Beyond disease treatment and prevention: From geroscience and molecular hallmarks to gerotherapeutics and precision geromedicine

Abstract

Geroscience—the interdisciplinary field investigating the causal relationship between the biology of aging and age-related chronic disease—has undergone a remarkable evolution since its formalization within the United States National Institutes of Health in the early 2010s. Grounded in the recognition that aging is the paramount modifiable risk factor for most noncommunicable diseases, geroscience has produced a coherent molecular taxonomy of aging processes (12 hallmarks), delineated proaging and antiaging molecular pathways (gerogenes, gerosuppressors, and gerozymes), and catalyzed a new clinical vocabulary—geroprotection, gerodiagnostics, and gerotherapeutics. Two institutional milestones anchor the field’s translational ambitions: the World Health Organization’s (WHO) codification of Ageing-Associated Decline in Intrinsic Capacity as International Classification of Disease (ICD)-11 code MG2A; and the United States Food and Drug Administration’s (FDA) acceptance of the Targeting Aging with Metformin (TAME) trial—the first prospective clinical trial designed to delay aging as a composite multidisease outcome, currently underway. The biomarker science of aging has advanced in parallel, from first-generation DNA methylation clocks to organ-specific plasma proteomic signatures capable of predicting various age-related diseases with clinical-grade precision. The gerotherapeutic landscape has expanded substantially. Metformin, which engages more aging hallmarks than any other candidate gerotherapeutic, provided the regulatory impetus for TAME; in a rigorous 40-month multiomics study in cynomolgus monkeys, it decelerated plasma proteomic biological age by 6.41 years—the strongest pharmacological evidence to date for systemic biological age modification in a primate model. Senolytics and senomorphics target senescent cell burden; SGLT-2 inhibitors are notable for their indirect senolytic mechanism, enhancing immunosurveillance of senescent cells glucagon-like peptide-1 (GLP-1) receptor agonists attenuate inflammaging; NAD+ precursors restore mitochondrial and sirtuin function; and the gerozyme (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) inhibitor offers a mechanistically distinct proregenerative approach with emerging relevance as an adjunct to GLP-1 receptor agonist therapy. Multidomain lifestyle programs address multiple aging hallmarks simultaneously and have demonstrated measurable intrinsic capacity improvement in randomized trials. Building on these foundations, this review proposes the Geroscience-Responsive Aging Care Ecosystem (GRACE)—a three-element service model operationalizing geroscience and gerotherapeutic evidence within the WHO Integrated Care for Older People (ICOPE) framework.