One particular area of research focuses on the phenomenon of dietary restriction, where lifespan is increased by restricting nutrient intake to roughly 65% of what animals would eat when allowed to feed ad libitum. In rodents, dietary restriction maintains most physiological processes in an apparently youthful state, and it delays the occurrence and/or progression of age-associated disease. In work completed during his post-doc in the Partridge lab, Dr. Pletcher described a molecular signature of aging and used it to show that, as it does in mammals, dietary restriction delayed significant changes in gene expression that occur in many different biological processes in the aging animal. He was also involved in work that showed that life-long adherence to a strict dietary restriction regime is not required for flies to experience longevity-extending benefits: as little as two days of diet restriction will suffice.
The traditional belief that the most important aspect of diet is its energetic (i.e., caloric) content is currently under challenge by hypotheses that focus on more subtle characteristics of the diet, such as its nutritional composition. For example, although there is ancillary evidence that certain diets, such as the protein-rich Atkins’ diet, may promote weight loss, the underlying mechanisms for its effect are unknown, as are the medium- and long-term consequences associated with such dietary imbalance. We have shown that in Drosophila, alterations in diet composition affect behavior, metabolism, and lifespan. Providing flies with a diet rich in protein but limiting in carbohydrates produced lean, reproductively-competent animals with a reduced appetite. This is shown in the plot above (left), which details triglyceride levels in adult flies maintained in different dietary conditions. Triglyceride is the main form of lipid storage in flies, and animals ranged from quite fat (red color) to lean (blue color). Excess dietary carbohydrates promoted obesity, which was magnified during aging. Interestingly dietary protein limited or reversed the affect of dietary carbohydrate regardless of its caloric value, and flies fed a balanced diet enjoyed the longest lifespan (notice the red color in the center of the second plot). These data reveal that diet composition, rather than caloric intake, modulates aging, appetite, and fat storage in flies, and we are engaged in studying the underlying genetic mechanisms that link diet with overall health and longevity in this species. We are currently working to understand the molecular mechanisms underlying these dietary effects. Discoveries in the lab include identification of new pathways involved in diet-dependent cellular detoxification and sleep regulation as well as characterization of new genes that may play a key role in nutrient homeostasis.
Recently, we have shown that longevity in general (and diet restriction in particular) is regulated by sensory neurons. In particular, olfaction and food-derived odors modulate fly lifespan. For example, mere exposure to nutrient-derived odorants can partially reverse the longevity-extending effects of dietary restriction. Furthermore, we have shown that mutation of odorant receptor Or83b results in severe olfactory defects, alters adult metabolism, enhances stress resistance, and extends lifespan. The figure on the left uses green fluorescent protein to identify those neurons that are important modulators of lifespan. They are sensory neurons confined to the third segment of the antennae and a pair of structures called the maxillary palps. Our findings indicate that olfaction affects adult physiology and aging in Drosophila possibly through perceived availability of nutritional resources and that olfactory regulation of lifespan is evolutionarily conserved. Currently we are working to dissect the neural circuitry that is important for modulating these effects. Discoveries in the lab include identification of specific neurons that modulate aging and physiology as well as characterization of the role of pheromones and social interactions on aging.
We also use Drosophila as a model for studying the role of inflammatory responses on aging. These processes, which originate from the innate immune system, have been implicated as predictors/initiators of, or contributors to, chronic diseases and conditions of human aging. Mechanisms of innate immunity are highly conserved across species, and work from our laboratory and others has established that flies exhibit remarkable upregulation of innate-immunity-related genes with advancing age. Expression of these genes is dependent on NFk-B like transcription factors, which are also critical mediators of mammalian inflammation. Very little is known about the aging immune system in flies, but recent work by our lab indicates that innate immunity and aging are closely linked in this species. We have discovered dramatic increases in transcript representation with age for several key immune-regulated genes. Some, but not all, of these increases were linked to the rate of aging because they were ameliorated in long-lived flies. We have found that old flies may have an impaired transcriptional response to bacterial infection and have isolated genes that are capable of dramatically augmenting immune function in both young and old flies. Discoveries in the lab include demostration of a role of insulin signaling in immune function and identification of molecular pathways that link diet with immune function.