Lysosomal metabolic pathways including LIPL-4 lipase, AMPK activation, and mTOR reduction signal through a soma-to-germline epigenetic axis to regulate transgenerational longevity in C. elegans, whereby intestinal upregulation of histone H3.3 variant HIS-71 is transported to the germline via the vitellogenin pathway, methylated at H3K79 by the germline-specific methyltransferase DOT-1.3, and transmitted across multiple generations to promote lifespan extension.

Epigenome is sensitive to metabolic inputs and crucial for aging. Lysosomes emerge as a signaling hub to sense metabolic cues and regulate longevity. We unveil that lysosomal metabolic pathways signal through the epigenome to regulate transgenerational longevity in Caenorhabditis elegans. We discovered that the induction of lysosomal lipid signaling and lysosomal AMP-activated protein kinase (AMPK), or the reduction of lysosomal mechanistic-target-of-rapamycin (mTOR) signaling, increases the expression of histone H3.3 variant and elevates H3K79 methylation, leading to lifespan extension across multiple generations. This transgenerational pro-longevity effect requires intestine-to-germline transportation of H3.3 and a germline-specific H3K79 methyltransferase, and can be recapitulated by overexpressing H3.3 or the H3K79 methyltransferase. This work uncovers a lysosome-epigenome signaling axis linking soma and germline to mediate the transgenerational inheritance of longevity.