Review
Molecular mechanisms linking calorie restriction and longevity

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Abstract

Calorie-restricted feeding retards the rate of ageing in mammalian and invertebrate species. The molecular mechanisms underlying this effect include a lower rate of accrual of tissue oxidative damage that is associated with a significantly lower rate of mitochondrial free radical generation in rodent species. To identify the important sites of control and regulation for mitochondrial free radical generation during ageing and calorie-restricted feeding, metabolic control analysis is being applied to the study of mitochondrial bioenergetics. With ageing an increase in the mitochondrial proton leak is observed in mouse hepatocytes and in rat skeletal muscle. Limited data suggest that calorie-restricted feeding lowers the inner mitochondrial membrane potential and this may explain the reduced rate of free radical generation. A lowered unsaturation/saturation index is observed for mitochondrial membrane lipids in calorie-restricted rodents resulting in an altered membrane structure and function. Plasma concentrations of insulin and triiodothyronine are significantly lower under calorie-restricted feeding conditions and these hormones exert transcriptional control over desaturase enzymes that are important in the control of membrane lipid unsaturation. A loss of double bonds should make the mitochondrial membranes more resistant to peroxidation damage and would also reduce the proton conductance of the membrane, raising the membrane potential at a given respiration rate. This effect however, appears to be offset by other membrane changes that may include increased activity of uncoupling proteins. These unidentified adaptations increase the proton leak in calorie-restricted animals resulting in a lowering of the membrane potential and ROS generation.

Introduction

Chronic restriction of calorie intake has been recognised to retard the rate of ageing in species covering a wide phylogenetic range (yeast to mammals) and to delay the appearance and intensity of many age-related pathologies in rodents. Calorie restriction and ageing has been most intensely studied in rodents, and in the invertebrate species C. elegans and D. melanogastor. Current work studying the squirrel and Rhesus monkey will determine whether the rate of ageing in primate species is also susceptible to manipulation by the same dietary means and if this experimental system has direct relevance to understanding human ageing [1].

The observation that underfeeding in rodents can modify the rate of ageing has been demonstrated repeatedly since the early report of McCay [2]. A consistent finding with relevance to the underlying mechanisms is that the essential manipulation is to limit the overall energy intake of the animal (30–60% of ad libitum intake) over a prolonged period of the post-weaning life-span, without compromising the supply of essential nutrients. This simple manipulation will extend mean and maximum life-span by greater than 40%. It is a robust strategy, being independent of animal strain, health status of the experimental animal colony and exact composition of the diet utilised. For details of the calorie restriction (CR) methodology, see Merry [3] or Yu [4]. The simplicity and wide-ranging anti-ageing effects induced, and the lack of alternative methodologies to slow mammalian ageing, explains its attraction as an experimental system with which to evaluate mechanisms of ageing.

Although this paradigm for retarding the rate of ageing has been known for over 70 years, an understanding of the biochemical mechanism underlying this effect has been slow to develop. Some insight into the underlying mechanism can be obtained from consideration of the survival data for calorie-restricted animals. A dose–response relationship between survival and the degree of energy restriction is observed over a wide range of energy intake (Fig. 1). The shape of the survival curve is unaltered, but displaced to the right on the time axis. A significant positive correlation exists between the increase in the survival parameters recorded (mean, maximum and average last decile survival) and the duration of the underfeeding regime [5] (Fig. 2). The longer the duration, and the greater the degree of CR feeding (within the limits tolerated by the species) during the post-weaning period of the life-span, the greater the effect on survival and the rate of ageing [5], [6]. Intriguing reports of a ‘memory imprint’ resulting in increased life-span after periods of short-term CR early in life have yet to be confirmed [7].

Full analysis of the available survival data characterises the molecular mechanism underlying the effect of CR as dose-dependent, dynamic, requiring the continuous constraint of low calorie intake to maintain the full effect on survival. Some studies have reported that the rate of ageing can be accelerated on return to full feeding [8]. An attenuation of the rate of accrual of oxidative damage with age is the most prominent molecular mechanism so far proposed that is commensurate with the survival data analysis and that has not been rejected by subsequent experimental evaluation.

Section snippets

Oxidative stress

Oxidative stress is defined as the irreversible modification of cellular components resulting from the impact of pro-oxidant generating processes [6]. It is now accepted that there is an elevation of oxidative stress in old compared to young animals and that CR feeding retards the accrual of accepted markers of oxidative damage, such as the tissue concentration of peroxidised lipids, protein carbonyls and oxidative damage to bases in genomic and mitochondrial DNA. The widespread effect of CR to

ROS generation

A number of studies have reported lower ROS generation in isolated mitochondria from CR animals [6], [19], [20], [21], [22], [23]. Calorie-restricted feeding is reported to decreased free radical generation exclusively at complex I in heart mitochondria and mostly at complex I in liver mitochondria [24], [25]. The widely measured ROS species are the superoxide anion and hydrogen peroxide. Data is not available for the generation of the hydroxyl radical or for reactive nitrogen species (RNS)

Mitochondrial bioenergetics

Metabolic control analysis, specifically top–down elasticity analysis, as developed by Brand and Brown [35], is now being used to develop an understanding of why the rate of mitochondrial ROS generation increases with ageing and how CR restricted feeding reduces this rate. Metabolic control analysis allows the identification of important sites of control within complex metabolic pathways, whereas top–down elasticity analysis is used to identify differences in pathway regulation under differing

Membrane composition

Calorie-restricted feeding induces a change in the composition of the polyunsaturated fatty acid component of mitochondrial and cellular membranes. This was first reported by Yu and co-workers and may explain the enhanced resistance to peroxidation damage with time [59], [60], [61], [62], [63], [64]. Calorie restriction feeding induces a lower unsaturation/saturation index, specifically increasing the content of more saturated fatty acids 18:2 (linoleic acid) and 18:3 (α-linolenic acid) and

Hormone control of membrane composition

The question arises as to why mitochondria and other cellular membranes should show these composition changes in response to CR feeding. A common methodology frequently employed to produce long-lived CR rodents is to feed the same diet as consumed by the control animals, but restricted in quantity [3], hence, the earlier term for this model system of ‘dietary restriction’. Compositional changes in the diet therefore, particularly in fatty acid composition, cannot account for this response. The

Uncoupling proteins and CR

It is recognised that rodents maintained on CR feeding are more sensitive to cold stress and are moderately compromised with respect to thermogenesis during the first 12–15 months of life. During this period they have a lower core temperature prior to feeding [79]. The activity and response of uncoupling proteins to CR feeding regimes is therefore of some interest but their involvement in controlling proton leak, membrane potential and ROS generation has not been determined in this animal

Invertebrate species

The majority of studies on the biochemical mechanisms that may underlie the effect of CR on the rate of ageing have been completed in rodent species, but CR is recognised to delay ageing in a range of invertebrate species that are more amenable to genetic manipulation. All the long-lived C. elegans mutants convey resistance to environmental stress including oxidative damage and heat-shock, supporting the findings from mammalian studies that oxidative stress is central to the ageing process.

Summary

Calorie-restricted feeding in rodents is associated with a slower rate of accrual of tissue oxidative damage to DNA, lipids and proteins. Age-related accrual of oxidative damage is a balance between ROS-induced generation rates, defence enzyme activities, tissue antioxidant concentrations, repair processes, chaperone protein concentrations, and molecular and cellular turnover rates. Two pathways leading to a lowered rate of generation of oxidative tissue damage with age have been discussed (

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