# Exploring Acetyl-CoA-Mediated Beta-Hydroxybutyrate Enrichment in Yeast: A Mechanistic Link to Longevity

## TL;DR

This study shows that yeast can produce a ketone body linked to longevity, even without typical enzymes, and suggests it can be used to study aging and potential therapies.

## Contribution

First detection of β-hydroxybutyrate in yeast and identification of its role in CR-mediated longevity.

## Key findings

- β-hydroxybutyrate is detected in yeast under CR and stationary-phase conditions.
- Mitochondrial acetyl-CoA metabolism and mtFAS pathways are critical for β-hydroxybutyrate enrichment.
- β-hydroxybutyrate supplementation extends yeast lifespan and shares mechanisms with CR.

## Abstract

Aging predisposes organisms to diseases ranging from diabetes to Alzheimer’s, driving interest in interventions like Caloric Restriction (CR), which extends lifespan across species. While CR’s benefits are well-documented, its metabolic mechanisms remain incompletely understood. This study investigates β-hydroxybutyrate (βHB), a ketone body, in CR-mediated longevity using Saccharomyces cerevisiae. Despite the absence of canonical ketogenesis enzymes (HMG-CoA lyase, OXCT1) in yeast, we detect βHB for the first time in stationary-phase and CR conditions via metabolomics, GC-MS, and luminescence assays. Alternative carbon sources and supplementing yeast media with acetoacetate drive βHB levels. In addition, we identify mitochondrial acetyl-CoA metabolism (ACS1) and mtFAS pathways to be critical for βHB enrichment during CR. βHB supplementation extends chronological lifespan dose-dependently, mirroring CR’s effects, and combined CR + βHB yields additive lifespan extension. Transcriptomic profiling reveals 156 overlapping genes and 268 βHB-exclusive targets, suggesting shared (TCA cycle, amino acid metabolism) and βHB-specific mechanisms (mitochondrial translation, stress response). These findings resolve yeast’s unexpected capacity for ketogenesis and establish it as a model for dissecting βHB’s role in aging. This work also elucidates conserved nodes linking ketogenesis to longevity and positions yeast as a platform for exploring CR-mimicking therapeutics.