Mechanistic Links Between the Gut Microbiome and Longevity Therapeutics

Aging is a multifactorial biological process marked by the progressive decline in cellular and physiological functions, increasing susceptibility to chronic diseases and mortality. Recent research has identified the gut microbiome as a key modulator of aging, influencing immune regulation, metabolic homeostasis, and neuroendocrine signaling. A diverse and balanced gut microbiota promotes healthspan by supporting gut barrier integrity, nutrient metabolism, and anti-inflammatory responses, whereas dysbiosis contributes to the onset and progression of age-related diseases, including neurodegeneration, cardiovascular conditions, cancer, and metabolic disorders. Currently, anti-aging interventions targeting key aging pathways, such as insulin/IGF-1 signaling, mTOR, AMPK, and sirtuins, are a major focus in the field of geroscience. Compounds such as metformin, rapamycin, anti-inflammatories, GLP-1 agonists, senolytics, spermidine, SGLT2 inhibitors, and sirtuin activators have shown lifespan extension in animal models. In humans, some of these interventions are associated with improvements in healthspan-related outcomes, including metabolic, cardiovascular, musculoskeletal, respiratory, cognitive and ocular functions. Notably, the gut microbiome may serve as both a mediator and modulator of these interventions, influencing drug metabolism, efficacy, and host responses. This review synthesizes current evidence on the gut microbiome's role in aging, examining its role as both mediator and modulator of longevity interventions and how microbiome-associated mechanisms intersect with emerging anti-aging therapeutics.