Pexophagy regulation in live animals and its role in aging and longevity

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.

Grant Number: 5R01AG079970-03
NIH Institute/Center: NIH
Principal Investigator: Kenneth Bohnert