Res Sq. 2024 Dec 05. pii: rs.3.rs-5278203. [Epub ahead of print]
Joao Passos,
Helene Martini,
Jodie Birch,
Francisco Marques,
Stella Victorelli,
Anthony Lagnado,
Nicholas Pirius,
Ana Franco,
Gung Lee,
Yeaeun Han,
Jennifer Rowsey,
Alexandre Gaspar-Maia,
Aaron Havas,
Rabi Murad,
Xue Lei,
Rebecca Porritt,
Oliver Maddocks,
Diana Jurk,
Sundeep Khosla,
Peter Adams.
Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.