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The pursuit of youth and longevity has accompanied human societies for millennia, evolving from mythological and esoteric traditions toward a scientific understanding of aging. Early concepts such as Greek ambrosia, Taoist elixirs, and medieval \"aqua vitae\" reflected symbolic or spiritual interpretations. A major conceptual transition occurred between the late nineteenth and early twentieth centuries, when aging began to be framed as a biological process. Pioneering ideas by Metchnikoff, together with early and sometimes controversial attempts such as Voronoff's grafting experiments, marked the first efforts to rationalize aging scientifically. In the mid-twentieth century, discoveries including the Hayflick limit, telomere biology, oxidative stress, and mitochondrial dysfunction established gerontology as an experimental discipline. Contemporary geroscience integrates these insights into a coherent framework linking cellular pathways to chronic disease risk. Central roles are played by nutrient-sensing networks such as mTOR, AMPK, and sirtuins, together with mitochondrial regulation, proteostasis, and cellular senescence. Interventions, including caloric restriction, fasting-mimicking diets, rapalogues, sirtuin activators, metformin, NAD boosters, senolytics, and antioxidant combinations such as GlyNAC, show consistent benefits across multiple model organisms, with early human trials reporting improvements in immune function, mitochondrial activity, and biomarkers of aging. Recent advances extend to epigenetic clocks, multi-omic profiling, gender-specific responses, and emerging regenerative and gene-based approaches. Overall, the evolution from historical elixirs to molecular geroscience highlights a shift toward targeting aging itself as a modifiable biological process and outlines a growing translational landscape aimed at extending healthspan and reducing age-related morbidity.

The identification of plasma proteins that systematically change with age and, independent of chronological age, predict accelerated decline of health is an expanding area of research. Circulating proteins are ideal translational “omics” since they are final effectors of physiological pathways and because physicians are accustomed to use information of plasma proteins as biomarkers for diagnosis, prognosis, and tracking the effectiveness of treatments. Recent technological advancements, including mass spectrometry (MS)‐based proteomics, multiplexed proteomic assay using modified aptamers (SOMAscan), and Proximity Extension Assay (PEA, O‐Link), have allowed for the assessment of thousands of proteins in plasma or other biological matrices, which are potentially translatable into new clinical biomarkers and provide new clues about the mechanisms by which aging is associated with health deterioration and functional decline. We carried out a detailed literature search for proteomic studies performed in different matrices (plasma, serum, urine, saliva, tissues) and species using multiple platforms. Herein, we identified 232 proteins that were age‐associated across studies. Enrichment analysis of the 232 age‐associated proteins revealed metabolic pathways previously connected with biological aging both in animal models and in humans, most remarkably insulin‐like growth factor (IGF) signaling, mitogen‐activated protein kinases (MAPK), hypoxia‐inducible factor 1 (HIF1), cytokine signaling, Forkhead Box O (FOXO) metabolic pathways, folate metabolism, advance glycation end products (AGE), and receptor AGE (RAGE) metabolic pathway. Information on these age‐relevant proteins, likely expanded and validated in longitudinal studies and examined in mechanistic studies, will be essential for patient stratification and the development of new treatments aimed at improving health expectancy. A review of studies that assessed proteins in micro‐specimens of biological fluids or tissues revealed that a substantial group of proteins change systematically with aging. These proteins are strong candidate for developing clinical tools aimed at measuring biological aging and predict changes in health span.

Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously, we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al., 2020). Here, we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome). We used data from the Dunedin Study 1972-1973 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets. DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge. DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience. This research was supported by US-National Institute on Aging grants AG032282, AG061378, AG066887, and UK Medical Research Council grant MR/P005918/1.

Biomarkers developed from DNA methylation (DNAm) data are of growing interest as predictors of health outcomes and mortality in older populations. However, it is unknown how epigenetic aging fits within the context of known socioeconomic and behavioral associations with aging-related health outcomes in a large, population-based, and diverse sample. This study uses data from a representative, panel study of US older adults to examine the relationship between DNAm-based age acceleration measures in the prediction of cross-sectional and longitudinal health outcomes and mortality. We examine whether recent improvements to these scores, using principal component (PC)-based measures designed to remove some of the technical noise and unreliability in measurement, improve the predictive capability of these measures. We also examine how well DNAm-based measures perform against well-known predictors of health outcomes such as demographics, SES, and health behaviors. In our sample, age acceleration calculated using “second and third generation clocks,” PhenoAge, GrimAge, and DunedinPACE, is consistently a significant predictor of health outcomes including cross-sectional cognitive dysfunction, functional limitations and chronic conditions assessed 2 y after DNAm measurement, and 4-y mortality. PC-based epigenetic age acceleration measures do not significantly change the relationship of DNAm-based age acceleration measures to health outcomes or mortality compared to earlier versions of these measures. While the usefulness of DNAm-based age acceleration as a predictor of later life health outcomes is quite clear, other factors such as demographics, SES, mental health, and health behaviors remain equally, if not more robust, predictors of later life outcomes.

Ageing and diabetes lead to similar organ dysfunction that is driven by parallel molecular mechanisms, one of which is cellular senescence. The abundance of senescent cells in various tissues increases with age, obesity and diabetes. Senescent cells have been directly implicated in the generation of insulin resistance. Recently, drugs that preferentially target senescent cells, known as senolytics, have been described and recently entered clinical trials. In this review, we explore the biological links between ageing and diabetes, specifically focusing on cellular senescence. We summarise the current data on cellular senescence in key target tissues associated with the development and clinical phenotypes of type 2 diabetes and discuss the therapeutic potential of targeting cellular senescence in diabetes.

[This corrects the article DOI: 10.3389/fimmu.2025.1570441.].

Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their “biological aging” (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies. The global population is aging, driving up age-related disease morbidity. Antiaging interventions are needed to reduce the burden of disease and protect population productivity. Young people are the most attractive targets for therapies to extend healthspan (because it is still possible to prevent disease in the young). However, there is skepticism about whether aging processes can be detected in young adults who do not yet have chronic diseases. Our findings indicate that aging processes can be quantified in people still young enough for prevention of age-related disease, opening a new door for antiaging therapies. The science of healthspan extension may be focused on the wrong end of the lifespan; rather than only studying old humans, geroscience should also study the young.

Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from short-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research owing to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with the model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population. This article is part of the theme issue ‘Evolution of the primate ageing process’.

Tissue regeneration requires coordination between resident stem cells and local niche cells 1 , 2 . Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity 3 was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing 4 ) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life. A lifetime cartography of in vivo senescent cells shows that they are heterogeneous. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing and arrests stem cell proliferation and tissue regeneration.

Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood-DNA-methylation measure that is sensitive to variation in pace of biological aging among individuals born the same year. We first modeled change-over-time in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in n = 954 members of the Dunedin Study born in 1972–1973. Rates of change in each biomarker over ages 26–38 years were composited to form a measure of aging-related decline, termed Pace-of-Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace-of-Aging, called DunedinPoAm for Dunedin(P)ace(o)f(A)ging(m)ethylation. Validation analysis in cohort studies and the CALERIE trial provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person’s pace of biological aging. People’s bodies age at different rates. Age-related biological changes that increase the risk of disease and disability progress rapidly in some people. In others, these processes occur at a slower pace, allowing those individuals to live longer, healthier lives. This observation has led scientists to try to develop therapies that slow aging. The hope is that such treatments could prevent or delay diseases like heart disease or dementia, for which older age is the leading risk factor. Studies in animals have identified treatments that extend the creatures’ lives and slow age-related disease. But testing these treatments in humans is challenging. Our lives are much longer than the worms, flies or mice used in the experiments. Scientists would have to follow human study participants for decades to detect delays in disease onset or an extension of their lives. An alternative approach is to try to develop a test that measures the pace of aging, or essentially “a speedometer for aging”. This would allow scientists to more quickly determine if treatments slow the aging process. Now, Belsky et al. show a blood test designed to measure the pace of aging predicts which people are at increased risk of poor health, chronic disease and an earlier death. First, data about chemical changes to an individual’s DNA, called DNA methylation, were analyzed from white blood cell samples collected from 954 people in a long-term health study known as “The Dunedin Study”. Using the data, Belsky et al. then developed an algorithm – named “DunedinPoAm” – that identified people with an accelerated or slowed pace of aging based on a single blood test. Next, they used the algorithm on samples from participants in three other long-term studies. This verified that those people the algorithm identified as aging faster had a greater risk of poor health, developing chronic diseases or dying earlier. Similarly, those identified as aging more slowly performed better on tests of balance, strength, walking speed and mental ability, and they also looked younger to trained raters. Additionally, Belsky et al. used the test on participants in a randomized trial testing whether restricting calories had potential to extend healthy lifespan. The results suggested that the calorie restriction could counter the effects of an accelerated pace of aging. The test developed by Belsky et al. may provide an alternate way of measuring whether age-slowing treatments work. This would allow faster testing of treatments that can extend the healthy lifespan of humans. The test may also help identify individuals with accelerated aging. This might help public health officials test whether policies or programs can help people lead longer, healthier lives.