Language
English
Publication Date
9-25-2025
Journal
Science
DOI
10.1126/science.adn8754
PMID
40997170
PMCID
PMC12831228
PubMedCentral® Posted Date
1-25-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
The epigenome is sensitive to metabolic inputs and crucial for aging. Lysosomes act as a signaling hub to sense metabolic cues and regulate longevity. We find that lysosomal metabolic pathways signal through the epigenome to regulate transgenerational longevity in Caenorhabditis elegans. Activation of lysosomal lipid signaling and lysosomal adenosine monophosphate-activated protein kinase (AMPK) or reduction of lysosomal mechanistic-target-of-rapamycin (mTOR) signaling increased expression of a histone H3.3 variant and increased its methylation on K79, leading to lifespan extension across multiple generations. This transgenerational pro-longevity effect required intestine-to-germline transportation of histone H3.3 and a germline-specific H3K79 methyltransferase, and was recapitulated by overexpressing H3.3 or the H3K79 methyltransferase. Thus, signals from a lysosome affect the epigenome and link the soma and germline to mediate transgenerational inheritance of longevity.
Keywords
Animals, Longevity, Caenorhabditis elegans, Lysosomes, Histones, Signal Transduction, Epigenome, TOR Serine-Threonine Kinases, Methylation, Caenorhabditis elegans Proteins, Germ Cells, AMP-Activated Protein Kinases, Epigenesis, Genetic, Histone-Lysine N-Methyltransferase
Published Open-Access
yes
Recommended Citation
Qinghao Zhang, Weiwei Dang, and Meng C Wang, "Lysosomes Signal Through the Epigenome to Regulate Longevity Across Generations" (2025). Faculty, Staff and Students Publications. 6471.
https://digitalcommons.library.tmc.edu/baylor_docs/6471