Dysregulation of DAF-16/FOXO3A-mediated stress responses accelerates oxidative DNA damage induced aging

Aditi U. Gurkar, Andria R. Robinson, Yuxiang Cui, Xuesen Li, Shailaja K. Allani, Amanda Webster, Mariya Muravia, Mohammad Fallahi, Herbert Weissbach, Paul D. Robbins, Yinsheng Wang, Eric E. Kelley, Claudette M.St Croix, Laura J. Niedernhofer, Matthew S. Gill

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

DNA damage is presumed to be one type of stochastic macromolecular damage that contributes to aging, yet little is known about the precise mechanism by which DNA damage drives aging. Here, we attempt to address this gap in knowledge using DNA repair-deficient C. elegans and mice. ERCC-1-XPF is a nuclear endonuclease required for genomic stability and loss of ERCC1 in humans and mice accelerates the incidence of age-related pathologies. Like mice, ercc-1 worms are UV sensitive, shorter lived, display premature functional decline and they accumulate spontaneous oxidative DNA lesions (cyclopurines) more rapidly than wild-type worms. We found that ercc-1 worms displayed early activation of DAF-16 relative to wild-type worms, which conferred resistance to multiple stressors and was important for maximal longevity of the mutant worms. However, DAF-16 activity was not maintained over the lifespan of ercc-1 animals and this decline in DAF-16 activation corresponded with a loss of stress resistance, a rise in oxidant levels and increased morbidity, all of which were cep-1/ p53 dependent. A similar early activation of FOXO3A (the mammalian homolog of DAF-16), with increased resistance to oxidative stress, followed by a decline in FOXO3A activity and an increase in oxidant abundance was observed in Ercc1-/- primary mouse embryonic fibroblasts. Likewise, in vivo, ERCC1-deficient mice had transient activation of FOXO3A in early adulthood as did middle-aged wild-type mice, followed by a late life decline. The healthspan and mean lifespan of ERCC1 deficient mice was rescued by inactivation of p53. These data indicate that activation of DAF-16/FOXO3A is a highly conserved response to genotoxic stress that is important for suppressing consequent oxidative stress. Correspondingly, dysregulation of DAF-16/FOXO3A appears to underpin shortened healthspan and lifespan, rather than the increased DNA damage burden itself.

Original languageEnglish (US)
Pages (from-to)191-199
Number of pages9
JournalRedox Biology
Volume18
DOIs
StatePublished - Sep 2018
Externally publishedYes

Fingerprint

DNA Damage
Aging of materials
Chemical activation
DNA
Oxidative stress
Oxidants
Oxidative Stress
Endonucleases
Pathology
Fibroblasts
DNA Repair-Deficiency Disorders
Genomic Instability
Animals
Repair
Morbidity
Incidence

Keywords

  • Aging
  • DAF-16/FOXO3A
  • DNA damage
  • Oxidative stress
  • Reactive oxygen species
  • Stress resistance

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

Cite this

Gurkar, A. U., Robinson, A. R., Cui, Y., Li, X., Allani, S. K., Webster, A., ... Gill, M. S. (2018). Dysregulation of DAF-16/FOXO3A-mediated stress responses accelerates oxidative DNA damage induced aging. Redox Biology, 18, 191-199. https://doi.org/10.1016/j.redox.2018.06.005

Dysregulation of DAF-16/FOXO3A-mediated stress responses accelerates oxidative DNA damage induced aging. / Gurkar, Aditi U.; Robinson, Andria R.; Cui, Yuxiang; Li, Xuesen; Allani, Shailaja K.; Webster, Amanda; Muravia, Mariya; Fallahi, Mohammad; Weissbach, Herbert; Robbins, Paul D.; Wang, Yinsheng; Kelley, Eric E.; Croix, Claudette M.St; Niedernhofer, Laura J.; Gill, Matthew S.

In: Redox Biology, Vol. 18, 09.2018, p. 191-199.

Research output: Contribution to journalArticle

Gurkar, AU, Robinson, AR, Cui, Y, Li, X, Allani, SK, Webster, A, Muravia, M, Fallahi, M, Weissbach, H, Robbins, PD, Wang, Y, Kelley, EE, Croix, CMS, Niedernhofer, LJ & Gill, MS 2018, 'Dysregulation of DAF-16/FOXO3A-mediated stress responses accelerates oxidative DNA damage induced aging', Redox Biology, vol. 18, pp. 191-199. https://doi.org/10.1016/j.redox.2018.06.005
Gurkar, Aditi U. ; Robinson, Andria R. ; Cui, Yuxiang ; Li, Xuesen ; Allani, Shailaja K. ; Webster, Amanda ; Muravia, Mariya ; Fallahi, Mohammad ; Weissbach, Herbert ; Robbins, Paul D. ; Wang, Yinsheng ; Kelley, Eric E. ; Croix, Claudette M.St ; Niedernhofer, Laura J. ; Gill, Matthew S. / Dysregulation of DAF-16/FOXO3A-mediated stress responses accelerates oxidative DNA damage induced aging. In: Redox Biology. 2018 ; Vol. 18. pp. 191-199.
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