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DNA damage is the biggest driving force behind accelerated aging!
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DNA damage is the biggest driving force behind accelerated aging!
Aging is a complex process leading to functional decline of multiple tissues and organs.
The aging process is closely associated with multiple features at the molecular, cellular, and physiological levels, such as genomic and epigenomic alterations, loss of protein homeostasis, decline in overall cellular and subcellular functions, and dysregulation of signaling systems.
However, the relative importance, inter-mechanisms, and hierarchical order of these aging features have not been elucidated.
Furthermore, it remains unknown whether the drivers of aging are of multiple origins or based on a single source of unity.
In recent years, an increasing number of studies have shown that DNA damage affects most aging phenotypes and may be a potential unifying factor driving aging.
Professor Björn Schumacher of the University of Cologne, Germany published a review article in Nature last year, clarifying how the main features of aging phenotypes return to DNA damage causally and mechanistically, and proposed that DNA damage may be the main cause of aging  ( figure 1).
Figure 1 DNA damage is a driver of aging 
The effect of DNA damage at the molecular level
DNA damage has a range of molecular consequences, such as genomic instability, telomere dysfunction, epigenetic alterations, protein stress, and impaired mitochondrial function.
Intrinsic genomic instability
Genomic instability refers to the tendency of the genome to mutate, that is, any permanent, transmissible change in the DNA sequence, such as base substitutions, deletions or insertions, copy number variations, chromosomal aberrations, or retrotransposition.
In a broader sense, genomic instability can refer to the chemical modification of DNA’s inherent characteristics, a process commonly referred to as DNA damage, that alters DNA structural and functional properties.
DNA damage includes spontaneous deamination and hydrolysis and many other chemical changes such as different types of breaks, gaps, gaps, abasic sites, adducts and interstrands, intrastrands and DNA-protein crosslinks, and other subtle chemical modification.
DNA damage impedes accurate replication, controlled transcription, and safe storage of genetic information.
During normal aging, DNA damage continues to occur on a large scale due to numerous exogenous and endogenous genotoxins.
It is estimated that as many as 10 5 DNA lesions occur in active mammalian cells every day , and while most of these lesions can be efficiently removed, some lesions that escape detection are unrepaired, repaired too late, or Wrong way to fix. DNA damage inevitably accumulates over time, making genomic instability a true hallmark of aging (Figure 2).
Figure 2: Molecular, cellular and systemic consequences of DNA damage  .
Genomic instability of telomere dysfunction
The discovery in the late 1980s that EST1 mutants of Saccharomyces cerevisiae undergo replicative senescence after telomere shortening popularized the concept of progressive telomere shortening driving the aging process.
In mammals, telomeres are composed of thousands of repeats of TTAGGG, covered by shelterin complexes, which help to form lariat-like T-loops that hide telomere ends and prevent DNA repair and damage response (DDR) Activation of the sensor  .
Due to incomplete synthesis of lagging strands during DNA replication, the number of telomeric repeats decreases with each cell division.
In the germline and some adult stem cells, this loss is compensated by telomerase.
During early development, telomerase is silent in most somatic cells, limiting the number of cell divisions until telomeres become very short.
Unprotected telomeres resemble persistent DNA double-strand breaks (DSBs) and trigger chronic DDR activation, leading to replicative senescence.
Genetic defects in telomere maintenance lead to human telomere pathologies, including dyskeratosis congenita, aplastic anemia, and lung and liver diseases that exhibit various features of progeria.
Telomere length in human tissue does not imply that telomeres become very short in normal aging, even in old age.
However, progressive telomere shortening may alter the expression of specific subtelomeric genes during aging, the in vivo relevance of which has not been established.
DNA damage-induced epigenetic changes
The epigenome includes DNA methylation and histone modifications and is unstable throughout the life cycle of somatic cells.
Chromatin modifications include phosphorylation, methylation, acetylation, ubiquitination, sumoylation, citrullination, and poly-ADP ribosylation, most of which also form part of the DDR.
Growing evidence suggests that DNA damage is a major driver of age-related epigenetic changes.
The DNA methyltransferase DNMT1 localizes to DNA repair sites, and many chromatin remodelers regulate the assembly of different repair mechanisms, lesion removal, and restoration of the original chromatin state, which may leave epigenetic marks.
For example, after repairing transcription-blocking lesions in C. elegans, deposition of H3K4me2 promoted the restoration of transcription of genes that regulate protein biosynthesis and homeostasis, resulting in increased lifespan.
DDR in human cells leads to loss of H3K27me3, thereby promoting cellular senescence  (Figure 3).
Phosphorylated histone variant γH2AX forms foci at DSB sites and accumulates in various mouse tissues with age, suggesting that DNA damage results in persistent chromatin changes.
These studies demonstrate that the continuous induction of DNA damage and repair of tens of thousands of damages per day leaves epigenetic marks that lead to cell-to-cell epigenetic heterogeneity during aging.
Figure 3: DDR in human cells leads to loss of H3K27me3, thereby promoting cellular senescence 
DNA damage-induced protein stress
The protein homeostasis pathway controls protein synthesis, folding and degradation. Several age-related diseases are associated with protein misfolding and aggregation, including Alzheimer’s disease and Parkinson’s disease.
Misfolded proteins occur when structural changes affect solubility, leading to protein aggregation. In recent years, an increasing number of studies have linked DNA damage to protein stress, with defective transcription-coupled repair accelerating neurodegeneration in the C. elegans model of Cockayne syndrome, underscoring the role of DNA damage in driving A prerequisite role in age-related neuronal pathology.
In addition, defects in chaperone proteins, the ubiquitin-proteasome system, and autophagy can lead to the accumulation of misfolded proteins.
DDR itself enables endonuclease inositol-requiring protein 1α (IRE1α) and a key regulator of the endoplasmic reticulum unfolded protein response (ER-UPR), XBP1, to be induced in DNA repair-deficient mice with progeria.
Autophagy is also induced by DNA damage signals and is required for survival in the presence of persistent DNA damage. When unrepaired DNA damage drives cellular senescence, they exhibit a chronic aging-associated secretory phenotype.
Taken together, these observations support a central role for DNA damage, mutation and epimutation as a major cause of proteotoxic stress that increases with age.
As organelles regulating energy and metabolic homeostasis, mitochondria have long been implicated in aging, primarily as a major source of ROS, and in aging-related diseases such as Parkinson’s disease and sarcopenia.
The most prevalent hypothesis for age-related mitochondrial dysfunction is based on the accumulation of somatic mutations in the mitochondrial genome as a result of errors during replication and the absence of most active complex repair pathways in the nucleus.
Mice expressing a proofreading-deficient mitochondrial DNA polymerase have significantly increased mitochondrial DNA (mtDNA) mutations and display multiple symptoms of premature aging.
Increased mtDNA mutations are associated with loss of cytochrome C oxidase activity in aged skeletal muscle fibers, in the substantia nigra and hippocampus of normal aged brains, and in various other tissues. However, it is unclear whether the frequency of such mtDNA mutations during natural aging is sufficient to cause phenotypic effects.
Thus, although the role of mtDNA mutations in aging remains controversial, there are several aspects that have not been well explored, including the effect of DNA damage itself (as opposed to mutation) on mitochondrial DNA replication and transcription, as well as damage in the nuclear genome. Over 1,000 mitochondrial genes.
DNA damage determines cell fate
DNA damage can have dramatic effects on cell fate, especially as cells enter senescence and stem cell exhaustion.
Cellular senescence permanently inhibits proliferation in response to various stresses, most of which are associated with DNA damage.
Compounds such as bleomycin, doxorubicin, or cisplatin induce cellular senescence and cause irreparable DNA damage, resulting in DNA fragments with senescence-enhancing chromatin alterations (DNA-SCARS).
Furthermore, DNA damage is also responsible for oncogene-induced senescence, and oncogene activation leads to replication stress and subsequent DSBs.
Mitochondrial dysfunction-related senescence is not directly caused by genotoxins, but may also be driven by DNA damage given the aforementioned association with mitochondrial dysfunction.
Thus, cellular senescence appears to be tightly coupled with the DDR, or, like senescence associated with mitochondrial dysfunction, may be indirectly related to DNA damage.
Stem cell exhaustion
Adult stem cell depletion results in reduced stem cell numbers and reduced function. Different types of stem cells have different DDR mechanisms.
For example, quiescent hematopoietic stem cells (HSCs) and hair follicle stem cells use rapid, low-fidelity non-homologous end joining, while circulating HSCs, intestinal stem cells, and embryonic stem cells favor more accurate homologous recombination.
Conversely, irreparable damage leads to premature differentiation of melanocyte stem cells and aging hair follicle stem cells, depleting the stem cell pool.
In addition, accumulation of DNA damage has been observed in HSCs in humans and mice, as well as in muscle, gut, mesenchymal, neural, skin, and germinal stem cells.
The potential role of DNA damage in HSCs is well documented. During aging, HSCs increase in number but decrease in pluripotency, making them more myeloid-prone, and DNA damage is marked in aging HSCs due to replication stress.
Like most adult stem cells, HSCs are predominantly quiescent, which provides some protection against endogenous genotoxic stresses such as metabolic ROS.
Accumulated DNA damage is thus increasingly recognized as a driver of stem cell exhaustion during aging.
Systemic effects of DNA damage
DNA damage has systemic effects on the organism through endocrine signaling, inflammatory responses, and metabolic alterations.
Signaling mechanisms influence aging phenotypes
The importance of signaling mechanisms in aging has become apparent since mutations in insulin-like signaling (ILS) in C. elegans can extend lifespan.
Several signaling pathways have been shown to regulate lifespan in diverse species including yeast and mammals.
Interventions such as caloric restriction can be anti-aging in part by inhibiting signaling cascades such as the ILS and mTOR pathways  (Figure 4).
Instead, inflammatory signals are often thought to promote a range of age-related diseases.
Figure 4: The role of mTOR signaling in aging 
DDR is a potent activator of inflammatory responses. DNA damage triggers innate immune responses and modulates systemic stress signaling in Caenorhabditis elegans.
Inflammatory responses were also observed in DNA-repair-deficient mice with progeria, and these mice acted as antiaging responses by inhibiting the somatotropin (including ILS), thyrotropin, and prolactin axes.
Thus, the DDR exerts multiple effects on age-related changes in local and systemic communication mechanisms by affecting the inflammatory and endocrine signaling components that influence the aging process.
Antiaging response affects genome stability
Nutritional interventions affect aging and longevity in animals. Calorie restriction was the most effective health and longevity intervention, first observed in rats in the 1930s, and this conclusion holds true for species ranging from yeast to mammals.
Caloric restriction may exert its lifespan-extending effects through specific nutrient-sensing pathways, including the mTOR pathway regulated by ILS, sirtuins, and AMPK.
In addition to ILS depletion in DNA repair-deficient progeria mice and worms discussed above, the DDR kinase ATM phosphorylates several key proteins in the ILS-mTOR pathway following DNA damage.
Taken together, substantial evidence suggests that DNA damage affects key signaling mechanisms that regulate lifespan and trigger the antiaging effects of caloric restriction in model organisms by affecting ILS, sirtuins, AMPK, and mTOR.
Endogenous and exogenous DNA damage accumulates over time, progressively impeding cellular function and increasing the body’s susceptibility to aging-related diseases.
Therefore, fundamental interventions to alleviate aging-related diseases should restore genome integrity by reducing DNA damage and enhancing DNA repair.
For example, reducing exogenous DNA damage through UV protection and avoiding smoking has been shown to reduce the risk of aging-related diseases.
In addition, dietary interventions may be able to control some endogenous sources of DNA damage, but most spontaneous damage is still unavoidable.
Enhancing DNA repair remains a formidable challenge due to the intricacies of the repair machinery.
Since it was proposed that DNA damage and DNA repair are major determinants of aging, and the discovery that DNA repair defects can accelerate the development of various age-related pathologies, researchers have made great strides in unraveling the relationship between DNA damage and aging.
It provides a direction to further explore the mechanism of DNA damage in the development of aging pathology, solve the aging process from the root, and open up ideas for dealing with aging-related diseases.
 Björn Schumacher, et al. The central role of DNA damage in the ageing process. Nature. 592: 695-703 (2021).
 Fumagalli, M, et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012).
 Ito, T., et al. Regulation of cellular senescence by polycomb chromatin modifiers through distinct DNA damage- and histone methylation-dependent pathways. Cell Rep. 22, 3480–3492 (2018).
 Saxton, RA, Sabatini, DM mTOR signaling in growth, metabolism, and disease. Cell. 168, 960–976 (2017).
DNA damage is the biggest driving force behind accelerated aging!
(source:internet, reference only)