The Science

Identifying Conserved Longevity Genes

Table 1

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

Figure 1

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 project 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.

Sensory mechanisms of dietary restriction in C. elegans

We have developed a novel method to study dietary restriction (DR) in C. elegans, referred to as bacterial deprivation (BD), which allows us to use the standard agar plate life span assay without using genetic mimics of DR that may have pleiotropic effects. BD behaves similarly to other methods of DR, and it extends life span independently of the insulin/IGF-like signaling pathway. A detailed description of the BD method

is described in our 2006 Aging Cell Paper.

In unpublished studies, we have determined that BD extends life span independently of both age and food consumption. BD extends maximum life span regardless of the age at which BD is initiated, and BD animals that are returned to a normal bacterial diet have a life span that is intermediate between control fed animals and BD animals. Even when BD is initiated after the animals have stopped eating, at about 20 days of adulthood, there is a significant longevity benefit. This suggests the possibility that food sensing, in addition to food consumption, plays a role in life span extension by BD.

Previous work by the Kenyon Lab showed that some chemosensory mutants were very long-lived; however, our data suggests that these chemosensory pathways do not mediate the food sensing effect we observe because BD extends life span in these mutants.

Figure 1. Sandwich experiment.

More recently, we have determined that a soluble bacterial product limits life span in worms. One elegant demonstration of this is the "sandwhich experiment" where a bacterial lawn is positioned between two agar slabs. Nematodes that are kept on the surface of the top agar slab have a life span that is intermediate between that of control fed and BD (no bacterial food) animals.

We are currently designing experiments to identify both the bacterial product and the pathway used by worms to sense this product. Our data is consistent with similar findings in flies from the Pletcher Lab, suggesting that the role of food sensing in longevity may be evolutionarily conserved.

The Kaeberlein Lab was recently awarded a Glenn/AFAR Breakthroughs in Gerontology Grant to support this project.

Yeast Aging

The budding yeast Saccharomyces cerevisiae has been used as a model of organismal and cellular aging for more than 50 years. Yeast provides many advantages over other model systems, including short life span, well characterized genetic and molecular methods, low relative cost, cell type homogeneity, and a vast organismal information base. Although it remains to be determined which aspects of aging in yeast are relevant to aging in multicellular eukaryotes, evidence for a high degree of evolutionary conservation of aging pathways has lent credibility to yeast as an important model organism in aging-related research.

Figure 1.

Two different types of aging have been studied in yeast: replicative and chronological (see Figure 1). The replicative life span of a yeast cell refers to the number of daughter cells produced by a mother cell prior to senescence; while chronological life span measures the length of time a yeast cell can survive under non-proliferative conditions. The ability to monitor both the replicative and chronological aging of a yeast cell is fortuitous, as it allows for independent analysis of the aging process in both dividing and non-dividing cells. Yeast replicative aging may serve as a suitable model for the aging of mitotically active cell types in multicellular eukaryotes, such as human stem cell populations. Chronological aging, on the other hand, models the aging process of post-mitotic cell types like muscle and brain.

For more detailed descriptions of the methods and history of yeast aging research, please see the following review articles: