The New Middle Ages

A Longer, Better Life
By SARA DAVIDSON
Sara Davidson talks to two medical scientists about how the body ages and the research on trying to extend our healthy life span.
Participants: Lenny GUARENTE, PH.D.: Novartis professor of biology at M.I.T. and author of “Ageless Quest: One Scientist’s Search for Genes That Prolong Youth.”; Robert N. BUTLER, M.D.: Founding director of the National Institute on Aging, a founder of the Alzheimer’s Disease Association and winner of a Pulitzer Prize in 1976 for “Why Survive? Being Old in America.” He heads the International Longevity Center.; SARA DAVIDSON: Author, most recently, of “Leap! What Will We Do With the Rest of Our Lives?”
Dr. GUARENTE, scientists like J. Craig Venter, one of the first to map the human genome, feel that increasing life span should not be the goal of science. Why are you attempting to prolong life?
LENNY GUARENTE: The research that I’m involved in is not about extending life after people are infirm. I don’t think of life span as the gold standard. The gold standard is health span. All the indicators from the laboratory are that the genes we’re studying and the kinds of drugs we would be developing would extend health span. If you can extend health span, and you also happen to extend life span, so be it. That’s a side benefit.
Have you identified genes that can extend health and life span?
GUARENTE: The genes we study counteract aging. First we studied yeast cells, and it took us eight years to identify a gene called SIR2, which protects the cells from damage during the aging process. Then we did a similar experiment in a more complex critter, the roundworm, and what was remarkable is, we identified the same gene. That told us that this type of gene is performing an antiaging function broadly in nature.
Do humans have this gene?
GUARENTE: There’s one gene in our genome, SIRT1, that would be a dead ringer for this one — the technical term is ortholog — but we also have six other genes that have a related sequence to this. They’re called sirtuins, and they’re all going to play a role, but I think the dead ringer is undoubtedly the most important based on experiments that have been done.
You assert a fairly radical concept: that these longevity genes have the power to keep the body supercharged and maintaining its natural repair activities regardless of age. Does that mean we could live, what, another 20, 30 years? Fifty?
GUARENTE: We think the sirtuin genes are there to recognize lack of food or other stressful situations and to spring into action to create a physiology that will promote longevity. The evolutionary value is that in times of stress — food scarcity, for example — this gene would slow down the aging process and keep you alive longer, so that when times are better, you could reproduce.
But how long would the gene work? Maybe it only operates temporarily?
GUARENTE: We can gauge this by asking what happens in rodents on a calorie-restricted diet, which mimics food scarcity and activates the SIR2 gene. Do they live forever? No. They live up to 50 percent longer. So in a perfect world, one would hope that we could live 50 percent longer than the current expected life span.
In our lifetimes, could this happen?
GUARENTE: I think one can expect perhaps another decade of robust health.
ROBERT BUTLER: A lot of it comes down to our willingness in this country to make an investment in the biology of aging. Historically, we’ve devoted our energies and money to studying one disease at a time. At the same time, we have neglected targeting the underlying risk factor of aging.
Are you saying that aging itself leads to disease?
BUTLER: Why does 50 percent of all cancer occur after 65? Why does 80 percent occur after age 50? As we age, there are changes at the cellular molecular level that predispose us to disease and disability. But so far, no government, no foundation, no corporation anywhere in the world has fully embraced the importance of longevity science. If we could target aging, that would have an impact on diseases.
What do you mean “target” aging?
GUARENTE: Slow down aging in the same way that calorie restriction slows down aging. Bob makes an important point about diseases and aging. I believe that the two are intertwined and experimentally this has been demonstrated by using modern strains of mice that have been genetically altered to get specific diseases — for example, neurodegenerative diseases or cancer, or cardiovascular disease or diabetes — and to see whether calorie restriction will either postpone or prevent these diseases. The general finding is that calorie restriction forestalls many of these diseases. The hypothesis is that if one could activate the sirtuin genes — not by a calorie-restricted diet but pharmacologically — then this would have an impact on the diseases of aging.
How close are we to such a drug being available?
GUARENTE: Ten, maybe 15 years. I think the drugs that aim at sirtuins, for example, will be tested initially for a particular disease, say, diabetes. And it will turn out that the drugs have broader benefits than one initially imagined.
What about resveratrol? There has been a lot of publicity about this substance that’s found in red wine. Does it do the same thing as calorie restriction?
GUARENTE: It’s a natural product, made by plants, and recently one of my former postdoctoral students, David Sinclair, found that resveratrol can regulate the activity of SIRT1.
Do you take resveratrol?
GUARENTE: No, partly because neutraceuticals are not regulated by the F.D.A. If I was sure of the quality control, I would consider it, but I’m still not certain I would do it, because you may have to take a lot — one or two grams a day.
What intrigues me is that I read that if fruit flies are fed resveratrol, they live longer and can eat all they want.
GUARENTE: More strikingly, there were two reports published last fall studying resveratrol in mice. In a study, researchers fed mice a high-fat diet, and the mice lived a somewhat shortened life span because of the high-fat diet. Another group of mice were administered resveratrol along with the high-fat diet, and a lot of those bad effects were reversed, and they lived longer than the fat mice not fed resveratrol. So I think that’s a good start.
But aren’t you worried that people who like to eat a lot of fat and sugar will think, if I just take resveratrol, I can eat anything?
GUARENTE: You could imagine that some people would consider a compound like this as a license to go wild, but there’s already an enormous problem with our diet, and we have to do something about it.
BUTLER: Several of us recently wrote an article in The New England Journal of Medicine in which we predicted, with great pain, that as things are now proceeding with regard to Type 2 diabetes in 10-year-old children, we may soon have a situation in which our children live less long than their parents. We need to educate kids early about the importance of nutrition.
There are substances on the market now that claim to prolong life — and people are spending billions on them. What’s the distinction between these products and the drugs that you’re hoping to develop?
GUARENTE: Well, that’s really simple. Any product on the market that claims to extend life — don’t believe it.
BUTLER: That’s true. We don’t yet have the means to delay, stop or reverse aging. And in fact, we don’t even have the means to evaluate or measure whether a substance prolongs life. We have yet to create biomarkers that would measure, short of death, actual changes in the body that reflect aging.
Let’s turn to what many of us fear most about growing older — losing our minds. Dr. BUTLER, you led a panel last year on the state of Alzheimer’s research that warned that America doesn’t recognize Alzheimer’s as a health crisis. Why is it a crisis?
BUTLER: It afflicts about four and a half million people now. As baby boomers grow older and live longer, there could be 14 million afflicted — about triple what it is now — by 2030 if we don’t find a means of prevention and treatment.
Why can’t we make it a national priority to find a treatment for Alzheimer’s the way we once did with polio and AIDS?
BUTLER: We’ve had a history of understanding infectious diseases and vaccines since Pasteur. The problem is, the central nervous system is very complex. We don’t know much about neurological diseases and how to treat them.
GUARENTE: I would chime in that my perspective is that there has been progress in understanding the key components involved in the disease — the genes and proteins. Genes compose the blueprint for making proteins, and in the case of Alzheimer’s, one of these proteins goes awry and precipitates the disease.
Are you saying Alzheimer’s is genetically determined?
BUTLER: It’s genetically based, but genes have to express themselves in the environment.
Has there been any progress in early detection?
BUTLER: Yes, through what’s called positron emission tomography, the PET scan, a group in Pittsburgh has found ways of tagging agents in the brain that make it possible to make early identification of amyloid, which is part of the plaque that builds up with Alzheimer’s.
How feasible is it to do this testing widely?
BUTLER: It’s expensive, and I don’t think it’s a good idea for the public at large because we don’t have a treatment. But for research, it’s fantastic because the earlier that we can make the identification, the more we can introduce potential interventions, like drugs being developed that would prevent or dissolve the accumulation of amyloid.
GUARENTE: I would just point out that Alzheimer’s would be in the group of diseases that has aging as an underlying risk factor, so being able to manipulate the aging process, I think, would also have implications for Alzheimer’s.
BUTLER: For me, one of the most disturbing experiences is putting a fully incapacitated Alzheimer’s patient in front of a mirror and asking him who he is, and he doesn’t know. It’s just shocking to see that happen to human beings — they don’t even recognize themselves. Elie Wiesel, the Nobel Prize winner who wrote “Night,” said we are our memories. Which I think is a beautiful statement of the significance of memory, because when you’re older, you also tend to review your life and to try to come to terms with it, and if you have Alzheimer’s, you’re denied that opportunity.
Do we know why it hits women more than men?
BUTLER: There are some who think that being female is a risk factor, but it may simply be that there are more women that live longer than men. As you know, there are about 250 women for every 100 men over 85, which is when Alzheimer’s begins to take the greatest hit.
Is dementia in the same family as Alzheimer’s or is it different? For example, my mother, who is 93, is in perfect physical shape, but she has no short-term memory. She does not seem to have Alzheimer’s because she knows who we are, and she can go over every line of her tax return, but five minutes later she won’t remember she saw it.
BUTLER: There are many types of dementia, which result from different causes. The most common is Alzheimer’s, which is characterized by neurofibrillary tangles — misshaped proteins — and plaques. The second most common is multi-infarct dementia, which is the result of small, repeated strokes. Scientists who are studying Alzheimer’s have differentiated three categories for research purposes. The first is what’s called age-associated memory impairment. These are the kinds of things ordinary people are going through: forgetfulness, not remembering why you’ve walked into a room or where you put the paper you were just holding in your hand. If you’re in this category, we have no data that suggest you’re necessarily on your way to Alzheimer’s.
The second category is mild cognitive impairment — getting confused on the street, not remembering you’re supposed to have coins when you get on a bus. At that point, the conversion rate to the third — full-blown Alzheimer’s — sadly, is very high. After three years, about half the people will not be able to take care of themselves, but the conversion is not total. Some people plateau and seem to go on for a long time.
How do you know when to be concerned?
BUTLER: One of the rules we use as clinicians is: if you forget your keys, that’s not so terrible, but if you forget what a key is for, that becomes serious.
Where do you think the breakthroughs will come from in understanding diseases of the brain?
GUARENTE: We are looking at genes, because from our perspective everything starts with genetics. Genetics is a key that opens a door that you can walk through, and now you can see: here’s what we should be studying. Antiaging genes like sirtuins carry the blueprint for proteins that might be able to ameliorate the cellular damage that accumulates with aging, like oxidation of molecules in cells. The next step, which is a difficult one, would be to develop drugs that stimulate the sirtuins, bolstering the repair of damage in cells. But I’m optimistic that can be achieved.
There’s a lot of advice given about how to maintain a healthy body, but do we know how to maintain a healthy brain and prevent dementia?
BUTLER: I’m afraid there’s a lot of romance in the literature suggesting that we can stop Alzheimer’s disease by cognitive exercises.
Like doing crossword puzzles? My mother has done them all her life, but she lost her memory anyway.
BUTLER: Just as exercise keeps the body in optimal shape, exercise — both physical and mental — can keep the brain in optimal shape in terms of thinking clearly, making judgments and solving problems. But having a healthy body doesn’t prevent you from getting cancer. Similarly, maintaining a healthy brain doesn’t prevent you from having memory loss or getting Alzheimer’s.
GUARENTE: My feeling is slightly different. I think we can tip the odds a little bit by our lifestyles and by avoiding things that we know are bad, like smoking, like trans fats, like excess body fat. Is it a prevention? Absolutely not, but we’re stacking the odds a little bit away from disease.
Let’s talk for a minute philosophically. What kind of society will we have if everybody is living to 100, and the whole culture skews older?
BUTLER: You could have asked that same question in 1900, when the average life expectancy was 47. Someone might have said, what are we going to do when we have all these 55- and 60-year-olds around? Society adjusts. People think we can’t afford older people because of Social Security and Medicare. But there’s a growing body of knowledge by hard-nosed economists of all ideological persuasions — University of Chicago, Yale, Harvard, the RAND Corporation — that as societies become more long-living and healthier, that actually creates greater wealth. Bloom and Canning up at Harvard have shown that if you identify nations that have a five-year difference in life expectancy, the one that has a greater life expectancy also has greater wealth. Older people create silver markets, so that one person’s cost, like health costs, is another person’s income, asset or job.
What about the institution of marriage? If you’re going to live to 100 and get married at 22 or 25. ...
BUTLER: Oh, you are evil.
Are you still going to vow “till death do us part”?
BUTLER: There’s a demographer, Peter Uhlenberg, who said that divorce is a substitute for death, because in the old days there was enough death, unfortunately, particularly of women in childbirth, that the men would remarry. Someone even calculated that marriage now lasts about as long as it did then, but it was ended then by death rather than by divorce. So maybe you’re onto something.
Are you concerned that extending life span could double the number of people alive and overwhelm the planet’s resources?
GUARENTE: I don’t believe that mitigating the diseases of aging will lead to overpopulation, because in most of the developed world birthrates are low or declining.
BUTLER: They’re falling in the developing world as well. There’s a distinction between advancing life expectancy and breaking the genetic barrier. Every species has a predetermined genetic life span. Certain fish live about a year. Some turtles live 200 years. Humans have about 110, 120 years at the outside of their genetic life span. We’re talking about increasing healthy years within that life span.