Mitochondrial dysfunction has long been implicated in aging and numerous age-onset diseases. Therefore, identifying interventions that can be applied in aged animals to improve mitochondrial homeostasis would be highly desirable towards the goal of prolonging healthspan. Mitochondrial autophagy (mitophagy) is an autophagic quality control mechanism that removes dysfunctional mitochondria. Recently, we identified novel roles for Parkin, an E3 ubiquitin ligase that functions to promote mitophagy, in the modulation of Drosophila aging. Recent evidence indicates that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. Indeed, we have shown that the anti-aging effects of Parkin are associated with a shift in mitochondrial dynamics towards increased fission. Moreover, we have now discovered that up-regulating Drp1, a Dynamin-related protein that catalyzes mitochondrial fission, for a limited period of time in mid-life is sufficient to prolong lifespan and healthspan. Furthermore, we show that up-regulation of Drosophila p62, an autophagy adaptor reported to mediate mitophagy, in mid-life also slows organismal aging. In characterizing alterations in mitochondrial dynamics during aging, we find that a mid-life shift towards mitochondrial fusion is linked to the accumulation of dysfunctional mitochondria. Remarkably, we have discovered that short-term induction of Drp1, in mid-life, restores mitochondrial morphology and function to a youthful state. In recent years, a number of drugs that increase lifespan in mammals have been identified. However, long-term treatment with any drug can cause deleterious side effects. Therefore, it would be advantageous to identify the cellular mechanisms that mediate the anti-aging effects and/or identify transient interventions that can induce these cellular changes. Here, we show that feeding the putative anti-aging drug metformin, for a limited period of time to aged flies, activates Drp1 and induces mitochondrial fission in vivo. Here, we propose to build upon these groundbreaking discoveries by exploring three specific aims: 1) To examine the mechanisms by which a mid-life shift towards mitochondrial fission promotes healthy aging, 2) To examine the mechanisms by which mid-life induction of p62 promotes healthy aging, and 3) To examine the relationships between evolutionarily conserved anti-aging interventions including metformin, mitochondrial dynamics and mitophagy. The work proposed herein will provide fundamental insights into the molecular and cellular mechanisms of aging. At the same time, our studies may provide new therapeutic approaches, that can be applied for a limited period of time in mid- to late-life, to delay the onset and progression of aging and associated diseases.
Advanced age is the greatest risk factor for the prevalent diseases of developed countries: cancer, cardiovascular disease and neurodegeneration. We are using the powerful genetics of the fruit fly Drosophila to better understand the biological mechanisms of aging. The long-term goal of this research is to provide novel therapeutic targets to counteract age-related human diseases.
|Clark, Rebecca I; Walker, David W (2018) Role of gut microbiota in aging-related health decline: insights from invertebrate models. Cell Mol Life Sci 75:93-101|
|Salazar, Anna M; Resnik-Docampo, Martin; Ulgherait, Matthew et al. (2018) Intestinal Snakeskin Limits Microbial Dysbiosis during Aging and Promotes Longevity. iScience 9:229-243|
|Rana, Anil; Oliveira, Matheus P; Khamoui, Andy V et al. (2017) Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster. Nat Commun 8:448|
|Clark, Rebecca I; Salazar, Anna; Yamada, Ryuichi et al. (2015) Distinct Shifts in Microbiota Composition during Drosophila Aging Impair Intestinal Function and Drive Mortality. Cell Rep 12:1656-67|
|Icreverzi, Amalia; de la Cruz, Aida Flor A; Walker, David W et al. (2015) Changes in neuronal CycD/Cdk4 activity affect aging, neurodegeneration, and oxidative stress. Aging Cell 14:896-906|
|Hur, Jae H; Stork, Devon A; Walker, David W (2014) Complex-I-ty in aging. J Bioenerg Biomembr 46:329-35|
|Ulgherait, Matthew; Rana, Anil; Rera, Michael et al. (2014) AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep 8:1767-1780|
|Rana, Anil; Rera, Michael; Walker, David W (2013) Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proc Natl Acad Sci U S A 110:8638-43|
|Clark, Rebecca I; Tan, Sharon W S; Péan, Claire B et al. (2013) MEF2 is an in vivo immune-metabolic switch. Cell 155:435-47|
|Hur, Jae H; Bahadorani, Sepehr; Graniel, Jacqueline et al. (2013) Increased longevity mediated by yeast NDI1 expression in Drosophila intestinal stem and progenitor cells. Aging (Albany NY) 5:662-81|
Showing the most recent 10 out of 15 publications