PROJECT SUMMARY/ABSTRACT Advanced age is the key risk factor for most chronic diseases, including osteoporosis, contributing to enormous costs that will only worsen with our growing elderly population. Thus, there is a critical need to develop interventions that can prevent or reverse age-related diseases as a group and thereby maximize healthspan in humans. This may be feasible by targeting a fundamental aging mechanism ? cellular senescence. Emerging evidence suggests that senescent cells and their senescence-associated secretory phenotype (SASP) are promising therapeutic targets to prevent age-related diseases as a group. Indeed, because with advancing age senescent cells accumulate in multiple tissues in temporal and spatial synchrony with age-associated functional decline in both animals and humans, they have been hypothesized to disrupt tissue function and to promote degenerative pathologies. The causal link between senescence and age-related tissue dysfunction has been demonstrated in genetically modified progeroid mice (an accelerated aging model) expressing a ?suicide? transgene, which permits inducible elimination of senescent cells upon administration of a synthetic drug. This approach had a profound effect on enhancing healthspan by delaying the onset of aging pathologies in multiple tissues, including adipose, eye, and skeletal muscle. However, how senescent cells impact age-related bone loss and whether their removal can delay or prevent this loss remains unclear. The goal of the proposed studies is to test the hypothesis, for the first time, that the adverse effects of increased cellular senescence play a central role in age-related bone loss. This hypothesis is supported by preliminary data indicating that senescent cells, particularly senescent osteocytes, accumulate in bone with aging. As previous studies have used progeroid mice, there is a critical need to demonstrate a similar benefit of eliminating senescent cells in normal aged mice. Thus, in normal chronologically aged mice, the proposed studies will determine the extent to which systemic elimination of senescent cells through genetic and pharmacological approaches prevents age-related bone loss, and whether local elimination of senescent osteocytes is sufficient to prevent skeletal aging. Further, embedded in these studies will be analyses of highly enriched populations of osteocytes as well as other cell types in the bone microenvironment hypothesized to be of importance in mediating tissue damage in response to the SASP, thereby providing important mechanistic insights. These innovative approaches should lead to new hypotheses regarding the mechanisms by which senescent cells contribute to tissue dysfunction and the onset of age-related degenerative diseases. The significance of these studies is the provocative possibility that targeted elimination of senescent cells may prevent age-related diseases as group, potentially reducing polypharmacy and adverse drug interactions.
|Effective start/end date||8/1/16 → 7/31/21|
- National Institute of Arthritis and Musculoskeletal and Skin Diseases: $640,170.00
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