Fasting and aging: Mechanistic insights into epigenomic and transcriptional regulation of healthspan

Fasting is an effective physiological intervention eliciting global and cellular adaptations that can improve healthspan and lifespan. In addition to its metabolic effects, fasting is a state of modulation of aging-associated processes/adaptive cellular responses that drives an intense epigenomic and transcriptional remodeling response which preserves functional capacity during aging. Nutrient deprivation elicits the activation of evolutionarily conserved nutrient-sensing pathways including AMPK and sirtuins, which can modulate chromatin accessibility and transcriptomic programs. These changes impact critical epigenetic processes like histone modifications, DNA methylation, and non-coding RNAs which underline adaptive transcriptional programs that drive cellular maintenance, autophagy, and stem cell function. Recent studies also suggest that fasting-mediated epigenomic flexibility may help reduce age-related epigenetic drift, dampen chronic inflammation, and cellular adaptation/maintenance of cellular function across various tissues. Notably, these processes may link fasting to both lifespan and age-related disease resistance, including metabolic disorders, neurodegeneration, and cancer. This review aims to synthesize current knowledge on how fasting modulates epigenomic landscapes/influences epigenomic regulation and transcriptome to impact aging and healthspan. We highlight key molecular pathways, cell-type specific effects, and emerging translational opportunities, while also discussing challenges, limitations, and open questions that need to be addressed to leverage fasting-inspired approaches for healthspan to promote healthy aging.