From Geroscience to Gerotherapeutics: Can We Target the Biology of Aging?

1. Aging is increasingly being studied as a modifiable biological process

Geroscience is based on the observation that advancing age is the dominant risk factor for many chronic diseases.

But chronological age alone does not explain why two people of the same age can have very different health trajectories.

Research has therefore focused increasingly on the underlying biology of aging.

The current framework describes 12 interconnected hallmarks of aging. These include genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence, chronic inflammation and disrupted nutrient sensing.

These mechanisms interact across cells, tissues and organs.

This creates an important possibility: modifying shared aging mechanisms might eventually influence several age-related conditions simultaneously rather than addressing each disease only after it develops.

2. Biological-age measurement is becoming increasingly sophisticated

A major challenge for geroscience is determining whether an intervention actually changes the trajectory of biological aging.

Biomarkers have progressed substantially.

Early approaches included DNA methylation-based aging clocks. Newer methods integrate multiple biological signals and can examine aging at the level of individual organs.

The review highlights organ-specific plasma proteomic signatures capable of identifying accelerated aging in particular organs and predicting multiple age-related diseases.

These developments could help identify people with different patterns of biological aging and support more individualized approaches to prevention and treatment.

3. Metformin provides important pharmacological evidence — but not proof of slower aging in humans

Metformin is one of the most extensively studied candidate gerotherapeutics.

It influences multiple biological mechanisms associated with aging and has therefore become central to attempts to translate geroscience into clinical research.

The review highlights a 40-month multiomics study in cynomolgus monkeys in which metformin treatment was associated with a 6.41-year reduction in plasma proteomic biological age.

This is an important experimental finding.

But it was observed in non-human primates. It does not demonstrate that metformin slows biological aging or extends lifespan in healthy humans.

The authors also highlight the Targeting Aging with Metformin (TAME) initiative as an important translational step because it is designed to test whether targeting aging biology can delay multiple age-related diseases as a composite outcome rather than treating each disease independently.

4. Rapamycin shows the gap between strong preclinical evidence and human evidence

Rapamycin is one of the most prominent candidate gerotherapeutics.

The review describes extensive preclinical evidence supporting its effects on longevity and aging-related pathways.

Human evidence is much more limited.

The authors cite a systematic review of human studies that found some potentially beneficial effects but insufficient evidence to recommend rapamycin as a gerotherapeutic intervention for healthy adults outside clinical trials.

Rapamycin therefore illustrates a central challenge in longevity medicine: compelling effects in experimental models do not automatically translate into proven clinical benefits in humans.

5. Existing metabolic medicines may also influence aging-related pathways

Two major therapeutic classes have attracted increasing interest in geroscience: sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists.

These medicines already have established clinical indications and health benefits in appropriately selected patients.

The review discusses additional mechanisms that could be relevant to aging biology.

For sodium-glucose cotransporter-2 inhibitors, this includes a proposed indirect senolytic effect involving enhanced immune surveillance and clearance of senescent cells.

For glucagon-like peptide-1 receptor agonists, the authors highlight potential effects on chronic age-related inflammation, or inflammaging, alongside broader metabolic actions.

These findings make both drug classes important candidates for geroscience research.

However, their established benefits in specific diseases should be distinguished from evidence that they slow biological aging itself.

6. Senolytics and other emerging strategies target aging mechanisms more directly

Cellular senescence is one of the hallmarks of aging.

Senescent cells have permanently stopped dividing but can remain metabolically active. Their accumulation may promote inflammation and impair tissue function.

Senolytics are designed to selectively eliminate senescent cells.

Senomorphics aim instead to reduce their harmful biological activity without necessarily removing them.

Other emerging strategies discussed in the review include nicotinamide adenine dinucleotide precursors, intended to influence mitochondrial and sirtuin function.

The authors also describe inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as a mechanistically distinct proregenerative approach with potential relevance to tissue and muscle regeneration.

These approaches demonstrate how rapidly the gerotherapeutic landscape is expanding.

They also demonstrate the considerable distance between identifying a promising biological mechanism and establishing a safe and effective treatment for human aging.

7. Lifestyle remains an important component of geroscience

Gerotherapeutics does not mean that healthy aging depends only on medication.

The review emphasizes multidomain lifestyle interventions because they can influence several hallmarks of aging simultaneously.

Importantly, multidomain lifestyle programs have already demonstrated measurable improvements in intrinsic capacity in randomized clinical trials.

This provides an important clinical context for emerging pharmacological approaches.

Future gerotherapeutics should be considered alongside, rather than as replacements for, established strategies that support metabolic health, physical capacity and overall function.

8. Precision geromedicine could integrate biomarkers, function and targeted interventions

The authors propose the Geroscience-Responsive Aging Care Ecosystem (GRACE).

This three-element service model is designed to operationalize geroscience and gerotherapeutic evidence within the World Health Organization’s Integrated Care for Older People framework.

The broader concept is precision geromedicine.

Instead of relying on chronological age alone, future approaches could combine biological-age assessment, changes in intrinsic capacity, individual disease risk and appropriately selected interventions.

GRACE is a proposed clinical framework. Its effectiveness as an integrated model of care has not yet been established in prospective clinical trials.

The possibility of targeting the biology of aging is one of the most important developments in longevity medicine.

It could eventually move prevention beyond a disease-by-disease model toward identifying shared biological vulnerabilities earlier.

But this field also requires careful interpretation of evidence.

Metformin, rapamycin, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, senolytics and other candidate gerotherapeutics should be evaluated according to what has actually been demonstrated in humans.

Promising mechanisms matter.

Animal and primate studies matter.

Changes in biological-age biomarkers matter.

But the ultimate goal is not simply to produce a younger biomarker. It is to preserve health and function, delay age-related disease and extend the years of life lived in good health.

Geroscience has changed an important question in medicine.

Instead of asking only how individual age-related diseases should be treated, researchers are asking whether shared biological processes could be targeted before multiple diseases emerge.

The biological science supporting this concept has advanced considerably.

Clinical translation is at an earlier stage.

Some candidate gerotherapeutics are established medicines with proven benefits for specific diseases. Others have compelling effects in cells, animals or non-human primates. New biological-age biomarkers can measure increasingly complex aspects of aging.

These represent different levels of evidence.

A medication can reduce disease risk without proving that it slows aging. An intervention can influence a hallmark of aging without demonstrating longer healthspan. A biological-age biomarker can change without proving that a person will live longer or remain healthier.

Treating age-related disease, modifying an aging-related pathway, changing a biological-age biomarker and extending healthy human lifespan are different outcomes.

They should not be treated as interchangeable.