Dr. Pankaj Kapahi at the Buck Institute

BIO: Dr. Pankaj Kapahi is Professor at the Buck Institute. He received his BS with first class honors in Biochemistry with Medical Sciences from the St. Georges Hospital Medical School, University of London. In 1998, he received his PhD from the University of Manchester, UK. After receiving his PhD, Dr. Kapahi had his first postdoctoral position in Dr. Michael Karin’s Lab at the Department of Pharmacology, University of California, San Diego, CA, and moved to Dr. Seymour Benzer’s lab as a postdoc fellow in the California Institute of Technology, Pasadena, CA. Dr. Kapahi has been at the Buck Institute since the fall of 2004.

Dr. Kapahi’s lab is interested in understanding the role of nutrition and energy metabolism in aging and aging-related disease. During his research seminar at the Buck Institute, he summarized his lab’s projects, which fall under the following main topics:

  • The role of tissue-specific changes in mRNA translation in response to dietary restriction in an effort to examine their role in modulating metabolism, muscle activity and health span in fruit flies.
  • Molecular mechanisms that underlie α-Dicarbonyl related diabetic complications using worms.
  • The link between fat metabolism, spontaneous activity and aging.
  • The role of nutrients in modulating gut function and permeability.
  • Nutrient dependent changes in calcification and mineralization.
  • The role of circadian clocks in modulating nutrient responses.

SAGE sat down with Dr. Kapahi to ask a few more questions…

Q: Can you use plain English to explain what kind of research you are doing and what idea that you are trying to get into?

PK: Overall, the lab is interested in how nutrients influence aging and age related diseases and one of the things we are trying to focus on more now is developing models for age related complications such as for diabetic complications, for kidney stones, cardiovascular diseases, and gut permeability. We use invertebrates as models for these complex human diseases where it is necessary to understand the impact of biological time or aging. You have to study the models in the context of aging otherwise you’re not going to get the right answers for age related conditions. We are using the invertebrates because you can recapitulate these diseases in a much faster manner and then utilizing these models to identify genetic and pharmacological targets that might be useful for preventing or slowing them down.

Q: As you mention, there’s so many different ways that we can regulate aging like calorie restriction, rapamycin, exercise. If you wanted to try something for yourself, what kind of intervention would you try to slow the aging process?

PK: Things our grandmothers would say-eating well, sleeping well, and exercising. I’ve added another as a result of what we’re seeing with the circadian clock experiments, eating at the right time. I try to give a long gap between when I eat at night and in the morning. I used to go ahead and eat at 10pm, if I was hungry, which I have stopped now. Basically, when you eat at night you’re telling your gut and your liver to wake up and that’s not giving them time to rest or recover. There’s a very nice experiment by Satchin Panda’s lab on two populations of mice fed the same amount of calories – one at night and one in the day. The ones that eat during the day get fat. As mice are nocturnal – the ones that eat the same calories during the night are fine, they’re lean.

Q: How did you come up with the idea to study circadian clock and lifespan?

PK: One of the things we found in our earlier work was that under dietary restriction there’s an increase in both fatty acid synthesis and break down. This result just didn’t make sense. But one of the ideas was that maybe it’s temporally separated. Another possibility was that some tissues are involved in breakdown and some in synthesis, and idea for which we didn’t see evidence. However, we saw evidence for temporal changes in fat metabolism. When we looked at the circadian clock mutants we verified the temporal concept and it also showed that circadian clocks are an important part of the metabolic adaptation that takes place on dietary restriction. They are ensuring that the animal can synthesize fat at the right time and break it down appropriately. So that’s the general idea, which we will be examining further.

Q: You have so many different projects. Which one is the one you’re most excited about?

PK: That’s like asking which child you prefer. I think they’re all teaching us different things and I have a strong interest in understanding the basic mechanisms of aging. However, at the same time I think the schizophrenic part of me also wants to be able to understand the impact of aging on age-related diseases. One of the reasons we have expanded further is we’re trying to ask the question – can you use invertebrates for screening drugs and treating with drugs that might be relevant for humans. Some of the basic mechanisms, the work with the clocks and the gut permeability is wonderful but I am also very excited about models for age related diseases that we have created, for gut permeability, kidney stones and for diabetic complications – these are big problems clinically for which there aren’t many answers. We are now close to taking some of our findings into mice and one in human clinical trials.

Q: What will be the big picture that you’re trying to figure out in the next five years?

PK: One of the big picture ideas is questioning the universality of the aging process. Does aging occur the same way in diabetics, cancer patients and normal individuals? At the same time we are also trying to focus on a particular age-related diseases like diabetic complications, while also trying to achieve a deeper understanding in the invertebrate models and examine their relevance in mammalian models. We are trying to focus on findings that could be relevant for humans.

Q: Why did you come to the Buck Institute?

PK: I am very privileged to be at the Buck because I have always been interested in aging research and to be surrounded by all the researchers who also look at their area of research through the lens of aging is just amazing. It is wonderful to bounce ideas off to people who care deeply about aging compared to a place where only two or three people are approaching their research from an age-related angle. In our research whatever we find, for example effect of TOR, circadian clocks etc, is relevant to many of people at The Buck because they can ask those questions in their model systems and discover how it ties in with the questions they’re asking which is often related to age-related matters. It has been exciting to be part of discoveries that bridge expertise across labs, like our recent paper in collaboration with the Campisi lab, where we discovered that inhibition of TOR also inhibits the Senescence associated secretory phenotype (SASP).

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Image: hundreds of drosophila can be kept in a compact tube with media. This compact housing is part of what makes drosophila an ideal model organism to study. Photo courtesy of commons.wikimedia.org

Q: Why did you decide to study flies?

PK: During my PhD I was using cell culture models to study aging in different species and then I went into Michael Karin’s lab to study cellular stress response in aging. I thought this would be a good way for me to get further insight into the aging process. But while doing my studies I kept questioning if what I was working on was relevant to aging? I kept wondering if the pathways we were studying in cell culture would modulate lifespan or aging process. For that reason, I’m really glad I moved to Seymour’s lab to study a whole new model organism to help me understand aging better. Working with whole organisms is complex but it allows you to study how various tissues and systems integrate with each other to influence aging and diseases. This has allowed us to tackle more complex questions like how physical activity and circadian clocks influence lifespan.

Q: I have a very difficult question. Do you know how many people are in your lab?

PK: Yes! Well around twenty. I don’t know the exact number. You’re right.

Q: You’re famous for having the biggest lab in the Buck. What is the key to have so many grants and get funding to maintain it?

PK: When I started my lab it was hard getting funding and I probably developed a habit of writing many grants and it is a habit that has continued. I continue this habit because grant writing allows you to think about the different projects and how to put them together. I actively encourage all of my postdocs to write grants, it helps them develop their ideas, and to think about the problem from different perspectives. Grant writing helps refine ideas and strengthens communication skills, such as how to explain their study to the lay audience; how to explain their study to the experts; also how to frame their ideas in the context of the bigger picture. The other thing that I think helps to manage a big lab is to encourage the formation of subgroups. So there’s a group that does diabetic complications, a group that does kidney stones, a group that works on dietary restriction and aging. We try to have multiple subgroup meetings so there is a sense of three or four tight kit small labs, instead of just one large lab.

Q: It must be hard to keep track of everyone. You probably have a spreadsheet, don’t you?

PK: I do have a spreadsheet. Here is the spreadsheet (opened a file in his computer). There’s a place showing where all their benches are, projects and projects and papers they are doing. I think you need a critical mass to address difficult questions and you need people with different expertise…it’s sort of fun…it’s like Lego where you take very many pieces and try to build an interesting model.

Q: What kind of jobs are your postdocs taking after working in the lab?

PK: A number go into academia, or go into industry – those are the two most common.

Q: How do you help them get jobs?

PK: A lot of the effort is spent getting their projects working, getting funding and training in necessary skills like project design, communication and grant writing. All this builds their curriculum vitae for future work. Recently, someone had a job interview and he said he was very glad with the way he presented, even though he was the most junior candidate. He was able to effectively communicate his plan, rationale and aims. It is good to start practicing these skills early on because I think it is something you have to use throughout your life.

Q: What do you do for fun?

PK: I love playing sports – I play Frisbee, tennis and cricket. However, the most fun is spending time with my daughter and my wife. I’m learning a lot about life from my daughter. A lot of things that we take for granted and assume, become hard to explain when you are teaching a child. It’s very interesting to watch a child grow and try to explain the very simple thing which you’ve taken for granted and then you try to break it up in smaller steps and understand the process, “how do you explain discipline”; “how do you make someone motivated”; “how do you get someone to enjoy learning and asking questions?” All these things are very interesting to me.