The Metabolic Transition Between Fasting and Feeding Alters Aging‐Associated Metabolites, Lowers <scp>BCAAs</scp> , and Stimulates <scp>FGF21</scp> Production in Humans

Fasting-based interventions are gaining momentum as strategies to modulate longevity. Conversely, the same metabolic adaptations that once ensured survival during starvation now contribute to the global obesity epidemic. While previous studies have characterized metabolic changes during fasting, few have examined the refeeding phase, and most lack an integrated analysis of key hormonal and metabolic regulators, including insulin, leptin, adiponectin, free T3, FGF21, and the plasma metabolome. To address this gap, we profiled 134 plasma metabolites using mass spectrometry, covering pathways involved in lipid, amino acid, and ketone metabolism, in a cohort of 20 adults (mean age 52.2 ± 11.8 years, 55% women, BMI 28.8 ± 6.4 kg/m²) undergoing medically supervised prolonged fasting (mean duration 9.8 ± 3.1 days), followed by plant-based refeeding (5.3 ± 2.4 days). Fasting reduced metabolic rate, reflected by lower free T3 levels (p < 0.0001), and markedly reprogrammed the plasma metabolome, including shifts in seven aging-associated metabolites (glucose, 3-hydroxybutyric acid, glycine, glutamine, alanine, phenylalanine, and tyrosine). Notably, plasma branched-chain amino acid (BCAA) levels remained stable during fasting, suggesting active tissue release to support energy homeostasis alongside ketogenesis. Upon refeeding, 81% of metabolite levels normalized, yet BCAAs declined sharply (valine -45%, leucine -52%, isoleucine -48%; all p < 0.001), consistent with insulin-stimulated tissue uptake. Changes in BCAAs were inversely associated with a fivefold increase in FGF21 levels (243.2-1176 pg/mL, p = 0.0007), which occurred exclusively during refeeding, unlike in rodent models where FGF21 levels rise during fasting. Together, our findings identify refeeding as a critical window for modulating aging-related metabolites and highlight the importance of post-fast refeeding dynamics.