Fight Aging!

With the newfound acceptance of senescent cell accumulation as an important contributing cause of aging, a viewpoint that has really only flourished in the research community over the last five years or so, many fields of research relevant to aging are retrofitting senescent cells into their theories and understanding of the aging process. Today's open access paper is an example of this process. Researchers interested in the role of persistent cytomegalovirus (CMV) infection in the aging, a field that has itself seen a surge of interest over the past decade, link it to cellular senescence and the growth of chronic inflammation that occurs in old age.

CMV is a type of herpesvirus that is very prevalent in the population; near everyone is exposed to it at some point in time. There is good epidemiological evidence associating CMV exposure to worse health in later life. CMV provokes the adaptive immune system into specializing ever more resources to tackling it, a futile effort as it cannot be cleared from the body. It hides, latent, to emerge again. The thymus, where T cells of the adaptive immune system mature, atrophies with age, and the supply of new T cells diminishes. Without reinforcements, this continual specialization to CMV depletes the immune system of cells capable of handling other tasks.

One of those tasks is the destruction of senescent cells, rapidly enough to prevent their inflammatory secretions from disrupting tissue maintenance and organ function. The pace of clearance of senescent cells declines with age, and this is one of the contributing factors leading to an increased number of such errant cells in old tissues. Further, the pressure that CMV puts on the immune system produces other more direct issues, such as forcing a greater replication of immune cells that drives them into senescence faster than would otherwise be the case. Senescent immune cells are just as problematic as senescent cells in tissues.

The Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence

Clearance of senescent cells is an important role of the adaptive immune system in relation to healthy aging. This regulatory role can be compromised by aging itself, HIV infection, or many other immune stressors that weaken immune function and/or promote immunosenescence. The deficits in adaptive immunity observed in HIV/CMV co-infection, accompanied by an increased prevalence of age-associated pathologies termed accelerated aging, together comprise a unique setting within which to study senescent cell accumulation and its physiological impact.

Immunological stress, as imposed by chronic infection, chronic inflammation, or requirements for homeostatic proliferation, can promote progression of lymphocytes to cellular senescence and impose immune deficits that impair clearance of senescent cells from tissues, thus, compounding the accumulation of senescent cells and the negative implications of their senescence-associated secretory phenotype (SASP). The homing of abundant circulating CMV-specific CD8+ T cells to such inflamed tissues could fuel a further feedback loop of activation, proliferation, and telomere attrition. Therefore, not only are dysfunctional immune cells indirectly contributing to senescent cell accumulation, but are themselves progressing towards senescence, reinforcing a vicious cycle that may be a key factor in "premature aging" of persons living with HIV and unhealthy aging in others.

If CMV infection is a major factor in shifting the adaptive immune system towards chronic senescence, the most dramatic effects should be revealed in the context of HIV infection, where increased chronic inflammation and exaggerated anti-CMV immune responses may optimally promote progression of age-independent chronic immunosenescence. Within this setting, CMV infection is associated with CD8+ T-cell progression towards cellular senescence, increased inflammation, and greater risk of age-related morbidities. This may represent acceleration of the same effects that CMV infection produces in old elderly individuals who develop an immune risk profile with its connotations for immunosenescence, unhealthy aging and mortality. Extensive proliferation and oligoclonal dominance of CMV-specific CD8+ T cells are the hallmarks and potentially drivers of these associations.