Dr. Promislow is a Professor in the Departments of Pathology and Biology at the University of Washington. He attended Oxford University as a Rhodes Scholar, where he received his Ph.D. in 1990 on the biology of aging in natural populations of mammals. He has authored over 100 articles and books, and is internationally recognized for his work on the evolution of aging.
Recently, Dr. Promislow visited the Buck Institute to discuss how the field of metabolomics offers a unique and important perspective on the fundamental processes of aging. In his seminar, Dr. Promislow described his lab’s efforts to conduct high-resolution metabolomics profiling using systems biology approaches. He discussed that genotype, age, and the interaction between the two, have dramatic effects on metabolome profiles. He also demonstrated that manipulations that slow the aging process also alter the underlying network structure of the metabolome. This novel approach, which is easily translated to human studies, holds promise for identifying previously unrecognized signaling pathways that influence aging in natural populations.
We had the chance to pick Dr. Promislow’s brain on a number of topics:
Q: What is future direction of the metabolomics field with regards to aging?
DP: There are a lot of questions that still need to be answered. One of the things I am interested in is whether we can use changes and correlations to either predict or explain aging. For example, if we look at different genotypes, within the genotype, does the metabolic network predict how long we are going to live? One of the challenges we are facing is to get a causal mechanism that we can use to manipulate our experiment. The question is how you manipulate network structure. A network is made up by nodes and connected by edges. There are many ways to define edges and the way we define edges is by the correlations between two notes across samples. Is it possible to experimentally break an edge or add an edge between two metabolites? For example, people have done supplementary metabolite feeding experiments. Could you feed two metabolites to an animal and induce the positive correlation between metabolites that didn’t exist? We don’t know that answer yet. Alternatively, if you have a correlation between two metabolites that are in common pathway, could you knock out an enzyme to affect this correlation in terms of removing or adding an edge. This is called differential co-expression analysis, which is very useful to understand human diseases.
Q: Can you talk a little bit more about “The Dog Aging Project”?
DP: We started the project two years ago. We have put together a working group of leaders from the biogerontology field and the Canine Longevity Consortium and got funding from the NIA (National Institute on Aging). The main goal of Canine Longevity Consortium is to develop a long-term aging study in dogs nationwide. When I moved to the University of Washington, I talked to Dr. Matt Kaeberlein about this. Matt is very interested in rapamycin’s anti-aging effects, so we also started a rapamycin trial in dogs recently. Right now we are trying to get funding for the safety trial for rapamycin. People are very excited about it. There are a lot of dog owners who want their dogs to be part of this trial. Once we establish a safe dose, we are will test whether we can give rapamycin to dogs when they are healthy, but old enough to have a high risk of heart failure, to see if rapamycin can prevent the onset of aging related disease.
You can learn more about this study from the project’s website.
Q: Do you believe in a magic potion for extending lifespan/healthspan? Would you apply any therapy on yourself?
DP: I think the magic potion for healthspan that we already know is exercise and a healthy diet. I think that if everybody, at least in the US, has a healthy diet and exercises regularly, the life expectancy in this country will go up. Promoting exercise and a healthy diet in the US would have a greater effect than any drug treatment. Also in my work on flies, I learned that different genotypes react differently to different treatments. So the concern of using drugs to extend healthspan is that some genotypes react positively to some drugs in terms of having longer lifespan while some genotypes actually have shorter lifespans. Different genotypes also react to dietary restriction differently. So I think we need to be very circumspect about advocating any kind of lifespan/healthspan extending treatments in humans. We need to know that these treatments at least are not harmful first.
Q: How does evolutionary biology play a role in the aging research field?
DP: Evolutionary biology always makes us to think about variation. For example, we are interested in how different genotypes react to a specific drug treatment. We can actually map that variation and ideally we can identify genes that segregate in a natural population where particular alleles will predict how a fly responds to a drug. One thing that came out of evolutionary thinking is antagonistic pleiotropy, proposed by George Williams, which goes back to the original evolutionary models. Antagonistic pleiotropy occurs when one gene controls more than one trait where at least one of these traits is beneficial to the fitness and at least one is detrimental to the fitness. If a gene caused both increased reproduction in early life and aging in later life, then this gene would be favored by natural selection. Evolutionary biology gives us a conceptual framework for thinking about the genetics of aging. One of the best examples I can think of is Dr. Judith Campisi’s work. She thoughtfully brought together the hardcore molecular biology and evolutionary thinking. I think we need to know the architecture of genetic aging in the degree of specificity and accuracy that we are still far away from. As an evolutionary biologist, I think it is important to think about whether the gene or the pathway we discovered in the lab that regulate aging are important for explaining variation in aging in natural populations. Actually the pharmaceutical industry is very interested in pharmacogenomics, and I think there are a lot of opportunities in our field to embrace these questions.
Q: What would you like to suggest to our postdocs who want to pursue academic careers?
DP: First thing is to look at my book “The Chicago Guide to Landing a Job in Academic Biology.” The number one message in that book is publish. The currency of our field is publications. The other thing I would say is to find something that you are passionate about working on rather than something that might be easy to get funded. You should find something that can make you jump out of the bed in the next morning to plan the next experiment or to look at the data from yesterday. Life is too short to spend time working on problems that aren’t the ones that you really want to work on.
For more information about Dr. Promislow’s research, check out the Promislow Lab Website.