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Project Details
Description
Abstract
Although aging is extremely complex, the occurrence of genetic variants in humans that positively affect longevity
and health offer an ideal starting point for the systematic identification of molecular targets for interventions that
could extend human healthspan. Through genetic analysis of the Ashkenazi Jewish centenarian resource at the
Albert Einstein College of Medicine, this U19 identified multiple rare, functional genetic variants significantly
associated with healthy longevity, which represent potential targets for drug discovery. These include coding
variants in IGF1R, SIRT6, ATM, USP35, UBE3C, and BLM, as well as functional non-coding variants in FOXO3A,
SIRT6, SMAD3, and components of the IKK/NF-kB pathway, including p65, NFKB1/p50 and NFKB1a (IkBa).
However, the mechanism by which these variant gene products extend healthspan and lifespan still need to be
discovered and validated in model systems. During the previous funding period, we used the Ercc1-/∆ mouse
model of accelerated aging and aged wild-type mice to demonstrate that reduction in ATM and NF-kB activity,
achieved by ATM and p65/RelA haploinsufficiency, and overexpression of hSIRT6 reduced cellular senescence
and extended healthspan of mice. In addition, treatment of Ercc1-/∆ mice (in collaboration with Project 4) with a
novel IKK/NF-kB inhibitor (SR12343), a known ATM inhibitor (KU-55933), and a compound shown to stimulate
the mono–adenosine 5′-diphosphate (ADP)–ribosyltransferase (mADPRT) activity of SIRT6 (fucoidan) reduce
senescence and improve age-related phenotypes in mice. We also generated mice carrying a centenarian rare
variant in IGF-1R (Igf1rhR407H), mice heterozygous for Smad3, Foxo3a, and Usp35, as well as mice carrying
mutations in Sirt6 conferring loss of deacetylase or mADPRT activity, which are currently being analyzed. Our
data suggests that many of these rare variants reduce DNA damage and/or cellular senescence. Here, we
propose to expand these efforts to validate the role of additional rare variants identified by Projects 1 and 2 for
their ability to extend healthspan using our murine model of a human progeroid syndrome to accelerate analyses.
We also will continue to test compounds targeting the variant gene products and associated pathways provided
by Project 4 in both progeroid and aged wild-type mice. Overall, the aim of Project 3 is to use genetic approaches
to validate the pathways identified in Projects 1 and 2 as impacting healthspan in mice. We will determine the
impact of haploinsufficiency, overexpression, or specific mutations on animal health, molecular endpoints
associated with the hallmarks of aging, resilience, and geropathology in mice. We will also pharmacologically
target these pathways in mice, in collaboration with Project 4, to determine the impact on the same endpoints.
The successful completion of this project will validate the identified human variants as important for healthy aging
and identify novel therapeutic strategies with the potential to extend healthspan.
Status | Active |
---|---|
Effective start/end date | 8/1/23 → 7/31/24 |
Funding
- National Institute on Aging: $563,840.00
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Projects
- 1 Active
-
Genetic variant-based drug discovery targeting conserved pathways of aging
Vijg, J., Ladiges, W. C., Niedernhofer, L. J., Barzilai, N., Robbins, P. D., Suh, Y., Zhang, Z. & Robbins, P. D.
9/15/17 → 8/31/24
Project: Research project