Evaluating pexophagy as an early cellular marker of aging

项目总结/文摘

Project Summary/Abstract In animal species, aging occurs not only at an organismal level, but also at the level of cells. Understanding cellular processes that change with age is important for clarifying the molecular basis of age-related dysfunction and disease, and may point to robust biomarkers that can provide an accurate measure of the biological age of an individual. Within cells, organelles execute complex functions essential for cellular health and survival. How organelle homeostasis is regulated during aging represents an important current topic in aging research, as it may provide insight into the cellular events that drive age-related deterioration. In this proposal, we will investigate a new aspect of organelle homeostasis in relation to aging. Namely, the proposed studies will focus on pexophagy, or the autophagic destruction of peroxisomes, as an early event in somatic aging. Our lab has generated a fluorescent pexophagy sensor to monitor peroxisome turnover in live Caenorhabditis elegans. This reporter indicates that massive peroxisome turnover occurs in the C. elegans intestine during early aging; notably, the pexophagy sensor easily distinguishes worms on their first day of adulthood from those that are just a few days older. This raises an intriguing question: is pexophagy an early biomarker of aging, and, if so, how does it relate to longevity? The proposed studies will begin to address these questions through a series of experiments. To determine whether the timing and/or scope of pexophagy scales with lifespan, the pexophagy sensor will be expressed in the intestine of long-lived mutant strains and compared to wild-type animals at various time points during aging. As a complementary approach to gauge the potential of pexophagy as a cellular biomarker of aging, wild-type animals expressing the pexophagy sensor in the intestine will be segregated into two populations during young adulthood: those with higher levels of pexophagy, and those with lower levels of pexophagy. Subsequent lifespan analysis of the two populations will be performed to determine whether this cellular marker is predictive of lifespan from an early point in adulthood. Lastly, analysis of the pexophagy sensor will be extended to additional peroxisome-containing tissues to clarify whether age-related changes to pexophagy are specific to the intestine or occur synchronously in multiple tissues. Such analysis may suggest systemic control over this process, or may instead hint at tissue-specific differences in aging at the cellular and molecular level. Collectively, these studies will provide fundamental information on the cell biology of aging, and will conceptually advance our understanding of age-dependent modifications to organelle biology.