Senescent Cells and Changes in Systemic Factors in Aging

Senescent cells accumulate with age in all tissues, and contribute to aging via secreted signals that provoke inflammation and tissue restructuring. This portion of aging is a malfunction of a system that normally aids in regeneration and resistance to cancer. Senescent cell signaling is beneficial in the short term, attracting immune cells to areas of damage that should be policed for potentially cancerous cells, or coordinating the interactions of cells needed to efficiently heal an injury. In these cases, in a young individual, the senescent cells involved are quickly destroyed once their task is complete. It is when this needed destruction falters with age, and signaling becomes constantly present, that the problems start. As researchers examine the changing presence of factors in blood and tissue samples, many of these age-related alterations are traced back to the activity of senescent cells.

Extracellular vesicles (EVs) are membrane bound vesicles which vary from nanometer to micrometer in size and carry a diverse set of factors. Recently, our group investigated how circulating EVs change with age, the cell types responsible, and the response of these factors to rejuvenation therapies. Profiling of EV cargo revealed greater expression of inflammation-associated microRNAs such as miR-146a, miR-21, let-7a, and miR-223 in old plasma EVs compared with young. These microRNAs are predicted to target multiple intracellular signaling cascades which regulate cellular responses to external stimuli.

To determine the cell types responsible for changes in circulating EV microRNAs, we assessed EVs secreted by young and old peripheral blood mononuclear cells (PBMCs) in-vitro as well as plasma EVs isolated from old mice reconstituted with young or old bone marrow. However, EV microRNAs were similar in both models, suggesting that circulating cells have a minor contribution to the microRNAs identified this study. Further investigation into potential cell sources revealed that induction of senescence in-vitro and in-vivo, using gamma irradiation, mimicked the changes observed in old mice such as increased levels of circulating EVs and increased expression of EV associated miR-146a, mIR-21, and let-7a.

Interestingly, senolytic therapy using dasatinib + quercetin (D+Q) reduced the expression of these microRNAs in the plasma of old mice, supporting that senescent cells or the pathways targeted by these compounds contribute to increased expression in the circulation. Collectively, this data demonstrates that aging and cellular senescence leads to increased levels of circulating EVs, and that these EVs impair cellular responses to activation. Pharmacological targeting of senescent cells partially rejuvenated the microRNA profile and functional effects of old plasma EVs.

Senescent cells secrete cytokines, growth factors, and proteases which alter neighboring cell function. This secretome is collectively referred to as the senescent associated secretory profile (SASP) and the adverse effects of senescent cells are largely attributed to this profile. More recent definitions of the SASP have been expanded to include EVs. Secretion of EVs by senescent cells into the circulation could be one mechanism by which senescent cells promote cell dysfunction, as persistent uptake of senescent-EVs may lead to sustained changes in cellular function. Therefore, approaches aimed at targeting senescent cells may help reduce circulating senescent-EV levels and limit the impact senescent cells have on cells throughout the body.



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