Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity.
Late-life-initiated dietary interventions negligibly extend longevity or reduce frailty, yet the reason remains unknown. We investigated the age-related changes associated with the fasting response in adipose tissue of the short-lived killifish N. furzeri. Transcriptomic analysis revealed the presence of a fasting-like transcriptional program (FLTP) in old animals that is irrespective of their nutritional status and characterized by widespread suppression of anabolic processes. FLTP is associated with reduced expression of the AMPK {gamma}1 regulatory subunit. Accordingly, refeeding positively regulates {gamma}1 expression in young but not in old animals. Fish having sustained AMPK{gamma}1 activation had no sign of FLTP in old age and exhibited metabolic health and longevity. In humans, we found that {gamma}1 expression declines with age and is associated with multimorbidity and multidimensional frailty risk. Our study highlights the importance of the refeeding arm in promoting health and longevity and identifies the AMPK{gamma}1 complex as a potential target to prevent age-related diseases in humans.