Extended longevity mechanisms in short-lived progeroid mice: Identification of a preservative stress response associated with successful aging

Abstract

Semantic distinctions between "normal" aging, "pathological" aging (or age-related disease) and "premature" aging (otherwise known as segmental progeria) potentially confound important insights into the nature of each of the complex processes. Here we review a recent, unexpected discovery: the presence of longevity-associated characteristics typical of long-lived endocrine-mutant and dietary-restricted animals in short-lived progeroid mice. These data suggest that a subset of symptoms observed in premature aging, and possibly normal aging as well, may be indirect manifestations of a beneficial adaptive stress response to endogenous oxidative damage, rather than a detrimental result of the damage itself.

Relationship Between DNA Damage and Energy Metabolism: Evidence from DNA Repair Deficiency Syndromes

“…Liver transcriptome analysis confirmed a general downregulation of multiple components of the postnatal GH/IGF-1 axis. Nonetheless, in select mouse models of severe NER progeria, effects on serum IGF-1 and glycemic index can be transient, occurring prior to weaning but normalizing in animals that survive this apparent developmental bottleneck (van de Ven et al 2006). Global profiling of gene expression in liver confirmed a significant overlap between NER progeria and long-lived dwarfism (Schumacher et al 2008) consistent with the physiologic data.…”

“…Knockout mice are born normally, but are photosensitive and display an age-dependent loss of photoreceptor cells (van der Horst et al 2002;van der Horst et al 1997). Although they develop normally, CSB mice remain lean in adulthood and have normal lifespans (Dolle et al 2006).…”

“…This socalled "NER progeria" was first described in mice lacking the endonuclease Ercc1 (Melton et al 1998;Weeda et al 1997) and subsequently in a number of genetic models of NER deficiency, including CSB/XPA (Murai et al 2001), XPA/TTD (de Boer et al 1998), XPA/XPCS , CSB/XPC (Laposa, Huang, and Cleaver 2007) double homozygous mutants as well as XPG (Sun et al 2003) and XPF (Tian et al 2004) single homozygous mutants. Common metabolic features of NER progeria in mice include reduced blood glucose and reduced insulin, disproportionate reduction of white adipose tissue weight, and accumulation of triglycerides in the liver (van de Ven et al 2007). Although the cause of death is not clear, animals may inevitably succumb to hypoglycemia.…”

“…Ercc1 -/-mice show several metabolic adaptations that resemble those seen in DR, including decreased LDL and VLDL, increased HDL, and decreased serum glucose (Nevedomskaya et al 2010). Another common feature of NER progeria that may underlie the growth retardation is reduced mRNA and serum protein expression of IGF-1 van der Pluijm et al 2007;van de Ven et al 2006). Unlike long-lived endocrine deficient dwarfs (Ames, Snell) with reduced GH secretion due to defective anterior pituitary development (Bartke and Brown-Borg 2004), NER-deficient mice have an intact pituitary and normal to elevated GH levels, consistent with normal hypothalamic and pituitary function.…”

“…Roles for many of these functions have been proposed to be causative of one or more symptoms of CS, TTD or XP. However, due in large part to the high degree of overlap between symptoms in multiple different mouse models, where the effects of homozygous mutations can be interrogated against a standardized genetic and environmental background, it has been hypothesized that these conditions have a common underlying cause van de Ven et al 2007). Currently, the only known common function of each of the proteins, including CSA, CSB, XPD, XPB and XPG, is the transcription-coupled arm of NER.…”