Lysosomes signal through the epigenome to regulate longevity across generations

Area of Science:

• Epigenetics
• Molecular Biology
• Gerontology

Background:

• The epigenome influences aging and responds to metabolic signals.
• Lysosomes are key cellular hubs for sensing metabolism and regulating lifespan.

Purpose of the Study:

• To investigate how lysosomal metabolic pathways impact the epigenome and transgenerational longevity.
• To identify the molecular mechanisms linking lysosomal signaling to inherited lifespan extension.

Main Methods:

• Studied the nematode *Caenorhabditis elegans*.
• Manipulated lysosomal signaling pathways (lipid signaling, AMPK, mTOR).
• Analyzed histone H3.3 variant expression, H3K79 methylation, and histone transport between somatic and germ cells.

Main Results:

• Activation of lysosomal lipid signaling or AMPK, or reduction of mTOR, extended lifespan across multiple generations.
• These interventions increased histone H3.3 variant expression and H3K79 methylation.
• Transgenerational lifespan extension depended on intestine-to-germline transport of H3.3 and germline H3K79 methyltransferase activity.

Conclusions:

• Lysosomal metabolic pathways epigenetically regulate transgenerational longevity.
• Histone H3.3 and its methylation mediate the inheritance of longevity.
• Soma-to-germline communication of epigenetic information links lysosomes to inherited lifespan.