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.

Keywords: DNA damage; DNA repair; ageing; immunology; immunosenescence; senescence.

FIGURE 1

Types of DNA damaging agents, resulting lesions and canonical repair pathways that correct them. DNA experiences a variety of genotoxic insults from both endogenous and exogenous sources. These result in specific lesions that can be repaired via specific DNA repair pathways that are triggered by the DNA damage response (DDR). Damaged DNA is sensed, signalled, and repaired through a cascade of signalling mechanisms elicited by DNA sensors, tranducers, and effectors, which are specific to the DNA lesion type and repair pathway. Examples of such DDR proteins are illustrated. Abbreviations: O6-mG, O-6-methylguanine; 8-oxo-dG, 8-oxo-2′-deoxyguanosine; ICL, interstrand crosslink; HR, homologous recombination; NHEJ, non-homologous end joining; 53BP1, p53·-binding protein 1; MRN complex, Mre11/Rad50/Nbsl; PARP1, Poly [ADP-ribose] Polymerase 1; XP-proteins, Xeroderma Pigmentosum proteins; BRCA1, breast cancer gene 1; MDC1, Mediator of DNA Damage Checkpoint 1; RNF8, Ring Finger Protein 8; ATM, Ataxia-Telangiectasia Mutated; ATR, Ataxia Telangiectasia and Rad3-related; DNA-PK, DNA Protein Kinase complex; Chk1, Checkpoint Kinase 1; Chk2, Checkpoint Kinase 2.

FIGURE 2

Overview of the causes and consequences of DNA damage in both haematopoietic (T cell) and non-haematopoietic cells which contribute to immunosenescence. DNA-damaged immune and non-haematopoietic cell senescence are linked. During ageing, senescent cells increase in both compartments due to reduced senescent cell clearance, deficient DNA repair processes, and increased genotoxin abundance. Non-haematopoietic cells: Proliferating cells (PRO) experience genotoxicity from radiation, excessive replication, chemotherapeutic drugs, and radiomimetics to drive persistent DNA damage, proliferation arrest, and cellular senescence (SEN). The senescence-associated secretory phenotype (SASP) contains chemoattractants such as CXCL8 that draw in peripheral neutrophils. These induce oxidative damage in stromal cell telomeric DNA, called TelOxidation, propagating further paracrine senescence. The SASP component CCL2 attracts monocytes which secrete PGE₂ and suppress T cell functions. TGF-β in the SASP favours T_reg generation and a pro-suppressive, inadequate immune response during ageing. Haematopoietic cells: Effector T cells (T_eff) experience genotoxic injury from bacterial genotoxins viral infections short telomeres, reactive oxygen species (ROS) from dysfunctional mitochondria, and nutrient competition with regulatory T cells (T_regs). DNA-damaged T cells manifest senescent phentotypes in a sestrin- and ATM-dependent manner. Senescent T cells (T_sen) are dysfunctional and contribute to inflammageing with their inflammatory SASP, tissue cytotoxicity, and immune dysfunction during ageing.