Drosophila Flies in the Face of Aging

Drosophila Uber Alles

The invertebrate model organism Drosophila melanogaster has an unparalleled history of contributions to biology. Beginning with the Nobel prize awarded to Thomas Hunt Morgan in 1933 for the discovery of the role of chromosomes in heredity, there have been eight Nobel prizes awarded for research conducted in whole or in part using Drosophila (Figure 1). These discoveries ranged from X-ray mutagenesis to development, olfaction, immune function, and circadian rhythms. In addition to those lauded discoveries, there have been countless other contributions of Drosophila to biology, especially to the study of aging. In 1981, Rose and Charlesworth demonstrated that populations of Drosophila could be selected in the laboratory for increased life span, by selecting for female reproduction at late ages (1,2). Their studies demonstrated that life span is under genetic control and can be manipulated in the laboratory, and this breakthrough ushered in the modern era of aging research and genetics. Since then, Drosophila has been a leading model for the discovery and characterization of specific genes and pathways that affect aging and life span (3), including the role of diet (4), sex differences (5), the microbiome (6), and the mitochondria (7,8). Six reports in this issue of Journals of Gerontology Biological Sciences demonstrate the enduring power of Drosophila for revealing mechanisms of aging and life span, in particular the role of the diet, with implications for future interventions in human health.

Figure 1.

Timeline of Drosophila Nobel prizes and additional Drosophila research milestones. The Nobel prizes were awarded for research conducted entirely or in part using Drosophila (source: http://www.animalresearch.info/en/medical-advances/nobel-prizes/).

Laboratory Evolution and the Diet

Drosophila has played a pioneering role in the study of effects of diet on life span, dating back at least to 1917 and the studies of Loeb and Northrop (9). Dietary restriction (DR), which involves a reduction in total calories or a reduction in a specific dietary component such as protein, has emerged as a robust aging and life-span intervention across species, including Drosophila (10). Studies in Drosophila have been key in applying the concept of nutritional geometry to studies of aging and DR, including the importance of the ratio of protein to carbohydrate (4,11,12).

One long-standing hypothesis for how DR increases life span is that DR causes a redirection of resources away from reproduction towards somatic maintenance pathways that favor longevity. In their report in this issue, Zajitschek et al. (13) characterize Drosophila populations that were selected over 50 generations on diets with varying amounts of protein. They find limited correspondence between the evolution of female life span and reproduction (as measured by number of eggs laid) across the different dietary regimes, and they suggest this result argues against the prevailing model for DR life-span effects.

Diet Interactions With the Microbiome and Intestinal Stem Cells

Mammalian intestinal stem cells have been extensively studied for over three decades (14); however, their scarcity and isolated location in the intestinal crypts makes their analysis challenging. In 2006, two groups, Ohlstein and Spradling (15) and Micchelli and Perrimon (16), identified stem cells in the Drosophila midgut. Since then, Drosophila has become a leading model system for the study of interactions of intestinal stem cells with the diet and with the gut microbiome (17). During normal aging, the Drosophila intestinal stem cells hyperproliferate and produce mis-differentiated daughter cells, coincident with a disruption of normal gut structure called intestinal dysplasia (18). Both normal and pathogenic bacteria, as well as nutritional stress, can signal Drosophila intestinal stem cell division through activation of a EGFR/MAPK stress-response pathway (19). In a pioneering study in 1969, Bakula showed that a Bacillus species is a commensal of Drosophila, and that it is able to promote Drosophila larval development (20). Since then, the Drosophila microbiome has been shown to have similarities to the human microbiome, and to be important in the regulation of intestinal stem cell proliferation, metabolism, and life span (6).

There is great interest in identifying dietary supplements that might favor human gastrointestinal health. Because of the similarities in gut biology and microbiome between Drosophila and human, Drosophila can be useful for screening dietary supplements and studying their mechanisms. Glucomannan is a water-soluble polysaccharide derived from plants, that is used as a human food additive and as a dietary fiber supplement. Glucomannan has been reported to have health benefits in humans, including reducing cholesterol levels (21); however, possible effects on life span were previously unknown. In their study in this issue, Si et al. (22) show that in Drosophila, dietary glucomannan increases life span and reduces age-associated gut dysplasia and the expression of genes in the EGFR/MAPK and JAK/STAT stress-response pathways. Surprisingly, glucomannan also increased bacterial load and the innate immune response in the aging flies—markers that are sometimes thought to be negative. The results suggest glucomannan increases life span through favorable effects on intestinal stem cell proliferative homeostasis, perhaps involving increased abundance of beneficial microbes.

Diet Interactions With Metabolism and the Mitochondria

The complete Drosophila genome sequence was reported in 2000 (23), providing a methodological roadmap for the subsequent sequencing of the human genome in 2001 (24). These studies revealed that the majority of genes are conserved between Drosophila and human, including the majority of human disease genes. Because of this conservation, Drosophila is often used to decipher the mechanism for genes whose precise functions have eluded us in the human.

Prominin-1 (CD133) is a pentaspan transmembrane protein that marks mammalian stem cells. It is also one of the most commonly used markers for cancer stem cells, and is of great interest as a potential anti-cancer target (25). The subcellular localization of Prominin-1 suggests a possible role in cell membrane organization, but the precise functions of Prominin-1 have remained unclear. As described in this issue, Ryu et al. (26) generated null mutations of the related Drosophila gene prominin-like, and found that the mutant flies had decreased expression of insulin-like peptides and increased life span. RNAi knockdown of prominin-like in the insulin-producing cells (IPCs) of the adult brain recapitulated these effects, consistent with the conclusion that prominin-like regulates Drosophila life span by regulating insulin-like signaling, thereby providing insight into the functions of this conserved gene family.

Pioneering studies of Drosophila by Miquel and coworkers in the 1970s showed that aging is associated with the accumulation of damaged and abnormal mitochondria (27,28). Since then, mitochondrial maintenance failure has been found to be a common feature of aging across species, including Drosophila and humans (7). The Parkin gene was first identified in humans by mutations that predisposed individuals to Parkinson’s disease (PD) (29). Subsequent studies in Drosophila were key in determining that Parkin plays a critical role in mitochondrial maintenance. Treatments for PD are limited, and identifying a potential dietary intervention would be of great interest. In their study in this issue, Bajracharya et al. (30) utilize a parkin-null mutant strain of Drosophila, and determine that stearic acid supplementation of a diet with high protein-to-carbohydrate ratio can partly rescue mitochondrial and physiological function. The authors suggest that the protein-to-carbohydrate ratio and stearic acid may influence levels of bound fatty acids, and that fatty acid breakdown products might interact with mitochondrial membranes to improve function in parkin mutant flies. These results provide insight into possible future dietary interventions for PD.

Diet Interactions With the Mitochondria and Sex

There is increasing appreciation of the role of sex differences in the regulation of aging and life span across species (5,7), including sex-specific life-span effects of conserved mitochondrial regulatory factors such as p53 and Foxo. The maternal-only transmission of mitochondria to offspring is expected to result in greater negative effects of mitochondrial alleles in males than in females (the Frank and Hurst hypothesis (31)), and experimental support for this hypothesis has been reported for Drosophila (32,33). In their study in this issue, Nagarajan-Radha et al. (34) assay life span of a panel of Drosophila strains that differ only in their mitochondrial genotype, using two isocaloric diets that differ in the protein-to-carbohydrate ratio. They report that the mitochondrial genotype affected life span in both sexes, and that the pattern of life-span effects differed according to diet in males but not in females. The results support emerging evidence that the mitochondrial genotype regulates life span in response to diet, and provide further insight into sex differences (or lack thereof) in the effects of mitochondrial alleles.

Transgenerational Obesity

The current world-wide obesity epidemic has significant negative impacts on society, health, and quality of life. In their timely review article in this issue, Carter et al. (35) point out that the number of humans that are overweight now exceeds the number of humans that suffer from starvation. Importantly, not only does obesity negatively impact the health of the obese individual in terms of life span, cancer, and inflammatory diseases, it also has negative effects on offspring and grand-offspring (intergenerational effects). Carter et al. review studies in humans, rodents, and Drosophila that investigate how maternal (and sometime paternal) diet can affect subsequent generations. The data suggest that transmitted markers including DNA methylation, histone modifications, and maternal factors such as regulatory RNAs can affect metabolic regulatory pathways in the subsequent generations, including TOR and insulin-like nutrient-sensing pathways.

Conclusions

Drosophila has an extraordinary history of contributions to biology and to aging research. The six papers in this issue demonstrate that the pace of aging research using Drosophila continues to accelerate. The studies make use of the conservation of genes and physiology between Drosophila and human, and leverage the tractability of Drosophila for manipulating the diet and the genotype. The results illustrate the critical role of diet, including diet interactions with sex, mitochondria, stem cells, and the microbiome, and inform on possible future dietary interventions in human health. It seems likely that Drosophila will continue to lead in biology and aging research for some time to come.

Funding

This work was supported by a grant to JT from the Department of Health and Human Services, National Institutes of Health (NIH), National Institute on Aging (AG057741).

Conflicts of Interest

None reported.