Aging is the leading risk factor for most of the chronic diseases that account for the bulk of morbidity, mortality, and health care expenditures. Cellular senescence may contribute to age-related dysfunction and chronic diseases. We found agents that target senescent cells senolytic drugs. We anticipate that initial proof-of concept clinical trials of senolytic agents may be for disorders associated with localized accumulation of senescent cells, such as sites exposed to therapeutic radiation, pulmonary diseases, or arthritis. For these trials, it is necessary to develop methods to track changes in these accumulations in response to candidate senolytics. Our hypothesis is that senescent cells can be detected in experimental animals, and ultimately in humans, using imaging methods based on distinct characteristics of senescent cells. Two properties of senescent cells may make detection by positron emission tomographic (PET) imaging feasible: extracellular protein aggregation and glycolytic shifts.
Aim 1 is to develop imaging methods based on detecting protein aggregates produced by senescent cells. Senescent cells produce extracellular protein aggregates detectible by the dye, Pittsburgh compound B (PiB), and antibodies to specific aggregation-susceptible proteins. PiB is used for PET imaging of extracellular aggregates to diagnose Alzheimer's disease. We will optimize PiB PET imaging in mice in which we can visualize senescent cells by luminescence or GFP and selectively remove these cells. We will use the following animal models to image localized senescence: 1) single leg radiation, 2) a novel senescent cell transplanted mouse model, and 3) high fat-induced aortic plaques in ApoE knockout mice. PiB PET will be conducted before and after removing senescent cells and before and after rapamycin treatment, which reverses senescent preadipocyte protein aggregate formation. PiB PET images will be correlated with: 1) luminescence, 2) function (body composition, activity, leg muscle & metabolic function), and 3) protein aggregates, GFP+ senescent cells, and senescence markers at autopsy.
Aim 2 is to develop imaging methods based on the metabolic attributes of senescent cells. Glycolysis is increased in senescent cells. Fluorodeoxyglucose (FDG) PET is used to detect increased glucose utilization to locate cancers or track altered metabolic activity. To optimize FDG PET, we will image mice with localized senescent cell accumulations before and after eliminating senescent cells in vivo. We will validate findings by luminescence in vivo and GFP-positivity and senescence markers at autopsy. We will image mice before and after administering 2-deoxyglucose, which quenches FDG uptake. We will test if combining FDG with PiB PET augments sensitivity and specificity. Imaging methods will be of immense importance to localize senescent cell accumulations in vivo in non-genetically modified experimental animals as well as human subjects for initial proof-of-principle human trials of senolytics for localized cellular senescence-related diseases. Senolytic agents could be transformative. Methods are required to image localized accumulations of senescent cells.
Aging is the leading risk factor for most of the chronic diseases that account for the bulk of morbidity, mortality, and health care expenditures, 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, it is necessary to develop methods to locate senescent cells. We propose to do this using novel positron emission tomographic (PET) imaging methods based on distinct characteristics of senescent cells. These methods will be critical to localize senescent cell accumulations, dissect the role of cellular senescence in the genesis and progression of age- and senescence-related diseases, particularly those in which localized accumulations of senescent cells may contribute to pathology (including areas treated by radiation, lung diseases, vascular disease, or arthritis), and for clinical trials of interventions to eliminate senescent cels.
| 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 |
