Geroscience Roadmap Targets Aging Biology to Prevent Multiple Diseases at Once
A landmark review synthesizes 12 hallmarks of aging, emerging gerotherapeutics, and a new three-tier clinical care model to shift medicine from disease treatment to aging prevention.
Summary
This comprehensive review traces the evolution of geroscience from its NIH origins to a clinical discipline now equipped with molecular tools to measure and slow biological aging. The authors outline 12 hallmarks of aging, key molecular drivers (gerogenes, gerosuppressors, gerozymes), and four generations of biological age clocks — from DNA methylation to organ-specific plasma proteomics. The gerotherapeutic landscape reviewed includes metformin, senolytics, SGLT-2 inhibitors, GLP-1 receptor agonists, and NAD+ precursors. The review culminates in the GRACE model — a three-element care ecosystem aligning geroscience with the WHO ICOPE framework — spanning primary prevention in healthy midlife adults through rehabilitation of frail older patients.
Detailed Summary
Aging is the single greatest modifiable risk factor underlying nearly all major chronic diseases, yet medicine has historically addressed each condition in isolation. This review by Peng, Hsiao, and Chen from Taipei Veterans General Hospital and National Yang Ming Chiao Tung University argues that geroscience — the field linking aging biology directly to chronic disease — has matured sufficiently to reshape clinical practice. With Taiwan reaching super-aged status in 2025 and over two billion people projected to be aged 60+ by 2050, the urgency for a paradigm shift from disease-by-disease treatment to targeting shared aging biology has never been greater.
The molecular architecture of aging is organized around 12 hallmarks, arranged in a three-tier radial hierarchy: primary molecular damage (genomic instability, telomere attrition, epigenetic alterations, proteostasis loss, disabled macroautophagy), antagonistic responses (deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence), and integrative systemic phenotypes (stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis). The authors introduce and clearly define the gerogene–gerosuppressor–gerozyme triad: gerogenes (e.g., mTORC1, NF-κB, IGF-1/PI3K-AKT) drive aging when overactivated; gerosuppressors (e.g., AMPK, sirtuins SIRT1–7, FOXO factors) decelerate it; and gerozymes such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzymatically degrade regenerative signaling molecules like PGE2, suppressing tissue homeostasis across muscle, cartilage, nerve, bone marrow, and intestine.
Biological age measurement has progressed through four generations. First-generation epigenetic clocks (Horvath's 2013 pan-tissue clock) estimated chronological age from CpG methylation patterns. Second-generation clocks (PhenoAge, GrimAge) incorporated clinical phenotype data to predict mortality risk. Third-generation clocks like DunedinPACE measure the pace of aging in real time from blood samples. Fourth-generation platforms use organ-specific plasma proteomics to generate biological age estimates across up to 11 distinct organ systems simultaneously, enabling identification of which organs are aging fastest in a given individual — a critical advance for precision intervention.
The gerotherapeutic landscape reviewed is substantial. Metformin engages more aging hallmarks than any other candidate: in a rigorous 40-month multiomics study in cynomolgus monkeys, metformin decelerated plasma proteomic biological age by 6.41 years — the strongest pharmacological evidence to date for systemic biological age modification in a primate model. This mechanistic breadth provided regulatory impetus for the FDA-accepted TAME trial (Targeting Aging with Metformin), the first prospective clinical trial designed to delay aging as a composite multidisease outcome. SGLT-2 inhibitors are highlighted for an indirect senolytic mechanism — enhancing immunosurveillance of senescent cells — in addition to cardiovascular and metabolic benefits. GLP-1 receptor agonists attenuate inflammaging. The gerozyme inhibitor of 15-PGDH offers a mechanistically distinct proregenerative approach, with emerging relevance as an adjunct to GLP-1 therapy. NAD+ precursors (NMN, NR) restore mitochondrial function and sirtuin activity. Multidomain lifestyle programs addressing multiple hallmarks simultaneously have demonstrated measurable intrinsic capacity improvement in randomized trials.
The review's clinical culmination is the Geroscience-Responsive Aging Care Ecosystem (GRACE), a three-element service model operationalizing geroscience within the WHO ICOPE framework. Element I targets functionally intact adults aged 50+ with accelerated biological aging signals using epigenomic and proteomic clocks, resistance exercise, protein optimization (1.2–1.6 g/kg/day), Mediterranean diet, and sleep optimization. Element II addresses multimorbid older adults with structured deprescribing (STOPP/START), frailty prevention, and 6-monthly IC rescreening. Element III provides comprehensive geriatric assessment, progressive resistance training, cognitive rehabilitation, and advance care planning for frail individuals (Fried score ≥3; CFS 4–7; FI ≥0.25). All three elements are supported by shared gerodiagnostic infrastructure and the WHO ICD-11 MG2A code for aging-associated decline in intrinsic capacity, enabling bidirectional transitions between tiers as clinical status evolves.
Key Findings
- Metformin decelerated plasma proteomic biological age by 6.41 years in a 40-month multiomics study in cynomolgus monkeys — the strongest pharmacological evidence for systemic biological age modification in a primate model to date
- Fourth-generation plasma proteomic clocks can simultaneously assess biological aging across up to 11 distinct organ systems, enabling organ-specific precision intervention targeting
- SGLT-2 inhibitors exert an indirect senolytic mechanism by enhancing immunosurveillance-mediated clearance of senescent cells, extending their therapeutic relevance beyond glycemic and cardiovascular control
- The TAME trial — the first FDA-accepted clinical trial designed to delay aging as a composite multidisease outcome — is currently underway, representing a regulatory milestone for gerotherapeutics
- WHO ICD-11 code MG2A (Ageing-Associated Decline in Intrinsic Capacity) now provides a formal diagnostic classification, enabling reimbursement and systematic clinical tracking of biological aging decline
- Multidomain lifestyle interventions simultaneously addressing multiple aging hallmarks have demonstrated measurable intrinsic capacity improvement in randomized controlled trials
- The gerozyme 15-PGDH overaccumulates in aged muscle, cartilage, nerve, bone marrow, and intestine, degrading PGE2 and suppressing tissue regeneration; its inhibition restores regenerative capacity across these systems
Methodology
This is a narrative review article synthesizing evidence from the geroscience literature, drawing on landmark molecular biology studies, clinical trial data, regulatory milestones (TAME trial, FDA and WHO/ICD-11 decisions), and multiomics aging clock research. No original data were collected; the authors conducted a structured literature synthesis with defined terminology and a novel clinical framework (GRACE). Key evidence cited includes a 40-month primate multiomics study of metformin, multiple generations of epigenetic and proteomic clock validation studies, and randomized trials of multidomain lifestyle interventions.
Study Limitations
As a narrative review rather than a systematic review or meta-analysis, the article does not provide pooled effect sizes or formal risk-of-bias assessments; evidence quality across cited studies is heterogeneous. The primate metformin data (6.41-year biological age deceleration) has not yet been replicated in human trials, and the TAME trial results remain pending. No conflicts of interest were declared by the authors, though institutional affiliations with prominent geriatrics centers in Taiwan may reflect regional emphasis in the proposed GRACE model.
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