DNA damage—how and why we age?

  1. Matt Yousefzadeh
  2. Chathurika Henpita
  3. Rajesh Vyas
  4. Carolina Soto-Palma
  5. Paul Robbins
  6. Laura Niedernhofer  Is a corresponding author
  1. Institute on the Biology of Aging and Metabolism Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, United States
2 figures and 2 tables


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.

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).


Table 1
Estimated frequencies of DNA lesions caused by endogenous and common environmental sources of DNA damage.
Endogenous DNA adducts
DNA lesionDSBCytosine deaminationCyclopurine adductsDepyrimidination8-oxoGMalondialdehyde adductsAlkylation adductsDepurinationSSB
Frequency per cell per day101102102102103103103104104
DNA adducts caused by environmental exposures
GenotoxinSunlightBackground radiationIonizing radiation therapyOxaliplatin cancer therapy
LesionPhotodimersDamaged basesSSBDSBDamaged basesSSBIntra- and interstrand crosslinks
Frequency per cell per day102 in skin cells only102–50.25103103103
Table 2
Human genome instability diseases with age-associated symptoms.
DiseaseAffected genome stability pathwayMutated genesAging-associated symptomsRef(s)
Hutchinson-Guilford progeria syndromeChromatin organizationLMNAAlopecia, atherosclerosis, arthritis, cardiovascular disease, lipodystrophy, osteoporosis, skin aging and atrophyKudlow et al., 2007; Liu et al., 2005
Nestor-Guillermo progeria syndromeChromatin organizationBANF1Alopecia, atherosclerosis, arthritis, cardiovascular disease, lipodystrophy, osteoporosis, and pulmonary hypertensionCabanillas et al., 2011; Loi et al., 2016
Werner syndromeTelomeric maintenance and replication stressWRNAlopecia, atherosclerosis, arthritis, cardiovascular disease, cataracts, diabetes, sarcopenia, and increased risk of cancerKudlow et al., 2007; Sugimoto, 2014
Rothmund-Thomson syndromeDNA replication initiationRECQL4Alopecia, cataracts, osteoporosis, skin atrophy, and increased risk of cancerCroteau et al., 2012; Ghosh et al., 2012
Bloom syndromeDNA replication and recombinationBLMDiabetes, pulmonary disease, increased risk of cancerHanada and Hickson, 2007; de Renty and Ellis, 2017
XFE progeroid syndromeNER, ICL, and DSB repairERCC4Anemia, cardiovascular disease, kidney disease, neurodegeneration, osteoporosis, sarcopenia, sensory loss, and skin atrophyNiedernhofer et al., 2006
Xeroderma pigmentosumNER and translesion DNA synthesisXPA-G, XPVPremature skin photoaging, neurodegeneration, and increased incidence of skin cancerLehmann et al., 2011; Kraemer and DiGiovanna, 2015
Cockayne syndromeTranscription-coupled NERCSA, CSB, XPB, XPD, XPGAtaxia, cataracts, muscle atrophy, and neurodegenerationNance and Berry, 1992; Wilson et al., 2016
TrichothiodystrophyTranscription-coupled NERTTDA, TTDN1, XPB, XPDPremature bone marrow exhaustion and increased risk of cancerFaghri et al., 2008; de Boer et al., 2002
Fanconi anemiaICL repairFANCA-FANCWPremature bone marrow exhaustion and increased risk of cancerCeccaldi et al., 2016; Nalepa and Clapp, 2018
Ataxia telangiectasiaDNA damage responseATMPremature bone marrow exhaustion, diabetes, and neurodegenerationRothblum-Oviatt et al., 2016
Mandibular hypoplasia, deafness, progeroid features, lipodystrophy syndromePost-replication repair and translesion DNA synthesisPOLD1Diabetes, lipodystrophy, osteoporosis, steatosis, sensory lossWeedon et al., 2013
Ruijs-Aalfs syndromeProtein-DNA crosslink repairSPRTNAlopecia, atherosclerosis, cataracts, diabetes, premature graying of hair, osteoporosis, sarcopenia, and increased risk of cancerLessel et al., 2014
Alpers-Huttenlocher syndromeMitochondrial DNA replication and repairPOLG1Progressive neurodegeneration and liver diseaseNguyen et al., 2006

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Matt Yousefzadeh
  2. Chathurika Henpita
  3. Rajesh Vyas
  4. Carolina Soto-Palma
  5. Paul Robbins
  6. Laura Niedernhofer
DNA damage—how and why we age?
eLife 10:e62852.