Especially for cells that persist for long periods without dividing, such as neurons, protein degradation via autophagy is essential for preventing the accumulation of damaged molecules and keeping the cell running smoothly. (see On the benefits of eating oneself). Many of the key enzymes involved in autophagy are already known, but there are certainly other important players left to be discovered.
Using the Drosophila eye (a dispensable tissue in that organism, where subtle texture and color phenotypes can allow rapid screening of a wide range of phenotypes) as a model system, Simonsen et al. looked for genetic interactions with blue cheese, a known autophagic gene. The mutations they discovered allowed identification of new pathway components:
Linking Lysosomal Trafficking Defects with Changes in Aging and Stress Response in Drosophila
Defects in pathways that direct cellular components to the lysosome for degradation are often linked with a decrease in viability and with progressive disorders. Previously we had shown that blue cheese (bchs: Drosophila homologue of human Alfy) mutations lead to reduced longevity and the accumulation of ubiquitinated neural aggregates. A genetic modifier screen based on overexpression of Bchs in the eye was used to identify several potential genetic interactions, which included autophagic and endocytic trafficking genes as well as cytoskeletal and motor proteins and members of the SUMO and ubiquitin signaling pathways. We found that mutations in several of the genes identified in the screen also result in bchs-like phenotypes, including a reduction in adult lifespan and changes in ubiquitinated protein profiles. In addition, we show that Bchs modifiers belonging to the autophagic and trans-Golgi trafficking pathways also display defects in adult starvation response. Our data further support a role for Bchs/Alfy in the autophagic pathway and strongly indicate that autophagy plays an important role in aging and stress response.
The authors argue that the shortened lifespan of some of the new mutants points to a key role for autophagy in aging. One should generally be cautious of such logic, as it’s easier for mutation to shorten a lifespan than to lengthen it, and most mutations that shorten lifespan have nothing to do with aging. In this case, however, the authors not only demonstrate decreased longevity but also phenotypes that are suggestive of aging, specifically the accumulation of protein aggregates in neurons — a hallmark of many neurodegenerative diseases, and a phenomenon that occurs as a function of physiological age rather than chronological age (for a discussion of the situation in C. elegans see Pulling apart proteotoxicity). If the logic holds, these results indicate that autophagy genes are longevity-assurance genes, at least in the fly.
The interference of these mutations with the adult starvation response also provides a tantalizing hint that these genes are involved in the longevity-extending response to caloric restriction (CR), though a definitive statement on this question awaits a more detailed analysis in which flies of various genetic backgrounds are explicitly subjected to CR.
Critical now is the question of whether accelerating autophagy by overexpression of blue cheese or its genetic interactors will influence the lifespan in the other direction. Does overexpression result in faster autophagy, more efficient clearance of misfolded/aggregated proteins, and an increase in cell or organismal longevity?