Caloric restriction has been shown to increase life span in organisms from yeast to mice and was recently reported to reduce age-related mortality and disease in the rhesus monkey. Drugs that mimic the effects of caloric restriction are actively being developed in the hopes that they will prove therapeutic toward a variety of age-related diseases in people. Despite the potential benefits of such caloric restriction mimetics, there are examples in each of the model organisms commonly used in aging-related research demonstrating that specific genotypic changes can block the longevity benefits of caloric restriction. Some genetic variants even have their life span shortened by caloric restriction. Little is known about the mechanisms underlying such genotype-dependent responses to caloric restriction, however, and there is currently no way of predicting how individuals in a genetically heterogenous population (such as humans) will respond to caloric restriction. Obtaining such an understanding is critically important before caloric restriction mimetics can be applied to improve human health. The goal of this proposal is first to address this question on a genome-wide scale in the budding yeast Saccharomyces cerevisiae, second to extend these findings to the nematode Caenorhabditis elegans, and third to begin identification and testing of human functional variants corresponding to factors identified fron the yeast and nematode studies. This will be accomplished by determining the replicative life span response of 1500 single- gene deletion mutants to caloric restriction, defining genetic variants that respond abnormally to caloric restriction, and characterizing the molecular mechanisms accounting for these effects. Nematode homologs of abnormally responding variants will be identified and experiments will be performed on a subset of these variants to determine which genotype-dependent responses to caloric restriction are conserved across these two widely divergent eukaryotes. Human homologs will also be identified and, in cases where they complement the yeast mutation, known sequence variants will be tested for functional significance in the response to caloric restriction. In this way, we will begin to gain insight into the interplay between genotype and the response to caloric restriction as well as the molecular mechanism that underlie this interplay.
Drugs that mimic the beneficial health and longevity effects of caloric restriction are highly sought after and are thought to offer great promise for treating age-related diseases;however, animals studies have indicated that caloric restriction does not improve the longevity of all genotypes equally. A better understanding of which individuals are likely to benefit, or perhaps even be harmed, by caloric restriction is needed before the benefits of such treatments can be fully harnessed to improve healthspan in people.
|Sunshine, Anna B; Ong, Giang T; Nickerson, Daniel P et al. (2016) Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae. Aging Cell 15:317-24|
|Vermulst, Marc; Denney, Ashley S; Lang, Michael J et al. (2015) Transcription errors induce proteotoxic stress and shorten cellular lifespan. Nat Commun 6:8065|
|McCormick, Mark A; Delaney, Joe R; Tsuchiya, Mitsuhiro et al. (2015) A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging. Cell Metab 22:895-906|
|Cui, Hong-Jing; Liu, Xin-Guang; McCormick, Mark et al. (2015) PMT1 deficiency enhances basal UPR activity and extends replicative lifespan of Saccharomyces cerevisiae. Age (Dordr) 37:9788|
|Bitto, Alessandro; Wang, Adrienne M; Bennett, Christopher F et al. (2015) Biochemical Genetic Pathways that Modulate Aging in Multiple Species. Cold Spring Harb Perspect Med 5:|
|Kaya, Alaattin; Ma, Siming; Wasko, Brian et al. (2015) Defining Molecular Basis for Longevity Traits in Natural Yeast Isolates. NPJ Aging Mech Dis 1:|
|Sen, Payel; Dang, Weiwei; Donahue, Greg et al. (2015) H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes Dev 29:1362-76|
|Jafari, Gholamali; Wasko, Brian M; Tonge, Ashley et al. (2015) Tether mutations that restore function and suppress pleiotropic phenotypes of the C. elegans isp-1(qm150) Rieske iron-sulfur protein. Proc Natl Acad Sci U S A 112:E6148-57|
|Kaeberlein, Matt (2014) Rapamycin and ageing: when, for how long, and how much? J Genet Genomics 41:459-63|
|Wasko, Brian M; Kaeberlein, Matt (2014) Yeast replicative aging: a paradigm for defining conserved longevity interventions. FEMS Yeast Res 14:148-59|
Showing the most recent 10 out of 29 publications