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.
An overwhelming majority of individuals over age 65 suffer from at least two chronic degenerative diseases, including osteoporosis, an enormous public health problem as each year there are approximately 2 million osteoporosis-related fractures with a net cost to the US health care system of $17 billion. Thus, there is a compelling need for novel interventions to prevent and/or treat age-related disorders as a group, rather than treating each condition individually. These studies will provide a better understanding of the molecular events underlying elimination of senescence cells in enhancing healthspan, with a focus on the prevention of skeletal aging. PROJECT NARRATIVE The goal of this project is to better understand the mechanisms underlying elimination of senescence cells in enhancing healthspan, with a focus on the prevention of skeletal aging. These 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.
|Xu, Ming; Pirtskhalava, Tamar; Farr, Joshua N et al. (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246-1256|
|Khosla, Sundeep; Farr, Joshua N; Kirkland, James L (2018) Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis. J Clin Endocrinol Metab 103:1282-1290|
|Farr, Joshua N; Weivoda, Megan M; Nicks, Kristy M et al. (2018) Osteoprotection Through the Deletion of the Transcription Factor Ror? in Mice. J Bone Miner Res 33:720-731|
|Farr, Joshua N; Xu, Ming; Weivoda, Megan M et al. (2017) Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 23:1072-1079|
|Farr, Joshua N; Dimitri, Paul (2017) The Impact of Fat and Obesity on Bone Microarchitecture and Strength in Children. Calcif Tissue Int 100:500-513|