Can we Tweak the Aging Process?
Studies conducted with centenarians may hold the answer.

Americans today are living longer and healthier lives. In fact, centenarians are the fastest growing population in the United States . A lot of research is being done on the aging process, with researchers searching for both environmental and genetic clues on how to help people live longer, healthier lives. Nir Barzilai, M.D., former chief medic of the Israeli army and current director of the Institute for Aging Research at the Albert Einstein College of Medicine, answers the question: Can we tweak the aging process?

To what extent is longevity the result of environmental factors, as opposed to genetics?
According to demographers who assess the correlation between the ages of death of a parent and his or her child, the correct answer is that longevity is 80% environmentally determined and only 20% determined by genetics. However, medical progress has a significant effect on the age of death and so it is in fact very difficult to separate the environment from genetics. Furthermore, evidence suggests that by age 100 genetics plays a significantly larger role than the environment.

There has been concern regarding the implications of people living forever. In your opinion, is there a certain point beyond which people cannot age or is it possible for lifespan to be prolonged indefinitely?
Centenarians die of the same causes as everyone else ? only approximately 30 years later. This suggests that once we find the right switch ? a longevity gene ? we can increase the average life expectancy to 100 years. Getting beyond that, however, is something we don’t yet know much about.

How do we find that switch and how long will it take?
Longevity genes are genes that prevent age-related diseases. Their opposite can be called aging genes. People with a longevity gene will outlive those with an aging gene so if you follow a group of people as they get older, the frequency of the aging gene in the population will decrease while the frequency of the longevity gene in the population will increase. Of all the candidate genes identified thus far, only three have followed this pattern.

One of these genes is involved with the production of a peptide released from fat, and the other two are involved with lipoproteins, particles that regulate HDL, the bad cholesterol. Now, these particles come in different sizes. Studies have found that centenarians and children of centenarians have very large particle size, which has a large heritability coefficient of 0.4-0.7. Although this does not prove definitively that larger particles cause good health, it does establish a connection between the two.

Interestingly, we’ve found that different aging genotypes distinguish cognitive functioning in later life and that not all longevity genes have the same effects. In the future, we hope to be able to separate centenarians into disparate subgroups and match up these subgroups with their particular longevity or aging genotype.

How do you find and recruit centenarians?
It’s not as difficult as it may seem. Centenarians are actually the largest growing population in the United States . I am currently following 350 centenarians and have a four month waiting list. In general, centenarians are either referred to us or they see our name in the news and call us.

Recently, a lot of attention has been given to the effects of caloric restriction on aging. What is your perspective on this issue?
The breakthrough discoveries that have been in the spotlight recently were the results of studies that used nematodes, an organism that is a far cry from human beings. Although the concept and mechanism of caloric restriction are important, it may not actually be relevant or applicable to humans. For example, if you knock out the insulin-signaling pathway in nematodes, they live longer. If you knock out this pathway in people, they will develop diabetes, a disease caused by resistance to insulin.

Another important issue to keep in mind when evaluating new research is the research paradigm used. For example, a group of rats are split in half. Group A is allowed to eat however much it wants whereas group B, the caloric restriction group, is only fed 60% of what group A eats. The caloric restriction group lived an average of 35% longer than the group that was allowed to eat whatever they wanted. This seems to suggest that caloric restriction increases longevity. But there is another way to interpret these results. Rats in the wild run an average of nine miles per day searching for food whereas laboratory rats get little exercise and are therefore comparatively obese. This complicates the matter because instead of testing the effects of caloric restriction on average weight rats, we are now testing its effects on obese rats. And so the question becomes, is the obesity killing the rats or is the caloric restriction saving them? If it is the former, then caloric restriction will only lengthen life for the obese, which is something we already knew. If it is the latter, then caloric restriction should be practiced even by individuals of normal Body Mass Index (BMI), a measure that takes into account height and weight. The way in which the question is framed influences the meaning of the answer.

Many caloric restriction studies look at and emphasize only one marker of obesity, even though there are actually many markers. My research takes a different approach to the study of caloric restriction. Instead of looking at specific markers we are taking a more global perspective, focusing on understanding the mechanism of how the body senses nutrients and eventually how nutrients lead to adverse consequences. More specifically, we are concentrating on visceral fat, which is fat that accumulates around the abdomen. When visceral fat is removed the death rate decreases. This suggests that the key is the reduction of abdominal fat and not general caloric restriction.

What do you perceive to be the difficulties facing those doing aging research?
First of all, people are interested in specific diseases, but not in aging in general. Furthermore, young people don’t think about aging, and the elderly think that they are too old and that there is nothing they can do. Biotechnology companies are not interested in funding aging research because it takes too long to come up with something that is marketable to the public. And even though the budget for the National Institute of Aging is approximately twice that of other government agencies, it is still only able to fund nine percent of the grant proposals they receive.

What would your main take-away message be to our readers?
The Pope is on a trip and he finds out that he will be riding around in a Cadillac. He had always wanted to drive a Cadillac and so switched with the driver so that he could drive the car. He is then pulled over for speeding. The policeman looks at the driver and then calls the station. “I just pulled over someone really important,” he says. “How do you know,” asks the officer at the station. “I know because the Pope is his driver!”

The point is that things aren’t always the way they appear. When you hear about new scientific discoveries, you really must question the research paradigm used and then ask how the research is applicable to you.

Resources

Albert Einstein College of Medicine Longevity Genes Project : www.aecom.yu.edu/home/longevitygenesproject

National Institute on Aging: www.nia.nih.gov

International Longevity Center- USA: www.ilcusa.org