Dietary restriction (DR) has been reproducibly found to increase life span and delay age-associated diseases in many organisms, including mammals. The mechanism(s) by which DR promotes health, however, remain poorly understood. The overarching goal of this proposal is to fully characterize the genetic and molecular basis of life span extension and disease prevention from DR in the nematode Caenorhabditis elegans. These studies are likely to be highly relevant for human health and will identify candidate genetic targets for a variety of age-associated diseases, such as diabetes, heart disease, cancer, and Alzheimer's disease. C. elegans has served as one of the premier invertebrate models for characterizing pathways that modulate longevity. At least four methods of DR have been reported to increase life span in C. elegans;however, none has become widely accepted. This lack of consensus has impeded progress in understanding how DR relates to known modifiers of longevity. We have recently developed a novel DR method in C. elegans where adult animals are maintained on a nutrient-agar surface without bacterial food source (dietary deprivation = DD). DD increases adult life span by more than 50% and dramatically reduces disease phenotypes associated with expression of at least three different toxic peptides, including proteotoxic peptides implicated in the pathogenesis of Huntington's disease and Alzheimer's disease. Here we propose phenotypic, genetic, and genomic experiments to characterize life span extension and disease prevention by DD in C. elegans.
One aim of this work is to carry out a comprehensive comparative analysis (including global gene expression profiling) of DD with prior methods of DR in C. elegans. These experiments are important both because they will elucidate the relationship between different DR methods in C. elegans, and because they will improve confidence in future studies of DR in this organism. In subsequent aims, we will use information from this comparative analysis as a starting point for identifying genetic targets of DR. We will determine which of these targets are necessary and/or sufficient for life span extension and/or suppression of proteotoxic disease using a combination of RNAi knock-down and transgenic overexpression. Genetic and biochemical interactions between these targets of DR will be explored in follow-up studies.

Public Health Relevance

Dietary restriction has been shown to increase longevity and delay a wide range of age-associated diseases in many different organisms. We have developed a novel method for studying dietary restriction, and we have found that our method dramatically improves health in invertebrate models of Huntington's disease and Alzheimer's diseases. The goal of this proposal is to understand how dietary restriction increases longevity and retards disease. These studies will identify candidate therapeutic targets for several age-associated human diseases, including cancer, heart disease, diabetes, and Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Finkelstein, David B
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University of Washington
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Russell, Joshua Coulter; Burnaevskiy, Nikolay; Ma, Bridget et al. (2017) Electrophysiological measures of aging pharynx function in C. elegans reveal enhanced organ functionality in older, long-lived mutants. J Gerontol A Biol Sci Med Sci :
Kapahi, Pankaj; Kaeberlein, Matt; Hansen, Malene (2017) Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Res Rev 39:3-14
Chandler-Brown, Devon; Choi, Haeri; Park, Shirley et al. (2015) Sorbitol treatment extends lifespan and induces the osmotic stress response in Caenorhabditis elegans. Front Genet 6:316
Promislow, Daniel E L; Kaeberlein, Matt (2014) Development. Chemical warfare in the battle of the sexes. Science 343:491-2
Kaeberlein, Matt (2013) Deciphering the role of natural variation in age-related protein homeostasis. BMC Biol 11:102
Kaeberlein, Matt (2013) mTOR Inhibition: From Aging to Autism and Beyond. Scientifica (Cairo) 2013:849186
Leiser, Scott F; Fletcher, Marissa; Begun, Anisoara et al. (2013) Life-span extension from hypoxia in Caenorhabditis elegans requires both HIF-1 and DAF-16 and is antagonized by SKN-1. J Gerontol A Biol Sci Med Sci 68:1135-44
Johnson, Simon C; Rabinovitch, Peter S; Kaeberlein, Matt (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493:338-45
Kaeberlein, Matt (2013) Longevity and aging. F1000Prime Rep 5:5
Choi, Haeri; Schneider, Heather; Klum, Shannon et al. (2013) UV-photoconversion of ethosuximide from a longevity-promoting compound to a potent toxin. PLoS One 8:e82543

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