Cellular senescence is a stable proliferative arrest that is encountered by mammalian cells in response to cell extrinsic and intrinsic stresses, such as telomere dysfunction. In mammals, this stress response not only functions to suppress cancer development, but it also plays important roles during tissue repair and embryonic development. Cellular senescence, therefore, evolved to benefit the organism. The persistence of senescent cells in tissue, however, also has a substantial negative impact on health and fitness. For example, senescent cells accumulate with advancing age in various mammalian tissues and this accumulation of senescent cells has recently been show to be a major contributing factor to aging and the development of age-associated pathologies in mice. The aging-associated accumulation of senescent cells, however, is surprising, given that they can be efficiently cleared from tissue by innate and adapted immune responses under different circumstances in young animals, such as during tissue repair, as well as during embryonic and cancer development. One model that could explain why senescent cells accumulate with advancing age in mammalian tissue is that immune cells themselves increasingly become senescent as we age, thereby increasingly weakening immune responses that would otherwise clear senescent cells from aged tissue. This proposal tests the hypothesis that aging causes various subsets of human circulating immune cells to increasingly undergo telomere dysfunction-induced cellular senescence with advancing age, thereby resulting in an age-associated overall loss of immune cell function. Using a novel technique to detect senescent cells by flow cytometry, we propose to identify specific populations of human peripheral blood mononuclear cells (PBMCs) that increasingly undergo cellular senescence with advancing age. Additionally, we will characterize the transcriptome and epigenome of senescent PBMCs by RNA-seq and ATAC seq, respectively, not only to better define the senescence state of specific PBMC populations, but also to uncover potential targets for therapeutic interventions to modulate senescence responses of human PBMCs. Lastly, using immunofluorescence analysis and ex-vivo cultures of human PBMCs, we will reveal the causes and functional consequences of PBMC senescence in humans and test strategies to suppress them, with the overall goal of reducing immune cell senescence, improving immune function, and suppressing age-associated diseases.
The goal of this study is to identify peripheral blood mononuclear cell (PBMC) populations that increasingly undergo cellular senescence with advancing age in the human population, to characterize senescence of human PBMC subsets on the genomic level, and test strategies to suppress senescence of human circulating immune cells. Therapeutic interventions to suppress senescence of PBMC subsets has the potential to improve healthspan and suppressing age-associated diseases including pulmonary fibrosis, obesity, type 2 diabetes, sarcopenia, osteoarthritis, atherosclerosis, tau-dependent neurodegenerative diseases, including Alzheimer's disease, among others.
