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.