Dr. Sean Curran received his B.S. in Biochemistry from UCLA in 1999 and his Ph.D. in Biochemistry and Molecular Biology from UCLA in 2004. After receiving his PhD, Dr. Curran completed postdoctoral training at Harvard Medical School and Massachusetts General Hospital from 2004 to 2010. Dr. Curran joined the University of Southern California in 2010 and is currently an Associate Professor in Gerontology at the USC Davis School of Gerontology with joint appointments in Molecular and Computational Biology (USC Dana and David Dornsife College of Letters, Arts and Sciences) and Biochemistry and Molecular Biology (Keck School of Medicine of USC). Dr. Curran has received many awards and attentions including the 2016 Blavatnik National Awards for Young Scientists, the Ewald W. Busse Research Award, and the Hanson-Thorell Family Research Award, among others.

Sean-Currans

Sean P. Curran, Ph.D

Dr. Curran’s lab is interested in understanding the molecules, genes and cells that impact aging and age-related diseases. They utilize a multidisciplinary approach that combines genetics, functional genomics, biochemistry, cell and molecular biology, and physiology to comprehensively study the complexities of the universal process of aging. His lab illustrates how single genes – particularly genes that integrate diet availability and composition – function to modulate organismal homeostasis. During his talk at the Buck, he discussed how nematode worms (C. elegans) regulate the balance between surviving and reproducing during times of stress. When worms are exposed to external stresses such as oxidative stress or starvation, a protein called SKN-1 is activated. Activated SKN-1 can relocate the lipids from worms’ somatic cells (body cells) to germline cells (reproductive cells). This lipid relocation makes successful reproduction easier, but unfortunately also causes a shorter lifespan for the mother worm. The Curran lab also found that the lipid balance between somatic cells and germ cells can be regulated by diet, and specifically is mediated by omega-6 and omega-3 fatty acid.

Q: You found that dietary restriction can relocate the lipid from soma to germline, which is similar to SKN-1 gain-of-function (activation). However, dietary restriction is known to make worms live longer, while SKN-1 gain-of-function worms live shorter. How do you explain this?  

SC: Good question. It depends on when you expose the animals to stress. If you activate SKN-1 before the worms reach adulthood, the SKN-1 gain-of-function worms do much better than wildtype. For example, if you expose them to stress, the SKN-1 gain-of-function worms survive better than wildtype. But after they lose the lipids from the soma to the germline cells, they survive worse than wildtype. We think that the reason constitutively active SKN-1 worms don’t live longer is because of the movement of lipids from the soma to the germline to promote the necessity of reproduction. We think SKN-1 is part of dietary restriction pathway. SKN-1 is one of the downstream factors of the nutrient deprivation and I think dietary restriction is doing other things as well.

Q: If you restrict the diet of the worms and activate SKN-1 at the same time, will the worms lose the extended lifespan benefit from dietary restriction?  

SC: Yes. SKN-1 gain-of-function mutants do not respond to dietary restriction. I think this is because they have already perceived an environment where they are starved. We give them food but they think they are hungry. On top of that, if you actually starve them, they will live shorter.

Q: Do the SKN-1 gain-of-function mutant worms lay more eggs?  

SC: Oh that is a good question too. Actually they have slightly fewer progeny. It is not statistically significant. But the interesting thing is, they can lay eggs for longer period of time. So their reproductive period is longer than wildtype. And I think this is the benefit from the redistributed lipid.

Q: So this result is consistent with Dr. Coleen Murphy’s theory (see the interview here: http://sage.buckinstitute.org/reproductive-aging-an-interview-with-dr-coleen-murphy/). The period of reproduction is more important than the amount of progeny. Do you agree?

SC: Right. From the evolutionary point of view that is absolutely correct, especially for very short-lived animals. Having the capacity to be reproductive for 6 days instead of 4 days makes a big difference.

Q: Your study suggests that when the environment is stressful, the animals tend to live shorter and save energy for future generations. Have you found evidence to support this theory in mammals?

SC: This mechanism exists in order to promote reproduction under stress. For short-lived animals, when they perceive stress, the chances are that the stress will persist longer than their reproductive period. It is slightly counterintuitive. Someone could think that the animals want to survive better under stress, but maybe because their reproductive period is so short it is not possible to survive.

We started to look at these pathways in mice. Anecdotally, we found that the SKN-1 activation mice causes them to distribute their lipids slightly differently than wildtype. But we haven’t quantified that yet. I think where you carry the weight is more important how much you weigh. Where you carry the weight may have a bigger impact on healthspan.

Q: What is your goal for this project in the next year?

SC: We found out that stress could dramatically changes an animal’s physiology. When the animals are going through development and are under stress, the animals would try to wait for the stress to go away before developing. But if they are in their reproductive period, they sacrifice themselves for the next generations. So what would happen when the animals reach their post-reproductive stages? If we wait until reproduction is over, can we store the lipids in the somatic tissues and make the animals live longer? This is our next immediate goal. As I mentioned in my talk, this lipid distribution can be influenced by the type of food in their early development. I think it is fascinating. We are going to look into that too.

Q: So for us, maybe we should change our diet as we go into different stages of life?

SC: I think that is absolutely true. The problem is we don’t know how to do it. I bet there should be different optimized diets for different life stages: the development, adolescence, early adulthood, midlife, late adulthood. I just don’t think that we have the capacity to say what those diets are. We might need low protein in this period of life but high protein in another stage of life.

Q: What other projects are you doing in the lab?

SC: Another project that I didn’t talk about today is about genes that are essential for development but increase lifespan when you delete them after the animals reached adulthood. A lot of these genes induce “arrest”, meaning that when you delete these genes the animal stops developing but doesn’t die. They choose to arrest but they respond in a programed way to try to find a better environment to be reproductive. We are trying to classify these genes into a different type of “arrest”. Maybe the reason that they are long-lived when we delete the genes after the animals reach adulthood is that the deletions activate stress response in adulthood which gives them a survival benefit.

Q: Any career advice for postdocs?

SC: The advice that I gave to myself and postdocs in my lab is to always work on more than one thing. Don’t put all your eggs in one basket. You want something that you are very passionate about and let the science drives you. Also, be willing to take risks.