Dietary restriction (DR), or limited food intake without malnutrition, is known to protect against several age- related disorders and extends lifespan in many organisms, including mammals. However, the cellular and molecular mechanisms underlying this fascinating phenomenon remain poorly understood. We recently identified a critical role for the process of autophagy in the lifespan extension induced by DR in C. elegans (Hansen et al., PLoS Genetics, 2008). Autophagy is a conserved pathway by which cellular components are degraded and recycled. Specifically, we found that autophagy is induced in response to DR, and this induction is dependent on the FOXA transcription factor PHA-4, a known regulator of DR-induced longevity. Accordingly, we and others have found that several genes with functions in autophagy are required for these animals to live long. While establishing an important link between autophagy and the longevity response to DR, these studies did not address how DR induces autophagy at the cellular and molecular level to extend the lifespan of the organism. In particular, it remains unknown how the autophagy process contributes to organismal aging in terms of which tissues are critical, and what signaling machinery is engaged to select cellular components as cargo for degradation in response to DR. The goal of this application is to use genetic and biochemical approaches to characterize in which tissues autophagic turn-over is induced to affect longevity in adult C. elegans subjected to DR, as well as to identify novel regulators of autophagy with effects on longevity. Specifically, in Aim 1, we will use imaging techniques like TEM and develop new fluorescent reporters to detect autophagic events in different tissues of aging worms.
In Aim 2, we will examine in which tissues autophagy genes functions to modulate longevity, e.g., by tissue-specific, over-expression experiments. Finally, in Aim 3, we will characterize the genetic requirements for autophagy to increase lifespan by DR, and search for new modulators of autophagy, including factors important for autophagic cargo recognition in biochemical and genetic screens. Throughout these studies we will compare the DR longevity model to other longevity pathways that similarly rely on autophagy to extend lifespan, including the daf-2/insulin/IG-1 signaling pathway. Like DR, autophagy plays critical roles in many diseases, including age-related disorders like cancer and neurodegeneration. Understanding the regulation of autophagy and the conserved mechanisms linking autophagy and DR in multicellular organisms like C. elegans are likely to provide new important insights not only into aging but also help developing treatments for such age-related diseases.

Public Health Relevance

The US population of elderly people is rapidly growing and age-related diseases constitute a major health issue in our society. However, the cellular and molecular basis of aging and age-related disorders is poorly understood. This proposal aims to determine how autophagy - a cellular process of cytoplasmic degradation with major biological functions - modulates organismal aging. The proposed research has relevance to public health, because the mechanisms to be investigated are evolutionary conserved and the findings might ultimately provide therapies to treat aging-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG038664-02
Application #
8311644
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Velazquez, Jose M
Project Start
2011-08-15
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$382,200
Indirect Cost
$186,200
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Hansen, Malene; Kennedy, Brian K (2016) Does Longer Lifespan Mean Longer Healthspan? Trends Cell Biol 26:565-8
Gelino, Sara; Chang, Jessica T; Kumsta, Caroline et al. (2016) Intestinal Autophagy Improves Healthspan and Longevity in C. elegans during Dietary Restriction. PLoS Genet 12:e1006135
Seah, Nicole E; de Magalhaes Filho, C Daniel; Petrashen, Anna P et al. (2016) Autophagy-mediated longevity is modulated by lipoprotein biogenesis. Autophagy 12:261-72
McQuary, Philip R; Liao, Chen-Yu; Chang, Jessica T et al. (2016) C. elegans S6K Mutants Require a Creatine-Kinase-like Effector for Lifespan Extension. Cell Rep 14:2059-67
Lapierre, Louis R; Kumsta, Caroline; Sandri, Marco et al. (2015) Transcriptional and epigenetic regulation of autophagy in aging. Autophagy 11:867-80
Zhang, Hong; Chang, Jessica T; Guo, Bin et al. (2015) Guidelines for monitoring autophagy in Caenorhabditis elegans. Autophagy 11:9-27
Wilkinson, Deepti S; Jariwala, Jinel S; Anderson, Ericka et al. (2015) Phosphorylation of LC3 by the Hippo kinases STK3/STK4 is essential for autophagy. Mol Cell 57:55-68
Wilkinson, Deepti S; Hansen, Malene (2015) LC3 is a novel substrate for the mammalian Hippo kinases, STK3/STK4. Autophagy 11:856-7
Kumsta, Caroline; Ching, Tsui-Ting; Nishimura, Mayuko et al. (2014) Integrin-linked kinase modulates longevity and thermotolerance in C. elegans through neuronal control of HSF-1. Aging Cell 13:419-30
Nishimura, Mayuko; Kumsta, Caroline; Kaushik, Gaurav et al. (2014) A dual role for integrin-linked kinase and β1-integrin in modulating cardiac aging. Aging Cell 13:431-40

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