an altered secretome (the set of proteins secreted by a cell into the extracellular space). A greater abundance of senescent cells is associated with more physical impairments and increased mortality. Reducing the number of these cells in animal models extends lifespan and improves physical function, such as grip strength and mobility, and cardiac ejection fraction. However, potential health benefits of reducing senescent cells in humans remain unclear. CONCLUSIONS AND RELEVANCE: Therapies that inhibit aging biology, such as caloric restriction, metformin, senolytics, or rapalogs, may slow the development and progression of disease and functional decline in humans.
8AMPK: The energy sensor at the crossroads of aging and cancer.PubMed
Vasudevarao Penugurti, Rajesh Kumar Manne, Ling Bai, et al.
Semin Cancer Biol. 2024 Nov;106-107:15-27. doi: 10.1016/j.semcancer.2024.08.002. Epub 2024 Aug 26.
AMP-activated protein kinase (AMPK) is a protein kinase that plays versatile roles in response to a variety of physiological stresses, including glucose deprivation, hypoxia, and ischemia. As a kinase with pleiotropic functions, it plays a complex role in tumor progression, exhibiting both tumor-promoting and tumor-suppressing activities. On one hand, AMPK enhances cancer cell proliferation and survival, promotes cancer metastasis, and impairs anti-tumor immunity. On the other hand, AMPK inhibits cancer cell growth and survival and stimulates immune responses in a context-dependent manner. Apart from these functions, AMPK plays a key role in orchestrating aging and aging-related disorders, including cardiovascular diseases (CVD), Osteoarthritis (OA), and Diabetes. In this review article, we summarized the functions of AMPK pathway based on its oncogenic and tumor-suppressive roles and highlighted the importance of AMPK pathway in regulating cellular aging. We also spotlighted the significant role of various signaling pathways, activators, and inhibitors of AMPK in serving as therapeutic strategies for anti-cancer and anti-aging therapy.
9Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives.PubMed
Saghi Hakimi Naeini, Laleh Mavaddatiyan, Zahra Rashid Kalkhoran, et al.
Exp Gerontol. 2023 May;175:112154. doi: 10.1016/j.exger.2023.112154. Epub 2023 Mar 20.
Aging is a natural process that determined by a functional decline in cells and tissues as organisms are growing old, resulting in an increase at risk of disease and death. To this end, many efforts have been made to control aging and increase lifespan and healthspan. These efforts have led to the discovery of several anti-aging drugs and compounds such as rapamycin and metformin. Recently, alpha-ketoglutarate (AKG) has been introduced as a potential anti-aging metabolite that can control several functions in organisms, thereby increases longevity and improves healthspan. Unlike other synthetic anti-aging drugs, AKG is one of the metabolites of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, and synthesized in the body. It plays a crucial role in the cell energy metabolism, amino acid/protein synthesis, epigenetic regulation, stemness and differentiation, fertility and reproductive health, and cancer cell behaviors. AKG exerts its effects through different mechanisms such as inhibiting mTOR and ATP-synthase, modulating DNA and histone demethylation and reducing ROS formation. Herein, we summarize the recent findings of AKG-related lifespan and healthspan studies and discuss AKG associated cell and molecular mechanisms involved in increasing longevity, improving reproduction, and modulating stem cells and cancer cells behavior. We also discuss the promises and limitations of AKG for delaying aging and other potential applications.
10Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis.PubMed
Zhaoxian Cai, Xiaotian Wu, Zijun Song, et al.
Cell Discov. 2023 Oct 17;9(1):104. doi: 10.1038/s41421-023-00595-3.
Given the rapidly aging population, aging-related diseases are becoming an excessive burden on the global healthcare system. Metformin has been shown to be beneficial to many age-related disorders, as well as increase lifespan in preclinical animal models. During the aging process, kidney function progressively declines. Currently, whether and how metformin protects the kidney remains unclear. In this study, among longevity drugs, including metformin, nicotinamide, resveratrol, rapamycin, and senolytics, we unexpectedly found that metformin, even at low doses, exacerbated experimentally-induced acute kidney injury (AKI) and increased mortality in mice. By single-cell transcriptomics analysis, we found that death of renal parenchymal cells together with an expansion of neutrophils occurs upon metformin treatment after AKI. We identified programmed cell death by ferroptosis in renal parenchymal cells and blocking ferroptosis, or depleting neutrophils protects against metformin-induced nephrotoxicity. Mechanistically, upon induction of AKI, ferroptosis in renal parenchymal cells initiates the migration of neutrophils to the site of injury via the surface receptor CXCR4-bound to metformin-iron-NGAL complex, which results in NETosis aggravated AKI. Finally, we demonstrated that reducing iron showed protective effects on kidney injury, which supports the notion that iron plays an important role in metformin-triggered AKI. Taken together, these findings delineate a novel mechanism underlying metformin-aggravated nephropathy and highlight the mechanistic relationship between iron, ferroptosis, and NETosis in the resulting AKI.
11Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.PubMed
Min Wang, Tian Tian, Hong Zhou, et al.
J Neuroinflammation. 2024 Apr 2;21(1):81. doi: 10.1186/s12974-024-03072-0.
BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.
12Pentadecanoic Acid (C15:0), an Essential Fatty Acid, Shares Clinically Relevant Cell-Based Activities with Leading Longevity-Enhancing Compounds.PubMed
Stephanie Venn-Watson, Nicholas J Schork
Nutrients. 2023 Oct 30;15(21):4607. doi: 10.3390/nu15214607.
Pentadecanoic acid (C15:0) is an essential odd-chain saturated fatty acid with broad activities relevant to protecting cardiometabolic, immune, and liver health. C15:0 activates AMPK and inhibits mTOR, both of which are core components of the human longevity pathway. To assess the potential for C15:0 to enhance processes associated with longevity and healthspan, we used human cell-based molecular phenotyping assays to compare C15:0 with three longevity-enhancing candidates: acarbose, metformin, and rapamycin. C15:0 (n = 36 activities in 10 of 12 cell systems) and rapamycin (n = 32 activities in 12 of 12 systems) had the most clinically relevant, dose-dependent activities. At their optimal doses, C15:0 (17 µM) and rapamycin (9 µM) shared 24 activities across 10 cell systems, including anti-inflammatory (e.g., lowered MCP-1, TNFα, IL-10, IL-17A/F), antifibrotic, and anticancer activities, which are further supported by previously published in vitro and in vivo studies. Paired with prior demonstrated abilities for C15:0 to target longevity pathways, hallmarks of aging, aging rate biomarkers, and core components of type 2 diabetes, heart disease, cancer, and nonalcoholic fatty liver disease, our results support C15:0 as an essential nutrient with activities equivalent to, or surpassing, leading longevity-enhancing candidate compounds.
13Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank.PubMed
Shan Luo, Ian Chi Kei Wong, Celine Sze Ling Chui, et al.
Lancet Healthy Longev. 2023 Jul;4(7):e337-e344. doi: 10.1016/S2666-7568(23)00085-5.
BACKGROUND: Metformin, a first-line medication for type 2 diabetes, might also have a protective effect against ageing-related diseases, but so far little experimental evidence is available. We sought to assess the target-specific effect of metformin on biomarkers of ageing in the UK Biobank. METHODS: In this drug target mendelian randomisation study, we assessed the target-specific effect of four putative targets of metformin (AMPK, ETFDH, GPD1, and PEN2), involving ten genes. Genetic variants with evidence of causation of gene expression, glycated haemoglobin A (HbA), and colocalisation were used as instruments mimicking the target-specific effect of metformin via HbA lowering. The biomarkers of ageing considered were phenotypic age (PhenoAge) and leukocyte telomere length. To triangulate the evidence, we also assessed the effect of HbA on the outcomes using a polygenic mendelian randomisation design and assessed the effect of metformin use on these outcomes using a cross-sectional observational design. FINDINGS: GPD1-induced HbA lowering was associated with younger PhenoAge (β -5·26, 95% CI -6·69 to -3·83) and longer leukocyte telomere length (β 0·28, 0·03 to 0·53), and AMPKγ2 (PRKAG2)-induced HbA lowering was associated with younger PhenoAge (β -4·88, -7·14 to -2·62) but not with longer leukocyte telomere length. Genetically predicted HbA lowering was associated with younger PhenoAge (β -0·96 per SD lowering of HbA, 95% CI -1·19 to -0·74) but not associated with leukocyte telomere length. In the propensity score matched analysis, metformin use was associated with younger PhenoAge (β -0·36, 95% CI -0·59 to -0·13) but not with leukocyte telomere length. INTERPRETATION: This study provides genetic validation evidence that metformin might promote healthy ageing via targets GPD1 and AMPKγ2 (PRKAG2), and the effect could be in part due to its glycaemic property. Our findings support further clinical research into metformin and longevity. FUNDING: Healthy Longevity Catalyst Award, National Academy of Medicine, and Seed Fund for Basic Research, The University of Hong Kong.
14Multivariate genome-wide analysis of aging-related traits identifies novel loci and new drug targets for healthy aging.PubMed
Daniel B Rosoff, Lucas A Mavromatis, Andrew S Bell, et al.
Nat Aging. 2023 Aug;3(8):1020-1035. doi: 10.1038/s43587-023-00455-5. Epub 2023 Aug 7.
The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings; however, aging-related endpoints have been primarily assessed individually. Using data from these traits and multivariate genome-wide association study methods, we modeled their underlying genetic factor ('mvAge'). mvAge (effective n = ~1.9 million participants of European ancestry) identified 52 independent variants in 38 genomic loci. Twenty variants were novel (not reported in input genome-wide association studies). Transcriptomic imputation identified age-relevant genes, including VEGFA and PHB1. Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on mvAge (P value = 8.41 × 10). Similarly, genetically proxied thiazolidinediones (P value = 3.50 × 10), proprotein convertase subtilisin/kexin 9 inhibition (P value = 1.62 × 10), angiopoietin-like protein 4, beta blockers and calcium channel blockers also had beneficial Mendelian randomization estimates. Extending the drug-target Mendelian randomization framework to 3,947 protein-coding genes prioritized 122 targets. Together, these findings will inform future studies aimed at improving healthy aging.
15The Effects of Metformin on Weight Loss, Cardiovascular Health, and Longevity.PubMed
Ashwin A Pillai, Lara Melo, William H Frishman, et al.
Cardiol Rev. 2024 Dec 11. doi: 10.1097/CRD.0000000000000832.
Metformin, a biguanide derived from Galega officinalis, was first synthesized by Werner and Bell in 1922. Metformin was approved for the treatment of diabetes by the US Food and Drug Administration in 1994. It has since become the most widely used oral antidiabetic agent. The exact mechanisms by which metformin exerts its clinical effects remain the subject of ongoing research. Metformin interacts with multiple molecular pathways, and the downstream effects of which affect weight, cardiovascular health, and longevity. Metformin reduces hunger by mitigating insulin resistance in the hypothalamic pro-opiomelanocortin neurons. It enhances satiety by stimulating the enteral release of glucagon-like peptide 1. It also induces favorable changes to enteric microbiota, enhancing metabolism. These effects cumulatively contribute to metformin-induced weight loss. Metformin use has shown associations with improved cardiovascular outcomes including reduced all-cause mortality, lower rates of myocardial infarctions, and improved heart failure outcomes. Many of these actions are mediated through the direct activation of adenosine monophosphate-activated kinase (AMPK), which, in turn, enhances cellular energy production and endothelial nitric oxide synthase-mediated vascular relaxation. It antagonizes proinflammatory cytokines, reducing cardiac fibrosis and remodeling. The metformin-AMPK pathway may also explain the potential utility of metformin in mitigating aging. Acting through AMPK, it inhibits the mammalian target of rapamycin, leading to increased autophagy and cell growth. The metformin-AMPK-sirtuin pathway may also contribute to longevity. In this review, we will discuss the use of metformin in weight loss, cardiovascular health, and longevity, highlighting the historic background, molecular mechanisms, and current evidence.
16Integration of a fasting-mimicking diet programme in primary care for type 2 diabetes reduces the need for medication and improves glycaemic control: a 12-month randomised controlled trial.PubMed
Elske L van den Burg, Marjolein P Schoonakker, Petra G van Peet, et al.
Diabetologia. 2024 Jul;67(7):1245-1259. doi: 10.1007/s00125-024-06137-0. Epub 2024 Mar 28.
AIMS/HYPOTHESIS: The aim of this study was to evaluate the impact on metabolic control of periodic use of a 5-day fasting-mimicking diet (FMD) programme as an adjunct to usual care in people with type 2 diabetes under regular primary care surveillance. METHODS: In this randomised, controlled, assessor-blinded trial, people with type 2 diabetes using metformin as the only glucose-lowering drug and/or diet for glycaemic control were randomised to receive 5-day cycles of an FMD monthly as an adjunct to regular care by their general practitioner or to receive regular care only. The primary outcomes were changes in glucose-lowering medication (as reflected by the medication effect score) and HbA levels after 12 months. Moreover, changes in use of glucose-lowering medication and/or HbA levels in individual participants were combined to yield a clinically relevant outcome measure ('glycaemic management'), which was categorised as improved, stable or deteriorated after 1 year of follow-up. Several secondary outcome measures were also examined, including changes in body weight. RESULTS: One hundred individuals with type 2 diabetes, age 18-75 years, BMI ≥27 kg/m, were randomised to the FMD group (n=51) or the control group (n=49). Eight FMD participants and ten control participants were lost to follow-up. Intention-to-treat analyses, using linear mixed models, revealed adjusted estimated treatment effects for the medication effect score (-0.3; 95% CI -0.4, -0.2; p<0.001), HbA (-3.2 mmol/mol; 95% CI -6.2, -0.2 and -0.3%; 95% CI -0.6, -0.0; p=0.04) and body weight (-3.6 kg; 95% CI -5.2, -2.1; p<0.001) at 12 months. Glycaemic management improved in 53% of participants using FMD vs 8% of control participants, remained stable in 23% vs 33%, and deteriorated in 23% vs 59% (p<0.001). CONCLUSIONS/INTERPRETATION: Integration of a monthly FMD programme in regular primary care for people with type 2 diabetes who use metformin as the only glucose-lowering drug and/or diet for glycaemic control reduces the need for glucose-lowering medication, improves HbA despite the reduction in medication use, and appears to be safe in routine clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03811587 FUNDING: The project was co-funded by Health~Holland, Top Sector Life Sciences & Health, the Dutch Diabetes Foundation and L-Nutra.
17Metformin: Paradigm of therapeutic pleiotropism (1922-2025).PubMed
Alberto de Leiva Hidalgo, Ferran Morell Brotad
Med Clin (Barc). 2025 Dec;165(6):107189. doi: 10.1016/j.medcli.2025.107189. Epub 2025 Oct 8.
Werner and Bell synthesized metformin in 1922. In 2006, the International Diabetes Federation recognized metformin as the first-line drug for the treatment of type 2 diabetes. This review updates the pharmacological properties, adverse effects and therapeutic pleiotropism of metformin applied to the treatment of diabetes mellitus, gestational diabetes, polycystic ovary syndrome, appetite regulation, intestinal flora dysbiosis, cardiovascular and renal protection, treatment of idiopathic pulmonary fibrosis, reduction of risk and mortality from various neoplasms, and prolongation of lifespan.
18Metformin-enhances resilience via hormesis.PubMed
Edward J Calabrese, Evgenios Agathokleous, Rachna Kapoor, et al.
Ageing Res Rev. 2021 Nov;71:101418. doi: 10.1016/j.arr.2021.101418. Epub 2021 Aug 5.
The present paper demonstrates that metformin (MF) induced a broad spectrum of hormetic biphasic dose responses in a wide range of experimental studies, affecting multiple organ systems, cell types, and endpoints enhancing resilience to chemical stresses in preconditioning and co-current exposure protocols. Detailed mechanistic evaluations indicate that MF-induced hormetic-adaptive responses are mediated often via the activation of adenosine monophosphate-activated kinase (AMPK) protein and its subsequent upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). Hormesis-induced protective responses by MF are largely mediated via a vast and highly integrated anti-inflammatory molecular network that enhances longevity and delays the onset and slows the progression of neurodegenerative and other chronic diseases.
19We are all aging, and here's why.PubMed
Atharva Shinde, Gargi Deore, Kedar P Navsariwala, et al.
Aging Med (Milton). 2022 Oct 3;5(3):211-231. doi: 10.1002/agm2.12223. eCollection 2022 Sep.
Here, through this review, we aim to serve this purpose by first discussing the statistics and aging demographics, including the life expectancy of the world and India, along with the gender life expectancy gap observed throughout the world, followed by explaining the hallmarks and integral causes of aging, along with the role played by senescent cells in controlling inflammation and the effect of senescence associated secretory phenotype on longevity. A few of the molecular pathways which are crucial in modulating the process of aging, such as the nutrient-sensing mTOR pathway, insulin signaling, Nrf2, FOXO, PI3-Akt, Sirtuins, and AMPK, and their effects are also covered in paramount detail. A diverse number of ingenious research methodologies are used in the modern era of longevity exploration. We have attempted to cover these methods under the umbrella of three broad categories: in vitro, in vivo, and in silico techniques. The drugs developed to attenuate the aging process, such as rapamycin, metformin, resveratrol, etc. and their interactions with the above-mentioned molecular pathways along with their toxicity have also been reviewed in detail.
20Targeting the hallmarks of aging: mechanisms and therapeutic opportunities.PubMed
Fumihiro Sanada, Shinichiro Hayashi, Ryuichi Morishita
Front Cardiovasc Med. 2025 Jul 1;12:1631578. doi: 10.3389/fcvm.2025.1631578. eCollection 2025.
Aging is a complex biological process characterized by a gradual decline in cellular and physiological function, increasing vulnerability to chronic diseases and mortality. It involves a set of interconnected mechanisms known as the hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, and dysregulated nutrient sensing. These processes act at molecular, cellular, and systemic levels, contributing to age-related disorders such as neurodegeneration, cardiovascular disease, and metabolic syndromes. Emerging therapeutic strategies aim to delay or reverse aging by targeting specific hallmarks. These include senolytics to eliminate senescent cells, NAD boosters and mitophagy inducers to improve mitochondrial health, epigenetic reprogramming, and caloric restriction mimetics such as metformin and rapamycin to modulate nutrient-sensing pathways. Advances in regenerative medicine, gene editing, and organ cross-talk modulation are also contributing to the development of personalized, multi-targeted anti-aging therapies. Integration of omics technologies and biomarker research is expected to enhance our ability to monitor biological aging and optimize interventions for healthy longevity. This review highlights the current understanding of the hallmarks of aging and explores potential treatment strategies in light of our recent findings.