Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging

Andria R. Robinson, Matthew J. Yousefzadeh, Tania A. Rozgaja, Jin Wang, Xuesen Li, Jeremy S. Tilstra, Chelsea H. Feldman, Siobhán Q. Gregg, Caroline H. Johnson, Erin M. Skoda, Marie Céline Frantz, Harris Bell-Temin, Hannah Pope-Varsalona, Aditi U. Gurkar, Luigi A. Nasto, Renã A.S. Robinson, Heike Fuhrmann-Stroissnigg, Jolanta Czerwinska, Sara J. McGowan, Nadiezhda Cantu-MedellinJamie B. Harris, Salony Maniar, Mark A. Ross, Christy E. Trussoni, Nicholas F La Russo, Eugenia Cifuentes-Pagano, Patrick J. Pagano, Barbara Tudek, Nam V. Vo, Lora H. Rigatti, Patricia L. Opresko, Donna B. Stolz, Simon C. Watkins, Christin E. Burd, Claudette M.St Croix, Gary Siuzdak, Nathan A. Yates, Paul D. Robbins, Yinsheng Wang, Peter Wipf, Eric E. Kelley, Laura J. Niedernhofer

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1-/∆ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/∆ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/∆ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/∆ mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1-/∆ mice to an extent identical to naturally-aged WT mice. Increased enzymatic production of ROS and decreased antioxidants contributed to the elevation in oxidative stress in both Ercc1-/∆ and aged WT mice. Chronic treatment of Ercc1-/∆ mice with the mitochondrial-targeted radical scavenger XJB-5–131 attenuated oxidative DNA damage, senescence and age-related pathology. Our findings indicate that nuclear genotoxic stress arises, at least in part, due to mitochondrial-derived ROS, and this spontaneous DNA damage is sufficient to drive increased levels of ROS, cellular senescence, and the consequent age-related physiological decline.

Original languageEnglish (US)
Pages (from-to)259-273
Number of pages15
JournalRedox Biology
Volume17
DOIs
StatePublished - Jul 1 2018

Fingerprint

DNA Damage
Oxidation-Reduction
Genes
Aging of materials
Genome
Reactive Oxygen Species
DNA
Repair
Mammals
Oxidative stress
Endonucleases
Pathology
Animals
Antioxidants
Cells
Tissue
Cell Aging
Oxidative Stress

Keywords

  • Aging
  • Cellular senescence
  • Endogenous DNA damage
  • Free radicals
  • Genotoxic stress
  • Oxidative lesions
  • Reactive oxygen species

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

Cite this

Robinson, A. R., Yousefzadeh, M. J., Rozgaja, T. A., Wang, J., Li, X., Tilstra, J. S., ... Niedernhofer, L. J. (2018). Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biology, 17, 259-273. https://doi.org/10.1016/j.redox.2018.04.007

Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. / Robinson, Andria R.; Yousefzadeh, Matthew J.; Rozgaja, Tania A.; Wang, Jin; Li, Xuesen; Tilstra, Jeremy S.; Feldman, Chelsea H.; Gregg, Siobhán Q.; Johnson, Caroline H.; Skoda, Erin M.; Frantz, Marie Céline; Bell-Temin, Harris; Pope-Varsalona, Hannah; Gurkar, Aditi U.; Nasto, Luigi A.; Robinson, Renã A.S.; Fuhrmann-Stroissnigg, Heike; Czerwinska, Jolanta; McGowan, Sara J.; Cantu-Medellin, Nadiezhda; Harris, Jamie B.; Maniar, Salony; Ross, Mark A.; Trussoni, Christy E.; La Russo, Nicholas F; Cifuentes-Pagano, Eugenia; Pagano, Patrick J.; Tudek, Barbara; Vo, Nam V.; Rigatti, Lora H.; Opresko, Patricia L.; Stolz, Donna B.; Watkins, Simon C.; Burd, Christin E.; Croix, Claudette M.St; Siuzdak, Gary; Yates, Nathan A.; Robbins, Paul D.; Wang, Yinsheng; Wipf, Peter; Kelley, Eric E.; Niedernhofer, Laura J.

In: Redox Biology, Vol. 17, 01.07.2018, p. 259-273.

Research output: Contribution to journalArticle

Robinson, AR, Yousefzadeh, MJ, Rozgaja, TA, Wang, J, Li, X, Tilstra, JS, Feldman, CH, Gregg, SQ, Johnson, CH, Skoda, EM, Frantz, MC, Bell-Temin, H, Pope-Varsalona, H, Gurkar, AU, Nasto, LA, Robinson, RAS, Fuhrmann-Stroissnigg, H, Czerwinska, J, McGowan, SJ, Cantu-Medellin, N, Harris, JB, Maniar, S, Ross, MA, Trussoni, CE, La Russo, NF, Cifuentes-Pagano, E, Pagano, PJ, Tudek, B, Vo, NV, Rigatti, LH, Opresko, PL, Stolz, DB, Watkins, SC, Burd, CE, Croix, CMS, Siuzdak, G, Yates, NA, Robbins, PD, Wang, Y, Wipf, P, Kelley, EE & Niedernhofer, LJ 2018, 'Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging', Redox Biology, vol. 17, pp. 259-273. https://doi.org/10.1016/j.redox.2018.04.007
Robinson AR, Yousefzadeh MJ, Rozgaja TA, Wang J, Li X, Tilstra JS et al. Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biology. 2018 Jul 1;17:259-273. https://doi.org/10.1016/j.redox.2018.04.007
Robinson, Andria R. ; Yousefzadeh, Matthew J. ; Rozgaja, Tania A. ; Wang, Jin ; Li, Xuesen ; Tilstra, Jeremy S. ; Feldman, Chelsea H. ; Gregg, Siobhán Q. ; Johnson, Caroline H. ; Skoda, Erin M. ; Frantz, Marie Céline ; Bell-Temin, Harris ; Pope-Varsalona, Hannah ; Gurkar, Aditi U. ; Nasto, Luigi A. ; Robinson, Renã A.S. ; Fuhrmann-Stroissnigg, Heike ; Czerwinska, Jolanta ; McGowan, Sara J. ; Cantu-Medellin, Nadiezhda ; Harris, Jamie B. ; Maniar, Salony ; Ross, Mark A. ; Trussoni, Christy E. ; La Russo, Nicholas F ; Cifuentes-Pagano, Eugenia ; Pagano, Patrick J. ; Tudek, Barbara ; Vo, Nam V. ; Rigatti, Lora H. ; Opresko, Patricia L. ; Stolz, Donna B. ; Watkins, Simon C. ; Burd, Christin E. ; Croix, Claudette M.St ; Siuzdak, Gary ; Yates, Nathan A. ; Robbins, Paul D. ; Wang, Yinsheng ; Wipf, Peter ; Kelley, Eric E. ; Niedernhofer, Laura J. / Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. In: Redox Biology. 2018 ; Vol. 17. pp. 259-273.
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abstract = "Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1-/∆ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/∆ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/∆ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/∆ mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1-/∆ mice to an extent identical to naturally-aged WT mice. Increased enzymatic production of ROS and decreased antioxidants contributed to the elevation in oxidative stress in both Ercc1-/∆ and aged WT mice. Chronic treatment of Ercc1-/∆ mice with the mitochondrial-targeted radical scavenger XJB-5–131 attenuated oxidative DNA damage, senescence and age-related pathology. Our findings indicate that nuclear genotoxic stress arises, at least in part, due to mitochondrial-derived ROS, and this spontaneous DNA damage is sufficient to drive increased levels of ROS, cellular senescence, and the consequent age-related physiological decline.",
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AU - Tilstra, Jeremy S.

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AU - Skoda, Erin M.

AU - Frantz, Marie Céline

AU - Bell-Temin, Harris

AU - Pope-Varsalona, Hannah

AU - Gurkar, Aditi U.

AU - Nasto, Luigi A.

AU - Robinson, Renã A.S.

AU - Fuhrmann-Stroissnigg, Heike

AU - Czerwinska, Jolanta

AU - McGowan, Sara J.

AU - Cantu-Medellin, Nadiezhda

AU - Harris, Jamie B.

AU - Maniar, Salony

AU - Ross, Mark A.

AU - Trussoni, Christy E.

AU - La Russo, Nicholas F

AU - Cifuentes-Pagano, Eugenia

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AU - Tudek, Barbara

AU - Vo, Nam V.

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AU - Opresko, Patricia L.

AU - Stolz, Donna B.

AU - Watkins, Simon C.

AU - Burd, Christin E.

AU - Croix, Claudette M.St

AU - Siuzdak, Gary

AU - Yates, Nathan A.

AU - Robbins, Paul D.

AU - Wang, Yinsheng

AU - Wipf, Peter

AU - Kelley, Eric E.

AU - Niedernhofer, Laura J.

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