Identification of tissue-specific transcriptional markers of caloric restriction in the mouse and their use to evaluate caloric restriction mimetics.

Caloric restriction (CR) without malnutrition has been shown to retard several aspects of the aging process and to extend lifespan in different species. There is strong interest in the identification of CR mimetics (CRMs), compounds that mimic the beneficial effects of CR on lifespan and healthspan without restriction of energy intake. Identification of CRMs in mammals is currently inefficient due to the lack of screening tools.

A conserved transcriptional signature of delayed aging and reduced disease vulnerability is partially mediated by SIRT3.

Aging is the most significant risk factor for a range of diseases, including many cancers, neurodegeneration, cardiovascular disease, and diabetes. Caloric restriction (CR) without malnutrition delays aging in diverse species, and therefore offers unique insights into age-related disease vulnerability. Previous studies suggest that there are shared mechanisms of disease resistance associated with delayed aging, however quantitative support is lacking.

An adipocentric perspective of resveratrol as a calorie restriction mimetic.

Adipose tissue is an active endocrine organ that responds to changes in energy balance and influences whole-body physiology. Adipose tissue dysfunction with obesity is associated with metabolic disease, neurodegeneration, inflammation, and cancer, whereas calorie restriction (CR) decreases both adiposity and disease risk. Although resveratrol does not affect obesity, it mimics long-term CR by increasing both life span in model organisms and health span in rodents.

Transcriptomics and Metabonomics Identify Essential Metabolic Signatures in Calorie Restriction (CR) Regulation across Multiple Mouse Strains.

Calorie restriction (CR) has long been used to study lifespan effects and oppose the development of a broad array of age-related biological and pathological changes (increase healthspan). Yet, a comprehensive comparison of the metabolic phenotype across different genetic backgrounds to identify common metabolic markers affected by CR is still lacking. Using a system biology approach comprising metabonomics and liver transcriptomics we revealed the effect of CR across multiple mouse strains (129S1/SvlmJ, C57BL6/J, C3H/HeJ, CBA/J, DBA/2J, JC3F1/J).

Differential effects of krill oil and fish oil on the hepatic transcriptome in mice.

Dietary supplementation with ω-3 polyunsaturated fatty acids (ω-3 PUFAs), specifically the fatty acids docosahexaenoic acid (DHA; 22:6 ω-3) and eicosapentaenoic acid (EPA; 20:5 ω-3), is known to have beneficial health effects including improvements in glucose and lipid homeostasis and modulation of inflammation. To evaluate the efficacy of two different sources of ω-3 PUFAs, we performed gene expression profiling in the liver of mice fed diets supplemented with either fish oil (FO) or krill oil (KO). We found that ω-3 PUFA supplements derived from a phospholipid krill fraction (KO) downregulated the activity of pathways involved in hepatic glucose production as well as lipid and cholesterol synthesis.

Gene expression profiling reveals differential effects of sodium selenite, selenomethionine, and yeast-derived selenium in the mouse.

The essential trace mineral selenium is an important determinant of oxidative stress susceptibility, with several studies showing an inverse relationship between selenium intake and cancer. Because different chemical forms of selenium have been reported to have varying bioactivity, there is a need for nutrigenomic studies that can comprehensively assess whether there are divergent effects at the molecular level. We examined the gene expression profiles associated with selenomethionine (SM), sodium selenite (SS), and yeast-derived selenium (YS) in the intestine, gastrocnemius, cerebral cortex, and liver of mice.

Use of stringent selection parameters for the identification of possible selenium-responsive marker genes in mouse liver and gastrocnemius.

Selenium is a trace element that, although toxic in higher concentrations, is essential for human and animal health. In this study, we looked at microarray-based gene expression patterns from liver and gastrocnemius tissues in mice fed either a selenium-deficient diet or diets containing sodium selenite, selenomethionine, or a yeast-derived selenium supplement. A p value cutoff of 0.

Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice.

Background: Aging results in a progressive loss of skeletal muscle, a condition known as sarcopenia. Mitochondrial DNA (mtDNA) mutations accumulate with aging in skeletal muscle and correlate with muscle loss, although no causal relationship has been established.

Methodology/principal Findings: We investigated the relationship between mtDNA mutations and sarcopenia at the gene expression and biochemical levels using a mouse model that expresses a proofreading-deficient version (D257A) of the mitochondrial DNA Polymerase gamma, resulting in increased spontaneous mtDNA mutation rates.

Ten putative contributors to the obesity epidemic.

The obesity epidemic is a global issue and shows no signs of abating, while the cause of this epidemic remains unclear. Marketing practices of energy-dense foods and institutionally-driven declines in physical activity are the alleged perpetrators for the epidemic, despite a lack of solid evidence to demonstrate their causal role. While both may contribute to obesity, we call attention to their unquestioned dominance in program funding and public efforts to reduce obesity, and propose several alternative putative contributors that would benefit from equal consideration and attention.

A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice.

Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg(-1) day(-1)), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles.

Dynamic regulation of PGC-1alpha localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response.

There is increasing evidence that longevity and stress resistance are connected, but the mechanism is unclear. We report that mitochondria are regulated in response to oxidative stress and calorie restriction through a shared mechanism involving peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC-1alpha). We demonstrate that PGC-1alpha subcellular distribution is regulated, and its transcriptional activity is promoted through SIRT1-dependent nuclear accumulation.

Regulation of UCP1 and UCP3 in arctic ground squirrels and relation with mitochondrial proton leak.

Uncoupling protein (UCP) 1 (UCP1) catalyzes a proton leak in brown adipose tissue (BAT) mitochondria that results in nonshivering thermogenesis (NST), but the extent to which UCP homologs mediate NST in other tissues is controversial. To clarify the role of UCP3 in mediating NST in a hibernating species, we measured Ucp3 expression in skeletal muscle of arctic ground squirrels in one of three activity states (not hibernating, not hibernating and fasted for 48 h, or hibernating) and housed at 5 degrees C or -10 degrees C. We then compared Ucp3 mRNA levels in skeletal muscle with Ucp1 mRNA and UCP1 protein levels in BAT in the same animals.

Energy restriction lowers the expression of genes linked to inflammation, the cytoskeleton, the extracellular matrix, and angiogenesis in mouse adipose tissue.

Using high-density oligonucleotide microarrays, we examined the actions of energy restriction (ER) on the expression of >11,000 genes in epididymal white adipose tissue (WAT) of 10- to 11-mo-old male C57Bl6 mice. Four groups were studied: controls not subjected to food restriction (CO), food-restricted 18 h before being killed (FR), short-term ER for 23 d (SER), and long-term ER for 9 mo (LER). As we reported previously, compared with CO mice, FR and SER minimally influenced the gene expression profiles; however, 345 transcripts of 6,266 genes determined to be expressed in WAT were significantly altered by LER.

The retardation of aging by caloric restriction: its significance in the transgenic era.

The retardation of aging and diseases by caloric restriction (CR) is a widely-studied and robust phenomenon. Recent publications describe transgenic and other mutant rodents displaying lifespan extension, and the rapid pace at which these animals are being generated raises the possibility that the importance of the CR paradigm is declining. Here we discuss these models and evaluate the evidence whether or not the aging process is retarded based on longevity, disease patterns and age-associated biological changes.

Tissue-specific depression of mitochondrial proton leak and substrate oxidation in hibernating arctic ground squirrels.

A significant proportion of standard metabolic rate is devoted to driving mitochondrial proton leak, and this futile cycle may be a site of metabolic control during hibernation. To determine if the proton leak pathway is decreased during metabolic depression related to hibernation, mitochondria were isolated from liver and skeletal muscle of nonhibernating (active) and hibernating arctic ground squirrels (Spermophilus parryii). At an assay temperature of 37 degrees C, state 3 and state 4 respiration rates and state 4 membrane potential were significantly depressed in liver mitochondria isolated from hibernators.