Berberine as a multi-hallmark modulator of aging: From AMPK and mitophagy to inflammaging and the SASP

Berberine, a naturally occurring isoquinoline alkaloid found in several medicinal plants such as Berberis spp. and Coptis chinensis has long been used in traditional medicine. Recent evidence positions berberine as a pleiotropic modulator of multiple interconnected hallmarks of aging, making it a promising candidate for geroprotective interventions. This review critically examines the molecular mechanisms through which berberine influences energy metabolism, mitochondrial homeostasis, proteostasis, chronic inflammation, and cellular senescence. Berberine activates AMP-activated protein kinase (AMPK) via mild mitochondrial complex I inhibition, restoring cellular energy balance and suppressing mTOR-dependent anabolic pathways. Enhanced AMPK signaling stimulates autophagic flux and mitophagy, promoting clearance of damaged mitochondria and aggregated proteins. At the mitochondrial level, berberine improves respiratory efficiency, limits pathological excessive reactive oxygen species production while preserving physiological redox signaling, and upregulates endogenous antioxidant defenses through Nrf2. Furthermore, berberine exerts anti-inflammatory effects by inhibiting NF-κB nuclear translocation and reducing the transcription of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β). Notably, berberine acts as a senomorphic agent, attenuating the senescence-associated secretory phenotype (SASP) without inducing widespread apoptosis, partly through modulation of p16 and cyclin expression. By integrating these molecular insights, this review positions berberine as a multi-target geromodulator that addresses deregulated nutrient sensing, mitochondrial dysfunction, impaired proteostasis, chronic inflammation, and cellular senescence in a coordinated manner. The translational potential, pharmacokinetic challenges, and safety considerations of berberine in the context of healthy aging are also discussed.