Fight Aging!

Researchers here report on evidence for CD4+ T cells to be important in keeping senescent cell numbers under control in later life, an interaction mediated by the presence of cytomegalovirus (CMV). CMV is a persistent viral infection that is near ubiquitous in the older population, and which coerces ever more of the immune system to become specialized to fight it, to the detriment of other functions.

We know that the number of senescent cells in tissues grows with age, slowly, and that the immune system appears to become less efficient at removing these cells, leading to an imbalance between creation and destruction. A lingering burden of senescent cells produces inflammatory, disruptive signaling that harms cell and tissue function, contributing to degenerative aging.

One point here is that while researchers show CD4+ T cells to be capable of destroying senescent cells, and a higher count of these cells correlating with lesser numbers of senescent cells, this is not a conclusive proof that CD4+ T cells are the ones undertaking most of the work. CD4+ T cell counts could well be a reflection of the health and capacity of other components of the immune system that are also attacking senescent cells.

Boosting the body's anti-viral immune response may eliminate aging cells

Researchers found more senescent cells in the old skin compared with young skin samples. However, in the samples from old individuals, the number of senescent cells did not increase as individuals got progressively older, suggesting that some type of mechanism kicks in to keep them in check. Experiments suggested that once a person becomes elderly, certain immune cells called killer CD4+ T cells are responsible for keeping senescent cells from increasing. Indeed, higher numbers of killer CD4+ T cells in tissue samples were associated with reduced numbers of senescent cells in old skin.

When they assessed how killer CD4+ T cells keep senescent cells in check, the researchers found that aging skin cells express a protein, or antigen, produced by human cytomegalovirus, a pervasive herpesvirus that establishes lifelong latent infection in most humans without any symptoms. By expressing this protein, senescent cells become targets for attack by killer CD4+ T cells. "Our research enables a new therapeutic approach to eliminate aging cells by boosting the anti-viral immune response. We are interested in utilizing the immune response to cytomegalovirus as a therapy to eliminate senescent cells in diseases like cancer, fibrosis, and degenerative diseases."

Cytotoxic CD4+ T cells eliminate senescent cells by targeting cytomegalovirus antigen

Senescent cell accumulation has been implicated in the pathogenesis of aging-associated diseases, including cancer. The mechanism that prevents the accumulation of senescent cells in aging human organs is unclear. Here, we demonstrate that a virus-immune axis controls the senescent fibroblast accumulation in the human skin. Senescent fibroblasts increased in old skin compared with young skin. However, they did not increase with advancing age in the elderly.

Increased CXCL9 and cytotoxic CD4+ T cells (CD4 CTLs) recruitment were significantly associated with reduced senescent fibroblasts in the old skin. Senescent fibroblasts expressed human leukocyte antigen class II (HLA-II) and human cytomegalovirus glycoprotein B (HCMV-gB), becoming direct CD4 CTL targets. Skin-resident CD4 CTLs eliminated HCMV-gB+ senescent fibroblasts in an HLA-II-dependent manner, and HCMV-gB activated CD4 CTLs from the human skin. Collectively, our findings demonstrate HCMV reactivation in senescent cells, which CD4 CTLs can directly eliminate through the recognition of the HCMV-gB antigen.