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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online August 19, 2004 as doi:10.1096/fj.03-1464fje. |
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* Department of Biological Sciences, Southern Methodist University, Dallas, Texas, USA;
Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, California, USA
1Correspondence: Department of Biological Sciences, Southern Methodist University, 6501 Airline Road, Dallas, TX 75275, USA. E-mail: borr{at}mail.smu.edu
SPECIFIC AIMS
Restriction of caloric intake, without causing malnutrition, has been reported to prolong life spans in a broad range of phylogenetic groups, ostensibly by regulating basic mechanism(s) of biological aging. The main purpose of this study was to test the generality of this phenomenon using an insect model, the housefly, Musca domestica, which is amenable to rigorous control of food intake. The specific objectives of this study were to 1) establish a longevity-promoting food source and 2) determine the effects of caloric restriction on the life span, rate of oxygen consumption, and fertility of male houseflies.
PRINCIPAL FINDINGS
1. Life spans of houseflies fed different diets
This set of experiments was designed to investigate the survival times of houseflies fed different types of food, so that a longevity-promoting food source could be identified to test the effects of caloric restriction. Flies were fed: sucrose (diet i), glucose (diet ii), fructose (diet iii), trehalose (either anhydrous or trehalose dihydrate, diet iv), and mixtures of sucrose, powdered skim milk, and dried whole egg (either 6:6:1 by volume, diet v; 6:6:1 enriched with 6 volumes of powdered whey protein, diet vi; or 80:17:3 by weight, diet vii). The 6:6:1 ratio is normally provided to houseflies in breeder cages to ensure high fertility, while the 80:17:3 ratio was selected on the basis of amounts eaten in a pilot study, during which flies were given access to each component of the mixture in a separate container. The life span of flies fed sucrose alone was longer than the life spans of flies fed diets also containing proteins and/or lipids (Fig. 1
), or any other food source except fructose, which neither consistently increased nor decreased longevity.
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2. Effects of caloric restriction on life span and senescence in male houseflies
To determine the relationship between caloric intake and life span, adult flies were administered sucrose ad libitum (AL), 100%, 90%, 80%, 70%, 60%, or 50%, beginning at 4 days of age. The amount designated 100% was the mean weight of sucrose consumed per day, during the 3–4 days before caloric restriction was initiated. The respective mean life spans of these groups were 34.0, 29.1, 26.8, 26.2, 24.6, 24.5, and 11.3 days. The AL group lived longest (both mean and maximum life span), while caloric restriction progressively shortened the life span of male houseflies (Fig. 2
). Caloric restriction also shortened or failed to increase the life spans of flies fed a complex diet containing powdered milk and egg in addition to sucrose.
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A study was also conducted to investigate the effects of caloric restriction on the proportion of flies entering a senescent, flightless state prior to death. This proportion declined progressively as the severity of caloric restriction was increased and the mean life span decreased, suggesting that the proximate cause of death in CR flies was insufficient food intake rather than acceleration of the normal aging process.
3. Effects of caloric restriction on the rate of oxygen consumption and male fertility
This study was conducted to determine whether the relatively longer life spans of flies fed AL could be accounted for by a decrease in metabolic rate. AL flies were compared with those given 75% of the normal amount of sucrose consumed during the first 3–4 days of adult life (CR). Measurements were made at six different ages, ranging from 4–18 days. There was no consistent difference in the rate of oxygen consumption between AL and CR flies. Thus, the life-shortening effects of CR were not mitigated by compensatory alterations in the rate of metabolism. A related question was whether the longer life spans of male flies fed sucrose could arise as a "trade-off" effect involving decreased reproductive ability. Sucrose feeding did not compromise the ability of male houseflies to sire a fertile progeny.
A schematic overview of the principal findings, implications, and conclusions of this study is presented in Fig. 3
.
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CONCLUSIONS AND SIGNIFICANCE
Caloric restriction failed to extend the life span of male houseflies fed sucrose, which promoted a longer life span than diets also containing proteins and/or lipids. Calorically restricted flies exhibited a progressively shorter life span with increasing severity of CR. There was little or no beneficial effect of CR when the diet contained sources of protein and lipids, although the life-shortening effect of CR was most pronounced on the sucrose diet.
Results of previous studies indicate that caloric restriction extends the life spans of a broad range of species; however, the present finding that the life span of houseflies is shortened by decreased food intake indicates that the life-extending effects of caloric restriction are not universal. In particular, the present results are seemingly inconsistent with those reported in a closely-related insect species, the fruit fly, Drosophila melanogaster. A careful examination of the findings in Drosophila raises questions about the purported beneficial effects of CR in that species. Caloric restriction in Drosophila was administered by altering the concentrations of glucose and yeast in the medium, and no attempt was made to ascertain the actual amount of food consumed by the flies. Dilution of nutrients in the food medium does not ensure that the flies are calorically restricted, because they might compensate by increasing their food intake, thereby consuming an equivalent number of calories as flies on nutrient-rich food. Altering the composition of the food could also affect its texture, or stickiness, leading to differences in mortality unrelated to the caloric intake.
A related consideration in the studies of CR in Drosophila is that the higher concentrations of glucose and yeast in the control medium could plausibly facilitate more rapid bacterial proliferation, which could contribute to premature death. This conjecture is consistent with the high incidence of early adult mortality in the Drosophila studies. Furthermore, one of the most dramatic age-related changes reported in these flies was an increase in transcription of genes associated with the detection of and response to microbes, particularly bacteria, leading the authors to conclude that infection was a primary cause of death in laboratory cultures of Drosophila. The life span of the control flies was 25.4 days, which is half of the normal value reported by some of the same authors, using flies in the same genetic background. Indeed, Drosophila cohorts with longer control life spans exhibited a maximum of only 10% extension of life span by CR vs. >80% extension in the study with short life spans. The apparent discrepancy between findings in Musca and Drosophila may have arisen because restriction of caloric intake was inferred but not rigorously documented in Drosophila, and the experimental design may have resulted in artificial shortening of the life spans of control flies. The effect observed in Musca, using strictly controlled intake of a homogenous and longevity-promoting food source, suggests that caloric restriction causes starvation and decreases the life span of insects.
Results obtained in this study suggest a possible explanation for the contrasting effects of CR in flies and rodent species. A well recognized feature of calorically restricted rodents is the decrease in their body temperature, which is suggestive of a slowing of the metabolic rate. A large body of field studies indicates that decreased availability of food results in a depressed rate of metabolism in feral rodents, ostensibly contributing to their survival under adverse conditions. In contrast, the present finding that the rate of oxygen consumption of calorically restricted flies remains comparable to that of AL-fed flies suggests that houseflies are unable to adjust their metabolic rate in response to changes in the availability of food. Caloric restriction appears to be associated with increased life spans only in species where it induces an alteration of the metabolic rate, suggesting that such metabolic adaptability is a key causal factor in the extension of life span by CR.
FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-1464fje;
This article has been cited by other articles:
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  J. R. Speakman and C. Hambly Starving for Life: What Animal Studies Can and Cannot Tell Us about the Use of Caloric Restriction to Prolong Human Lifespan J. Nutr., April 1, 2007; 137(4): 1078 - 1086. [Abstract] [Full Text] [PDF]
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 M. Leslie Craving an answer. Sci. Aging Knowl. Environ., February 15, 2006; 2006(6): nf7 - nf7. [Abstract] [Full Text]
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