Wednesday, February 5, 2025
2/5/2025
Project Summary/Abstract Aging often manifests as physiological decline at an organismal level. However, the aging process has its roots at the level of cells; changes to molecules and cellular compartments ultimately underlie physiological decline and age-related disease pathology. Clarifying cellular causes of aging has the potential to inform strategies to promote longer, healthier lives, and may also reveal unexpected elements of cell biology relevant to animal health and disease. My lab has begun analysis of a new aspect of cell biology in aging: degradation of peroxisomes by autophagy. Peroxisomes are membrane-bound eukaryotic organelles that are critical to cell health and organismal viability; they carry out essential oxidative reactions, and they also eradicate toxins. Remarkably, we have found that peroxisome degradation by autophagy (‘pexophagy’) specifically occurs in young-adult animals during early aging, signifying that this may be one of a collection of initiating events in the aging process. Indeed, using the nematode Caenorhabditis elegans as a model organism, we have discovered that the rate of pexophagy may scale with aging. Animals that show accelerated peroxisome degradation in early age die prematurely, whereas animals in which pexophagy is inhibited live long. Moreover, turnover of this organelle may entail unique regulation, as we have found that pexophagy during aging, as during starvation, occurs at non-canonical autophagic lysosomes, which are tubular in structure and morphologically dynamic. We are now poised to make significant advancements in understanding the regulation of pexophagy, particularly in a live-animal system, and its role in aging and longevity. In the proposed research project, we will perform unbiased genetic screens to uncover regulators and effectors of pexophagy in live animals during starvation and aging. To date, we know of only a handful of regulatory genes. An expectation is that we may identify factors involved in the signaling of this event, or adapters that potentially link peroxisomes to tubular lysosomes in these contexts. In addition, we will perform detailed analysis of gene knockdowns that we have already described to feed into the regulation of age- dependent pexophagy, with the goal of determining mechanisms that contribute to lifespan extension upon pexophagy inhibition. In sum, these studies will provide information on a previously unexplored cellular aspect of aging possibly relevant to novel longevity mechanisms.
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