Metabolic Reprogramming in Dietary Restriction

Abstract

It is widely accepted that energy intake restriction without essential nutrient deficiency delays the onset of aging and extends life span. The mechanism underlying this phenomenon is still unknown though a number of different, nonmutually exclusive explanations have been proposed. In each of these, different facets of physiology play the more significant role in the mechanism of aging retardation. Some examples include the altered lipid composition model, the immune response model and models describing changes in endocrine function. In this paper we propose the hypothesis that metabolic reprogramming is the key event in the mechanism of dietary restriction, and the physiological effects at the cellular, tissue and organismal level may be understood in terms of this initial event.Dietary restriction (DR) is the most successful intervention tested to date in mammals which greatly extends maximum life span and keeps animals 'younger longer' [1][2][3]. Consequently, any hypothesis about the etiology of aging must reconcile the effects of DR on aging. With increased knowledge of the mechanism of DR, we stand to gain a considerable insight into the process of aging.We propose that a change in the regulation of energy metabolism in response to DR is the primary step in the retardation of aging ( fig. 1). First we describe the evidence in support of metabolic reprogramming, a switch to an altered metabolic state, by DR in mice. Next we consider evidence for metabolic shifts in other model organisms where life span is extended by DR or by genetic manipulation. Then we focus on changes in mitochondrial energy metabolism with age and DR in mammals. Next we will explore the effects of altered mitochondrial function in the context of reactive oxygen species (ROS) generation and oxidative stress. Finally we describe the metabolic and morphological changes in white adipose tissue that we believe are a result of altered mitochondrial function. We propose that the activation of adipose tissue through metabolic reprogramming is critical to the mechanism of DR and that it leads to the changes in the animal physiology that are described in the models indicated above. Metabolic Reprogramming in Tissues from Dietary-Restricted AnimalsThe inverse linear relationship between calorie intake and life span in mice [4] suggests that genes central to energy metabolism may be critical in the underlying mechanism of DR in

Energy Restriction Does Not Compensate for the Reduced Expression of Hepatic Drug-Processing Genes in Mice with Aging

“…Energy restriction (ER) has been extensively investigated as an intervention that both extends lifespan and delays age-related diseases in laboratory animals (Anderson and Weindruch, 2007). It has been proposed that caloric restriction might produce beneficial effects by reprogramming energy metabolism (Anderson and Weindruch, 2007).…”

“…It has been proposed that caloric restriction might produce beneficial effects by reprogramming energy metabolism (Anderson and Weindruch, 2007). However, the exact effects of ER on hepatic drug metabolism remain unknown.…”

Effect of exercise and calorie restriction on biomarkers of aging in mice

“…Therefore, using body weight as a proxy of energy balance, this study compared long-term exercise and calorie restriction under carefully-matched conditions on markers purportedly related to aging in mammals. Specifically, beneficial actions of calorie restriction have been attributed to an attenuation of oxidative damage (4), reductions in total body fat (3), improved endocrine and metabolic profiles (1), and alterations in the balance of cell death and survival (8). Therefore, this study assessed the effect of calorie restriction and exercise on body composition, markers of energy metabolism, oxidative stress, and hormesis.…”

Biology of Human Aging and Recent Nutrition Therapy

“…Consequently, metabolic reprogramming by induction of CR may be a crucial point in the mechanism for the extension of life span [13]. Investigations of yeast, worms, flies and mice would indicate a certain role for nutrient which is responsive signaling molecules including SIRT1, mTOR and PGC-1α in aging and CR [18]. How are these findings related to the aging mechanism?…”