Metabolism sits at the center of modern aging research. Aging is now framed by its underlying biology rather than by chronology, following the 2013 Cell paper by Lopez-Otin and colleagues that grouped what drives cellular aging into a small set of hallmarks. The updated 2023 version in Cell lists twelve of them. Three of them, mitochondrial dysfunction, deregulated nutrient-sensing, and chronic inflammation, form the metabolic core. Interventions that engage these pathways have moved into human trials, though the earliest headline claims have not held up cleanly on closer inspection.
The 12 hallmarks of aging give the field a shared vocabulary
The hallmarks framework, first published by Lopez-Otin, Blasco, Partridge, Serrano, and Kroemer in 2013 and expanded in 2023, sets three criteria for what counts as a hallmark of aging: the change appears with age, accelerating it accelerates aging, and reversing it delays aging. The 2023 version lists twelve interconnected hallmarks, from genomic instability to dysbiosis. Several are metabolic in the strict sense (mitochondrial dysfunction, deregulated nutrient-sensing, disabled macroautophagy), and several more are downstream of metabolism, notably chronic inflammation and altered intercellular communication.
The authors describe the framework as one where “aging is driven by hallmarks fulfilling the following three premises: their age-associated manifestation, the acceleration of aging by experimentally accentuating them, and the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them.” It is a research scaffolding, not a treatment plan, but it explains why so many aging interventions cluster around a small number of pathways.
Mitochondria decline in number and function with age
Mitochondria are the organelles that generate most of a cell’s adenosine triphosphate (ATP). With age, their number falls, their membrane potential drops, and they leak more reactive oxygen species, molecules that damage the surrounding cell. Skeletal muscle shows this decline particularly clearly, which is one reason muscle mass and strength fall in later life even in people who stay active.
Exercise is the single most effective intervention against this trend. Both aerobic and resistance training stimulate mitochondrial biogenesis, the growth of new mitochondria, and improve the function of existing ones. The effect is measurable in older adults within weeks of starting a program.
Nutrient-sensing pathways shift the balance between growth and repair
Cells sense nutrient availability through a handful of pathways, chief among them mTOR, which promotes cell growth when nutrients are plentiful, and AMP-activated protein kinase (AMPK), which promotes cellular repair and recycling when they are scarce. In young cells, these pathways balance growth and maintenance. In older cells, mTOR tends to run high and AMPK low, tilting the balance toward continuous growth signaling and away from the housekeeping processes, such as autophagy, that clear damaged proteins and organelles.
Chronic caloric excess pushes this imbalance further; sustained caloric restriction, in animal studies, extends lifespan and reverses several hallmarks. Whether the same is true in humans, at achievable intake levels and without harm, is one of the field’s biggest unsettled questions.
Rapamycin and metformin are the two most-studied candidate drugs
Two prescription drugs have driven most of the geroscience trial activity. Rapamycin, an mTOR inhibitor originally used to prevent transplant rejection, extends lifespan in mice across multiple studies. In humans, the PEARL trial reported in 2025 that low-dose weekly rapamycin was safe over 48 weeks in a healthy adult cohort and produced a lean-tissue benefit in women, but missed its primary endpoint of reducing visceral fat. Metformin, a first-line type 2 diabetes drug, has decades of observational data suggesting lower mortality and cancer incidence in the diabetic populations who take it. The definitive metformin trial, TAME (Targeting Aging with Metformin), was designed to enroll about 3,000 non-diabetic adults aged 65 to 79 and test whether metformin delays a composite of cardiovascular events, cancer, dementia, and death. It has not yet launched.
The taurine story shows how quickly a finding can reverse
In 2023, a study in Science by Singh and colleagues reported that circulating taurine falls with age in mice, monkeys, and humans, that supplementing taurine extends lifespan and healthspan in mice, and that lower taurine levels correlated with several age-related diseases in a human cohort. The paper generated substantial coverage and a wave of supplement sales.
Two years later, a study by Marcangeli and colleagues published in Aging Cell (2025) directly tested the human end of that hypothesis and found no association between circulating taurine and age, muscle mass, strength, physical performance, or mitochondrial function. The authors concluded that taurine deficiency is unlikely to be a primary driver of aging in humans. The animal work stands; the human translation does not.
What the evidence cannot yet answer
Two questions dominate the field. The first is whether any candidate drug can slow the composite outcomes that matter, cardiovascular events, cancer, dementia, and death, in generally healthy adults. TAME was designed to answer that for metformin and has not yet started. The second is whether the animal-to-human translation for any of the leading interventions holds. The taurine reversal is a cautionary case; caloric restriction in humans has been harder to sustain and less dramatic in effect than in short-lived model species; senolytic drugs that clear aged cells have shown mixed results in early clinical trials. The interventions with the most consistent human evidence remain the ones that have been recommended for a century: aerobic and resistance exercise, adequate protein, quality sleep.
References
- Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell, 2023; 186: 243-278. DOI: 10.1016/j.cell.2022.11.001
- Singh P, Gollapalli K, Mangiola S, et al. Taurine deficiency as a driver of aging. Science, 2023; 380: eabn9257. DOI: 10.1126/science.abn9257
- Marcangeli V, Youssef L, Dulac M, et al. Experimental evidence against taurine deficiency as a driver of aging in humans. Aging Cell, 2025. DOI: 10.1111/acel.70191
- Moel M, Harinath G, Lee V, et al. Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results. Aging, 2025. DOI: 10.18632/aging.206235
- Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metabolism, 2016; 23: 1060-1065. DOI: 10.1016/j.cmet.2016.05.011