Dietary restriction, mortality trajectories, risk and damage

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Abstract

Restriction of food intake extends lifespan in evolutionarily diverse organisms, including mammals. Dietary restriction (DR) also delays the appearance of ageing-related damage and pathology and keeps organisms in a youthful state for longer. DR has hence been suggested to lower the rate of ageing. Analysis of mortality rates can be used to test this idea. During ageing, mortality rates in general increase, approximately exponentially. Lifespan can be extended either by a reduction in the rate of increase in mortality rate with age or a lowering of the initial rate of mortality. A reduction in the slope of a mortality trajectory has generally been taken to indicate that the rate of ageing has been lowered. Data on the effects of temperature on mortality in Drosophila are in accordance with this idea. Lowered temperature extends lifespan solely by lowering the slope of the mortality trajectory and flies with a hotter thermal history have permanently elevated death rates. In contrast, lowering of the initial rate of mortality has been taken to leave the rate of ageing unaffected. In Drosophila and in mice, but not in rats, DR extends lifespan by lowering the initial mortality rate. In Drosophila, the effect of DR is acute, and mortality rate switches rapidly between DR and control values with the corresponding changes in nutritional regime. DR in Drosophila therefore has no impact upon the rate of ageing. Possible mechanisms by which DR can both delay damage and pathology and yet act acutely to determine mortality rates are discussed. In rodents, some phenotypes associated with DR, including microarray profiles, show rapid switching with changed nutritional regime, pointing to potentially acute effects of DR in mammals.

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.

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