Dietary restriction, mortality trajectories, risk and damage
Introduction
Dietary restriction (DR), the reduction of nutrient intake without malnutrition, was first shown to prolong lifespan in rats in 1935 (McCay et al., 1935). Since then, the effects of DR in rodents have been extensively analysed (Masoro, 1995, Masoro, 1996, Masoro, 1997a, Masoro, 1997b, Masoro, 1998a, Masoro, 1998b, Masoro, 1998c, Masoro, 2000, Masoro, 2001, Yu and Chung, 2001, Chung et al., 2001, Chung et al., 2002, Kim et al., 2002, Merry, 2002, Cho et al., 2003, Lambert and Merry, 2004a, Lambert et al., 2004b, Merry, 2004), and application of DR has been extended to primates, with preliminary results pointing to positive effects on lifespan (Lane et al., 2002, Lane et al., 2004, Mattison et al., 2003). There are also indications of health benefits of DR in humans (Fontana et al., 2004). Reduction of nutrient intake has been shown to extend lifespan in diverse invertebrate organisms, including model organisms: the yeast Saccharomyces cerevisiae (Jiang et al., 2000, Jiang et al., 2002, Anderson et al., 2003, Kaeberlein et al., 2004, Lin et al., 2004), the nematode worm Caenorhabditis elegans (Klass, 1977, Lakowski and Hekimi, 1998, Houthoofd et al., 2003) and the fruit fly Drosophila (Chapman and Partridge, 1996). DR is therefore a candidate for a ‘public’, evolutionarily conserved mechanism through which longevity can be extended. Although it is not yet proven that the molecular mechanisms by which DR extends lifespan are the same in different organisms, the almost universal extension of lifespan by reduced nutrient intake is suggestive of evolutionary conservation of mechanisms.
The ageing process is characterised by an increase in the likelihood of death and a decline in fecundity with advancing age. Some organisms, for instance ones that grow during adulthood, can show an increase in both survival probability and fecundity over part of the adult lifespan. The ageing process is most obvious in organisms such as nematode worms, insects, birds and many mammals, that grow only slightly or not at all once adulthood is reached (Hamilton, 1966, Charlesworth, 1980, Finch, 1990, Vaupel et al., 2004). In these organisms, death rates in general increase approximately exponentially with age during adulthood, although departures from this pattern, such as a slowing down of the rate of increase with age, can occur at late ages (Vaupel et al., 1998). During ageing, there is an increasing incidence of multiple forms of damage and pathology, some or all of which are presumably causal in the decline in organismal function and viability.
Mortality rates during ageing can be described in terms of two important parameters: the initial, baseline mortality rate, which is age-independent, and the rate at which mortality rate increases with age (Finch, 1990). Interventions, genetic and environmental, that increase lifespan can do so by decreasing the baseline mortality rate (i.e. the Gompertz intercept parameter), lowering the rate at which mortality increases with age (the slope of the mortality trajectory) or both (Pletcher et al., 2000). It has been argued that a reduction in the slope of a mortality trajectory as a result of an intervention that extends lifespan indicates that longevity has been increased by a reduction in the rate of ageing itself (Finch, 1990). For instance in Drosophila, the mutants methuselah (Lin et al., 1998) and Indy (Marden et al., 2003), both of which have been shown to increase lifespan, do so by lowering the slope of the mortality trajectory, and have been suggested therefore to reduce the rate of ageing. In contrast, in industrialised human societies worldwide, lifespan has been increasing for over-a-century, entirely by a reduction in initial mortality rates, with no reduction in the slope of the mortality trajectory (Wilmoth, 2000). This lowering of the mortality trajectory has been taken to indicate that overall health at all ages has improved, but that the underlying process of accumulation of ageing-related damage has not been ameliorated.
Dietary restriction (DR) in rodents delays the appearance of ageing-related decline in function and pathology and keeps the animals in a youthful state for longer. Because DR in rodents appears to slow down or delay decline in both viability and health, it has been suggested to slow down the rate of ageing itself (Masoro, 1998a). In the remainder of this paper, we describe some recent findings about the effects of DR on mortality in Drosophila, and discuss their possible implications for the interpretation of mortality trajectories, for the underlying mechanisms by which DR extends lifespan and for the effects of DR on the ageing process in mammals.
Section snippets
Dietary restriction in Drosophila
Dietary restriction (DR) can be applied in Drosophila by dilution of the food medium (Chapman and Partridge, 1996). As food concentration is reduced from a maximum, lifespan increases to a peak under DR, and then declines through starvation with further reduction in nutrients. In contrast, daily and lifetime egg-production of females decreases throughout this concentration range as the food is diluted (Fig. 1). The nutrient level that maximises lifespan is therefore lower than the one that
Risk, damage and lethal endgame
The finding that DR produces an acute reduction in the risk of death while leaving accumulation of ageing-related damage unaffected opens the way to identification of candidate molecular mechanisms, both for the acute response to DR and for ageing-related damage. For instance, RNA expression-profiling of chronic DR and control flies during adulthood (Pletcher et al., 2002) has identified three classes of genes, based on characteristics of their expression profiles: (i) those that changed at the
Implications for the effects of DR in mammals
The relative roles of reduced risk and damage in the extension of lifespan by DR in rodents have not been evaluated. Some studies have reported no extension of lifespan with late-onset DR (Lipman et al., 1995, Lipman et al., 1998, Forster et al., 2003). However, the level of DR needed to optimise lifespan varies for both different sexes (Magwere et al., 2004) and genotypes (Clancy et al., 2002) and it seems likely that the level of the DR regime imposed on old individuals was too severe in
Conclusions and wider implications
The finding that the effects of DR on mortality in Drosophila are mediated by an acute reduction in risk of death, together with the limited existing data from rodents, suggest that the relative contributions of amelioration of risk and ageing-related damage in extension of lifespan by DR in rodents should be properly evaluated. In addition, the finding that the effect of DR can be acute raises the issue of whether the same is true of the effects of mutations that increase lifespan. Directly
Acknowledgements
We thank Matthew D.W. Piper, Brian J. Merry and Aubrey de Grey for stimulating and informative discussion and the BBSRC and the Wellcome Trust for financial support.
References (63)
- et al.
Modulation of glutathione and thioredoxin systems by calorie restriction during the ageing process
Exp. Gerontol.
(2003) - et al.
Effect of age and caloric intake on protein oxidation in different brain regions and on behavioural functions of the mouse
Arch. Biochem. Biophys.
(1996) - et al.
The physiologic, neurologic, and behavioural effects of caloric restriction related to ageing, disease, and environmental factors
Environ. Res.
(1997) The moulding of senescence by natural selection
J. Theor. Biol.
(1966)- et al.
Lifetime breeding success in fully fed and dietary restricted female CFY Sprague–Dawley rats. 1. Effect of age, housing conditions and diet on fecundity
Mech. Ageing Dev.
(1985) - et al.
Life extension via dietary restriction is independent of the Ins/IGF-1 signalling pathway in Caenorhabditis elegans
Exp. Gerontol.
(2003) - et al.
Distinct roles of processes modulated by histone deacetylases Rpd3p, Hdalp, and Sir2p in life extension by caloric restriction in yeast
Exp. Gerontol.
(2002) - et al.
Modulation of redox-sensitive transcription factors by calorie restriction during ageing
Mech. Ageing Dev.
(2002) Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span
Mech. Ageing Dev.
(1977)- et al.
The effect of ageing and caloric restriction on mitochondrial protein density and oxygen consumption
Exp. Gerontol.
(2004)
Exogenous insulin can reverse the effects of caloric restriction on mitochondria
Biochem. Biophys. Res. Commun.
Lifespan extension by dietary restriction in female Drosophila melanogaster is not caused by a reduction in vitellogenesis or ovarian activity
Exp. Gerontol.
Dietary restriction
Exp. Gerontol.
Hormesis and the anti-ageing action of dietary restriction
Exp. Gerontol.
Caloric restriction and ageing: an update
Exp. Gerontol.
Calorie restriction in rhesus monkeys
Exp. Gerontol.
The effect of retarded growth upon the length of life span and upon the ultimate body size
J. Nutr.
Molecular mechanisms linking calorie restriction and longevity
Int. J. Biochem. Cell. Biol.
The effect of reproductive activity on the longevity of male Drosophila melanogaster is not caused by an acceleration of ageing
J. Insect Physiol.
Genome-wide transcript profiles in ageing and calorically restricted Drosophila melanogaster
Curr. Biol.
The retardation of ageing in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake
J. Nutr.
Demography of longevity: past, present, and future trends
Exp. Gerontol.
Yeast life-span extension by calorie restriction is independent of NAD fluctuation
Science
Genomic profiling of short- and long-term caloric restriction effects in the liver of ageing mice
Proc. Natl. Acad. Sci. U.S.A.
Female fitness in Drosophila melanogaster: an interaction between the effect of nutrition and of encounter rate with males
Proc. R Soc. Lond. B Biol. Sci.
Evolution in Age-Structured Populations
The inflammation hypothesis of ageing: molecular modulation by calorie restriction
Ann. NY Acad. Sci.
Molecular inflammation hypothesis of ageing based on the anti-ageing mechanism of calorie restriction
Microsc. Res. Tech.
Dietary restriction in long-lived dwarf flies
Science
Temporal linkage between the phenotypic and genomic responses to caloric restriction
Proc. Natl. Acad. Sci. U.S.A.
Longevity, Senescence and the Genome
Cited by (82)
Metabolic changes may precede proteostatic dysfunction in a Drosophila model of amyloid beta peptide toxicity
2016, Neurobiology of AgingCitation Excerpt :Aging may be considered as the time-dependent accumulation of deficits in protective functions that result in a multisystem syndrome defined by increased fragility and propensity to die (Kirkwood and Austad, 2000; Partridge and Gems, 2002). In many organisms, this produces a log-linear increase in mortality rates with time (Curtsinger et al., 1992; Partridge et al., 2005). In some respects, the gradient of the mortality trajectory may be understood as the rate of physiological aging with chronological time.
Life equations for the senescence process
2015, Biochemistry and Biophysics ReportsCitation Excerpt :A line of evidence has shown that temperature reduction in both poikilotherms and homeotherms extends lifespan [33-40] [34–41]. It was observed that when Drosophila flies were switched from 27 °C to 18 °C environments at various adult ages, the increased mortality driven by life at a higher temperature persisted in the switched flies compared to the 18 °C control flies [39,40], but the subsequent rate of increase in mortality with age at 18 °C was lower than in the flies permanently at 27 °C. To test if the new mortality equation can explain the effect of temperature on lifespan, a simple expression, Eq. (21), for describing the relationship between the average lifespan (LE0) and body temperature was derived from the new mortality rate equation.
A theoretical model of the evolution of actuarial senescence under environmental stress
2015, Experimental GerontologyCitation Excerpt :If correlations among traits are a sufficient constraint on the evolution of multiple stress resistance traits, the model considered here might be appropriate (Cohen et al., 2012), but if there is physiological canalisation or if traits evolve independently, the dramatic effects of the synergistic model might be diminished. Variation in lifespan can, of course, arise through age-independent changes in baseline mortality as well as the ageing component of mortality (Partridge et al., 2005; Simons et al., 2013). Our model framework only considers effects of extrinsic stress on age-dependent mortality, yet baseline mortality may also be sensitive to sources of anthropogenic-induced stress.
How perceived predation risk shapes patterns of aging in water fleas
2015, Experimental GerontologyIntrinsic and extrinsic mortality reunited
2015, Experimental Gerontology