The International Journal of Biochemistry & Cell Biology
ReviewMolecular mechanisms linking calorie restriction and longevity
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 (
References (89)
- et al.
The effect of retarded growth upon the length of the life-span and ultimate body size
J. Nutr.
(1935) Ageing and oxidative stress: modulation by dietary restriction
Free Radic. Biol. Med.
(1996)- et al.
Effect of age-related lipid peroxidation on membrane fluidity and phospholipase-A2—modulation by dietary restriction
Mech. Ageing Dev.
(1992) - et al.
Lipid peroxidation contributes to age-related membrane rigidity
Free Radic. Biol. Med.
(1995) - et al.
Brain synaptosomal ageing: free radicals and membrane fluidity
Free Radic. Biol. Med.
(1995) - et al.
Modulation of cardiac mitochondrial membrane fluidity by age and calorie intake
Free Radic. Biol. Med.
(1999) - et al.
Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during ageing and in response to food restriction in the mouse
Mech. Ageing Dev.
(1994) - et al.
Caloric and carbohydrate restriction in the kidney—effects on free-radical metabolism
Exp. Gerontol.
(1994) - et al.
Ageing of the liver: age-associated mitochondrial damage in intact hepatocytes
Hepatology
(1996) - et al.
Human epidermal-cells progressively lose their cardiolipins during ageing without change in mitochondrial transmembrane potential
Mech. Ageing Dev.
(1994)
Nitric oxide and mitochondrial respiration
Biochim. Biophys. Acta
The causes and functions of mitochondrial proton leak
Biochim. Biophys. Acta Bioenerg.
A decrease of free-radical production near-critical sites is the cause of maximum longevity in animals
Comp. Biochem. Physiol.
The quantitative contributions of mitochondrial proton leak and ATP turnover reactions to the changed respiration rates of hepatocytes from rats of different thyroid status
J. Biol. Chem.
Mitochondrial proton leak and the uncoupling protein 1 homologues
Biochem. Biophys. Acta
Restriction of energy intake, energy expenditure, and ageing
Free Radic. Biol. Med.
Uncoupling: new approaches to an old problem of bioenergetics
Biochim. Biophys. Acta
Does food restriction retard ageing by reducing metabolic rate
J. Nutr.
Energy restriction reduces metabolic rate in adult male Fisher-344 rats
J. Nutr.
Energy restriction and metabolic rate
J. Nutr.
Anti-lipoperoxidation action of food restriction
Biochem. Biophys. Res. Commun.
Effect of chronic food restriction in ageing rats. Part I. Liver subcellular membranes
Mech. Ageing Dev.
Effect of chronic food restriction in ageing rats. Part II. Liver cytosolic antioxidants and related enzymes
Mech. Ageing Dev.
Fatty acid composition of adipose tissue in aged rats—effects of dietary restriction and exercise
Exp. Gerontol.
Modulation of age-related alterations in membrane composition and receptor-associated immune functions by food restriction in Fischer-344 rats
Mech. Ageing Dev.
Mitochondrial membrane peroxidizability index is inversely related to maximum life-span in mammals
J. Lipid Res.
Effect of age and caloric restriction on insulin receptor binding and glucose transporter levels in ageing rats
Exp. Gerontol.
Long-term food restriction depresses serum thyroid hormone concentrations in the rat
Mech. Ageing Dev.
Cardiolipins and biomembrane function
Biochim. Biophys. Acta
Energy metabolism in uncoupling protein-3 gene knockout mice
J. Biol. Chem.
Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3
J. Biol. Chem.
Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression
FEBS Lett.
UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged
FEBS Lett.
Expression of uncoupling protein-3 and mitochondrial activity in the transition from hypothyroid to hyperthyroid state in rat skeletal muscle
FEBS Lett.
Cloning and characterization of the 5′-flanking region of the human uncoupling protein-3 (UCP3) gene
Biochem. Biophys. Res. Commun.
Calorie restriction in primates: will it work and how will we know?
J. Am. Geriatr. Soc.
Nutritional influences on ageing of Fischer-344 rats. Part I. Physical, metabolic and longevity characteristics
J. Gerontol.
The rate of free radical production as a determinant of the rate of ageing: evidence from the comparative approach
J. Comp. Physiol. Ser. B
Influence of age, exercise, and dietary restriction on oxidative stress in rats
Ageing Clin. Exp. Res.
Food restriction prevents an age-associated increase in rat liver beta-adrenergic receptors
J. Gerontol.
Cited by (249)
Intermittent fasting favorably modulates adipokines and potentially attenuates atherosclerosis
2023, Biochemical PharmacologyEnergy constraint and compensation: Insights from endurance athletes
2023, Comparative Biochemistry and Physiology -Part A : Molecular and Integrative PhysiologyPhytotherapeutic targeting of the mitochondria in neurodegenerative disorders
2023, Advances in Protein Chemistry and Structural BiologyCaloric restriction increases levels of taurine in the intestine and stimulates taurine uptake by conjugation to glutathione
2021, Journal of Nutritional Biochemistry