[tt] NYT: A Longer, Better Life

[Premise Checker]

A Longer, Better Life
New York Times, 7.5.6
http://select.nytimes.com/preview/2007/05/06/magazine/1154674303607.html

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 Scientists Search for
Genes That Prolong Youth.; Robert N. BUTLER, M.D.: Founding director
of the National Institute on Aging, a founder of the Alzheimers
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 Im involved in is not about
extending life after people are infirm. I dont think of life span as
the gold standard. The gold standard is health span. All the
indicators from the laboratory are that the genes were 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. Thats 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: Theres 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. Theyre called
sirtuins, and theyre 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,
weve 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 thats found in red wine. Does it do the same thing as
calorie restriction?

GUARENTE: Its 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 Im 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 thats a good start.

But arent 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 theres 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. Whats the distinction
between these products and the drugs that youre hoping to develop?

GUARENTE: Well, thats really simple. Any product on the market that
claims to extend life dont believe it.

BUTLER: Thats true. We dont yet have the means to delay, stop or
reverse aging. And in fact, we dont 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.

Lets 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
Alzheimers research that warned that America doesnt recognize
Alzheimers 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 dont find a
means of prevention and treatment.

Why cant we make it a national priority to find a treatment for
Alzheimers the way we once did with polio and AIDS?

BUTLER: Weve had a history of understanding infectious diseases and
vaccines since Pasteur. The problem is, the central nervous system
is very complex. We dont 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 Alzheimers, one of these
proteins goes awry and precipitates the disease.

Are you saying Alzheimers is genetically determined?

BUTLER: Its genetically based, but genes have to express themselves
in the environment.

Has there been any progress in early detection?

BUTLER: Yes, through whats 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 Alzheimers.

How feasible is it to do this testing widely?

BUTLER: Its expensive, and I dont think its a good idea for the
public at large because we dont have a treatment. But for research,
its 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 Alzheimers 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 Alzheimers.

BUTLER: For me, one of the most disturbing experiences is putting a
fully incapacitated Alzheimers patient in front of a mirror and
asking him who he is, and he doesnt know. Its just shocking to see
that happen to human beings they dont 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 youre older, you also tend to review your
life and to try to come to terms with it, and if you have
Alzheimers, youre 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 Alzheimers begins to take the greatest hit.

Is dementia in the same family as Alzheimers 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 Alzheimers
because she knows who we are, and she can go over every line of her
tax return, but five minutes later she wont remember she saw it.

BUTLER: There are many types of dementia, which result from
different causes. The most common is Alzheimers, 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
Alzheimers have differentiated three categories for research
purposes. The first is whats called age-associated memory
impairment. These are the kinds of things ordinary people are going
through: forgetfulness, not remembering why youve walked into a room
or where you put the paper you were just holding in your hand. If
youre in this category, we have no data that suggest youre
necessarily on your way to Alzheimers.

The second category is mild cognitive impairment getting confused on
the street, not remembering youre supposed to have coins when you
get on a bus. At that point, the conversion rate to the third
full-blown Alzheimers 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, thats 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: heres 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 Im optimistic that can be achieved.

Theres 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: Im afraid theres a lot of romance in the literature
suggesting that we can stop Alzheimers 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 doesnt prevent you from getting cancer.
Similarly, maintaining a healthy brain doesnt prevent you from
having memory loss or getting Alzheimers.

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 were stacking the odds a
little bit away from disease.

Lets 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 cant afford older people because of
Social Security and Medicare. But theres 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
persons cost, like health costs, is another persons income, asset or
job.

What about the institution of marriage? If youre 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: Theres 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 youre onto something.

Are you concerned that extending life span could double the number
of people alive and overwhelm the planets resources?

GUARENTE: I dont believe that mitigating the diseases of aging will
lead to overpopulation, because in most of the developed world
birthrates are low or declining.

BUTLER: Theyre falling in the developing world as well. Theres 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. Were talking about increasing healthy years within that
life span.