Nuclear Genomic Instability and Aging

Abstract

The nuclear genome decays as organisms age. Numerous studies demonstrate that the burden of several classes of DNA lesions is greater in older mammals than in young mammals. More challenging is proving this is a cause rather than a consequence of aging. The DNA damage theory of aging, which argues that genomic instability plays a causal role in aging, has recently gained momentum. Support for this theory stems partly from progeroid syndromes in which inherited defects in DNA repair increase the burden of DNA damage leading to accelerated aging of one or more organs. Additionally, growing evidence shows that DNA damage accrual triggers cellular senescence and metabolic changes that promote a decline in tissue function and increased susceptibility to age-related diseases. Here, we examine multiple lines of evidence correlating nuclear DNA damage with aging. We then consider how, mechanistically, nuclear genotoxic stress could promote aging. We conclude that the evidence, in toto, supports a role for DNA damage as a nidus of aging.

Proteomics of Long‐Lived Mammals

“…Alternatively, the cell may be designed to trigger other hallmarks if one is initiated. Several hereditary premature aging syndromes (such as Werner Syndrome or Hutchison Gilford Progeria) implicate genome instability and/or loss of nuclear integrity as an underlying commonality that may trigger the other hallmarks . Interestingly, calorie restriction (CR) or dietary restriction (DR) improves healthspan and increases lifespan in many species suggesting a common underlying connection between metabolism and avoidance of the hallmarks to increase longevity .…”

<p>Overexpression of Progerin Results in Impaired Proliferation and Invasion of Non-Small Cell Lung Cancer Cells</p>

“…15,16 Double-strand DNA breaks (DSBs) are powerful activators of DNA damage repair and can induce cell cycle arrest to repair damage; however, they can lead to cellular senescence when unresolved. 17,18 Progerin-induced replication stress facilitates premature senescence in HGPS. 19,20 Cells from HGPS patients exhibited activated p53 signaling due to the accumulation of γ-H2AX, 21 so we hypothesized that γ-H2AX initiated DNA repair and caused cell cycle arrest in A549-PG cells.…”

Metformin Modulates the Mechanisms of Ageing

“…DNA lesions can cause mutations, block transcription and replication but can also trigger DNA damage response (DDR), which implies mechanisms that intervene and arrest cell cycle progression, resulting in the repair of almost all the alterations that occur within the genome. However, when DNA damage is extensive and prevails over repair, DDR effectors trigger cell death (apoptosis) or cell senescence, contributing to ageing and age-related diseases [46,47]. In fact, in ageing, DNA damage overtakes DNA repair, leading to genomic instability, a fact sustained by studies showing accumulation of DNA alterations in old tissues [48].…”

“…Collectively, DNA damage as a culprit in ageing is highlighted by the accrual of sources of damage, i.e. oxidative stress (the oxidative stress theory of ageing) associated with the mitochondrial theory of ageing, as mitochondria is the primary source of ROS, increased activation of the DDR, mutations and presence of senescent cells along with a decreased capacity for DNA repair [47]. Among these factors oxidative stress is a well-known pathogenic mechanism and seems to be the most important one [49].…”

“…Senescence is an age hallmark that stands out as a response triggered by genomic instability and telomere attrition resulting in growth arrest, thus limiting the proliferation of aged and damaged cells [22,46,47,86]. A second important feature of senescent cells is the development of a peculiar secretome, termed as the senescence-associated secretory phenotype (SASP), which encompasses cytokines, chemokines and proteases, resulting in a pro-inflammatory state [87,88].…”