By Chong He and Karen Ring

Dr. Scott Pletcher

Dr. Scott Pletcher

Dr. Scott Pletcher is an Associate Professor in the Department of Molecular and Integrative Physiology and Geriatrics Center at the University of Michigan. The goal of Dr. Pletcher’s lab is to identify and investigate genetic mechanisms that are important in aging and age-related diseases in humans by focusing on equivalent, conserved processes in the fruit fly model, Drosophila melanogaster. He views aging as a “physiological behavior” and is seeking to understand the neural mechanisms of its coordination and execution.

In a recent seminar at the Buck Institute, Dr. Pletcher discussed how substances like water and sugar can initiate changes in aging processes by specifically affecting sensory neurons. His lab found that in flies, bitter tastes have negative effects on lifespan while sweet tastes had positive effects. Interestingly, the ability to taste water had the most significant impact: flies that couldn’t taste water lived up to 40% longer. One possible explanation for these results is that flies that can’t taste water might compensate for this perceived water shortage by converting large amounts of their own body fat into water.

Dr. Pletcher also discussed how specific neural circuits and/or brain regions are actively involved in modulating aging. He specifically focused on the roles of pheromone sensing and putative reward circuits in extending lifespan. When normal male fruit flies are housed with other male flies that are genetically altered to produce female pheromones, the normal males have the expectation to mate but are unable to do so. As a consequence, these “sexually frustrated” male flies had decreased fat storage, reduced stress response, and shortened lifespan. Dr. Pletcher also discovered that ppk23-mediated pheromone perception and the protein neuropeptide F (NPF) sexual reward system are involved with the initiation of physiological changes that impact fat metabolism, stress resistance, and lifespan. Dr. Pletcher concluded that many aspects of healthy aging are likely shared across taxa when expectations defined by sensory perception are accompanied by appropriately rewarding experiences.

Q: Evolutionarily, how would you explain why male flies that have never seen a female live longer than they would otherwise?

SP: Maybe when there are no females around, it’s similar to a situation where there is no food, and the male flies enter a state where they are trying to extend lifespan until they can mate. Another explanation could be that when flies develop an expectation to mate, they might start doing something that will be beneficial when they mate. But if they don’t mate, this change could be deleterious to their health or lifespan. But we haven’t yet found the evidence to support this hypothesis. It is unclear whether it’s a direct effect of some compounds that is driving a shorter lifespan or if it’s more of a global change in metabolism and physiology.

Q: What is the next chapter of the NPF story?

SP: We are currently investigating the role of NPF in aging and whether other types of input sensors fit into the same reward system. One hypothesis is that there might be brain regions that are important for receiving different types of information from the environment and integrating them to direct physiological downstream processes, and NPF plays a central role in these processes. So if we knock out NPF, this could compound the effects of environmental change, such as water, pheromones, food, etc. We think that there is a central part of the brain, which can evaluate the environment and alter lifespan.

Q: How did you become interested in studying social effects on lifespan regulation and what do you want to achieve with these studies?

SP: There is more and more information on how sensory receptors can affect aging. In human epidemiological studies, scientists found that if you’re around an unhealthy person, you might become unhealthy too. We are interested in learning how social interactions and sensory perception affect lifespan and healthspan. We are currently collaborating with a few mouse labs to answer these questions. Some of the studies we are conducting involve putting mice on a restricted diet while housing them near other mice that get to eat food. We then ask whether deprivation in this type of environment affects glucose intolerance or other physiological characteristics in the dietary restricted mice. Ultimately, we want to understand how environmental perception affects lifespan. We want to determine what’s happened in cells that cause lifespan changes at the molecular level. However, we are also interested in determining whether there’s a specific region of brain where lifespan is consistently manipulated when you stimulate those neurons−in another word, a longevity regulatory center.

Q: How does the concept of “behavior aging” fit into the general field of aging?

SP: I think it is just another approach used to understand aging. What I’ve found interesting is figuring out how to use techniques from neuroscience to understand how signals transmit to influence aging processes. In other words, aging can be changed by neuronal manipulation just like it can by dietary restriction. Aging has characteristics that you can identify and study through behavior. I think the principle of what we’re doing is based on the assumption that by targeting how the environment controls the development of organisms, we can achieve substantial lifespan extensions and health improvements.

Q: What would you like to suggest to our postdocs who want to pursue academic careers?

SP: I think everyone says, “work hard and publish a lot”. What I usually tell my postdocs is that you should do whatever you find exciting. During my career, I always studied what I liked to study at the time. During graduate school, I was studying evolutionary genetics. I did my postdoc because I wanted to learn math and computer programming. Now I’ve shifted back to genetics in flies, and I’m doing weird stuff with behavior. I always just follow what I love to do. Being fundable is a big concern, but you don’t want to be overly concerned about it. Make sure that a big component of your decision is what you love to do. One other suggestion is to be distinguishable from your PI with respect to your research and accomplishments.

For more on Dr. Pletcher’s research, go to the Pletcher Laboratory website.