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.

Keywords: Aging; DNA damage; DNA repair; genetics; genome instability; genomics; progeria.

Figure 1.. Schematic representation of signaling events within a cell that enable DNA damage to promote aging.

Depicted are various stressors that can lead to genome instability and activation of the DNA damage response (DDR). The DDR (light blue) leads to cell cycle arrest (green). If signaling persists, apoptosis or senescence ensues. Senescence can affect neighboring, undamaged cells.

Figure 2.. Mechanisms by which DNA damage could promote aging.

DNA damage, including damage at telomeres (center), once detected, if not repaired, can interfere with replication or transcription, resulting in the activation of signaling events that alter cell physiology. One outcome of these signaling events is apoptosis, which while depleting important cells like stem cells or neurons may not be the most potent driver of aging. DNA damage can also result in mitochondrial dysfunction, impaired autophagy, metabolic changes, and the triggering of cellular senescence (small circles). These live but physiologically altered cells are predicted to be a more potent driver of aging and disease. Endpoints used to measure these consequences of DNA damage are indicated with arrows in the larger circles. These outcomes are all interconnected in that mitochondrial dysfunction can cause metabolic changes, impaired autophagy and proteostasis, more DNA damage, and senescence. This creates a cycle of increasing damage and dysfunction, which can spread to other cells via SASP, that is likely the proximal cause of aging and the diseases associated with it (outer circle).