T Cell Replicative Senescence in Human Aging

Abstract

The decline of the immune system appears to be an intractable consequence of aging, leading to increased susceptibility to infections, reduced effectiveness of vaccination and higher incidences of many diseases including osteoporosis and cancer in the elderly. These outcomes can be attributed, at least in part, to a phenomenon known as T cell replicative senescence, a terminal state characterized by dysregulated immune function, loss of the CD28 costimulatory molecule, shortened telomeres and elevated production of pro-inflammatory cytokines. Senescent CD8 T cells, which accumulate in the elderly, have been shown to frequently bear antigen specificity against cytomegalovirus (CMV), suggesting that this common and persistent infection may drive immune senescence and result in functional and phenotypic changes to the T cell repertoire. Senescent T cells have also been identified in patients with certain cancers, autoimmune diseases and chronic infections, such as HIV. This review discusses the in vivo and in vitro evidence for the contribution of CD8 T cell replicative senescence to a plethora of age-related pathologies and a few possible therapeutic avenues to delay or prevent this differentiative end-state in T cells. The age-associated remodeling of the immune system, through accumulation of senescent T cells has far-reaching consequences on the individual and society alike, for the current healthcare system needs to meet the urgent demands of the increasing proportions of the elderly in the US and abroad.

Beneficial and Detrimental Effects of Antiretroviral Therapy on HIV-Associated Immunosenescence

“…An increase in the incidence of diseases related to dysfunctional mitochondria and associated with premature ageing (i.e., cardiovascular disease, diabetes, kidney and liver disease, metabolic disorders, osteoporosis, and lipodystrophy) has been described in patients under HAART [1, 3, 8, 119]. An accumulation of mitochondrial DNA (mtDNA) mutations has been also found to increase with age, and aberrant mtDNA rep­lication contributes to premature ageing phenotypes [120-123].…”

Cellular senescence impact on immune cell fate and function

“…Cellular senescence, especially telomere‐dependent senescence, has been known for years to occur in immune cells (for review, Chou & Effros, 2013). Recent work suggests that the onset of cellular senescence can also be used by the immune system to guide immune cell fate decision, regulate immune responses, and control tissue homeostasis during the entire life of an individual.…”

Biomolecular bases of the senescence process and cancer. A new approach to oncological treatment linked to ageing

“…With normal ageing, there is a systemic reduction in naïve circulating T cells and rise in memory T cells that have undergone several rounds of antigen-induced replication (Saule et al 2006). Importantly, with lifelong repetitive antigenic stimulation, memory T cells show signs of senescence (Chou & Effros, 2013). In particular, senescent CD8+ T cells have shorter telomeres, lose the ability to express key co-stimulatory molecules (like CD28) and lose cytotoxic capacity, switching instead to a proinflammatory phenotype being their accumulation associated with impaired immunity (Chou & Effros, 2013;Saurwein-Teissl et al 2002).…”

“…Importantly, with lifelong repetitive antigenic stimulation, memory T cells show signs of senescence (Chou & Effros, 2013). In particular, senescent CD8+ T cells have shorter telomeres, lose the ability to express key co-stimulatory molecules (like CD28) and lose cytotoxic capacity, switching instead to a proinflammatory phenotype being their accumulation associated with impaired immunity (Chou & Effros, 2013;Saurwein-Teissl et al 2002). These age-related changes are also characteristic of individuals with recurrent viral infections.…”