The study of yeast replicative aging has been instrumental in defining mechanistic aspects of aging, in identifying conserved eukaryotic aging genes, and has led to some of the best candidates for anti-aging drugs currently under development. However, the traditional micro-dissection lifespan assay is laborious and time consuming, making it impossible to perform large library screens of thousands of molecules. Here we propose to develop a novel high throughput method to systematically identify small molecules that delay aging, and to test the promising candidates in worms and in human cells.
In Aim 1, we will develop a high-throughput method based on a novel genetic system and deep sequencing to measure the effect on lifespan of thousands of small molecules, including FDA approved drugs and the library of natural products. We will also screen small molecule drugs that target the human homologs of known yeast longevity genes. Small molecules identified to extend yeast lifespan in Aim 1 will be funneled into Aim 2, which describes efforts to determine (1) whether the drugs have conserved effects on aging using C. elegans, and (2) whether the drugs can ameliorate age-associated hallmarks in a human cell culture model of aging. Together these two aims will generate a set of drugs that set the stage for testing in mammals. The importance of expanding the repertoire of drugs that extend lifespan and delay aging cannot be underscored. Each new small molecule not only serves as a probe to define the mechanisms driving aging but also represents a new potential class of drugs that may extend human healthspan.

Public Health Relevance

We have entered an era where drugs and other small molecules are beginning to be identified that extend lifespan, delay the onset of age-related diseases and improve function with age, in other words extend healthspan. This proposal uses one of the premier model organisms for aging research, yeast, to significantly expand the repertoire of small molecules that delay aging. After identification, small molecules will be tested for their ability to delay aging in another model organism, worms, and to ameliorate age-associated hallmarks in human cells. These studies will set the stage for tests in mammals and generate a set of drugs that can potentially extend human healthspan.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG060129-02
Application #
9788255
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2018-09-30
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118