In groundbreaking new research published in Science, scientists have uncovered a novel mechanism by which lifespan-extending changes in the lysosomes of the nematode Caenorhabditis elegans are transmitted across generations via epigenetic modification. This discovery fundamentally challenges the classical view that inheritance is strictly encoded within the DNA sequence, revealing instead that cellular organelles once thought to serve primarily catabolic functions also operate as pivotal signaling hubs that influence transgenerational longevity.
Lysosomes have long been characterized as the cell’s “recycling centers” responsible for degradation and turnover of biomolecules. However, emerging evidence now positions lysosomes as dynamic regulators of cellular metabolism and signaling pathways. In this landmark study, Meng Wang and her team from the HHMI Janelia Research Campus demonstrate that upregulation of specific lysosomal enzymes in C. elegans can extend the organism’s lifespan by up to 60 percent. Strikingly, the offspring of these genetically modified worms, despite lacking the enzyme overexpression, exhibited similarly prolonged lifespans for up to four subsequent generations. This phenomenon signposts an epigenetically inherited trait where longevity signals transcend genetic inheritance.
Mechanistically, the researchers uncovered that mitochondria-to-nuclear signaling is not the sole pathway influencing longevity epigenetics; instead, lysosome-driven pathways induce modifications in histone proteins—key chromatin components that regulate gene accessibility and transcription. Specifically, changes in lysosomal metabolism stimulate the expression and mobilization of a distinct histone variant that transits from somatic cells to the germline. This transport occurs via nutrient carrier proteins that deliver the modified histones to developing oocytes, integrating longevity signals directly into the reproductive lineage without altering the underlying DNA sequence.
Histone modifications, including methylation and acetylation, constitute an important dimension of the epigenome, dictating the functional state of the genome by modulating chromatin architecture and thereby gene expression profiles. The team’s data pointed to elevated levels of histone H3 lysine 79 dimethylation (H3K79me2) in long-lived worms relative to controls, correlating with altered lysosomal functions initiated by the overexpressed enzyme. This epigenetic mark appears crucial in relaying the lysosomal “signal” to the germline, ultimately impacting progeny health and longevity.
The transference of epigenetic information from somatic to germ cells contravenes the traditional Weismann barrier—the principle that hereditary information generally flows from germline to somatic cells but not vice versa. By revealing a pathway that enables histone-mediated communication between soma and germline, the study opens a new paradigm in hereditary biology. It provides a molecular basis for how environmental and metabolic states experienced by parents can be encoded into chromatin modifications and inherited by offspring, thereby influencing phenotypic traits without changes in DNA sequence.
Importantly, the activation of this lysosome-epigenome axis was induced not only through genetic manipulation but also physiologically via environmental cues such as fasting. Fasting triggers a shift in lysosomal metabolism that activates the same histone variants and promotes their transmission to germline cells. This finding provides a direct mechanistic link between environmental stress responses and heritable adaptations, illustrating how metabolic states can be epigenetically “memorized” and passed along lineage lines.
The implications of this research extend far beyond C. elegans longevity. Many environmental stressors, including dietary changes, toxin exposure, or psychological stress, influence organismal physiology and can induce epigenetic changes. By deciphering the molecular conduits—namely lysosomal signaling and histone modification—that transmit this information across generations, the study provides a valuable framework for understanding complex transgenerational phenomena observed in higher organisms, including mammals.
This work also sheds light on potential mechanisms underlying previously puzzling epidemiological observations, such as how parental malnutrition or stress can have lasting impacts on offspring health, disease susceptibility, and aging patterns. Epigenetic inheritance mediated by histone modifications transported between somatic and germline compartments may represent the missing link explaining these transgenerational effects, with lysosomes acting as critical signaling platforms rather than mere custodians of cellular waste.
In conclusion, Meng Wang’s research revolutionizes our understanding of biological inheritance by demonstrating that lysosomes communicate longevity information via the epigenome, effectively connecting somatic environmental states to germline epigenetic programming. Histones thereby act not only as DNA-packaging elements but also as mobile carriers of inheritable information that embody physiological memories. This discovery opens new avenues for interventions aimed at healthspan extension and provides a conceptual blueprint for exploring epigenetic inheritance mechanisms in diverse species.
The study underscores lysosomes’ expanding role from degradative compartments to central regulators of cellular and organismal health, intricately interwoven with chromatin dynamics and gene expression control. Future research guided by these insights may reveal novel strategies to modulate epigenetic inheritance pathways and combat age-related diseases by harnessing the lysosome-histone axis. Ultimately, this paradigm shift enriches the molecular dialogue between environment, cell biology, and heredity, promising transformative advances in biomedicine and evolutionary biology.
Subject of Research: Epigenetic inheritance, lysosomal signaling, longevity regulation across generations in C. elegans
Article Title: Lysosomes signal through the epigenome to regulate longevity across generations
News Publication Date: 25-Sep-2025
Web References: DOI: 10.1126/science.adn8754
Image Credits: Meng Wang
Keywords: Epigenetic inheritance, Cell biology, Lysosomes, Histones, Epigenetic markers, Epigenetics
Tags: Caenorhabditis elegans lifespan studycellular organelles in aging researchepigenetic modifications in lifespangroundbreaking research on lifespan extensionHHMI Janelia Research Campus discoverieshistone modifications and gene regulationlifespan extension through enzyme upregulationlongevity inheritance mechanismslysosomal function in cellular signalingmitochondrial signaling and longevitynovel findings in epigeneticstransgenerational longevity in nematodes
