Dietary composition specifies consumption, obesity, and lifespan in Drosophila melanogaster

The inability to properly balance energy intake and expenditure with nutrient supply forms the basis for some of today's most pressing health issues, including diabetes and obesity. Mechanisms of nutrient homeostasis may also lie at the root of dietary restriction, a manipulation whereby reduced nutrient availability extends lifespan and ameliorates age-related deteriorations in many species. The traditional belief that the most important aspect of the diet is its energetic (i.e. caloric) content is currently under scrutiny. Hypotheses that focus on diet composition and highlight more subtle characteristics are beginning to emerge. Using Drosophila melanogaster , we asked whether diet composition alone, independent of its caloric content, was sufficient to impact behavior, physiology, and lifespan. We found that providing flies with a yeast-rich diet produced lean, reproductively competent animals with reduced feeding rates. Excess dietary sugar, on the other hand, promoted obesity, which was magnified during aging. Addition of dietary yeast often limited or reversed the phenotypic changes associated with increased dietary sugar and vice versa, and dietary imbalance was associated with reduced lifespan. Our data reveal that diet composition, alone and in combination with overall caloric intake, modulates lifespan, consumption, and fat deposition in flies, and they provide a useful foundation for dissecting the underlying genetic mechanisms that link specific nutrients with important aspects of general health and longevity.     

Sex-specific fitness effects of nutrient intake on reproduction and lifespan

Diet affects both lifespan and reproduction [1-9], leading to the prediction that the contrasting reproductive strategies of the sexes should result in sex-specific effects of nutrition on fitness and longevity [6, 10] and favor different patterns of nutrient intake in males and females. However, males and females share most of their genome and intralocus sexual conflict may prevent sex-specific diet optimization. We show that both male and female longevity were maximized on a high-carbohydrate low-protein diet in field crickets Teleogryllus commodus, but male and female lifetime reproductive performances were maximized in markedly different parts of the nutrient intake landscape. Given a choice, crickets exhibited sex-specific dietary preference in the direction that increases reproductive performance, but this sexual dimorphism in preference was incomplete, with both sexes displaced from the optimum diet for lifetime reproduction. Sexes are, therefore, constrained in their ability to reach their sex-specific dietary optima by the shared biology of diet choice. Our data suggest that sex-specific selection has thus far failed fully to resolve intralocus sexual conflict over diet optimization. Such conflict may be an important factor linking nutrition and reproduction to lifespan and aging.     

The growth hormone receptor gene‐disrupted mouse fails to respond to an intermittent fasting diet

The interaction of longevity‐conferring genes with longevity‐conferring diets is poorly understood. The growth hormone receptor gene‐disrupted (GHR‐KO) mouse is long lived; and this longevity is not responsive to 30% caloric restriction, in contrast to wild‐type animals from the same strain. To determine whether this may have been limited to a particular level of dietary restriction, we subjected GHR‐KO mice to a different dietary restriction regimen, an intermittent fasting diet. The intermittent fasting diet increased the survivorship and improved insulin sensitivity of normal males, but failed to affect either parameter in GHR‐KO mice. From the results of two paradigms of dietary restriction, we postulate that GHR‐KO mice would be resistant to any manner of dietary restriction; potentially due to their inability to further enhance insulin sensitivity. Insulin sensitivity may be a mechanism and/or a marker of the lifespan extending potential of an intervention.     

Ant workers die young and colonies collapse when fed a high-protein diet

A key determinant of the relationship between diet and longevity is the balance of protein and carbohydrate in the diet. Eating excess protein relative to carbohydrate shortens lifespan in solitary insects. Here, we investigated the link between high-protein diet and longevity, both at the level of individual ants and colonies in black garden ants, Lasius niger. We explored how lifespan was affected by the dietary protein-to-carbohydrate ratio and the duration of exposure to a high-protein diet. We show that (i) restriction to high-protein, low-carbohydrate diets decreased worker lifespan by up to 10-fold; (ii) reduction in lifespan on such diets was mainly due to elevated intake of protein rather than lack of carbohydrate; and (iii) only one day of exposure to a high-protein diet had dire consequences for workers and the colony, reducing population size by more than 20 per cent.     

The role of lipid metabolism in aging,lifespan regulation,and age‐related disease

An emerging body of data suggests that lipid metabolism has an important role to play in the aging process. Indeed, a plethora of dietary, pharmacological, genetic, and surgical lipid‐related interventions extend lifespan in nematodes, fruit flies, mice, and rats. For example, the impairment of genes involved in ceramide and sphingolipid synthesis extends lifespan in both worms and flies. The overexpression of fatty acid amide hydrolase or lysosomal lipase prolongs life in Caenorhabditis elegans, while the overexpression of diacylglycerol lipase enhances longevity in both C. elegans and Drosophila melanogaster. The surgical removal of adipose tissue extends lifespan in rats, and increased expression of apolipoprotein D enhances survival in both flies and mice. Mouse lifespan can be additionally extended by the genetic deletion of diacylglycerol acyltransferase 1, treatment with the steroid 17‐α‐estradiol, or a ketogenic diet. Moreover, deletion of the phospholipase A2 receptor improves various healthspan parameters in a progeria mouse model. Genome‐wide association studies have found several lipid‐related variants to be associated with human aging. For example, the epsilon 2 and epsilon 4 alleles of apolipoprotein E are associated with extreme longevity and late‐onset neurodegenerative disease, respectively. In humans, blood triglyceride levels tend to increase, while blood lysophosphatidylcholine levels tend to decrease with age. Specific sphingolipid and phospholipid blood profiles have also been shown to change with age and are associated with exceptional human longevity. These data suggest that lipid‐related interventions may improve human healthspan and that blood lipids likely represent a rich source of human aging biomarkers.     

Drosophila melanogaster as a model system for the evaluation of anti-aging compounds

Understanding the causes of aging is a complex problem due to the multiple factors that influence aging, which include genetics, environment, metabolism and reproduction, among others. These multiple factors create logistical difficulties in the evaluation of anti-aging agents. There is a need for good model systems to evaluate potential anti-aging compounds. The model systems used should represent the complexities of aging in humans, so that the findings may be extrapolated to human studies, but they should also present an opportunity to minimize the variables so that the experimental results can be accurately interpreted. In addition to positively affecting lifespan, the impact of the compound on the physiologic confounders of aging, including fecundity and the health span-the period of life where an organism is generally healthy and free from serious or chronic illness-of the model organism needs to be evaluated. Fecundity is considered a major confounder of aging in fruit flies. It is well established that female flies that are exposed to toxic substances typically reduce their dietary intake and their reproductive output and display an artifactual lifespan extension. As a result, drugs that achieve longevity benefits by reducing fecundity as a result of diminished food intake are probably not useful candidates for eventual treatment of aging in humans and should be eliminated during the screening process.     

High calorie diet augments age-associated sleep impairment in Drosophila

The fruit fly, Drosophila melanogaster is an established model used for aging and longevity studies and more recently for sleep studies. Mammals and Drosophila share various physiological, pathological, pharmacological and genetic similarities in these processes. In particular, sleep is essential for survival in both species and both have age-associated sleep quality alterations. Here we report that a high calorie diet, which accelerates the aging process and reduces lifespan across species, also accelerates age-associated sleep changes in Drosophila. These changes are more evident in the dopamine transporter mutant, fumin, that displays a short sleep phenotype due to enhanced dopaminergic signaling. With normal food, fumin mutants sleep for only one third of the time that the control flies do, but still show equivalent longevity. However, when on a mildly high calorie diet, their sleep length shows a marked decrease and they have a reduced longevity. These data indicate that the age-associated change in sleep in Drosophila is a physiologically regulated aging process that is tightly linked to calorie intake and that the dopamine level plays an important role. In addition, this provides another evidence that sleep is essential for the longevity of Drosophila.     

Dietary fat composition influences glomerular and proximal convoluted tubule cell structure and autophagic processes in kidneys from calorie‐restricted mice

Calorie restriction (CR) has been repeatedly shown to prevent cancer, diabetes, hypertension, and other age‐related diseases in a wide range of animals, including non‐human primates and humans. In rodents, CR also increases lifespan and is a powerful tool for studying the aging process. Recently, it has been reported in mice that dietary fat plays an important role in determining lifespan extension with 40% CR. In these conditions, animals fed lard as dietary fat showed an increased longevity compared with mice fed soybean or fish oils. In this paper, we study the effect of these dietary fats on structural and physiological parameters of kidney from mice maintained on 40% CR for 6 and 18 months. Analyses were performed using quantitative electron microcopy techniques and protein expression in Western blots. CR mitigated most of the analyzed age‐related parameters in kidney, such as glomerular basement membrane thickness, mitochondrial mass in convoluted proximal tubules and autophagic markers in renal homogenates. The lard group showed improved preservation of several renal structures with aging when compared to the other CR diet groups. These results indicate that dietary fat modulates renal structure and function in CR mice and plays an essential role in the determination of health span in rodents.     

The role of insulin-like signalling in the regulation of ageing

Inactivation of insulin-like growth factor I (IGF-I) signalling pathways have been shown to extend lifespans in various lower species, including the nematode Caenorhabditis elegans. In order to investigate this relationship in a mammalian species, a series of experiments were carried out with a mouse model heterozygous for a mutation in the IGF-I receptor gene. These heterozygous mice only had slight post-natal growth retardation, but had a lifespan 26% longer than normal. Their fertility and dietary intake were unaffected. The mechanism for increased lifespan in these mutant mice appears to be enhanced resistance to oxidative stress: heterozygous mice had a greater survival rate subsequent to severe oxidative stress generated in vivo than wild-type mice, and cells from heterozygous animals had a better resistance to hydrogen peroxide in vitro than cells from wild-type animals. Resistance to oxidative stress in these mutant animals could be caused by decreased phosphorylation of molecules downstream of the IGF-I receptor in the IGF-I signalling pathway, one of which is thought to be p66shc. Whether this link between reduced IGF-I signalling and longevity is conserved in other mammalian species, including humans, is presently not known. If it was, it could have implications for growth hormone therapy, which increases serum IGF-I levels.     

Contributions of juvenile and adult diet to the lifetime reproductive success and lifespan of a spider

Food availability can vary widely for animals in nature and can have large effects on growth, reproduction and survival. While the consequences of food limitation for animals have been extensively studied, significant questions still remain including how ontogenetic variation in food availability contributes to lifetime reproductive success. We tested the effects of juvenile and adult food limitation on the lifetime reproductive success and lifespan of bridge spiders, Larinioides sclopetarius. Food availability was manipulated (low or high) over the entire juvenile and adult stage in a full‐factorial design and reproductive output and lifespan were measured. Juvenile and adult food limitation both reduced lifetime egg and hatchling production with effect sizes that were not significantly different from each other. Unlike some other arthropods, where juvenile food limitation reduces fecundity by reducing adult body size, body size was not affected by juvenile diet in bridge spiders. Clutch size was also significantly reduced by both juvenile and adult food limitation. The effect of adult diet on clutch size was stronger than that of juvenile diet. Juvenile and adult food limitation both extended total lifespan, and adult food limitation extended adult longevity (i.e. time from maturation to death). However, juvenile food limitation decreased adult longevity, in contrast to what would be predicted by dietary or caloric restriction. Compensatory feeding and growth are widely recognized mechanisms through which animals can ameliorate some of the negative effects of periods of food limitation. Yet our results combined with studies of a range of other species suggest that there may be lasting consequences of juvenile food limitation on lifetime reproductive success that cannot be compensated for by adult feeding in some species.     

Having it all: historical energy intakes do not generate the anticipated trade-offs in fecundity

An axiom of life-history theory, and fundamental to our understanding of ageing, is that animals must trade-off their allocation of resources since energy and nutrients are limited. Therefore, animals cannot "have it all"--combine high rates of fecundity with extended lifespans. The idea of life-history trade-offs was recently challenged by the discovery that ageing may be governed by a small subset of molecular processes independent of fitness. We tested the "trade-off" and "having it all" theories by examining the fecundities of C57BL/6J mice placed onto four different dietary treatments that generated caloric intakes from -21 to +8.6% of controls. We predicted body fat would be deposited in relation to caloric intake. Excessive body fat is known to cause co-morbidities that shorten lifespan, while caloric restriction enhances somatic protection and increases longevity. The trade-off model predicts that increased fat would be tolerated because reproductive gain offsets shortened longevity, while animals on a restricted intake would sacrifice reproduction for lifespan extension. The responses of body fat to treatments followed our expectations, however, there was a negative relationship between reproductive performance (fecundity, litter mass) and historical intake/body fat. Our dietary restricted animals had lower protein oxidative damage and appeared able to combine life-history traits in a manner contrary to traditional expectations by having increased fecundity with the potential to have extended lifespans.     

Behavioral, physical, and demographic changes in Drosophila populations through dietary restriction

Dietary restriction (DR) is a valuable experimental tool for studying the aging process. Primary advancement of research in this area has relied on rodent models, but attention has recently turned toward Drosophila melanogaster. However, little is known about the baseline effects of DR on wild-type Drosophila and continued experimentation requires such information. The findings described here survey the effects of DR on inbred, wild-type populations of Canton-S fruit flies and demonstrate a robust effect of diet on longevity. Over a circumscribed range of dietary conditions, healthy lifespan varies by as much as 121% for wild-type Drosophila females. Significant differences are also observed for male flies, but the magnitude of the DR effect is less robust. Mortality analyses of the survivorship data reveal that this variation in lifespan can be attributed to a modulation of the rate parameter for the mortality function - a change in the demographic rate of aging. Since the feeding of fruit flies is less easily controlled than that of rodents, this research also addresses the validity of applying a DR model to Drosophila populations. Feeding and body weight data for flies given the various dietary conditions surveyed indicate that Drosophila on higher-calorie diets consume a similar volume of food to those on a low-calorie diet, resulting in different levels of calorie intake. Fertility and activity levels demonstrate that the diets surveyed are comparable, and that increasing the calorie content of laboratory food up to twice the normal concentration is not pathologic for experimental fly populations.     

Caenorhabditis elegans integrates food and reproductive signals in lifespan determination

Dietary restriction extends lifespan and inhibits reproduction in many species. In Caenorhabditis elegans, inhibiting reproduction by germline removal extends lifespan. Therefore, we asked whether the effect of dietary restriction on lifespan might proceed via changes in the activity of the germline. We found that dietary restriction could increase the lifespan of animals lacking the entire reproductive system. Thus, dietary restriction can extend lifespan independently of any reproductive input. However, dietary restriction produced little or no increase in the long lifespan of animals that lack germ cells. Thus, germline removal and dietary restriction may potentially activate lifespan-extending pathways that ultimately converge on the same downstream longevity mechanisms. In well-fed animals, the somatic reproductive tissues are generally completely required for germline removal to extend lifespan. We found that this was not the case in animals subjected to dietary restriction. In addition, in these animals, loss of the germline could either further lengthen lifespan or shorten lifespan, depending on the genetic background. Thus, nutrient levels play an important role in determining how the reproductive system influences longevity.     

Independent chemical regulation of health and senescent spans in Drosophila

Curcumin feeding of Drosophila larvae or young adults inhibits TOR and other known longevity genes and induces an extended health span in a normal-lived Ra strain adult. Combining larval curcumin feeding with an adult dietary restriction (DR) diet does not yield an additive effect. The age-specific mortality rate is decreased and is comparable with that of genetically selected long-lived La animals. Feeding Ra adults with the drug their whole life, or only during the senescent span, results in a weak negative effect on median longevity with no increase in maximum lifespan. The La strain shows no response to this DR mimetic. Thus, curcumin acts in a life stage-specific manner to extend the health span. Histone deacetylase inhibitors decrease the longevity of Ra animals if administered over the health span only or over the entire adult lifespan, but these inhibitors increase longevity when administered in the transition or senescent spans. Their major effect is a reduction in the mortality rate of older flies, raising the possibility of reducing frailty in older organisms. Their life stage-specific effects are complementary to that of curcumin. Use of stage-specific drugs may enable targeted increases in health or senescent spans, and thus selectively increase the quality of life.     

Cholesterol and copper in the liver of rabbit inbred strains with differences in dietary cholesterol response

In order to investigate whether cholesterol intake influences the hepatic copper content of rabbits, we compared the hepatic copper content of two rabbit inbred strains after feeding the animals a control or a cholesterol-rich diet. One strain was not reactive to dietary cholesterol (IIIVO/JU), whereas the other strain was reactive to dietary cholesterol (AX/JU). The coefficient of inbreeding (F) >0.95 for both strains. Dietary cholesterol-reactive rabbits when compared with their non-reactive counterparts had a higher hepatic copper content. The consumption of a hypercholesterolemic diet decreased liver copper concentration (expressed in micro g/g dry weight) in both strains of rabbits, which was (in part) due to dietary-induced hepatomegaly. A decrease in the absolute hepatic copper content was found only in the dietary cholesterol-reactive inbred strain. It is discussed that differences in glucocorticoid levels may be responsible for the strain difference in liver copper content. The cholesterol effect on the hepatic copper content in the reactive strain might be caused by an increased bilirubin secretion.     

New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen

Most of our knowledge about the regulation of aging comes from mutants originally isolated for other phenotypes. To ask whether our current view of aging has been affected by selection bias, and to deepen our understanding of known longevity pathways, we screened a genomic Caenorhabditis elegans RNAi library for clones that extend lifespan. We identified 23 new longevity genes affecting signal transduction, the stress response, gene expression, and metabolism and assigned these genes to specific longevity pathways. Our most important findings are (i) that dietary restriction extends C. elegans' lifespan by down-regulating expression of key genes, including a gene required for methylation of many macromolecules, (ii) that integrin signaling is likely to play a general, evolutionarily conserved role in lifespan regulation, and (iii) that specific lipophilic hormones may influence lifespan in a DAF-16/FOXO-dependent fashion. Surprisingly, of the new genes that have conserved sequence domains, only one could not be associated with a known longevity pathway. Thus, our current view of the genetics of aging has probably not been distorted substantially by selection bias.     

Effects of nutritional components on aging

Nutrients including carbohydrates, proteins, lipids, vitamins, and minerals regulate various physiological processes and are essential for the survival of organisms. Reduced overall caloric intake delays aging in various organisms. However, the role of each nutritional component in the regulation of lifespan is not well established. In this review, we describe recent studies focused on the regulatory role of each type of nutrient in aging. Moreover, we will discuss how the amount or composition of each nutritional component may influence longevity or health in humans.