The central role of DNA damage in immunosenescence

Abstract

Ageing is the biggest risk factor for the development of multiple chronic diseases as well as increased infection susceptibility and severity of diseases such as influenza and COVID-19. This increased disease risk is linked to changes in immune function during ageing termed immunosenescence. Age-related loss of immune function, particularly in adaptive responses against pathogens and immunosurveillance against cancer, is accompanied by a paradoxical gain of function of some aspects of immunity such as elevated inflammation and increased incidence of autoimmunity. Of the many factors that contribute to immunosenescence, DNA damage is emerging as a key candidate. In this review, we discuss the evidence supporting the hypothesis that DNA damage may be a central driver of immunosenescence through senescence of both immune cells and cells of non-haematopoietic lineages. We explore why DNA damage accumulates during ageing in a major cell type, T cells, and how this may drive age-related immune dysfunction. We further propose that existing immunosenescence interventions may act, at least in part, by mitigating DNA damage and restoring DNA repair processes (which we term “genoprotection”). As such, we propose additional treatments on the basis of their evidence for genoprotection, and further suggest that this approach may provide a viable therapeutic strategy for improving immunity in older people.

Associations between the New DNA-Methylation-Based Telomere Length Estimator, the Mediterranean Diet and Genetics in a Spanish Population at High Cardiovascular Risk

“…Telomere attrition is a phenomenon that arises from cellular replication and is expedited by diverse environmental conditions, including inflammation and oxidative stress [126][127][128]. Oxidative stress has been recognized as a physiological factor contributing to telomere shortening, which in turn is associated with human aging by several mechanisms [127][128][129][130][131][132][133][134]. Overall, it has been suggested that the repair of oxidative damage in telomeric DNA is comparatively less efficient than in other chromosome regions [126,135].…”

Mechanisms of PM10 Disruption of the Nrf2 Pathway in Cornea

“…In the lung, PM 10 exposure has been linked to senescence [9]. One of the causes of senescence is DNA damage [10]. PM 10 induces DNA damage by oxidative stress, which causes double-strand breaks (DSBs) [10].…”

“…PM 10 induces DNA damage by oxidative stress, which causes double-strand breaks (DSBs) [10]. DNA damage mobilizes phosphoinositide 3kinase-related protein kinases (PIKKs), as well as ataxia telangiectasia-mutated (ATM), and Rad-3-related kinase (ATR) [10]. These kinases activate tumor suppressor p53 further downstream [10,11].…”

“…DNA damage mobilizes phosphoinositide 3kinase-related protein kinases (PIKKs), as well as ataxia telangiectasia-mutated (ATM), and Rad-3-related kinase (ATR) [10]. These kinases activate tumor suppressor p53 further downstream [10,11]. Based on the amount of DNA damage, the cell responds by inducing either apoptosis or cellular senescence [11].…”