Matt Kaeberlein

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Email: EMAIL
Lab website: http://www.kaeberleinlab.org


Research in the Kaeberlein Lab is focused on understanding the basic mechanisms of aging and developing therapies for age-associated diseases by targeting the pathways that modulate aging.

Identifying conserved longevity genes

We believe that one effective approach toward developing therapies for age-associated diseases is to focus on evolutionarily conserved longevity factors. The rationale behind this approach is that if a particular gene functions to modulate aging in evolutionarily divergent model organisms, then there is a good chance that this gene will have a similar function in humans. Once these genes are identified, it will be possible to develop drugs specifically targeting the gene(s) of interest. If these drugs increase life span or delay the onset of age-associated disease in mice, they will be good candidates for human clinical trials. We have recently identified 25 homolog pairs that similarly modulate aging in yeast and worms. As part of the Consortium for the Determination of Public Pathways Regulating Longevity, we are vigorously pursuing the identification and validation of additional evolutionarily conserved longevity determinants using yeast, worm, and mouse models.

Molecular mechanisms of dietary restriction

Dietary restriction mimetics represent one of the best bets for rapidly developing therapies that modulate the rate of aging. Dietary restriction (DR, also referred to caloric restriction or calorie restriction, CR) is known to slow aging and delay disease in many different organisms, including yeast, worms, flies, and mice. While it is not yet known whether dietary restriction can increase human life span to the extent observed in laboratory animals, it is very likely that dietary restriction would improve human healthspan and delay a variety of age-related pathologies in people.

The Kaeberlein Lab has several projects aimed toward understanding how DR acts at a genetic and molecular level. By understanding how DR works, we will be able to take a rational approach to developing therapies that mimic dietary restriction. One area of particular interest in our lab is the role that TOR (target of rapamycin) signaling plays in the response to DR. Our group and others have shown that DR reduces TOR signaling, and (like DR) reduced TOR signaling is sufficient to increase life span in yeast, worms, and flies. We are currently studying downstream components of the TOR pathway in order to understand at a molecular level how TOR modulates aging in response to nutrient availability. We are also interested in testing the possibility that chemicals targeting this pathway may act as DR mimetics. One such compound is the TOR inhibitor rapamycin, which we have previously shown can increase life span in simple organisms. Rapamycin is currently being tested for its effects on life span in mice as part of the NIA Interventions Testing Program.

Understanding the relationship between aging and protein homeostasis.

Evidence from work in the Kaeberlein lab and other labs suggests the hypothesis that loss of protein homeostasis plays a causal role in aging. Several age-associated neurodegenerative diseases in people, such as Alzheimer's disease and Huntington's disease, are caused by loss of protein homeostasis due to expression of a toxic protein. We are currently attempting to understand how protein homeostasis changes with age in C. elegans and working to identify novel genetic and pharmacological modifiers of proteotoxicity in nematode models of Huntington's and Alzheimer's diseases. We have reported that DR dramatically delays disease progression in these models and have, thus far, identified more than 50 genes and compounds that have a similar effect. It is our hope that these studies will contribute to the development of effective therapies for treating human diseases of proteotoxicity.

For additional information, please see our website: http://www.kaeberleinlab.org. To download selected publications go to http://www.kaeberleinlab.org/papers.html.


Selected Relevant Publications