Aging is the biggest risk factor for most of the chronic diseases that account for the bulk of morbidity, mortality, and health expenditures in the US. A key mechanism that likely contributes to both age-related dysfunction and these chronic diseases is cellular senescence. Our goal is to devise interventions based on targeting senescent cells to ameliorate age-related chronic diseases as a group. To do so, model systems that are tractable to manipulation are needed to discover effects of targeting senescent cells on dysfunction. Our hypothesis is that transplanting senescent cells will induce adverse aging-like phenotypes that non- senescent cells will not. We found that transplanting senescent fat cell progenitors -preadipocytes- into rodents caused sustained glucose intolerance and cardiac dysfunction, while non-senescent cells did not. We propose developing a model that could accelerate senolytic drug development and understanding about cellular senescence.
Aim 1 is to optimize and characterize the senescent cell transplantation model. We will: 1) determine the relation between transplanted senescent cell numbers and extent of resulting metabolic and cardiovascular dysfunction, 2) compare effects of transplanting cells in which senescence has been caused by different inducers (drugs, radiation, metabolites), 3) determine how long transplanted senescent cells survive, 4) track where transplanted senescent cells go, 5) examine effects of transplanting senescent cells into different sites in recipients, and 6) test if transplanting replication- or radiation-induced senescent human cells into immunodeficient rodents is a viable model.
Aim 2 is to develop methods for manipulating pathways in transplanted senescent cells so mechanisms through which senescent cells cause dysfunction can be elucidated. To test if eliminating transplanted senescent cells alleviates glucose intolerance and cardiovascular dysfunction, preadipocytes to be transplanted will be transduced with a lentivirus comprising a constitutive promoter driving a drug-inducible suicide gene -ATTAC- and green fluorescence protein. The drug, AP20187, which activates the suicide gene, will have little effect on the recipients' own cells. By administering AP20187 to animals that have been transplanted with these transduced cells, we will be able to test epistatically if eliminating these cells reverses senescence-associated metabolic and cardiovascular dysfunction. We will use a similar transduction approach to express shRNA's in transplanted senescent cells in order to manipulate expression of key genes involved in the genesis of the SASP. Our overall goal is to devise clinical interventions to remove senescent cells or ameliorate the SASP in non-genetically modified individuals. The transplanted senescent cell model will be highly useful in: 1) dissecting the role of cellular senescence in the genesis and progression of age-related dysfunction, 2) testing effects of varying senescent cell burden, 3) identifying pathways in senescent cells that are responsible for adverse phenotypes, and 4) developing and testing pharmacological interventions for eliminating senescent cells or preventing their effects.
Aging is the biggest risk factor for most of the chronic diseases that account for the bulk of morbidity, mortality, and health care costs, including cancers, heart attacks, vascular disease, strokes, dementias, and diabetes. Cellular senescence, a state in which cells stop dividing but release factors that damage other cells, may contribute to both age-related dysfunction and chronic diseases. Our long term goal is to devise interventions based on targeting senescent cells to ameliorate age-related chronic diseases as a group. To do so, model systems that we can manipulate are needed to discover ways to target senescent cells so function can be restored. We propose a model in which senescent cells are transplanted into animals without senescent cells. This will allow us to determine the impact of senescent cells on function, vary the kinds of senescent cells transplanted, and manipulate genes in the senescent cells being transplanted to find out how senescent cells cause dysfunction, and test drugs and other interventions that remove senescent cells.
| 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 |
| 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 |
| Schafer, Marissa J; Miller, Jordan D; LeBrasseur, Nathan K (2017) Cellular senescence: Implications for metabolic disease. Mol Cell Endocrinol 455:93-102 |
| Xu, Ming; Bradley, Elizabeth W; Weivoda, Megan M et al. (2017) Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice. J Gerontol A Biol Sci Med Sci 72:780-785 |
