Projects per year
Project Details
Description
ABSTRACT (OVERALL)
Aging is the greatest risk factor for most common chronic human diseases and a logical target for developing
interventions to prevent, mitigate or reverse multiple age-related morbidities. Over the past two decades, genetic
and pharmacologic interventions targeting conserved pathways of growth and metabolism have consistently led
to substantial extension of the lifespan and healthspan in model organisms as diverse as nematodes, flies and
mice. It is imperative to extend the results obtained with model organisms to aging humans. In this proposed
renewal of our U19 project “Genetic variant-based drug discovery targeting conserved pathways of aging” we
propose to continue using human centenarians to identify genetic variants as targets for developing drugs that
improve human healthy aging. During the first funding period, we identified rare variants and longevity pathways
in our centenarian cohort including coding variants in IGF-1R, SIRT6, and ATM, and functional non-coding
variants in FOXO3A, SIRT6 and components of the IKK/NF-B pathway, RelA/p65, NFKB1/p50 and NFKB1a
(IB). Having established the feasibility of using the genetics of human centenarians to identify genes and
pathways as candidates for potential drug targets for promoting human healthspan, the focus of this renewal
application will be to expand the program through whole exome analysis of our own, significantly expanded
cohort and other centenarian cohorts, further gene functionalization, the use of novel mouse models of
accelerated aging to validate the role of the rare variants and pathways in healthy longevity, and expansion of
our pipeline of screening for candidate interventions. To accomplish these goals, we propose an interdisciplinary
approach, making full use of the latest advances in cellular genomics, high-throughput functional screening, stem
cell biology, mouse and human genetics and drug screening. This renewal application is comprised of four
projects. Project 1: Genetic analysis of extreme human longevity (Zhang, Dong, and Vijg); Project 2: Identification
of functional genetic rare variants (Suh and Yu), Project 3: Validation and characterization of rare variants in
mouse models of aging (Niedernhofer) and Project 4: Development of novel therapeutics targeting the identified
variants and pathways (Robbins and Gorbunova). There is also one Research Resource Core for Data
Integration and Sharing (Core B; Zhang and Dong) as well as an Administrative Core (Core A; Vijg, Robins and
Barzilai). We expect that the continued and expanded use of the human centenarian cohorts will allow us to
obtain more detailed genetic information critical for identifying targets for the development of drugs for extending
human healthspan, for example, by increasing resilience to Alzheimer’s Disease pathology.
Status | Active |
---|---|
Effective start/end date | 9/15/17 → 8/31/24 |
Funding
- National Institute on Aging: $444,098.00
- National Institute on Aging: $334,926.00
- National Institute on Aging: $1,812,559.00
- National Institute on Aging: $116,750.00
- National Institute on Aging: $76,552.00
- National Institute on Aging: $1,910,686.00
- National Institute on Aging: $1,812,656.00
- National Institute on Aging: $2,822,483.00
- National Institute on Aging: $334,926.00
- National Institute on Aging: $1,876,472.00
- National Institute on Aging: $773,955.00
- National Institute on Aging: $1,042,676.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.
-
Validation and characterization of the identified variants associated with human longevity in mouse models
8/1/23 → 7/31/24
Project: Research project
-
-
Development of novel therapeutics targeting the identified pathways associated with human longevity
8/1/23 → 7/31/24
Project: Research project