DNA damage—how and why we age?
- Institute on the Biology of Aging and Metabolism Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, United States
Figures
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).
Tables
Table 1
Estimated frequencies of DNA lesions caused by endogenous and common environmental sources of DNA damage.
Adapted from Friedberg, 2006; Lindahl, 1993; Sander et al., 2005; Sears and Turchi, 2012; Mouret et al., 2006.
| Endogenous DNA adducts | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| DNA lesion | DSB | Cytosine deamination | Cyclopurine adducts | Depyrimidination | 8-oxoG | Malondialdehyde adducts | Alkylation adducts | Depurination | SSB |
| Frequency per cell per day | 101 | 102 | 102 | 102 | 103 | 103 | 103 | 104 | 104 |
| DNA adducts caused by environmental exposures | |||||||||
| Genotoxin | Sunlight | Background radiation | Ionizing radiation therapy | Oxaliplatin cancer therapy | |||||
| Lesion | Photodimers | Damaged bases | SSB | DSB | Damaged bases | SSB | Intra- and interstrand crosslinks | ||
| Frequency per cell per day | 102 in skin cells only | 10 | 2–5 | 0.25 | 103 | 103 | 103 | ||
Table 2
Human genome instability diseases with age-associated symptoms.
| Disease | Affected genome stability pathway | Mutated genes | Aging-associated symptoms | Ref(s) |
|---|---|---|---|---|
| Hutchinson-Guilford progeria syndrome | Chromatin organization | LMNA | Alopecia, atherosclerosis, arthritis, cardiovascular disease, lipodystrophy, osteoporosis, skin aging and atrophy | Kudlow et al., 2007; Liu et al., 2005 |
| Nestor-Guillermo progeria syndrome | Chromatin organization | BANF1 | Alopecia, atherosclerosis, arthritis, cardiovascular disease, lipodystrophy, osteoporosis, and pulmonary hypertension | Cabanillas et al., 2011; Loi et al., 2016 |
| Werner syndrome | Telomeric maintenance and replication stress | WRN | Alopecia, atherosclerosis, arthritis, cardiovascular disease, cataracts, diabetes, sarcopenia, and increased risk of cancer | Kudlow et al., 2007; Sugimoto, 2014 |
| Rothmund-Thomson syndrome | DNA replication initiation | RECQL4 | Alopecia, cataracts, osteoporosis, skin atrophy, and increased risk of cancer | Croteau et al., 2012; Ghosh et al., 2012 |
| Bloom syndrome | DNA replication and recombination | BLM | Diabetes, pulmonary disease, increased risk of cancer | Hanada and Hickson, 2007; de Renty and Ellis, 2017 |
| XFE progeroid syndrome | NER, ICL, and DSB repair | ERCC4 | Anemia, cardiovascular disease, kidney disease, neurodegeneration, osteoporosis, sarcopenia, sensory loss, and skin atrophy | Niedernhofer et al., 2006 |
| Xeroderma pigmentosum | NER and translesion DNA synthesis | XPA-G, XPV | Premature skin photoaging, neurodegeneration, and increased incidence of skin cancer | Lehmann et al., 2011; Kraemer and DiGiovanna, 2015 |
| Cockayne syndrome | Transcription-coupled NER | CSA, CSB, XPB, XPD, XPG | Ataxia, cataracts, muscle atrophy, and neurodegeneration | Nance and Berry, 1992; Wilson et al., 2016 |
| Trichothiodystrophy | Transcription-coupled NER | TTDA, TTDN1, XPB, XPD | Premature bone marrow exhaustion and increased risk of cancer | Faghri et al., 2008; de Boer et al., 2002 |
| Fanconi anemia | ICL repair | FANCA-FANCW | Premature bone marrow exhaustion and increased risk of cancer | Ceccaldi et al., 2016; Nalepa and Clapp, 2018 |
| Ataxia telangiectasia | DNA damage response | ATM | Premature bone marrow exhaustion, diabetes, and neurodegeneration | Rothblum-Oviatt et al., 2016 |
| Mandibular hypoplasia, deafness, progeroid features, lipodystrophy syndrome | Post-replication repair and translesion DNA synthesis | POLD1 | Diabetes, lipodystrophy, osteoporosis, steatosis, sensory loss | Weedon et al., 2013 |
| Ruijs-Aalfs syndrome | Protein-DNA crosslink repair | SPRTN | Alopecia, atherosclerosis, cataracts, diabetes, premature graying of hair, osteoporosis, sarcopenia, and increased risk of cancer | Lessel et al., 2014 |
| Alpers-Huttenlocher syndrome | Mitochondrial DNA replication and repair | POLG1 | Progressive neurodegeneration and liver disease | Nguyen et al., 2006 |
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DNA damage—how and why we age?
eLife 10:e62852.
https://doi.org/10.7554/eLife.62852
