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Organelle-specific autophagy directs degradation of eukaryotic organelles under certain conditions. Like other organelles, peroxisomes are subject to autophagic turnover at lysosomes. However, peroxisome autophagy (pexophagy) has yet to be analyzed in a live-animal system, limiting knowledge on its regulation during an animal's life. Here, we generated a tandem-fluorophore reporter that enabled real-time tracking of pexophagy in live Caenorhabditis elegans. We observed that pexophagy occurred at a population of non-canonical, tubular lysosomes specifically during starvation and aging. Remarkably, in these contexts, tubular lysosomes were the predominant type of lysosome in the intestine, transforming from vesicles. Though we found that peroxisomes were largely eliminated in early adulthood, they appeared restored in new generations. We identified peroxisomal genes that regulated age-dependent peroxisome loss and demonstrated that modifying this process altered animal lifespan. These findings reveal new facets of peroxisome homeostasis relevant to aging and challenge the prevailing perception of lysosome homogeneity in autophagy.

Valosin-containing protein (VCP) binds and extracts ubiquitinated cargo to regulate protein homeostasis. While VCP has been studied primarily in aging and disease contexts, it also affects germline development. However, the precise molecular functions of VCP in the germline, particularly in males, are poorly understood. Using theDrosophilamale germline as a model system, we find that VCP translocates from the cytosol to the nucleus as germ cells transition into the meiotic spermatocyte stage. Importantly, nuclear translocation of VCP appears to be one critical event stimulated by testis-specific TBP-associated factors (tTAFs) to drive spermatocyte differentiation. LiketTAFmutants, spermatocyte gene expression fails to properly activate inVCP-RNAi testes, and germ cells arrest in early meiosis. At a molecular level, VCP activity supports spermatocyte gene expression by downregulating a repressive histone modification, mono-ubiquitinated H2A (H2Aub), at this developmental transition. Remarkably, experimentally blocking H2Aub inVCP-RNAi testes is sufficient to overcome the meiotic-arrest phenotype and to promote development through meiosis. Collectively, our data highlight VCP as a novel downstream effector of tTAFs that downregulates H2Aub to facilitate meiotic progression.SUMMARY STATEMENTVCP promotes the downregulation of mono-ubiquitinated H2A (H2Aub), potentially by driving H2A turnover. VCP-dependent downregulation of H2Aub occurs downstream of testis-specific TBP-associated factors and supports spermatocyte gene expression and differentiation.

Dietary restriction promotes longevity via autophagy activation. However, changes to lysosomes underlying this effect remain unclear. Using the nematode Caenorhabditis elegans, we show that induction of autophagic tubular lysosomes, which occurs upon dietary restriction or mTOR inhibition, is a critical event linking reduced food intake to lifespan extension. We find that starvation induces tubular lysosomes not only in affected individuals but also in well-fed descendants, and the presence of gut tubular lysosomes in well-fed progeny is predictive of enhanced lifespan. Furthermore, we demonstrate that expression of Drosophila SVIP, a tubular-lysosome activator in flies, artificially induces tubular lysosomes in well-fed worms and improves C. elegans health in old age. These findings identify tubular lysosomes as a new class of lysosomes that couples starvation to healthy aging.One-Sentence SummaryTubular lysosome induction promotes healthy aging.

Organelle-specific autophagy directs degradation of eukaryotic organelles under certain conditions. Like other organelles, peroxisomes are subject to autophagic turnover at lysosomes. However, peroxisome autophagy (pexophagy) has yet to be analyzed in a live-animal system, limiting knowledge on its regulation during an animal's life. Here, we generated a tandem-fluorophore reporter that enabled real-time tracking of pexophagy in live

Gamete development ultimately influences animal fertility. Identifying mechanisms that direct gametogenesis, and how they deteriorate with age, may inform ways to combat infertility. Recently, we found that lysosomes acidify during oocyte maturation in

The health of a cell requires proper functioning, regulation, and quality control of its organelles, the membrane-enclosed compartments inside the cell that carry out its essential biochemical tasks. Aging commonly perturbs organelle homeostasis, causing problems to cellular health that can spur the initiation and progression of degenerative diseases and related pathologies. Here, we discuss emerging evidence indicating that age-related defects in organelle homeostasis stem in part from dysfunction of the autophagy-lysosome system, a pivotal player in cellular quality control and damage clearance. We also highlight natural examples from biology where enhanced activity of the autophagy-lysosome system might be harnessed to erase age-related organelle damage, raising potential implications for cellular rejuvenation.