The central role of DNA damage in the ageing process

Abstract

Ageing is a complex, multifaceted process leading to widespread functional decline that affects every organ and tissue, but it remains unknown whether ageing has a unifying causal mechanism or is grounded in multiple sources. Phenotypically, the ageing process is associated with a wide variety of features at the molecular, cellular and physiological level-for example, genomic and epigenomic alterations, loss of proteostasis, declining overall cellular and subcellular function and deregulation of signalling systems. However, the relative importance, mechanistic interrelationships and hierarchical order of these features of ageing have not been clarified. Here we synthesize accumulating evidence that DNA damage affects most, if not all, aspects of the ageing phenotype, making it a potentially unifying cause of ageing. Targeting DNA damage and its mechanistic links with the ageing phenotype will provide a logical rationale for developing unified interventions to counteract age-related dysfunction and disease.

Figure 1.. DNA damage is the driver of ageing.

The nuclear and mitochondrial genomes are continuously damaged by exogenous agents (UV, X-rays, chemical compounds in food, water, air), endogenous sources such as reactive oxygen species (ROS), aldehydes and advanced glycation endproducts (AGEs) and spontaneous reactions (hydrolysis). Molecular consequences of time-dependent accumulating DNA damage are: i) genetic aberrations, such as mutations and chromosomal instability, and ii) stalling of RNA and DNA polymerases by DNA lesions, which provokes DNA damage signaling and interferes with primary DNA functioning. Cellular and tissue consequences of DNA damage include cell fate decisions such as cell death and senescence leading to functional loss of cells and organs, cancer, atrophy and inflammation.

Figure 2.. Molecular, cellular and systemic consequences of DNA damage.

DNA damage and the cellular DNA damage response (DDR) can impinge on molecular processes, alter cell fate and deregulate intercellular communication. DNA damage leads to mutations or chromosomal aberrations thus triggering genome instability. Critically shortened telomeres activate the DDR triggering cellular senescence. DNA repair leads to chromatin-remodeling, while the chromatin structure affects DNA damage susceptibility and repair access. The DDR affects autophagy, the UPR^ER and leads to a loss of protein complex stoichiometry. Mitochondrial dysfunction is driven by NAD+ deprivation by nuclear DNA repair, DNA damage-induced mitophagy defects, and altered mtDNA polymerase expression that affects mtDNA replication. DNA damage induces dampening of nutrient sensing pathways, which in turn affect DNA damage repair and signaling. Cellular senescence is induced in response to DNA damage. DNA damage causes exhaustion of stem cell pools through DDR-induced apoptosis, senescence, premature differentiation and alterations of the stem cell niche. The DDR impacts intercellular communication through inflammatory cytokines and dampened growth signaling.

Text Box 1 Figure.. Examples of progeroid syndromes caused by DNA repair defects.