Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice.

Marieke Van De Ven, Jaan Olle Andressoo, Valerie B. Holcomb, Marieke Von Lindern, Willeke M.C. Jong, Chris I. De Zeeuw, Yousin Suh, Paul Hasty, Jan H.J. Hoeijmakers, Gijsbertus T.J. Van Der Horst, James R. Mitchell

Research output: Contribution to journalArticle

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Abstract

How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age), including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPD(G602D/R722W)/XPA(-/-)) that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80(-/-) mouse. Specific (but not all) types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage.

Original languageEnglish (US)
JournalPLoS Genetics
Volume2
Issue number12
DOIs
StatePublished - Dec 15 2006
Externally publishedYes

Fingerprint

Progeria
Dwarfism
dwarfing
DNA Repair
stress response
hypoglycemia
animal models
somatomedins
DNA repair
signs and symptoms (animals and humans)
fibroblasts
Genomic Instability
mice
weaning
Somatomedins
senescence
Weaning
Hypoglycemia
erythroblasts
death

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Van De Ven, M., Andressoo, J. O., Holcomb, V. B., Von Lindern, M., Jong, W. M. C., De Zeeuw, C. I., ... Mitchell, J. R. (2006). Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice. PLoS Genetics, 2(12). https://doi.org/10.1371/journal.pgen.0020192

Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice. / Van De Ven, Marieke; Andressoo, Jaan Olle; Holcomb, Valerie B.; Von Lindern, Marieke; Jong, Willeke M.C.; De Zeeuw, Chris I.; Suh, Yousin; Hasty, Paul; Hoeijmakers, Jan H.J.; Van Der Horst, Gijsbertus T.J.; Mitchell, James R.

In: PLoS Genetics, Vol. 2, No. 12, 15.12.2006.

Research output: Contribution to journalArticle

Van De Ven, M, Andressoo, JO, Holcomb, VB, Von Lindern, M, Jong, WMC, De Zeeuw, CI, Suh, Y, Hasty, P, Hoeijmakers, JHJ, Van Der Horst, GTJ & Mitchell, JR 2006, 'Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice.', PLoS Genetics, vol. 2, no. 12. https://doi.org/10.1371/journal.pgen.0020192
Van De Ven, Marieke ; Andressoo, Jaan Olle ; Holcomb, Valerie B. ; Von Lindern, Marieke ; Jong, Willeke M.C. ; De Zeeuw, Chris I. ; Suh, Yousin ; Hasty, Paul ; Hoeijmakers, Jan H.J. ; Van Der Horst, Gijsbertus T.J. ; Mitchell, James R. / Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice. In: PLoS Genetics. 2006 ; Vol. 2, No. 12.
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