Giorgi Svanishvili 
Anatomical Researches and Skills Centre, Tbilisi, Georgia
Correspondence to: giorgisvanishvili85@gmail.com
Additional information
- Ethical approval: N/a
- Consent: N/a
- Funding: No industry funding
- Conflicts of interest: N/a
- Author contribution: Giorgi Svanishvili – Conceptualization, Writing – original draft, review and editing
- Guarantor: Giorgi Svanishvili
- Provenance and peer-review:
Commissioned and externally peer-reviewed - Data availability statement: N/a
Keywords: Telomere shortening, Mitochondrial dysfunction, Nonlinear aging, Senescence-associated secretory phenotype, Lipid metabolism disruptions.
Peer-review
Received: 31 December 2024
Revised: 15 January 2025
Accepted: 16 January 2025
Published: 28 January 2025
Abstract
Aging is a biological process marked by a gradual decline in physiological functions and increased susceptibility to chronic diseases, including cardiovascular diseases, diabetes, neurodegenerative disorders, and cancer. This review explores the molecular mechanisms driving aging, such as telomere shortening, mitochondrial dysfunction, issues in protein regulation, and inflammation caused by senescent cells. These processes contribute to cellular damage, tissue degeneration, and systemic dysfunction. Recent studies reveal the nonlinear nature of aging, with critical transitions at ages 44 and 60. At 44, metabolic and structural changes, including lipid metabolism disruptions and tissue instability, become evident. At 60, oxidative stress, immune dysfunction, and metabolic decline escalate, increasing the risks of cardiovascular disease, kidney dysfunction, and type 2 diabetes. These turning points highlight opportunities for targeted interventions to delay disease onset and improve healthspan. The review also examines potential therapies, including interventions aimed at mitochondrial function, proteostasis, and inflammation. By addressing key mechanisms of aging, these approaches aim to reduce the burden of age-related diseases and extend the period of healthy living. This review underscores the urgent need to address aging as a critical challenge for global healthcare. Understanding the molecular mechanisms and nonlinear dynamics of aging provides actionable insights for developing strategies to improve quality of life and reduce the societal impact of aging.
Introduction
Aging is an inevitable and multifaceted biological process characterized by a progressive decline in physiological function across all organ systems. This gradual deterioration is induced by the cumulative accumulation of damage over time in response to internal and external stressors. Importantly, aging is the predominant risk factor for numerous chronic diseases,1 including cardiovascular diseases (CVDs),2,3 neurodegenerative disorders like Alzheimer’s4 and Parkinson’s diseases,5 diabetes,6 cancer,7 and osteoporosis.8 As such, understanding the mechanisms of aging holds the key to uncovering new therapeutic strategies for age-related diseases and promoting healthier lifespans. Globally, the demographic landscape of aging is shifting rapidly. Advances in medical technology have significantly increased average life expectancy. Coupled with declining birth rates, this has led to an unprecedented rise in the aging population. According to the United Nations, by 2050, one in six people worldwide will be over the age of 65, with the number of individuals aged 80 or older expected to triple.9 While lifespan has increased, the healthspan—the period of life spent in good health—has not kept pace. This disparity poses substantial challenges for global healthcare systems and socioeconomic structures, emphasizing the urgency of promoting “healthy aging,” defined as the maintenance of functional independence and quality of life into older age. Aging will impose a formidable global socioeconomic burden, as it remains the primary risk factor for most chronic diseases.
On a molecular level, aging is driven by a variety of interconnected mechanisms. These include cellular senescence, stem cell exhaustion, telomere dysfunction, mitochondrial dysfunction, loss of proteostasis, and epigenetic changes. Cellular senescence—a permanent arrest of cell proliferation—was first reported in the 1960s and has since been identified as a major contributor to tissue aging and age-related pathologies.10 Senescent cells accumulate DNA damage, undergo epigenetic alterations, and exhibit metabolic dysregulation, all of which impair tissue repair and function. Importantly, cellular senescence is accompanied by the senescence-associated secretory phenotype (SASP), which triggers inflammatory responses and propagates aging signals throughout tissues, compounding systemic decline.11,12
Interestingly, aging does not progress in a simple linear fashion. Emerging evidence indicates that the risk of age-related diseases accelerates at specific points during the human lifespan. For instance, in the United States, the prevalence of cardiovascular diseases jumps from approximately 40% between the ages of 40 and 59 to over 75% between 60 and 79 and reaches 86% in individuals older than 80.13 Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, follow similar patterns, exhibiting critical turning points around the ages of 40 and 65, respectively.14,15 Nonlinear dynamics of aging have also been observed at the molecular level. Recent studies have revealed distinct nonlinear changes in RNA and protein expression, as well as DNA methylation patterns, with specific molecular transitions occurring at critical life stages.16 For example, certain DNA methylation sites display changes that follow a power law pattern during aging, suggesting key shifts in biological regulation during transitional periods such as the 30s, 40s, and 60s.17
Omics technologies—including genomics, transcriptomics, and proteomics—have revolutionized the study of aging by providing system-level insights into molecular changes across tissues and organisms. Transcriptomic studies have demonstrated that gene expression patterns vary greatly during aging and across tissues, implicating fundamental roles for inflammatory and developmental pathways. Proteomic analyses have highlighted changes in the protein composition of blood, which reflect systemic aging and the biological state of different tissues. For example, blood contains proteins derived from nearly all cell types, making it an invaluable resource for identifying biomarkers and understanding disease biology. These molecular alterations are not restricted to humans; studies on model organisms, such as flies and chimpanzees, have shown similar patterns of accelerated decline past middle and advanced age, suggesting evolutionary conservation of aging mechanisms.
The biological process of aging is plastic, meaning it can be influenced by environmental, genetic, and lifestyle factors. Historical studies have demonstrated the effects of caloric restriction in extending lifespan and delaying age-related diseases in mice and rats.18 Similarly, the discovery of long-lived genetic strains in model organisms such as C. elegans has paved the way for understanding pathways that regulate aging. Among these pathways, oxidative stress—mediated by reactive oxygen species (ROS)— has emerged as a central driver of aging and age-related pathologies.19 Chronic oxidative stress damages cellular components, contributing to telomere attrition, DNA damage, and mitochondrial dysfunction, all of which are hallmarks of aging.20,21 Furthermore, large-scale chromatin reorganization, including heterochromatin erosion, has been identified as an intrinsic feature of cellular senescence.22 This destabilizes the genome, activates transposable elements, and triggers inflammatory responses, highlighting the complex interplay between nuclear and cytoplasmic processes in aging.
Overall, aging represents a complex interplay of molecular, cellular, and systemic changes that contribute to functional decline and increased susceptibility to disease. While significant progress has been made in identifying the hallmarks of aging and its impacts, many questions remain unanswered, particularly regarding the nonlinear progression of aging and its molecular signatures. This review will explore the mechanisms underlying aging, its nonlinear dynamics, its relationship to age-related diseases, and the potential of emerging therapies to promote healthier aging. By gaining a deeper understanding of the aging process, we may unlock strategies to not only extend lifespan but also improve healthspan, thereby addressing one of the most pressing challenges of modern healthcare (Figure 1).
Molecular Mechanisms of Aging, Associated Diseases, and Interventions
At the molecular level, aging is driven by interconnected mechanisms that impair tissue repair, reduce regenerative potential, and lower physiological resilience to stress (Figure 2). Among these mechanisms, telomere shortening, DNA damage accumulation, metabolic alterations, and excessive production of ROS play pivotal roles. Telomere shortening—the progressive reduction of protective caps at the ends of chromosomes—limits cellular division and contributes to genomic instability, a manifestation of aging.23 Accumulated DNA damage, exacerbated by oxidative stress, disrupts cellular homeostasis and drives cells into a state of senescence. Senescent cells adopt a pro-inflammatory phenotype known as the SASP, secreting factors such as IL-6, IL-1β, and TNF-α, which propagate inflammation and damage neighboring cells.24
Credit: https://doi.org/10.1038/s41392-022-01251-0
Mitochondrial dysfunction is another central mechanism in aging, characterized by impaired oxidative phosphorylation (OXPHOS) and increased ROS production.25 ROS-induced oxidative damage to mitochondrial DNA (mtDNA), lipids, and proteins accelerates cellular aging and contributes to diseases such as Alzheimer’s disease (AD), diabetes, and cardiovascular disorders.24 Defective mitophagy, the process of clearing damaged mitochondria, leads to their accumulation, further impairing energy production and triggering chronic inflammation. Dysregulated mitochondrial dynamics, such as decreased fission and altered fusion, disrupt organelle quality control and exacerbate metabolic dysfunction, linking mitochondrial defects to a range of aging-related conditions.24
Findings associated with mitochondria and their role in aging are already well-established in preclinical studies. Mice with mutated mitochondrial DNA polymerase gamma (PolgD257A/D257A) exhibit a shortened lifespan, reduced mitochondrial content, impaired activity of electron transport chain (ETC) complexes, and increased apoptosis.26 Furthermore, oxidants generated by mitochondria are considered a major source of oxidative damage that accumulates with age.27 Recent studies identified five human plasma biomarkers linked to the SASP and increased mortality risk—GDF15, RAGE, VEGFA, PARC, and MMP2.28 The biological decline of these indicators is closely connected to mitochondrial dysfunction. Additionally, in Sod2−/− mice, the loss of mitochondrial superoxide dismutase (SOD2) led to an accumulation of senescent cells, impaired ETC complex II activity, and elevated oxidative stress, highlighting the role of mitochondria in aging and lifespan.29
Loss of proteostasis—the balance of protein synthesis, folding, and degradation—is a critical sign of aging. Proteostasis disruption results in the accumulation of misfolded and aggregated proteins, which impair cellular functions and activate stress responses. Autophagy, including selective forms such as mitophagy, and the ubiquitin-proteasome system (UPS) are key mechanisms for maintaining proteostasis.24 Their decline with age contributes to neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, by promoting protein aggregation and cellular toxicity. SASP plays a multifactorial role in aging-related diseases (Figure 3). The chronic inflammatory environment created by SASP factors accelerates tissue damage and systemic decline. For instance, proteases secreted by senescent cells degrade extracellular matrix components, impairing structural integrity in conditions like osteoarthritis and age-related macular degeneration.24 Growth factors such as TGF-β exacerbate fibrosis, while chemokines like MCP-1 recruit immune cells, amplifying inflammation and altering tissue homeostasis. These processes underscore the SASP’s contribution to the pathogenesis of diverse age-related disorders.24
Credit: https://doi.org/10.1038/s41392-022-01251-0
Molecular interventions targeting these pathways hold promise for mitigating aging-related diseases. Metformin, a widely studied antidiabetic drug, has shown the potential to reduce systemic inflammation and delay age-related diseases.30 However, long-term use of anti-aging therapies must consider potential side effects, emphasizing the need for individualized approaches. Advances in omics technologies, such as proteomics and metabolomics, provide tools to identify biomarkers and design targeted therapies. Future strategies may combine molecular interventions with lifestyle modifications to enhance healthspan and address the multifactorial nature of aging.
Humans’ Nonlinear Aging Nature at 44, and Then at 60
Human aging is a nonlinear process characterized by dynamic molecular changes and distinct inflection points, notably around the ages of 44 and 60. These transitions were identified through a longitudinal multi-omics dataset involving 108 participants aged 25–75, who were monitored over a median of 1.7 years (maximum of 6.8 years) (Figure 4). Female menopause normally occurs between the ages of 45 and 55,31 corresponding with important transition points in all groups. This is also supported by previous studies,32,33 which demonstrate that the transition point around 55 years is not primarily linked to female menopause but rather represents a common event in the aging process of both sexes.
Credit: https://doi.org/10.1038/s43587-024-00692-2
Most of the preclinical studies are rejecting menopause’s influence on metabolism and aging. However, menopause, caused by a decline in estrogen levels, triggers symptoms that affect physical, mental, and sexual health. Estrogen receptors, found throughout the brain—including the hypothalamus (key for temperature regulation, sleep, and circadian rhythms) and regions crucial for learning and memory like the prefrontal cortex, hippocampus, and amygdala—are disrupted during menopause.34,35 This estrogen loss during perimenopause deactivates systems that regulate brain glucose metabolism, forcing the brain to switch to ketone body metabolism as an alternative energy source. This metabolic shift leads to hypometabolism, reduced mitochondrial function, oxidative damage, and increased β-amyloid accumulation, which contribute to neuronal dysfunction.36,37 The dataset, encompassing 135,239 biological features and over 246 billion data points derived from blood, stool, skin swabs, oral swabs, and nasal swabs, provided a robust framework for identifying key age-related molecular changes.38 The first crest at age 44 is marked by significant disruptions in lipid and alcohol metabolism. Pathways such as plasma lipoprotein remodeling (adjusted P = 2.269 × 10−9), chylomicron assembly (adjusted P = 9.065 × 10−7), and alcohol metabolism (adjusted P = 8.485 × 10−7) show early dysregulation. These changes suggest increased susceptibility to CVDs and metabolic disorders, driven by altered energy homeostasis. Shifts in caffeine metabolism (adjusted P = 0.00378) reflect broader systemic changes in enzymatic activity and metabolic efficiency, underscoring the metabolic reorganization occurring at this age.38
Structural integrity begins to decline, with dysregulation in extracellular matrix (ECM) components such as glycosaminoglycans (GAGs) and phosphatidylinositols, which are crucial for skin and muscle stability. ECM structural components (adjusted P = 3.32 × 10−8), actin filament organization (adjusted P = 8.406 × 10−9), and cell adhesion pathways (adjusted P = 3.618 × 10−5) highlight reductions in tissue elasticity and strength. These molecular patterns align with observable declines in skin hydration and muscle mass, setting the stage for accelerated aging-related structural deficits.38 At age 60, molecular changes intensify, signifying advanced functional decline and elevated disease risks. Oxidative stress becomes a predominant driver of aging, with pathways associated with ROS production and mitochondrial dysfunction showing significant upregulation. Modules related to mRNA stability, such as mRNA destabilization (adjusted P = 0.0032) and positive regulation of mRNA metabolic processes (adjusted P = 0.00177), highlight widespread disruptions in cellular homeostasis and repair. Autophagy, a key process for clearing damaged cellular components, also exhibits nonlinear changes, exacerbating cellular dysfunction.38
Immune system alterations, indicative of immunosenescence, are prominent at this age. Acute-phase response (adjusted P = 2.851 × 10−8), zymogen activation (adjusted P = 4.367 × 10−6), and mononuclear cell differentiation pathways (adjusted P = 9.352 × 10−8) signify a chronic inflammatory state. This systemic inflammation compromises the immune system’s efficiency and accelerates tissue damage. Simultaneously, kidney function and carbohydrate metabolism exhibit marked declines, as evidenced by elevated blood urea nitrogen and glucose levels, respectively, correlating with increased risks of type 2 diabetes (T2D) and renal dysfunction.38 Structural integrity further deteriorates, with ECM-related pathways such as GAG binding (adjusted P = 4.093 × 10−6) and phosphatidylinositol binding (adjusted P = 7.832 × 10−6) showing dysregulation.
Muscle function is notably affected, with declines in structural components of muscle (adjusted P = 0.0162) aligning with accelerated muscle mass loss. These changes are consistent with sarcopenia, a hallmark of advanced aging.38 The transitions at 44 and 60 share common molecular hallmarks, including disruptions in lipid metabolism, ECM stability, and caffeine metabolism (adjusted P = 0.0162). However, they differ in emphasis: the crest at 44 focuses on metabolic reorganization and early structural changes, while the crest at 60 is dominated by oxidative stress, immune dysfunction, and advanced metabolic decline. These distinctions underscore the multifaceted nature of aging and its progression.38 The identification of these nonlinear milestones emphasizes the need for tailored, age-specific interventions. At age 44, strategies targeting lipid metabolism and ECM integrity, combined with lifestyle modifications, could delay the onset of metabolic and structural disorders. At age 60, therapeutic approaches should focus on reducing oxidative stress, enhancing mitochondrial function, and mitigating immune senescence. By integrating multi-omics data with personalized healthcare, we can better address the complexities of aging, extend healthspan, and improve quality of life.
Limitations and Ethical Considerations
While this review provides valuable insights into the molecular mechanisms and nonlinear dynamics of aging, several limitations must be acknowledged. First, the complex interplay between genetic, environmental, and lifestyle factors influencing aging remains incompletely understood. Future research must address how these factors interact across diverse populations to refine intervention strategies. Ethical concerns around healthspan extension are also worth discussing. Advances in anti-aging treatments may worsen existing gaps in healthcare access, disproportionately benefiting persons from wealthy countries or socioeconomic groups. These limitations and ethical problems underline the value of interdisciplinary collaboration in creating fair, effective, and sustainable strategies for aging and health span extension.
Conclusion
Aging is a complex biological process that drives the decline of physiological functions and increases the risk of chronic diseases such as cardiovascular diseases, diabetes, neurodegenerative disorders, and cancer. This review has explored the key mechanisms of aging, including telomere shortening, mitochondrial dysfunction, proteostasis disruption, and inflammation caused by the SASP. These mechanisms collectively contribute to cellular damage, tissue degeneration, and systemic decline. Recent findings emphasize the nonlinear nature of aging, with critical turning points at 44 and 60 years of age. At 44, early metabolic and structural changes become evident, such as lipid and alcohol metabolism disruptions and declines in skin and muscle integrity. By 60, oxidative stress, immune dysfunction, and metabolic deterioration escalate, increasing the risks of cardiovascular and kidney diseases, type 2 diabetes, and other chronic conditions. Recognizing these transitions provides new opportunities for targeted interventions to delay disease progression and extend healthspan.
The societal and healthcare implications of aging are profound. A rapidly growing aging population increases the burden of age-related diseases, necessitating strategies to promote healthier aging. By focusing on early identification of biomarkers and interventions targeting key molecular pathways, it is possible to prevent or delay the onset of chronic diseases, reduce healthcare costs, and improve the quality of life for older adults. In conclusion, understanding the mechanisms and nonlinear progression of aging is essential for developing effective approaches to enhance healthspan and reduce the burden of age-related diseases. Insights from this review provide a foundation for future research and interventions aimed at addressing the challenges of aging in an increasingly aging world.
References
1 Niccoli T, Partridge L. Ageing as a risk factor for disease. Curr Biol. 2012;22:R741-52.
https://doi.org/10.1016/j.cub.2012.07.024
2 Kaufman P, Poliakoff H. Studies on the aging heart; the pattern of rheumatic heart disease in old age (a clinical pathological study). Ann Intern Med. 1950;32:889-904.
https://doi.org/10.7326/0003-4819-32-5-889
3 Yan M, Sun S, Xu K, Huang X, Dou L, Pang J, et al. Cardiac aging: From basic research to therapeutics. Oxid Med Cell Longev. 2021;2021:9570325.
https://doi.org/10.1155/2021/9570325
4 Cortes-Canteli M, Iadecola C. Alzheimer’s disease and vascular aging: JACC focus seminar. J Am Coll Cardiol. 2020;75:942-51.
https://doi.org/10.1016/j.jacc.2019.10.062
5 Hoehn MM, Yahr MD. Parkinsonism: Onset, progression and mortality. Neurology. 1967;17:427-42.
https://doi.org/10.1212/WNL.17.5.427
6 Wilkerson HL. Problems of an aging population: Public health aspects of diabetes. Am J Public Health Nations Health. 1947;37:177-188.
https://doi.org/10.2105/AJPH.37.2.177
7 Berben L, Floris G, Wildiers H, Hatse S. Cancer and aging: Two tightly interconnected biological processes. Cancers (Basel). 2021;13(6):1400. https://doi.org/10.3390/cancers13061400.
https://doi.org/10.3390/cancers13061400
8 Grunewald M, Kumar S, Sharife H, Volinsky E, Gileles-Hillel A, Licht T, Permyakova A, et al. Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span. Science. 2021;373:eabc8479.
https://doi.org/10.1126/science.abc8479
9 United Nations, Department of Economic and Social Affairs. World Social Report 2023: Chapter 1. United Nations
2023 [cited 2024 Dec 17]. Available from: https://www.un.org/development/desa/dspd/wp-content/uploads/sites/22/2023/01/2023wsr-chapter1-.pdf
10 Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614-36.
https://doi.org/10.1016/0014-4827(65)90211-9
11 Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I, et al. Autophagy in healthy aging and disease. Nat Aging. 2021;1:634-50.
https://doi.org/10.1038/s43587-021-00098-4
12 Bell CG, Lowe R, Adams PD, Baccarelli AA, Beck S, Bell JT, et al. DNA methylation aging clocks: Challenges and recommendations. Genome Biol. 2019;20:249.
https://doi.org/10.1186/s13059-019-1824-y
13 Rodgers JL, Jones J, Bolleddu SI, Vanthenapalli S, Rodgers LE, Shah K, et al. Cardiovascular risks associated with gender and aging. J Cardiovasc Dev Dis. 2019;6:19.
https://doi.org/10.3390/jcdd6020019
14 Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013.
https://doi.org/10.1038/nrdp.2017.13
15 Hy LX, Keller DM. Prevalence of AD among whites: A summary by levels of severity. Neurology. 2000;55:198-204.
https://doi.org/10.1212/WNL.55.2.198
16 Márquez EJ, Chung C-H, Marches R, Rossi RJ, Nehar-Belaid D, Eroglu A, et al. Sexual-dimorphism in human immune system aging. Nat Commun. 2020;11:751.
https://doi.org/10.1038/s41467-020-14396-9
17 Li J, Xiong M, Fu X-H, Fan Y, Dong C, Sun X, et al. Determining a multimodal aging clock in a cohort of Chinese women. Med. 2023;4:825-48.
https://doi.org/10.1016/j.medj.2023.06.010
18 McCay CM, Maynard LA, Sperling G, Barnes LL. The Journal of Nutrition. Volume 18 July-December, 1939. Pages 1-13. Retarded growth, life span, ultimate body size and age changes in the albino rat after feeding diets restricted in calories. Nutr Rev. 1975;33:241-3.
https://doi.org/10.1111/j.1753-4887.1975.tb05227.x
19 Mossad O, Batut B, Yilmaz B, Dokalis N, Mezö C, Nent E, et al. Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N(6)-carboxymethyllysine. Nat Neurosci. 2022;25:295-305.
https://doi.org/10.1038/s41593-022-01027-3
20 Li Z, Zhou D, Zhang D, Zhao J, Li W, Sun Y, et al. Folic acid inhibits aging-induced telomere attrition and apoptosis in astrocytes in vivo and in vitro. Cereb Cortex. 2022;32:286-97.
https://doi.org/10.1093/cercor/bhab208
21 Tracy TE, Madero-Pérez J, Swaney DL, Chang TS, Moritz M, Konrad C, et al. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell. 2022;185:712-8.e714.
https://doi.org/10.1016/j.cell.2021.12.041
22 Liu Z, Ji Q, Ren J, Yan P, Wu Z, Wang S, et al. Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging. Dev Cell. 2022;57(11):1347-68.e12. https://doi.org/10.1016/j.devcel.2022.05.004.
https://doi.org/10.1016/j.devcel.2022.05.004
23 Frenck RW Jr, Blackburn EH, Shannon KM. The rate of telomere sequence loss in human leukocytes varies with age. Proc Natl Acad Sci USA. 1998;95:5607-10.
https://doi.org/10.1073/pnas.95.10.5607
24 Guo J, Huang X, Dou L, Yan M, Shen T, Tang W, et al. Aging and aging-related diseases: From molecular mechanisms to interventions and treatments. Sig Transduct Target Ther. 2022;7:391. https://doi.org/10.1038/s41392-022-01251-0
https://doi.org/10.1038/s41392-022-01251-0
25 Smith AL, Whitehall JC, Bradshaw C, Gay D, Robertson F, Blain AP, et al. Age-associated mitochondrial DNA mutations cause metabolic remodelling that contributes to accelerated intestinal tumorigenesis. Nat Cancer. 2020;1:976-89.
https://doi.org/10.1038/s43018-020-00112-5
26 Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429:417-23.
https://doi.org/10.1038/nature02517
27 Shigenaga MK, Hagen TM, Ames BN. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci. 1994;91:10771-8.
https://doi.org/10.1073/pnas.91.23.10771
28 St Sauver JL, Weston SA, Atkinson EJ, Mc Gree ME, Mielke MM, White TA, et al. Biomarkers of cellular senescence and risk of death in humans. Aging Cell. 2023;22:e14006.
https://doi.org/10.1111/acel.14006
29 Velarde MC, Flynn JM, Day NU, Melov S, Campisi J. Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin. Aging (Albany NY). 2012;4:3-12.
https://doi.org/10.18632/aging.100423
30 Soukas AA, Hao H, Wu L. Metformin as anti-aging therapy: Is it for everyone? Trends Endocrinol Metab. 2019;30(10):745-55. https://doi.org/10.1016/j.tem.2019.07.015.
https://doi.org/10.1016/j.tem.2019.07.015
31 Akahashi TA, Johnson KM. Menopause. Med Clin North Am. 2015;99:521-34.
https://doi.org/10.1016/j.mcna.2015.01.006
32 Lehallier B, Gate D, Schaum N, Nanasi T, Lee SE, Yousef H, et al. Undulating changes in human plasma proteome profiles across the lifespan. Nat Med. 2019;25:1843-50.
https://doi.org/10.1038/s41591-019-0673-2
33 Fehlmann T, Lehallier B, Schaum N, Hahn O, Kahraman M, Li Y,
et al. Common diseases alter the physiological age-related blood microRNA profile. Nat Commun. 2020;11:5958.
https://doi.org/10.1038/s41467-020-19665-1
34 Scheyer O, Rahman A, Hristov H, Berkowitz C, Isaacson RS, Diaz Brinton R, et al. Female sex and Alzheimer’s risk: The menopause connection. J Prev Alzheimers Dis. 2018;5:225-30.
https://doi.org/10.14283/jpad.2018.34
35 McEwen BS, Akama KT, Spencer-Segal JL, Milner TA, Waters EM. Estrogen effects on the brain: Actions beyond the hypothalamus via novel mechanisms. Behav Neurosci. 2012;126:4-16.
https://doi.org/10.1037/a0026708
36 Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E. Perimenopause as a neurological transition state. Nat Rev Endocrinol. 2015;11:393-405.
https://doi.org/10.1038/nrendo.2015.82
37 Yin F, Yao J, Sancheti H, Feng T, Melcangi RC, Morgan TE, et al. The perimenopausal aging transition in the female rat brain: Decline in bioenergetic systems and synaptic plasticity. Neurobiol Aging. 2015;36:2282-95.
https://doi.org/10.1016/j.neurobiolaging.2015.03.013
38 Shen X, Wang C, Zhou X, Zhou W, Hornburg D, Wu S, et al. Nonlinear dynamics of multi-omics profiles during human aging. Nat Aging. 2024;4:1619-34. https://doi.org/10.1038/s43587-024-00692-2
https://doi.org/10.1038/s43587-024-00692-2
