Gene expression profile of aging and its modification by caloric restriction, alpha-lipoic acid, and coenzyme Q10 in mice.

摘要

The gene expression profile of the aging process was analyzed in skeletal muscle, brain and heart of mice using high-density oligonucleotide microarrays. Skeletal muscle aging resulted in a differential gene expression pattern indicative of a marked stress response and lower expression of metabolic and biosynthetic genes. Most alterations were either completely or partially prevented by caloric restriction (CR), the only intervention known to retard aging in mammals. Brain aging resulted in an inflammatory response, oxidative stress and reduced neurotrophic support. CR selectively attenuated the age-associated induction of genes encoding inflammatory and stress responses in brain. Cardiac aging resulted in a metabolic shift from fatty acid to carbohydrate metabolism, increased expression of extracellular matrix genes and reduced protein synthesis. CR resulted in gene expression indicative of preserved fatty acid metabolism, decreased innate immune activity and a marked cytoskeletal reorganization in heart. To investigate antioxidants effect on cardiac aging, gene expression alterations induced by α-lipoic acid (LA) and coenzyme Q₁₀ (CQ) were analyzed. LA resulted in alterations in gene expression consistent with lower expression of major histocompatibility complex component genes, reduction in the expression of stress-induced genes involved in protein folding, and reduced expression of genes involved in protein turnover. CQ resulted in increased expression of genes involved in oxidative phosphorylation, a reduction in expression of genes involved in the complement pathway, reduced expression of stress induced genes involved in protein folding and repair, and reduced expression of genes involved in protein synthesis and turnover. These observations provide evidence that supplementation with dietary supplements is associated with specific transcriptional alterations consistent with a state of lower oxidative stress, but that such alterations have no impact on the cardiac aging process at a global level. Taken as a whole, the studies described above suggest that CR retards aging at the transcriptional level, and that transcriptional alterations can serve as tissue-specific biomarkers of the aging process.