Dietary restriction in Drosophila

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Abstract

The fruit fly Drosophila is a useful organism for the investigation of the mechanisms by which dietary restriction (DR) extends lifespan. Its relatively short generation time, well-characterised molecular biology, genetics and physiology and ease of handling for demographic analysis are all major strengths. Lifespan has been extended by DR applied to adult Drosophila, by restriction of the availability of live yeast or by co-ordinate dilution of the whole food medium. Lifespan increases to a maximum through DR with a progressive dilution of the food and then decreases through starvation as the food is diluted further. Daily and lifetime fecundities of females are reduced by food dilution throughout the DR and starvation range. Standard Drosophila food ingredients differ greatly between laboratories and fly stocks can differ in their responses to food dilution, and a full range of food concentrations should therefore be investigated when examining the response to DR. Flies do not alter the time that they spend feeding in response to DR. Both mean and maximum lifespan are extended by DR. The nutrients critical for the response to DR in Drosophila require definition. The extension of lifespan in response to DR is very much greater in females than in males. Two nutrient-sensing pathways, the insulin/IGF-like and TOR pathways, have been implicated in mediating this response of lifespan to DR in Drosophila, as have two protein deacetylases, dSir2 and Rpd3, although the precise nature of this interaction remain to be characterised. Although female fecundity is reduced by DR, the response of lifespan to DR appears normal in sterile females, possibly implying that reduced fecundity is not necessary for extension of lifespan by DR. There is no reduction in metabolic rate or in the rate of generation of superoxide and hydrogen peroxide from isolated mitochondria in response to DR. DR acts acutely and rapidly (within 48 h) to reduce the mortality of flies that are fully fed to the level found in animals exposed to DR throughout life. This rapid mortality rate recovery provides a powerful framework within which to further investigate the mechanisms by which DR extends lifespan.

Introduction

Extension of lifespan by dietary restriction (DR) was first discovered in rodents (McCay et al., 1935), and the phenomenon has been most intensively studied in mice and rats (Chung et al., 2002, Kim et al., 2002, Masoro, 1998, Masoro, 2000, Masoro, 2002, Merry, 2002, Weindruch and Walford, 1988, Yu and Chung, 2001). Reduction of nutrient intake also extends lifespan in diverse invertebrate species and has become the subject of detailed study in model organisms, including the yeast Saccharomyces cerevisiae (Anderson et al., 2003, Jiang et al., 2000, Jiang et al., 2002, Kaeberlein et al., 2004, Lin et al., 2000, Lin et al., 2004, Sinclair, 2005, Guarente, 2005), the nematode worm Caenorhabditis elegans (Houthoofd et al., 2003, Johnson et al., 1990, Klass, 1977, Lakowski and Hekimi, 1998; Walker et al., 2005) and the fruit fly Drosophila melanogaster (Chapman and Partridge, 1996, Chippindale et al., 1993, Partridge et al., 1987). The molecular mechanisms by which DR extends lifespan have not been fully revealed in any organism and it therefore remains unproven that extension of lifespan by DR is accomplished by similar mechanisms in different species. However, the almost universal extension of lifespan by reduced nutrient intake is suggestive of evolutionary conservation. Information on the mechanisms by which DR extends lifespan in these invertebrates is therefore likely to inform our understanding of the process in mammals.

The fruit fly D. melanogaster has many strengths as a model organism for the study of extension of lifespan by DR. Unlike either yeast or C. elegans, but similar to humans, Drosophila is an obligate aerobe, which may have a bearing on the types of ageing-related damage that are accumulated. Drosophila is also an excellent organism for studies of demography, which have been particularly informative about the mechanisms by which DR reduces mortality rate (Mair et al., 2003). The fly has all the usual advantages of a model organism for genetic manipulation and molecular and physiological analysis. It is also dioecious (has separate females and males) and can therefore be used to investigate sex differences in response to DR.

Two important questions about DR in any organism are: (1) What are the mechanisms by which nutrients are sensed and the response to DR initiated and controlled? (2) What forms of adverse physiology, damage or pathology are ameliorated by DR to reduce death rate? In this review, we consider what is known about the response to DR in Drosophila, focusing particularly on these issues. Several studies have examined the effects of pre-adult nutrition on adult lifespan in Drosophila, and found no extension of lifespan with reduction of food supply (e.g. Tu and Tatar, 2003, Zwaan et al., 1991). We therefore confine our attention to the effects of DR that is applied solely during the adult period.

Section snippets

Dietary restriction in Drosophila

Laboratory cultures of Drosophila are maintained on a food medium that consists of nutritional components dissolved or suspended in an agar gel. The precise composition of the food medium varies considerably between different laboratories and medium types, but the usual ingredients include sugar, killed yeast and corn flour or corn meal. In addition, the surface of the food medium can be seeded with live yeast that grows on the nutrient gel and is used as a food supply by Drosophila. DR in

Mechanisms initiating and controlling the response to DR in Drosophila

A basic dichotomy in the way that lifespan might be extended by DR is either through tissue-specific nutrient-sensing followed by neural or endocrine signalling to other sites, or through direct sensing of nutrients by cells throughout the body. In C. elegans, ablation of chemosensory neurons extends lifespan, which could indicate that neural sensing of nutrients is important in the extension of lifespan by DR (Alcedo and Kenyon, 2004, Apfeld and Kenyon, 1999). Work on the role of

The mechanisms by which DR reduces death rate in Drosophila

A notable feature of the response to DR in rodents is that the appearance of multiple forms of ageing-related damage, pathology and disease is delayed, and the animals are maintained in a youthful state for longer (Berrigan et al., 2002, Iwasaki et al., 1988a, Iwasaki et al., 1988b, Masoro, 2002, Weindruch and Walford, 1988). These features make the mechanisms by which DR extends lifespan of compelling interest. However, a major problem in identifying the mechanisms by which DR reduces death

Summary and future directions

Considerable progress has been made in developing robust protocols for extension of lifespan by DR in Drosophila. However, some basic features of the responses of lifespan and fecundity require further definition. Calories per se may not be the critical determinant of the increase in lifespan, and this issue requires exploration. Work with defined diets would help to resolve this and to standardise protocols in different laboratories.

At least two signalling systems, the IIS and TOR pathways,

Acknowledgements

We thank Scott Pletcher for his comments on the MS, two anonymous reviewers for helpful comments, the BBSRC and the Wellcome Trust for financial support and the Rank Prize Fund for providing the impetus for this review.

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