Dietary methylmercury and fatty acids affect the lipid metabolism of adipose tissue and liver in rainbow trout.

Methylmercury (MeHg) is a pervasive environmental contaminant in aquatic ecosystems that can reach elevated concentrations in fish of high trophic levels, such as salmonids. The present study aims at investigating the individual and combined impacts of dietary MeHg and fatty acids on lipid metabolism in juvenile rainbow trout (Oncorhynchus mykiss) with a focus on two key organs, adipose tissue and liver. MeHg and fatty acids are both known to act on energy homeostasis although little is known about their interplay on lipid metabolism in fish.

Beyond the Lab: What We Can Learn about Cancer from Wild and Domestic Animals.

Cancer research has benefited immensely from the use of animal models. Several genetic tools accessible in rodent models have provided valuable insight into cellular and molecular mechanisms linked to cancer development or metastasis and various lines are available. However, at the same time, it is important to accompany these findings with those from alternative or non-model animals to offer new perspectives into the understanding of tumor development, prevention, and treatment.

The Catechins Profile of Green Tea Extracts Affects the Antioxidant Activity and Degradation of Catechins in DHA-Rich Oil.

This study investigated the effect of the catechins profile on the antioxidant activity of green tea extracts (GTEs) by comparing the antioxidant activity of an EGC-rich GTE (GTE1, catechin content: 58% EGC, 30.1% EGCG, 7.9% EC, and 3.

Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 (IRS1) in mice.

Dietary restriction (DR) is the most widely studied non-genetic intervention capable of extending lifespan across multiple taxa. Modulation of genes, primarily within the insulin/insulin-like growth factor signalling (IIS) and the mechanistic target of rapamycin (mTOR) signalling pathways also act to extend lifespan in model organisms. For example, mice lacking insulin receptor substrate-1 (IRS1) are long-lived and protected against several age-associated pathologies.

Mild Suppression of Hyperinsulinemia to Treat Obesity and Insulin Resistance.

Insulin plays roles in lipid uptake, lipolysis, and lipogenesis, in addition to controlling blood glucose levels. Excessive circulating insulin is associated with adipose tissue expansion and obesity, yet a causal role for hyperinsulinemia in the development of mammalian obesity has proven controversial, with many researchers suggesting it as a consequence of insulin resistance. Recently, evidence that specifically reducing hyperinsulinemia can prevent and reverse obesity in animal models has been presented.

Reducing insulin via conditional partial gene ablation in adults reverses diet-induced weight gain.

Excess circulating insulin is associated with obesity in humans and in animal models. However, the physiologic causality of hyperinsulinemia in adult obesity has rightfully been questioned because of the absence of clear evidence that weight loss can be induced by acutely reversing diet-induced hyperinsulinemia. Herein, we describe the consequences of inducible, partial insulin gene deletion in a mouse model in which animals have already been made obese by consuming a high-fat diet.

Proteostasis and ageing: insights from long-lived mutant mice.

The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age-related disease, and thus improving late-life health and vitality.

A causal role for hyperinsulinemia in obesity.

Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments.

Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces β Cell Proliferation.

Pancreatic β cells are mostly post-mitotic, but it is unclear what locks them in this state. Perturbations including uncontrolled hyperglycemia can drive β cells into more pliable states with reduced cellular insulin levels, increased β cell proliferation, and hormone mis-expression, but it is unknown whether reduced insulin production itself plays a role. Here, we define the effects of ∼50% reduced insulin production in Ins1(-/-):Ins2(f/f):Pdx1Cre(ERT):mTmG mice prior to robust hyperglycemia.

Fibroblasts derived from long-lived insulin receptor substrate 1 null mice are not resistant to multiple forms of stress.

Reduced signalling through the insulin/insulin-like growth factor-1 signalling (IIS) pathway is a highly conserved lifespan determinant in model organisms. The precise mechanism underlying the effects of the IIS on lifespan and health is currently unclear, although cellular stress resistance may be important. We have previously demonstrated that mice globally lacking insulin receptor substrate 1 (Irs1(-/-) ) are long-lived and enjoy a greater period of their life free from age-related pathology compared with wild-type (WT) controls.

A comparative cellular and molecular biology of longevity database.

Discovering key cellular and molecular traits that promote longevity is a major goal of aging and longevity research. One experimental strategy is to determine which traits have been selected during the evolution of longevity in naturally long-lived animal species. This comparative approach has been applied to lifespan research for nearly four decades, yielding hundreds of datasets describing aspects of cell and molecular biology hypothesized to relate to animal longevity.

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage.

Insulin receptor substrate-1 null (Irs1 (-/-)) mice are long lived and importantly they also demonstrate increased resistance to several age-related pathologies compared to wild type (WT) controls. Currently, the molecular mechanisms that underlie lifespan extension in long-lived mice are unclear although protection against oxidative damage may be important. Here, we determined both the activities of several intracellular antioxidants and levels of oxidative damage in brain, skeletal muscle, and liver of Irs1 (-/-) and WT mice at 80, 450, and 700 days of age, predicting that long-lived Irs1 (-/-) mice would be protected against oxidative damage.

Dietary restriction increases skeletal muscle mitochondrial respiration but not mitochondrial content in C57BL/6 mice.

Dietary restriction (DR) is suggested to induce mitochondrial biogenesis, although recently this has been challenged. Here we determined the impact of 1, 9 and 18 months of 30% DR in male C57BL/6 mice on key mitochondrial factors and on mitochondrial function in skeletal muscle, relative to age-matched ad libitum (AL) controls. We examined proteins and mRNAs associated with mitochondrial biogenesis and measured mitochondrial respiration in permeabilised myofibres using high resolution respirometry.

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan.

Accumulation of DNA lesions compromises replication and transcription and is thus toxic to cells. DNA repair deficiencies are generally associated with cellular replicative senescence and premature aging syndromes, suggesting that efficient DNA repair is required for normal longevity. It follows that the evolution of increasing lifespan amongst animal species should be associated with enhanced DNA repair capacities.

Higher levels of heat shock proteins in longer-lived mammals and birds.

Cellular stress resistance is generally associated with longevity, but the mechanisms underlying this phenotype are not clear. In invertebrate models there is a clear role for heat shock proteins (Hsps) and organelle-specific unfolded protein responses (UPR) in longevity. However, this has not been demonstrated in vertebrates.

Folate deficiency increases mtDNA and D-1 mtDNA deletion in aged brain of mice lacking uracil-DNA glycosylase.

Strong epidemiological and experimental evidence links folate deficiency and resultant hyperhomocysteinemia with cognitive decline and neurodegeneration. Here, we tested the hypothesis that uracil misincorporation contributes to mitochondrial pathology in aged brain following folate deprivation. In a 2 × 2 design, 14-month-old mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls were subjected to a folate-deficient versus a regular diet for six weeks.

Plasma IGF-1 is negatively correlated with body mass in a comparison of 36 mammalian species.

In mammals, insulin-like growth factor-1 (IGF-1) is positively correlated with adult body mass, in comparisons made within a given species. In mice, IGF-1 deficiency is associated with dwarfism, whereas IGF-1 overproduction in transgenic animals causes gigantism. Surprisingly, the opposite is true in an inter-species context.

Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species.

Previous studies have shown that longevity is associated with enhanced cellular stress resistance. This observation supports the disposable soma theory of aging, which suggests that the investment made in cellular maintenance will be proportional to selective pressures to extend lifespan. Maintenance of protein homeostasis is a critical component of cellular maintenance and stress resistance.

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species.

The free radical theory of ageing posits that accrual of oxidative damage underlies the increased cellular, tissue and organ dysfunction and failure associated with advanced age. In support of this theory, cellular resistance to oxidative stress is highly correlated with life span, suggesting that prevention or repair of oxidative damage might indeed be essential for longevity. To test the hypothesis that the prevention of oxidative damage underlies longevity, we measured the activities of the five major intracellular antioxidant enzymes in brain, heart and liver tissue of 14 mammalian and avian species with maximum life spans (MLSPs) ranging from 3 years to over 100 years.

Mitochondrial redox metabolism: aging, longevity and dietary effects.

Mitochondrial redox metabolism has long been considered to play important roles in mammalian aging and the development of age-related pathologies in the major oxidative organs. Both genetic and dietary manipulations of mitochondrial redox metabolism have been associated with the extension of lifespan. Here we provide a broad overview of the circumstantial evidence showing associations between mitochondrial reactive oxygen species (ROS) metabolism, aging and longevity.

Mitochondria, cellular stress resistance, somatic cell depletion and lifespan.

The causes of aging and determinants of maximum lifespan in animal species are multifaceted and complex. However, a wealth of experimental data suggests that mitochondria are involved both in the aging process and in regulating lifespan. Here we outline a somatic cell depletion (SCD) model to account for correlations between: (1) mitochondrial reactive oxygen species and lifespan; (2) mitochondrial antioxidant enzymes and lifespan; (3) mitochondrial DNA mutation and lifespan and (4) cellular stress resistance and lifespan.

Upregulation of intracellular antioxidant enzymes in brain and heart during estivation in the African lungfish Protopterus dolloi.

The African slender lungfish, Protopterus dolloi, is highly adapted to withstand periods of drought by secreting a mucous cocoon and estivating for periods of months to years. Estivation is similar to the diapause and hibernation of other animal species in that it is characterized by negligible activity and a profoundly depressed metabolic rate. As is typically observed in quiescent states, estivating P.

In vitro measurement of DNA base excision repair in isolated mitochondria.

Mitochondrial DNA (mtDNA) is in relatively close proximity to reactive oxygen species (ROS) arising from spontaneous superoxide formation during respiration. As a result, it sustains oxidative damage that may include base modifications, base loss, and strand breaks. mtDNA replication past sites of oxidative damage can result in the introduction of mutations.

Mechanisms of stress resistance in Snell dwarf mouse fibroblasts: enhanced antioxidant and DNA base excision repair capacity, but no differences in mitochondrial metabolism.

Dermal fibroblasts from long-lived Snell dwarf mice can withstand a variety of oxidative and non-oxidative stressors compared to normal littermate controls. Here, we report differences in the levels and activities of intracellular antioxidant and DNA repair enzymes between normal and Snell dwarf mice fibroblasts cultured under a variety of conditions, including: 3% and 20% ambient O(2); the presence and absence of serum; and the addition of an exogenous oxidative stress. The only significant difference between normal and dwarf cells cultured in complete medium, at 20% O(2), was an approximately 40% elevation of glutathione peroxidase (GPx) activity in the mutant cells.

Intracellular antioxidant enzymes are not globally upregulated during hibernation in the major oxidative tissues of the 13-lined ground squirrel Spermophilus tridecemlineatus.

Hibernating mammals exhibit oxidative stress resistance in brain, liver and other tissues. In many animals, cellular oxidative stress resistance is associated with enhanced expression of intracellular antioxidant enzymes. Intracellular antioxidant capacity may be upregulated during hibernation to protect against oxidative damage associated with the ischemia-reperfusion that occurs during transitions between torpor and arousal.