Work

Lysosomes signal through the epigenome to regulate longevity across generations

Year: 2025

Type: article

Abstract: The epigenome is sensitive to metabolic inputs and is crucial for aging. Lysosomes act as a signaling hub to sense metabolic cues and regulate longevity. We found 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 the expression of a histone H3.3 variant and increased its methylation on K79, leading to life-span extension across multiple generations. This transgenerational prolongevity 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 germ line to mediate transgenerational inheritance of longevity.

Source: Science

DOI: 10.1126/science.adn8754

Authors: Qinghao Zhang, Weiwei Dang, Meng C. Wang

Institutions: Baylor College of Medicine, Howard Hughes Medical Institute, Janelia Research Campus

Language: English

Topic: Genetics, Aging, and Longevity in Model Organisms

Subfield: Aging

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: Howard Hughes Medical Institute, National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases

Awards: G2053725305, G3567839671, G7463500495