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.
