Caloric Restriction Mediated Endogenous Ketogenesis and β-Hydroxybutyrate-Mediated Longevity in Budding Yeast 192 views

Caloric restriction (CR) reliably extends lifespan across diverse organisms, yet the metabolic mediators of this effect remain incompletely defined. Here, β‑hydroxybutyrate (βHB) is identified as a CR‑induced metabolite in Saccharomyces cerevisiae, with robust enrichment in stationary phase under low‑glucose and respiratory conditions, but not in other longevity‑promoting regimens. Comprehensive metabolomics, targeted LC‑MS, and luminescence‑based assays demonstrate endogenous βHB accumulation and reveal that ACS1‑dependent acetyl‑CoA supply and the mitochondrial fatty acid synthesis (mtFAS) pathway are essential for CR‑induced βHB production, whereas canonical β‑oxidation and TCA cycle routes are dispensable. Isotopic tracing establishes bidirectional interconversion between βHB and acetoacetate and uncovers endogenous βHB dehydrogenase‑like activity in yeast cell extracts. Exogenous βHB supplementation extends yeast chronological lifespan and improves stress resilience, and we find that βHB‑mediated lifespan extension is preserved in Caenorhabditis elegans. Transcriptomic profiling shows that βHB elicits a methionine‑restriction‑like program converging on proteostasis. Chronological lifespan assays in cells lacking ACS1 establish that βHB, but not CR, can partially rescue the short lifespan of this mutant, placing βHB downstream of Acs1-mediated acetyl-CoA synthesis. These findings position budding yeast as a genetically tractable model for ketone body metabolism and identify βHB‑linked acetyl‑CoA signaling as a conserved node coupling CR to cellular longevity.

PHD (Doctor of Philosophy)

Beta-hydroxybutyrate; Lifespan; Yeast; C elegans; Longevity; Ketone bodies; Acetyl-CoA

English

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2026-04-22