Lysosomes signal through the epigenome to regulate longevity across generations.
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| Title: | Lysosomes signal through the epigenome to regulate longevity across generations. |
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| Authors: | Zhang, Qinghao, Dang, Weiwei, Wang, Meng C. |
| Source: | Science. 9/25/2025, Vol. 389 Issue 6767, p1353-1360. 8p. |
| Subjects: | Lysosomes, Genetics of longevity, Caenorhabditis elegans, Adenosine monophosphate, Epigenetics, Histones |
| 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. Editor's summary: In some model organisms, starvation is known to induce epigenetic changes that extend the life span of progeny of the hungry parent. Zhang et al. investigated the mechanism of these effects in the roundworm Caenorhabditis elegans (see the Perspective by Bohnert). Their studies implicated an enzyme, lysosomal lipase-like 4 (LIPL-4), in the process. From there, the authors pieced together parts of a pathway in which increased activity of LIPL-4 activated signaling in intestinal lysosomes led to increased transcription and production of a variant of histone H3.3. Protein-tagging experiments indicated that the histone could be transferred to the germline, where it was modified by a methyltransferase and transmitted to progeny, thus extending their life span. —L. Bryan Ray [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| 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. Editor's summary: In some model organisms, starvation is known to induce epigenetic changes that extend the life span of progeny of the hungry parent. Zhang et al. investigated the mechanism of these effects in the roundworm Caenorhabditis elegans (see the Perspective by Bohnert). Their studies implicated an enzyme, lysosomal lipase-like 4 (LIPL-4), in the process. From there, the authors pieced together parts of a pathway in which increased activity of LIPL-4 activated signaling in intestinal lysosomes led to increased transcription and production of a variant of histone H3.3. Protein-tagging experiments indicated that the histone could be transferred to the germline, where it was modified by a methyltransferase and transmitted to progeny, thus extending their life span. —L. Bryan Ray [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adn8754 |
