Metabolic Profiling of Accelerated Aging ERCC1^d/− Mice

Abstract

Aging is a fundamental biological process for which the mechanism is still largely unknown due to its complex and multifactorial nature. Animal models allow us to simplify this complexity and to study individual factors separately. As there are many causative links between DNA repair deficiency and aging, we studied the ERCC1(d/-) mouse, which has a modified ERCC1 gene, involved in the Nucleotide Excision Repair, and as a result has a premature aging phenotype. Profiling of these mice on different levels can give an insight into the mechanisms underlying the aging phenotype. In the current study, we have performed metabolic profiling of serum and urine of these mice in comparison to wild type and in relation to aging by (1)H NMR spectroscopy. Analysis of metabolic trajectories of animals from 8 to 20 weeks suggested that wild type and ERCC1(d/-) mutants have similar age-related patterns of changes; however, the difference between genotypes becomes more prominent with age. The main differences between these two genetically diverse groups of mice were found to be associated with altered lipid and energy metabolism, transition to ketosis, and attenuated functions of the liver and kidney.

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

“…Liver transcriptome analysis of Ercc1 -/-and CSB/XPA mice revealed altered expression of genes involved in carbohydrate and oxidative metabolism and peroxisome biogenesis suggestive of increased glycogen www.intechopen.com synthesis, decreased glycolysis, and decreased oxidative metabolism . Global metabolic profiling by NMR revealed that Ercc1 -/-mice have altered lipid and energy metabolism and a shift toward ketosis when compared to age-matched controls (Nevedomskaya et al 2010). 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).…”

“…Global metabolic profiling by NMR revealed that Ercc1 -/-mice have altered lipid and energy metabolism and a shift toward ketosis when compared to age-matched controls (Nevedomskaya et al 2010). 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).…”

Comparison of mice with accelerated aging caused by distinct mechanisms

“…This suggests that the mutant mice develop somewhat normally until they reach sexual maturity and then ‘accelerate aging’. Several metabolic changes are also consistent with organ insufficiency and/or failure, including increased glucose, citrate and succinate in the urine, and decreased hippuric acid secretion indicative of kidney dysfunction and metabolic alkalosis, decreased taurine and allantoin (urine) and increased glutamine and alanine (serum) indicative of liver dysfunction (Nevedomskaya and others 2010). Interestingly these serum and urine changes preceded the pronounced physical changes observed in the Ercc1 -/Δ mice.…”

“…The development of age-dependent motor abnormalities, disruption of neuromuscular connectivity at the neuromuscular junction, degeneration of motor neurons and spontaneous peripheral neurodegeneration (de Waard and others 2010; Goss and others 2011) supports the idea that neurons are particularly vulnerable to endogenous DNA damage when not repaired. Ercc1 -/Δ mice also have altered energy metabolism, with a shift to ketosis (Nevedomskaya and others 2010). They have a relative change of lipoprotein levels compared to wild-type mice, with a decrease in LDL and VLDL and increase in HDL in mutant animals (Nevedomskaya and others 2010; Smith and others 2012).…”

“…Ercc1 -/Δ mice also have altered energy metabolism, with a shift to ketosis (Nevedomskaya and others 2010). They have a relative change of lipoprotein levels compared to wild-type mice, with a decrease in LDL and VLDL and increase in HDL in mutant animals (Nevedomskaya and others 2010; Smith and others 2012). Metabolic profiling of Ercc1 -/Δ mice revealed that at younger ages (<10 weeks) there is no significant difference between wild-type and mutant mice.…”