DNA damage—how and why we age?

Abstract

Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality. Many factors contribute to aging, such as the time-dependent accumulation of macromolecular damage, including DNA damage. The integrity of the nuclear genome is essential for cellular, tissue, and organismal health. DNA damage is a constant threat because nucleic acids are chemically unstable under physiological conditions and vulnerable to attack by endogenous and environmental factors. To combat this, all organisms possess highly conserved mechanisms to detect and repair DNA damage. Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. The drawback is that these cancer avoidance mechanisms promote aging. Here, we review evidence that DNA damage plays a causal role in aging. We also provide evidence that genotoxic stress is linked to other cellular processes implicated as drivers of aging, including mitochondrial and metabolic dysfunction, altered proteostasis and inflammation. These links between damage to the genetic code and other pillars of aging support the notion that DNA damage could be the root of aging.

Signatures of adaptive evolution in platyrrhine primate genomes

“…The maintenance of genomic stability is considered a major factor underlying human longevity with the accumulation of macromolecular damage, such as DNA damage, one of the most significant factors contributing to aging (49). We recover signatures of selection on DNA damage and repair related genes for both the robust and gracile capuchin branches independently, including enriched terms such as "double strand break repair", "cellular response to DNA damage stimulus", "DNA repair", and "DNA damage".…”

The Role of Senescent Cells in Acquired Drug Resistance and Secondary Cancer in BRAFi-Treated Melanoma

“…These cellular stressors lead to permanent activation of the DNA damage response (DDR) through ataxia telangiectasia mutated (ATM). The activated DDR results in the stabilization of tumor suppressor protein 53 (p53) and its transcriptional targets cyclin-dependent kinase inhibitor 1 (p21 CIP1 ) and cyclin-dependent kinase inhibitor 2A (p16 INK4a ), resulting in cell cycle arrest through inhibition of cyclin dependent kinases which prevent the phosphorylation of retinoblastoma (RB) and entrance into S phase of the cell cycle [ 25 , 26 , 27 , 28 ]. Senescent cells are characterized by increased cell size, senescent-associated beta-galactosidase (SA-β-gal) activity [ 29 ], upregulation of anti-apoptotic pathways [ 30 , 31 ], decreased lamin B1 [ 32 ], and a senescence-associated secretory phenotype (SASP) [ 33 ].…”

Association between Food Intake, Clinical and Metabolic Markers and DNA Damage in Older Subjects

“…It has been suggested that there is an association between age and DNA damage [ 12 ]. Specifically, several factors can contribute in increasing the levels of DNA damage, from both intrinsic and extrinsic sources [ 13 ]. Aging is considered as a progressive and biological phenomenon that leads to loss of physiological integrity and to an impairment of numerous functions, at the molecular, cellular, tissue and organ level [ 12 , 13 ].…”

“…Specifically, several factors can contribute in increasing the levels of DNA damage, from both intrinsic and extrinsic sources [ 13 ]. Aging is considered as a progressive and biological phenomenon that leads to loss of physiological integrity and to an impairment of numerous functions, at the molecular, cellular, tissue and organ level [ 12 , 13 ]. Several causes of aging have been hypothesized including an exacerbation of oxidative stress attributed to an imbalance between oxidant molecules and the antioxidant defence mechanisms [ 13 ].…”

“…Aging is considered as a progressive and biological phenomenon that leads to loss of physiological integrity and to an impairment of numerous functions, at the molecular, cellular, tissue and organ level [ 12 , 13 ]. Several causes of aging have been hypothesized including an exacerbation of oxidative stress attributed to an imbalance between oxidant molecules and the antioxidant defence mechanisms [ 13 ]. This condition brings an accumulation of damage to macromolecules such as DNA but also carbohydrates, lipids, and proteins [ 14 ].…”