Hallmarks of T cell aging

Abstract

ge erodes every physiological function and affects most, if not all, cell types of our body through a series of mechanisms that range from the loss of genomic stability and epigenetic alterations to the loss of proteostasis, deficient nutrient signaling, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and deviant intercellular communication. Most of these 'hallmarks of aging' 1 have been defined in non-vertebrate animal models (such as nematodes and flies) that lack sophisticated adaptive immune systems, suggesting that the principal mechanisms of aging would precede the evolution of B and T lymphocytes and thus relegating these cell types to homeostatic functions that are not central to the core of the aging process.Notwithstanding this conceptual construction, there is ample evidence in mice that T lymphocytes undergo major age-dependent changes that gradually compromise their physiological function, correlating with, and perhaps even explaining, the tendency to develop autoimmune, autoinflammatory, infectious, and malignant diseases in late life 2 . Thus, T cell aging may be one of the principal manifestations of 'immunosenescence' , the time-dependent loss of immune-system vigor that compromises the elimination of noxious elements (such as microbes or malignant cells) while increasing unwarranted overreactions that lead to autoinflammatory and autoimmune disease 3 . Reflecting the fact that circulating (and, to a lesser degree, tumor-infiltrating) T lymphocytes are among the rare cell types that are easily accessible to biomedical investigation, abundant data from humans corroborate the idea that T lymphocytes undergo an important functional deterioration as health declines, placing this cell type in the limelight of human aging research 4 .Recent experiments performed in mice reveal that genetic strategies to accelerate T cell aging, such as the T lymphocyte-specific knockout of the mitochondrial transcription factor A (TFAM), causes not only an immunometabolic dysfunction that drives T cell senescence, but also a general, body-wide deterioration of health with multiple aging-related features, including metabolic, musculoskeletal, cardiovascular, and cognitive alterations 5 . Thus, premature

The Dynamics of B Cell Aging in Health and Disease

“…Aging is also associated with crucial changes in the adaptive immune response. Aged T cells displayed reduced proliferative capacity and an increased production of pro-inflammatory cytokines (8,9), thereby contributing to a chronic state of low-grade inflammation, called 'inflammaging'. The age-related defects in CD4 + T cell helper function also impaired B cell responses (10).…”

Senescence and Aging: Does It Impact Cancer Immunotherapies?

“…In opposition, others demonstrated that human CD57-positive and CD57-negative T cells exhibit similar proliferation properties [105]. Altogether, it appears that T cells undergo cellular aging and senescence and that their functions are intrinsically or extrinsically diminished [94]. Keeping in mind that human T cells collected from a 60-year-old donor already displayed high levels of senescence markers, it is easy to speculate that the efficacy of ICI is likely already diminished at that age [59].…”

“…A big question in the field is whether T cells truly become senescent during aging and if it affects their functions [ 94 ]. The first evidence came when the expression of the senescence marker p16 was found increased in circulating T cells collected from both aged mice and humans [ 95 , 96 ].…”

Aging and Cancer: The Waning of Community Bonds

“…While very effective in keeping cancer at bay during our reproductive years, the immune system itself undergoes a progressive decline with aging, contributing to the establishment of the so-called "immunosenescence" [35,36]. For instance, aging is characterized by a decline in macrophage metabolic and immune function, with a reduced clearance and immunosurveillance capacity [37].…”

“…T cell response undergoes major age-dependent changes that gradually compromise its main functionality. Thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, loss of proteostasis, and eventually senescence have all been reported to affect T lymphocyte function, and consequently, the proper activation of a complete adaptive response [35].…”