Abstract
Ageing is a complex biological process for which underlying biochemical changes are still largely unknown. We performed comparative profiling of the cellular proteome and metabolome to understand the molecular basis of ageing in Caspase-2-deficient (Casp2−/−) mice that are a model of premature ageing in the absence of overt disease. Age-related changes were determined in the liver and serum of young (6–9 week) and aged (18–24 month) wild-type and Casp2−/− mice. We identified perturbed metabolic pathways, decreased levels of ribosomal and respiratory complex proteins and altered mitochondrial function that contribute to premature ageing in the Casp2−/− mice. We show that the metabolic profile changes in the young Casp2−/− mice resemble those found in aged wild-type mice. Intriguingly, aged Casp2−/− mice were found to have reduced blood glucose and improved glucose tolerance. These results demonstrate an important role for caspase-2 in regulating proteome and metabolome remodelling during ageing.
Highlights
Ageing is a complex biological process involving the accumulation of cellular damage and degeneration of repair systems over time resulting in perturbed homeostasis, physiological decline, age-related disease and death
As our data showed a higher abundance of oxidative phosphorylation (OXPHOS) complex proteins in aged Casp2−/− versus WT mice, we investigated whether there was any difference in mitochondrial size, number and function in vivo
Ageing was associated with upregulation of enzymes involved in carbohydrate and amino-acid metabolism, downregulation of numerous mitochondrial and ribosomal proteins and altered mitochondrial function
Summary
Ageing is a complex biological process involving the accumulation of cellular damage and degeneration of repair systems over time resulting in perturbed homeostasis, physiological decline, age-related disease and death. Caspase-2 (Casp2) is the most evolutionarily conserved member of the caspase family of proteases, known for their roles in apoptosis and inflammatory responses.[6,7] Casp[2] has been shown to have both apoptotic and non-apoptotic functions in stress response pathways, maintaining genomic integrity, tumour suppression and ageing.[6,7,8,9,10,11] In the presence of oncogenic stress, Casp[2] deficiency in mice results in enhanced cellular transformation, genomic instability and increased tumorigenesis.[9,10,12] Casp2-deficient (Casp2−/−). Rat Casp[2] increases in response to high-fat diet,[17,18] and human CASP2 is transcriptionally regulated by the sterol
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