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Research Newsletter-Fall/Winter 2012

Viviana Perez, Ph.D.


An interview with Viviana Perez, Ph.D.
Assistant Professor of Biochemistry and Biophysics
LPI Principal Investigator

Q. Youíre from South America. Were you born and raised in Chile?

A. Yes. I was born in Santiago, and I lived there until I moved to San Antonio, Texas, in 2004.

Q. Where did you attend college?

A. I went to the University of Chile and also did my Ph.D. there.

Q. In what subject did you earn your Ph.D.?

A. Biomedical science. At that time I was working with Dr. Sierra investigating the function of one protein that is overexpressed with age in rats.

Q. What brought you to the United States?

A. Aging research.

Q. Where did you go for that?

A. I came to the University of Texas Health Science Center at San Antonio.

Q. What attracted you to the Linus Pauling Institute?

A. The diversity, the emphasis on healthy aging and micronutrients, and the future application to translate my research to humans.

Q. And you didnít feel you could do that as successfully at your institution in Texas?

A. The strength of the Barshop Institute for Longevity and Aging Studies at the University of Texas, where I worked, is the study of the basic biology of aging, not on translational research.

Q. Do you continue to collaborate with your colleagues there?

A. Yes, I do. I am constantly talking with them, and we are publishing papers together.

Q. How do you like LPIís new building?

A. Itís beautiful. I like the big windows, and the laboratories are open, which allows you to interact with people in other laboratories. Itís a very nice building.

Q. Functionally, do the laboratories have everything you need to carry out your research?

A. Oh yes, they have everything that we need to do our work.

Q. What got you interested in aging research?

A. When I was in my second year of graduate school, I didnít know what I would like to do. And it was at that time Dr. Sierra moved to Chile. In a seminar, he talked about aging and why aging is important to study. I realized that he was rightówe care much about diseases, for example, heart problems and Alzheimerís disease, but those diseases are all associated with aging. If we can delay aging, we can delay not only those diseases but almost all chronic diseases.

Q. So an important risk factor for some of those diseases is advanced age?

A. Exactly.

naked mole rats

Q. In your longevity research, you study the naked mole rat. Why is that rodent especially interesting in research on aging?

A. The naked mole rat is interesting because it has a lifespan much longer than expected, considering its body mass. We expect species that have a similar body mass to have similar lifespans, but this is not true for naked mole rats. For example, a mouse with a body mass similar to the naked mole rats lives, in the best conditions, around three and a half years. The naked mole rat lives 30 years! We donít know the exact mechanisms for that yet, but the oxidative stress hypothesis of aging doesnít seem to be applicable to this animal. Interestingly, they live healthily their whole life until the end, when their physiological condition declines rapidly, and then they die. That is what we want to achieve in humansóto maximize ďhealthspan.Ē

Q. You are a member of the LPI Healthy Aging Program, which focuses on increasing healthspan. What exactly is healthspan?

A. Healthspan is the period of your lifespan when you are productive and without chronic diseases and conditions that limit your daily living. That is what the Healthy Aging Program in LPI wants to achieve—an increase in healthspan. In other words, we would like to compress morbidity so most of your life can be disease-free and full of productive vitality.

Q. If you compress morbidity, it would then occur towards the end of your lifespan instead of being chronic.

A. Exactly! The idea is to delay all chronic diseases until the end and then die. The goal is to add life to your years, not necessarily years to your life.

Q. Are there any other rodents that live nearly as long as the naked mole rat?

A. For rodents, it is the exception. But among other small mammals, like bats, we also observe differences in lifespanósome bats live shorter and some live longer. For example, evening bats live six years, but short tail bats live around 30 years.

Q. Where is the naked mole rat found, and how does it live in its natural environment?

A. Itís found in the northeast of south Africa, around Kenya. They live underground where the temperature is around 29-30 degrees Celsius (84-85 degrees Fahrenheit), with 100% humidity.

Q. Since it lives underground, does its environment have elevated carbon dioxide levels?

A. Yes, since they are strictly subterranean, but they seem to be insensitive to CO2 levels. Dr. Buffenstein from San Antonio has data indicating that these animals may have adapted to their environment by overexpressing Nrf2, a transcription factor that regulates the response to stress.

Q. What do they eat?

A. In the wild, they eat tubers and bulbs. They obtain all the water that they need through their food.

Q. Do they get enough calcium for skeletal development from these tubers? They presumably donít need vitamin D.

A. Yes, their vitamin D levels are very low because they are subterranean. However, when their calcium status was examined, they looked okay. They are not deficient in calcium, and calcium metabolism appears to be independent of vitamin D in these creatures.

Q. You found that the proteasome may play a role in the naked mole ratís longevity. What is the proteasome and how does it affect aging?

A. The proteasome is a mechanism or pathway in cells that degrades abnormal proteins. For example, if you have a damaged protein that got misfolded or aggregated as a result of an oxidative modification, and it cannot be repaired, the ubiquitin proteasome system will get rid of it. If the protein is not in good shape, it will be labeled with ubiquitin, which then will be recognized by the proteasome, which degrades it, releasing the amino acids that then can be used to make new proteins.

mole hills

Q. How does the proteasome work in the naked mole rat?

A. We found that proteasome activity is 30% higher in the naked mole rat compared to mice. We also measured the ubiquitin protein level, which is an indirect measure of proteasome activity. Incredibly, the level of ubiquitinated proteins in the naked mole rat didnít change with age and remained very low, unlike in mice, which is low when young but increases dramatically with age.

Q. How relevant is that to humans?

A. In studies with human skin fibroblasts, researchers found that proteasome activity declines with age. Several publications have shown that proteasome activity in different species declines with age, so a decline in proteasome activity is associated with the aging process in general.

Q. Why would protein stability be beneficial?

A. Proteins actually carry out all the functions in cells. For example, most enzymes are proteins, and if they are not working well, many physiological functions will decline or fail. If the protein gets damaged a little but is still working, the cell is not going to spend energy to repair this damage because itís working adequately. But if the protein is not functional or starts aggregating, itís going to be degraded because it will cause more damage to the overall cellular function.

Q. What damages proteins?

A. Oxidative stress is one of the major causes of damage to proteins.

Q. Is there any method for improving proteasome activity?

A. Dietary restriction increases proteasome activity. Other strategies have been tried in animals, tissues, or cells that increase proteasome activity, but you donít know if they will be safe for humans. There is another mechanism called autophagy that also degrades proteins. Itís more versatile than the proteasome. Autophagy not only takes care of damaged proteins but damaged cell organelles as well. This seems more important because, for example, when the mitochondria get old, we need to replace them, and autophagy will accomplish this. It may be better to find ways to improve autophagy rather than proteasome activity in humans.

Q. Youíve done several studies on thioredoxin, a sulfur-containing antioxidant enzyme, in mice. Does thioredoxin affect lifespan in mice?

A. Yes. We used a transgenic mouse model that has increased levels of thioredoxin. We found that thioredoxin was one of the few enzymes that increased median lifespan in mice. We didnít find a significant increase in maximum lifespan, but the median lifespan was extended, meaning that morbidity was compressed and the healthy part of the aging curve was extended.

Q. The free radical or oxidative stress hypothesis of aging postulates that free radicals causing oxidative stress damage biomolecules like DNA and proteins, and this damage accumulates with time, causing age-related disease and leading to death. How well do you think this hypothesis holds up in light of all the accumulated evidence?

A. During my post-doctoral studies in San Antonio, Texas, I spent most of my time trying to test the oxidative stress theory of aging. From these studies we can say that oxidative stress plays a role mostly in age-related diseases rather than in longevity itself. This was a very important observation. Therefore, based on these and other results, it is necessary to modify this hypothesis. Why? If oxidative stress is really the key for aging, then if you increase antioxidant enzymes that are going to get rid of oxidants like hydrogen peroxide and superoxide, then that should translate into a longer lifespan, but it doesnít. Even though there is less damage to macromolecules like DNA, proteins, and lipids, animals donít live longer if we increase the antioxidant status. So that is telling us that for lifespan itself, oxidative stress is not the problem. But feeding mice a high-fat, unhealthy diet will increase the rate of metabolic disease, and mice deficient in antioxidant enzymes will develop disease earlier than wild-type mice. Transgenic mice that have elevated levels of antioxidant enzymes will be more protected. So antioxidants can help protect against some of the age-related diseases, even if they donít increase lifespan.

Q. You are also interested in the possible link between caloric restriction and lifespan. What is caloric restriction?

A. Caloric restriction is a paradigm that was proposed a long time ago, around 1930 or so. It aims to decrease the amount of calories that an animal consumes, but it is not malnutritionóthere are sufficient vitamins and minerals, so it is only the amount of calories that is decreased. This has been well studied in mice and rats and is so far the only paradigm that will increase lifespan and healthspan in several species.

Q. Why would caloric restriction affect lifespan?

A. Nobody knows the specific mechanism, but we know that dietary restriction is an intervention that affects several parameters of aging. For example, dietary restriction decreases oxidative stress and oxidative damage, improves mitochondrial function, increases proteasome activity and autophagy, and improves protein homeostasis. Dietary restriction also improves several physiological parameters, such as insulin sensitivity. In other words, the whole system works better.

Q. In a controlled environment, it is very easy to control the diet and limit the amount of calories that the animals get. Would it be practical for people to adopt this kind of strategy in anticipation of increased lifespan and/or protection against age-related disease?

A. No, I think it would be impractical for most people, mainly because itís not enjoyable. Also, as you mentioned, it is an intervention that has been done in a clean environment that minimizes exposure to pathogens. This is important because caloric or dietary restriction can impair some responses of the immune system. For example, dietary restriction protects against some infections but increases the risk for others. Furthermore, to get the maximum beneficial effect, you have to drastically limit calories, which is not acceptable to most people.

Q. Is that why scientists have looked for chemical compounds that might mimic calorie restriction by engaging similar molecular mechanisms?

A. Yes, that was the goal several years ago when people started looking for mimetics of dietary restriction. Studies in invertebrates that can be easily manipulated genetically have established molecular pathways that are altered by dietary restriction. Certain chemicals or supplements, including resveratrol, metformin, and rapamycin, are being cataloged as dietary restriction mimetics. Of these three, the only one that increased lifespan and healthspan in mice was rapamycin.

Q. What is rapamycin?

A. Rapamycin is an antibiotic found in the soil of Easter Island. Itís a natural compound used clinically for organ transplants and for cancer patients because it has immunosuppressive and antiproliferative effects.

Q. What effect does rapamycin have on mice? Are there any side effects?

A. Rapamycin extends lifespan not only in mice but also in invertebrates, such as fruit flies. And in mice, it not only increases maximum lifespan but also increases healthspan. The side effects in mice are cataracts and testicular atrophy.

Q. Does it affect body weight, insulin sensitivity, or antioxidant status?

A. Studies in mice, rats, and humans have shown that rapamycin induces glucose intolerance and insulin resistance. No effects on antioxidant status have been published, and some studies suggest that long-term rapamycin use reduces body weight.

Q. Have people been given rapamycin long enough to observe any adverse side effects like cataracts observed in rodents?

A. Not that Iím aware of. In humans, rapamycin is only given to patients with cancer or used in combination with other drugs for tissue transplantation, and it may be that the treatment is not long enough to observe those side effects.

Q. Why is rapamycin used in those particular medical conditions?

A. For its immunosuppressive and antiproliferative effects. For example, in organ transplant patients, rapamycin is used in combination with cyclosporine. Rapamycin decreases rejection of the new organ, but the mechanism is not really clear. In cancer, it also reduces the proliferation of cancer cells.

Q. What about effects on gene expression? Have they been studied in mice?

A. We have done one study on gene expression in mice, and our results showed that rapamycin has some similarities to dietary restriction. However, dietary restriction has a massive effect on gene expression compared to rapamycin.

Q. You also mentioned resveratrol and metformin. Resveratrol has attracted a lot of attention because itís present in wine and available as a supplement. How effective is resveratrol on some of these parameters compared to rapamycin?

A. Resveratrol mainly works when the animal is under metabolic stress, so it only extends lifespan and healthspan when the animal is fed a high-fat diet. Resveratrol enhances lipid metabolism and other mitochondrial functions in normal mice, but published data show that it doesnít affect lifespan.

Q. There has been some concern about dosage. For instance, when you try to extrapolate to humans, the resveratrol dose that might be needed to achieve results that you observe in rodents would be impossibly high. Is that true?

A. Yes, this is true. The Intervention Testing Program from the National Institute on Aging (NIA) has been testing the effect of resveratrol on lifespan in mice, and so far, they didnít find an effect on lifespan even with high doses.

Q. What do you think about the recently published study by scientists at the NIA that reported that long-term caloric restriction for about 25 years in monkeys did not affect lifespan?

A. It doesnít surprise me! Dietary restriction works in organisms ranging from yeast to mice. The question is whether it will work in our closest biological relatives, the primates. A previous study done in monkeys in Wisconsin had published results different from those we observed in this study from NIA. Why? Well, I think there are several possible reasons. For example, the diet used in the Wisconsin study was high in sucrose, which can be considered a metabolic stress. Also, the genetic background of the monkeys used in the NIA study is diverse compared to the homogenous genetic background of monkeys used in the Wisconsin study, and we know from previous studies done in mice that the benefits of dietary restriction depend on the genetic background of the animal. For example, it was observed that dietary restriction had a deleterious effect in some animals. The ďad libitumĒ control monkeys in the NIA study were not really fed without restraint; there were some restrictions. So there are differences, including diet, genetic background, and other factors, between these two studiesóand, therefore, they produced different results.

Q. Where is your research heading?

A. I am very involved trying to establish whether rapamycin is a dietary restriction mimetic. If it is, it has the potential for translation to humans because it is already used clinically. If we can identify molecular mechanisms and ways to diminish side effects, it would be a good option for increasing healthspan in humans.

Q. Obesity is associated with increased oxidative stress and inflammation, both of which are hallmarks of chronic age-related diseases like heart disease, cancer, and diabetes. Does the current obesity problem in the United States concern you with respect to healthspan?

A. I agree that obesity is a big concern for our society and as a researcher, I think we can do something to improve healthspan in this group of people. However, I think itís important to create public consciousness about this problem. For example, we have to educate society about the importance of eating healthful food and exercising.

Q. What do you like to do when you are not in the lab?

A. I take care of my daughter. She keeps me busy! My family likes outdoor activities, and we often ride our bikes.

Last updated November 2012