Senescent cells are created constantly throughout life in response to a range of circumstances, but only begin to accumulate in later life, once there is an imbalance between processes of creation (as a response to cell damage, for example) and processes of destruction (such as immune surveillance of senescent cells). Senescent cells secrete a potent mix of signals that, when sustained over time, provokes chronic inflammation and alters nearby cell behavior and tissue structure in detrimental ways. Researchers are only now attempting to catalog exactly how senescent cells cause harm, given the advent of senolytic therapies that allow a good assessment of the degree to which senescent cell accumulation contributes to specific degenerative processes in aging.
The sympathetic nervous system (SNS) is involved in a multitude of biological phenomena including stress, energy utilization, and physical activity; crucial physical functions that are regulated by the SNS include hemodynamics, temperature regulation, and metabolism. Overactivity of the SNS can result in types of chronic diseases, including cardiovascular disorders and hypertension. Multiple lines of evidence have demonstrated that sympathetic nerve density increases in tumor tissues.
Cellular senescence is implicated in several lines of aging-related disorders. However, the potential molecular mechanisms by which cellular senescence modulates age-related pathologies remain largely unexplored. Herein, we report that the density of sympathetic fibers (SFs) is significantly elevated in naturally aged mouse tissues and human colon adenoma tissues compared to the SFs densities in the corresponding young mouse tissues and human non-lesion colon tissues.
A dorsal root ganglion (DRG) and human diploid fibroblast co-culture assay revealed that senescent cells promote the outgrowth of SFs, indicating that the senescent cells induce recruitment of SFs in vitro. Additionally, subcutaneous transplantation of fibroblasts in nude mice shows that transplanted senescent fibroblasts promote SFs infiltration. Intra-articular senolytic molecular injection can reduce SFs density and inhibit SFs infiltration caused by senescent cells in osteoarthritis (OA), suggesting senescent cells promote the infiltration of SFs in vivo in aged tissues. Notably, the elevated level of SFs contributes to impaired cognitive function in naturally aged mice, which can be reversed by treatment with propranolol hydrochloride, a non-selective β receptor blocker that inhibits sympathetic nerve activity (SNA) by blocking non-selective β receptors.
Taken together, this study concludes that senescent cells secrete netrin-1 that mediates SFs outgrowth and infiltration, which contributes to aging-related disorders. This suggests that clearing senescent cells or inhibiting SNA is a promising therapeutic strategy for improving sympathetic nervous system (SNS) hyperactivity-induced aging-related pathologies.