Geroscience's 'North Star': Moving from Treating Disease to Targeting Aging Itself

It was once assumed that aging was simply an inevitable, untreatable process — something to be managed rather than intervened upon. Physicians treated heart disease with statins, diabetes with insulin, dementia with cognitive therapies, and cancer with surgery or chemotherapy. Each disease was approached as a distinct entity, with its own clinic, its own specialists and its own drugs.

A radical question is now being asked by a growing community of scientists and clinicians. What if the diseases of aging—heart disease, diabetes, dementia, cancer, osteoarthritis and frailty—are not separate problems but different expressions of a single underlying process? What if the biology of aging itself could be targeted, not one disease at a time, but all of them simultaneously?

This question is the foundation of geroscience.

According to a 2026 review published in Molecules, geroscience represents a paradigm shift from traditional clinical trials that focus on single-disease outcomes toward evaluating interventions that target the fundamental biology of aging itself, thereby delaying the onset or progression of multiple chronic conditions at the same time. The goal is not merely to extend the number of years lived, but to extend the number of years lived in good health—what researchers call healthspan.

In 2026, the first clinical toolkit for prescribing "gerotherapeutics" is beginning to take shape. This toolkit includes validated pharmacological agents, biomarker-based monitoring strategies and lifestyle interventions that target the core molecular pathways of aging. For the first time, clinicians have the opportunity to move beyond disease management toward the prevention of aging itself.

The Hallmarks of Aging: A Unifying Framework

The scientific foundation of geroscience rests upon a conceptual framework known as the hallmarks of aging. First proposed by López‑Otín and colleagues in 2013 and updated several times since, the hallmarks represent the fundamental biological processes that drive aging across all organ systems.

According to the 2025 update, the current list of hallmarks now numbers twelve, with two new members recently added: extracellular matrix alterations and psychosocial factors. The complete list includes genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation and dysbiosis.

It is important to understand that these hallmarks are not independent. A 2026 editorial in GeroScience emphasised that all the hallmarks are tightly interconnected in a systems biology network, so that affecting one hallmark will also result in changes in all others. The deterioration of health with aging is not a single catastrophic failure but the result of a constellation of multiple small decrements in function over time, affecting multiple systems.

The challenge for clinical translation, as noted in the same editorial, is that a small decline in any of these functions is still compatible with life as long as the organism is able to compensate by attaining a new homeostatic equilibrium. It is precisely this compensatory capacity—or its loss—that determines whether an individual ages healthily or develops multiple chronic conditions.

The False Choice of Healthspan Versus Lifespan

A persistent debate in the geroscience community has been whether the field should prioritise extending healthspan (years lived in good health) or lifespan (total years lived). According to a March 2026 editorial in Aging, this framing represents a false choice. The only mission that is both scientifically coherent and clinically meaningful, the authors argued, is healthy life extension: more years in full health.

The urgency of this mission is underscored by global data. World Health Organization data from 2000 to 2019 showed that life expectancy increased more than healthy life expectancy, meaning that additional years were lived with disease or disability. A cross‑national analysis quantified the global "healthspan to lifespan gap" at approximately 9.6 years. In the United States, this gap exceeds twelve years. Modern medical systems are delivering more years, but not necessarily more good years.

The goal of geroscience, as articulated in the editorial, is health‑adjusted survival: extending lifespan while proportionally expanding function, resilience and independence. Success should be measured by Health‑Adjusted Life Expectancy (HALE) and Quality‑Adjusted Life Years (QALYs), which weight survival by functional status.

Key Pharmacological Gerotherapeutics

Four major classes of pharmacological agents are currently being investigated as gerotherapeutics. Each targets one or more of the hallmarks of aging and is in various stages of clinical development.

Metformin: The Diabetes Drug That Might Slow Aging

Metformin, a medication that has been used for decades to treat type 2 diabetes, has emerged as one of the most promising candidates for repurposing as a gerotherapeutic. Several large observational studies have found that people with diabetes taking metformin often outlive those without diabetes, suggesting effects beyond blood sugar control. One meta‑analysis showed a 7% lower risk of death in metformin users compared to healthy individuals and a 28% reduction compared to diabetics on other drugs.

The mechanism of action of metformin is believed to involve activation of AMPK (AMP‑activated protein kinase), a cellular energy sensor that helps cells manage energy more efficiently. By activating AMPK, metformin helps cells stay healthier longer and reduces chronic inflammation, a major contributor to age‑related diseases like heart disease, cancer and dementia.

The most important ongoing study is the TAME (Targeting Aging with Metformin) trial. Funded by the American Federation for Ageing Research and running across fourteen US clinical sites, TAME is recruiting approximately 3,000 adults aged 65 to 79 without diabetes and randomising them to 1,500 mg of metformin per day or placebo for six years. It is the first large‑scale clinical trial designed to determine whether metformin can delay the onset of multiple age‑related diseases in healthy older adults. The FDA has agreed in principle that if TAME is successful, "aging" itself could be considered a medical indication.

Rapamycin: The Immunosuppressant with Lifespan‑Extending Effects

Rapamycin, originally developed as an immunosuppressant for organ transplant recipients, has demonstrated remarkable lifespan‑extension effects in animal models. According to a 2026 review, rapamycin remains the most extensively studied geroprotective compound in animal models, where it has been shown to consistently extend lifespan even when administered late in life. Rapamycin's lifespan extension in genetically heterogeneous mice remains a landmark, demonstrating that modulation of a conserved pathway can extend both median and maximal lifespan.

The translation of rapamycin into humans began with small‑scale studies focused on immune function. A pivotal trial demonstrated that low‑dose everolimus, a rapamycin derivative, enhanced the immune response to influenza vaccination in elderly adults, suggesting improved immunocompetence. A 2024 randomised trial reported that once‑weekly rapamycin in older adults improved physical performance and lean muscle mass without major adverse events.

However, caution is warranted. A 2025 review from George Washington University warned that while trials show rapamycin extends lifespan in mice, there is no clear evidence from human studies that it can do the same for healthy adults. Some small studies show that low‑dose rapamycin may improve immune function and markers of aging, but the results are inconsistent and based on limited data. The researchers cautioned that if you are a healthy adult considering rapamycin to live longer or healthier, there is no strong scientific proof yet that the drug works for that purpose.

Senolytics: Eliminating Zombie Cells

Cellular senescence is a state in which cells stop dividing but remain metabolically active, secreting a cocktail of inflammatory molecules known as the senescence‑associated secretory phenotype (SASP). These "zombie cells" accumulate with age and contribute to multiple age‑related diseases.

Senolytics are drugs that selectively eliminate senescent cells. According to a 2026 review, senolytics such as dasatinib plus quercetin (D+Q), navitoclax and fisetin selectively eliminate senescent cells by targeting anti‑apoptotic pathways like BCL‑2 and PI3K/Akt, reducing SASP and alleviating conditions including osteoarthritis (OA), intervertebral disc degeneration (IVDD) and brain injury.

Several clinical trials are underway. Fisetin is in Phase I/II trials (NCT04210986) for osteoarthritis of the knee and Phase II (NCT04313634) for skeletal health. An ongoing Phase II senolytic trial supported by the Alzheimer's Drug Discovery Foundation is evaluating dasatinib and quercetin in Alzheimer's disease.

An important caution was provided by a 2026 clinical guidance document: senolytic therapy should not be used outside of clinical trials in older adults with chronic diseases, regardless of their multimorbidity burden, as these agents remain investigational with insufficient safety and efficacy data in humans.

NAD+ Precursors: Recharging the Cell's Energy Currency

Nicotinamide adenine dinucleotide (NAD+) is a critical cofactor involved in hundreds of cellular processes, including energy metabolism, DNA repair and epigenetic regulation. NAD+ levels decline with age, contributing to mitochondrial dysfunction and metabolic decline.

According to a 2025 comprehensive review in Nature Aging, preclinical studies have demonstrated robust efficacy of NAD+ precursors—including nicotinic acid, nicotinamide, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN)—in extending both lifespan and healthspan in animal models. A pilot trial investigating NR supplementation in older adults with peripheral artery disease showed improvements in vascular health and cognitive function.

The review emphasised the need for further large‑scale studies to determine optimal dose, administration routes and frequency, as well as long‑term safety and interindividual variability in response.

The Clinical Toolkit: A Practical Framework for Clinicians

The transition from preclinical discoveries to human interventions represents one of the greatest challenges in geroscience. Unlike traditional clinical trials that focus on single‑disease outcomes, geroscience trials aim to evaluate interventions that target the fundamental biology of aging itself, thereby delaying the onset or progression of multiple chronic conditions simultaneously. This paradigm shift raises important methodological, regulatory and ethical questions regarding how to define success in the context of longevity medicine.

A translational framework for evidence‑based gerotherapeutics has been proposed, anchored in the concept of the skin as a sentinel and modulator of systemic aging. This approach allows ranking of candidate interventions based on their ability to prevent age‑related changes, illustrating how standardised challenge‑response models can compress evaluation timelines. Such accelerated evaluation models are particularly relevant for gerotherapeutics, where long‑term outcomes make traditional trial timelines impractical.

The New Vitals framework, presented at a 2025 conference, outlined three domains for gerotherapeutic monitoring: lifestyle programs (diet, exercise, sleep, supplements), clinic‑based regimens and pharmaceuticals. Companion diagnostic efforts that stratify responders and monitor efficacy were described as offering a proof of concept for personalised gerotherapeutics.

In practical terms, the 2026 clinical toolkit for gerotherapeutics includes the following components:

1. Biomarker assessment: Epigenetic clocks, inflammatory markers (IL‑6, TNF‑α, CRP), metabolic parameters and functional measures can be used to monitor biological age and response to interventions. A review in Molecules highlighted that IL‑6, TNF‑α and IL‑1β define the canonical inflammatory triad of aging, while MIF (macrophage migration inhibitory factor) emerges as a unique regulator that integrates immune and metabolic signals.

2. Intervention selection: Based on an individual's geromic profile and biomarker status, clinicians can select from a growing armamentarium of gerotherapeutics, including metformin for metabolic and inflammatory aging, rapamycin for immune and cellular aging, senolytics for senescent cell burden and NAD+ precursors for mitochondrial health.

3. Monitoring and adjustment: Serial biomarker measurements and functional assessments allow for dose adjustment and combination strategies.

Regulatory Landscape and Clinical Trial Design

A major barrier to the widespread adoption of gerotherapeutics is the regulatory framework. The FDA does not classify aging as a disease, identifying it instead as a natural, universal process. FDA approval requires that a drug be indicated for a specific, measurable disease or condition. Aging, which encompasses all organ systems, currently has no legally recognised single biomarker that can serve as the basis for drug approval.

However, change is on the horizon. If the TAME trial is successful, aging itself could be considered a medical indication, opening the door to regulatory pathways for gerotherapeutics. A petition has been filed to establish the Advanced Approval Pathway for Longevity Medicines (AAPLM), which includes three key provisions: a faster approval process for longevity medicine, transferable Priority Review Vouchers and patent extensions granted on a per‑indication basis.

From a clinical trial design perspective, drug development from a geroscience perspective would take greater account of effects of aging on clinical trial outcomes. The acceptable age range for participation in Alzheimer's disease clinical trials is 50 to 90, a 40‑year span that incorporates enormous age‑related change. Accounting for these effects is essential for the successful development of gerotherapeutics.

Economic Implications: The Cost of Not Targeting Aging

The economic burden of age‑related diseases is staggering. The global healthspan–lifespan gap of approximately nine years reflects the global rise in non‑communicable diseases, including obesity, type 2 diabetes, cardiovascular disease and neurodegenerative disorders. These conditions reduce quality of life, increase healthcare expenditures and limit economic productivity.

A 2026 editorial in the BMJ noted that as average GDP per person rises to around $15,000 to $20,000, average life expectancy across nations almost doubles. However, Britain is experiencing a sustained decline in healthy life expectancy and widening inequalities between places and social groups. Only the US has lower healthy life expectancy than the UK among comparable high‑income countries.

The economic case for gerotherapeutics is compelling. If healthy life expectancy could be increased by even a few years, the savings in healthcare costs and the gains in productivity would be enormous. A 2026 conference on healthy aging noted that the intersection of longevity science, digital health, insurance and AI is reshaping how healthcare systems may evolve.

Challenges and Cautions

It would be irresponsible to discuss gerotherapeutics without acknowledging the significant challenges that remain.

Off‑label use: At present, none of the gerotherapeutic agents discussed in this article are FDA‑approved specifically for the indication of slowing aging. Off‑label prescribing carries risks, particularly in older adults with multimorbidity and polypharmacy.

Long‑term safety: The long‑term safety of chronic gerotherapeutic use in healthy older adults remains unknown. Rapamycin, for example, can cause stomatitis, hyperlipidemia and insulin resistance. Chronic daily dosing is not tolerated, highlighting the importance of optimising schedules that preserve efficacy while minimising toxicity.

Patient selection: Not all older adults will benefit equally from gerotherapeutics. Biomarker‑based stratification is essential to identify responders and avoid adverse effects in those who may not benefit.

Equity and access: The cost of gerotherapeutic agents and the specialised monitoring they require may exacerbate existing health disparities. Ensuring equitable access across socioeconomic groups is a critical policy consideration.

A Surgeon's Reflection on the Changing Paradigm

After three decades in surgery, it has become clear that the most profound advances in medicine will come not from better scalpels or more precise imaging, but from understanding the fundamental biology that underlies disease. Geroscience offers the most coherent framework for this understanding: a recognition that aging itself is the common pathway through which most chronic diseases arise.

It is not a radical oversimplification to say that if aging can be slowed, heart disease, diabetes, dementia and many cancers can be delayed together. This is not immortality—it is not even close—but it is something perhaps more valuable: the compression of morbidity into the very last years of life.

The TAME trial, which is currently recruiting 3,000 older adults across fourteen US sites, represents the first systematic attempt to answer the question of whether a drug can slow human aging. Its results are expected in the coming years. If positive, they will fundamentally alter the practice of medicine. If negative, they will send the field back to the drawing board. Either outcome, it was noted, is progress.

The geroscience toolkit is not yet ready for routine clinical use. But it is being built, piece by piece, in laboratories and clinical trials around the world. The hallmarks of aging have been mapped. The pharmacological agents have been identified. The clinical trials are underway. The regulatory pathways are being established.

The north star of geroscience is healthy life extension: more years of life, and more life in those years. That goal, it was concluded, is worth pursuing with all the rigour and resources that modern medicine can muster.

References

1. Translational geroscience pathways and clinical trials. Molecules. 2025;30(22):4728.
2. Barzilai DA. Healthy life extension: Geroscience's north star. Aging. 2026;18:100-101.
3. Hallmarks of aging framework. Cell. 2013. Updated 2023, 2025.
4. Loss of molecular resilience as the ultimate outcome of aging biology. GeroScience. 2026;48:217-223.
5. Metformin and Longevity. GrowWithDrJoanette. 2026.
6. TAME trial status update. Progevita. 2026.
7. New review finds anti-aging drug popular but unproven in healthy adults. George Washington University Media Relations. August 2025.
8. Emerging strategies, applications and challenges of targeting NAD+ in the clinic. Nature Aging. 2025;5:1704-1731.
9. Senolytics in clinical trials. Journal of the Indian Academy of Geriatrics. 2026.
10. Gerotherapeutics: A translational framework. GeroScience. May 2026.
11. The New Vitals: Monitor, Personalize, and Validate Gerotherapeutics. Foresight Institute. September 2025.
12. FDA regulatory framework for aging interventions

Geroscience #LongevityMedicine #AntiAging #Biotech #HealthyAging #PrecisionMedicine #FutureOfMedicine #Epigenetics #ClinicalTrials #MedicalInnovation