Kaeberlein Lab Science
Identifying conserved longevity genes
We believe that an effective approach toward developing therapies for age-associated disease is to focus on evolutionarily conserved longevity factors. The rationale behind this approach is that if a particular gene functions to regulate aging in evolutionarily divergent model organisms, then there is a very good chance that that gene will have a similar function in humans. Once these genes are identified, then it will be possible to develop drugs specifically targeting the gene 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.
As part of the Consortium for the Determination of Public Pathways Regulating Longevity, we are vigorously pursuing the identification and validation of evolutionarily conserved determinants of longevity. In a paper recently published in Genome Research (download here), we described the identification of 25 homolog pairs that increase life span when knocked down in both yeast and worms (Table 1). One project in the lab is an effort to understand the mechanism(s) by which these conserved aging genes modulate longevity in both organisms. This project is funded in part by a New Scholar in Aging Award from the Ellison Medical Foundation.
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 will dramatically increase human life span, it is likely that dietary restriction will improve 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.
Like many other labs studying DR, we are interested in the potential utility of "dietary restriction mimetics". Dietary restriction mimetics are (as yet hypothetical) compounds that mimic the physiological response to dietary restriction (including slowing aging) without requiring reduced consumption of food. Resveratrol, a compound found in red wine, has recieved much attention as a potential dietary restriction mimetic (Figure 1) ; however, it remains to be determined whether resveratrol indeed recapitulates the health and longevity benefits associated with DR. Given our interest in TOR signaling, we are excited about the potential of compounds that target this pathway as potential DR mimetics. One such compound is the TOR inhibitor rapamycin (Figure 1). We have previously shown that rapamycin treatment can increase life span in yeast, and other groups are testing rapamycin as a potential anti-cancer compound in humans (anti-cancer effects are one hallmark of DR). Rapamycin is also currenty being tested for its effects on life span in mice as part of the NIA Interventions Testing Program.
