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Cohort-identified alpha aminobutyric acid extends lifespan in flies and mice through autophagy-dependent improvement of endothelial mitochondrial respiration

ABSTRACT: Healthy aging has become a global priority as populations age, yet achieving healthy longevity remains challenging. In the Kyotango Cohort Study of more than 800 older adults in Japan, plasma alpha-aminobutyric acid (AABA) levels were inversely associated with age and positively associated with physical performance. AABA concentrations were lower in the soleus muscles in aged mice, and its supplementation extended the lifespan and attenuated the age-related decline of athletic performance in Drosophila and mice. Single nucleus RNA sequencing in soleus muscles revealed similarities in the cell-type composition of young and AABA-treated old mice, with upregulation of autophagy-related genes in endothelial cells (ECs). AABA treatment increased the basal and maximal oxygen consumption rate, ATP production, and spare respiratory capacity in ECs. ATG5 silencing abolished the improvement of mitochondrial respiration in ECs supplemented with AABA, suggesting an involvement of autophagy. Metabolome analysis revealed that AABA increases Acetyl CoA level, which activate histone H3K9 acetylation and consequently upregulate autophagy. Systemic knockdown of autophagy in Drosophila attenuated AABA-associated lifespan extension. These findings suggest AABA as an endogenous regulator of autophagy that preserves physical function and promotes healthy longevity, highlighting its potential as a therapeutic target for healthy aging.

ORGANISM(S): Mus musculus

PROVIDER: GSE344016 | GEO | 2026/08/22

REPOSITORIES: GEO

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