Regulation of the Autophagy Pathway with Age and in Long-lived Animals

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PROJECT SUMMARY Macroautophagy (referred to as autophagy) is a major cellular recycling process by which cytosolic material is sequestered into double-membrane vesicles or autophagosomes (i.e., early steps of autophagy), which subsequently fuse with lysosomes to ensure cargo degradation (i.e., late steps of autophagy). This complex, multi-step process plays key roles in organismal development and age-related diseases, and numerous direct links exist between autophagy and aging, including that multiple conserved longevity paradigms require autophagy genes for their lifespan extension; the current paradigm suggest that such long-lived animals induce autophagic turnover in a beneficial manner, yet the underlying mechanisms remain elusive. Our research in the previous funding cycle has provided a deeper understanding of the relationship between autophagy and aging in the nematode C. elegans. First, our work using cytological markers has indicated an age-related decline in late-steps of autophagy with variable trajectories in different tissues. Moreover, we have observed a differential regulation of autophagy in long-lived mutants in a tissue-specific fashion. Second, we have discovered unexpected longevity roles for specific autophagy genes in C. elegans neurons, indicating possibly non-canonical functions different from lysosomal degradation, an emerging concept in the autophagy research field which has yet to be investigated in the context of aging. Finally, we have conducted unbiased genetic and biochemical screens to identify new candidate autophagy regulators and receptors, and together with our collaborators identified a small compound that increase autophagy in both mammalian cells and in C. elegans and extends lifespan. Our prior studies provide us with new and specific hypotheses that we aim to test in depth in this renewal. Specifically, we will use a powerful combination of genetic and biochemical approaches to ask if fusion- and/or lysosomal degradation is a limiting step of the autophagy process in relation to organismal aging and longevity (Aim 1); we will ask if neuronal autophagy genes affect aging by cell non-autonomous means (Aim 2); and, finally, we will ask if new candidate autophagy receptors and autophagy-modulating molecules possess roles in longevity and in disease models (Aim 3). Autophagy plays critical roles in many disorders, including age-linked diseases such as neurodegeneration. Understanding the regulation of autophagy and the conserved mechanisms by which autophagy affect aging in multicellular organisms like C. elegans are likely to provide new important insights not only into aging and may also help develop treatments for such age-related diseases, including neurodegenerative disorders.