The KAT2 Acetyltransferase PCAF-1 Couples Stress-Responsive Transcription to Proteostasis and Longevity

Aging erodes the capacity of cells to sense stress and maintain a functional proteome. Lysine acetyltransferases can link stress signals to gene expression, but whether boosting the activity of a single acetyltransferase can enhance stress responses to protect the aging proteome and extend healthspan remains unknown. Here we show that increasing the dosage of PCAF-1, the sole KAT2 family acetyltransferase in Caenorhabditis elegans, is sufficient to extend lifespan, preserve healthspan, and reprogram stress-responsive transcription. This program is conserved; mammalian orthologs of PCAF-1-induced genes are enriched among transcripts that decline upon KAT2A and KAT2B depletion. PCAF-1 strengthens inducible stress responses, attenuates the age-dependent decline in proteasomal degradation, and limits protein aggregation in C. elegans models of human neurodegenerative diseases, while preserving motility and survival. Mechanistically, PCAF-1 drives DAF-16/FOXO activation, and DAF-16 is required for both PCAF-1-dependent longevity and for protection against polyglutamine aggregation. These findings reveal a previously unrecognized mechanism by which KAT2 acetyltransferases promote longevity, positioning KAT2s as potential tunable regulators of proteostasis and healthspan during aging.