Wednesday, April 24, 2024
4/24/2024
Aging is characterized by an expansion in adipose tissue (i.e. obesity), which plays a key role in the pathophysiology of many aging-diseases, including type 2 diabetes, atherosclerotic vascular disease, Alzheimer’s disease, and some cancers. Adipose tissue is composed of adipocytes, immune cells, endothelial cells, stem/stromal cells, and previously uncharacterized cellular populations. Adipose tissue also contains cells that have undergone cellular senescence, a state characterized by the arrest of the cell cycle and a senescence-associated secretory phenotype (SASP), which induces inflammation, cytotoxicity, and metabolic dysfunction in other cells and tissues. Recent research suggests that aging is associated with changes in adipose cellular populations and subpopulations, and that these variations may be involved in the biology of aging and etiology of aging-related diseases. Yet, the precise profiling of adipose tissue cellular composition has been limited due to a lack of robust cell surface markers for the numerous cellular subpopulations. Single-cell (sc) RNA seq is a novel high-resolution methodology that enables global identification of cellular populations and subpopulations (known and newly identified) in tissues. We have developed a single nuclei (sn)RNA-seq based method (a variation of scRNA-seq) that allows excellent identification, separation and clustering of adipose cellular populations, including mature adipocytes, immune cells, endothelial cells, and mesenchymal stem cells. Although snRNA-seq also is a promising tool for identification and characterization of cells undergoing senescence, it has not been used to more fully elucidate the importance of such cells in the biology of aging and the etiology of aging-related metabolic diseases. In Aim 1 we will conduct adipose tissue molecular profiling via snRNA-seq in three cohorts at baseline: younger lean, older lean, and older obese individuals. We will develop molecular atlases in these subjects to test the hypothesis that both aging and aging plus obesity will have distinct adipose tissue molecular profiles. In a subgroup of older obese subjects we will also test whether a lifestyle intervention changes the global molecular profile in adipose tissue to a profile closer to that in younger and older lean individuals. In Aim 2 we will focus on the identification, quantification, and functional characterization of adipose tissue senescent cells. Sub Aim 2A will test the hypotheses that the amount and function (i.e. SASP) of adipose tissue senescent cells will be elevated with aging and further enhanced by obesity, and that the lifestyle intervention (from Aim 1) will reduce senescent cell burden in older obese subjects. In Sub Aim 2B we will administer senolytic agents to a subgroup of older obese subjects (from Aim 1) to determine whether clearance of senescent cells improves metabolic outcomes. This Sub Aim will directly test the cellular senescence theory and will serve as a positive control for the lifestyle intervention regarding its potential anti-senescence effect.
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