Mechanisms of tubular lysosome induction in animal health and longevity

Abstract Quality control machinery helps cells to remove damage and maintain optimal functionality. The autophagy- lysosome system is one critical component of the cellular quality control machinery. During autophagy, cargo is delivered via autophagosomes or other mediators to the acidic lysosome compartment, where pH-sensitive hydrolases digest the cargo and thereby recycle molecular “building blocks” and nutrients. Notably, autophagy- lysosome dysfunction is a conserved hallmark of aging; with age, autophagic activity declines, leading to a build- up of damage that contributes to degenerative disease. Identifying ways to boost lysosome function could reveal effective strategies to enhance animal health, particularly in older ages. Traditionally, lysosomes are depicted as vesicular organelles, and variation in lysosome activity is most attributed to differences in acidity. However, we have recently uncovered an alternative mechanism by which lysosome proficiency can be amplified: under high autophagic demands (such as during starvation or other stress), lysosomes dramatically alter their form, changing from vesicles to expansive, interconnected, tubular networks that show heightened degradative capacity. Importantly, preventing formation of tubular lysosomes (TLs) reduces autophagic turnover and negates the pro-longevity effects of food limitation, a longevity paradigm requiring high autophagic activity. In contrast, we have found that experimentally stimulating TL induction by genetic means improves animal health during aging and suppresses age-related disease phenotypes. By our model, lysosomes become rate-limiting in the autophagy process when they cannot transform into expanded tubular structures, and lysosome expansion into TLs establishes a larger, dynamic platform for search and capture of cargo, which becomes important under high autophagic demands and supports longevity under such conditions. In this study, we will apply our expertise in two invertebrate model organisms (C. elegans and Drosophila) to further investigate mechanisms of TL formation and their implications for healthy aging and prevention of age- dependent degenerative diseases. In Aim 1, we will survey the requirement of TLs in different longevity paradigms and test the ability of TLs to minimize gaps between healthspan and lifespan. In Aim 2, we will evaluate how new candidate TL regulators that control phosphoinositide biosynthesis, ATP transport, and lysosome-membrane dynamics contribute to TL activities in healthy aging. In Aim 3, we will test if TL induction can be applied to improve health and physiology in animal models of human degenerative diseases. These studies have the potential to redefine our picture of the cell while also pointing the way to healthier lifespans.