2. Academic Validation
  3. Mitochondrial metabolism and epigenetic crosstalk drive the SASP

Mitochondrial metabolism and epigenetic crosstalk drive the SASP

  • Res Sq. 2024 Dec 5:rs.3.rs-5278203. doi: 10.21203/rs.3.rs-5278203/v1.
Joao Passos 1,  Helene Martini 1,  Jodie Birch 2,  Francisco Marques 3,  Stella Victorelli 1,  Anthony Lagnado 1,  Nicholas Pirius 1,  Ana Franco 1,  Gung Lee 1,  Yeaeun Han 1,  Jennifer Rowsey 1,  Alexandre Gaspar-Maia 1,  Aaron Havas 4,  Rabi Murad 5,  Xue Lei 6,  Rebecca Porritt 4,  Oliver Maddocks 7,  Diana Jurk 1,  Sundeep Khosla 1,  Peter Adams 4
Affiliations

Affiliations

  • 1 Mayo Clinic.
  • 2 MRC London Institute of Medical Sciences.
  • 3 Albert Einstein College of Medicine.
  • 4 Sanford Burnham Prebys Medical Discovery Institute.
  • 5 University of California, Irvine.
  • 6 Sanford Burnham Prebys MDI.
  • 7 Faeth Therapeutics.
PMID: 39678326 DOI: 10.21203/rs.3.rs-5278203/v1
Abstract

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.

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