Metformin as a Geroprotective Agent: Multifaceted Mechanisms Targeting Cellular Senescence and Aging Hallmarks

Yiting Zhao, Lei Gao^*
Changchun University of Chinese Medicine, Changchun, China
* Corresponding Author: Lei Gao. Email: email

BIOCELL https://doi.org/10.32604/biocell.2026.083060

Received 28 March 2026; Accepted 21 May 2026; Published online 08 June 2026

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Abstract

Metformin is widely recognized for its pleiotropic effects on aging hallmarks, yet the evidence remains descriptive and mechanistically fragmented. This is a mechanism-focused narrative review; the evidence is illustrative rather than being systematically retrieved. We critically evaluate the proposed geroprotective mechanisms of metformin, including AMP-activated protein kinase activation (AMPK), mitochondrial complex I inhibition, senescence-associated secretory phenotype (SASP) suppression, and epigenetic modulation. While ample data support these pathways in preclinical models, resolving the relative contribution of these pathways requires: (i) locus-specific analysis of context-dependent H3K27me3 regulation (reported as both increased and decreased), and (ii) direct testing of AMPK-dependent versus AMPK-independent pathways in aged organisms using tissue-specific AMPK-knockout mice and chromatin profiling at SASP gene promoters. We provide specific, falsifiable predictions and experimental designs for each of these requirements in the main text. Existing studies have overgeneralized the senolytic capacity of metformin because they lack a comprehensive assessment of context-dependent effects. Further validation through rigorous human clinical trials (e.g., the ongoing Targeting Aging with Metformin study) is required, along with a clear dissection of AMPK-dependent versus AMPK-independent mechanisms, which is necessary to guide rational repurposing of metformin for aging intervention.