Interview with Bruce Ames, Professor of Molecular and Cell Biology
Number: 00S03. Issue: Spring 2000
Author[s]:
Andrew Hon, Jane Lo, Viet Nguyen, Negar Salehomoum
Keywords:
Abstract:
Professor Bruce Ames has been studying the mechanisms that cause DNA damage and its effects on aging and cancer development since the late 1960s. He has been researching and teaching at the University of California, Berkeley since 1967.
Ames believes that the key to aging well is a good diet and routine exercise. He eats a well-rounded Mediterranean diet, with lots of fruits and vegetables, in addition to taking a multivitamin supplement. As a workout, he and his wife enjoy gardening, and while their labs were on campus, they walked to work together.
He has been married for forty years to Giovanna Ferro-Luzzi Ames, also in the Department of Molecular and Cell Biology. In November 1999, their respective labs moved to the new Children?s Hospital Oakland Research Institute.
BSJ: How would you define aging?
Ames: We all sort of know what aging is ? all your systems
start deteriorating, and then you die. Your brain is not functioning as well,
and your muscles are not functioning as well. We?re trying to understand that
at a molecular level.
The theorists
who work on aging don?t think that the animal is dying for the benefit of the
tribe. Altruism is not a big thing with evolutionary biologists, just as it is
not with economists ? they [both] emphasize tradeoffs. Evolution is trying to
get you to spread your genes early and often, and maintaining the body is a
tradeoff with that, so it is a tradeoff between reproduction and maintenance.
Since for most
of evolutionary history, a 40-year-old was a really old person ? people were
dying of starvation, or disease, or getting eaten by lions. They did not live
to the ripe old ages we see now, so heart disease and cancer did not come into
the equation.
There are other
tradeoffs, too. For example, your immune system protects you against invaders
and saves you from dying an early age from a bacterial infection or viral
infection. But every time your white blood cells combat a bacterial infection,
they pour out mutagenic oxygen radicals and hypochlorite, to which is the same
chemical found in Clorox [liquid bleach]. White blood cells also put out
nitrogen oxide, and superoxide. Chronic infection in fact causes about 20% of
cancer, probably due in good part to these oxidants.
As we became
more interested in aging, we got very interested in the mitochondria.
Mitochondria, little organelles in the cell, are the power plants of the cell:
they make all the ATP that powers your brain, your muscles, and your
biochemistry. ATP is the high energy molecule that does the work of the body.
All that ATP is made in the mitochondria. Basically, the mitochondria are
rechargeable batteries. A potential across the membrane is made by burning fat
and carbohydrate (which means taking electrons off of them to create that
membrane potential). Those electrons are added to oxygen to give water.
With age, the
mitochondria becomes very heterogeneous, the membrane potential goes down;
cardiolipin, which is the key lipid in the mitochondrial membrane goes down,
the oxygen utilized goes down, the ATP formed goes down, and the oxidant
leakage goes up, so the cell starts oxidizing it. We think that is a major
contributor to aging.
The mitochondria
are decaying, so you are not getting enough energy, and your defense systems
are not working as well, and you are making more oxidants, and the whole system
is a vicious cycle, going downhill. This contributes to cancer, heart disease,
impaired brain function and all these degenerate diseases that come along with
aging.
BSJ: Is this part of the natural process?
Ames: Yes, it is all natural. Which does not mean you cannot
influence it, but it is all natural. It happens because of these accumulated
tradeoffs, old people are not in the prime of reproductive life, and so,
basically, evolution does not care about them very much. Some of the things
that helped you when you were young hurt you when you are old.
BSJ: How does DNA become damaged?
Ames: When you "bleed electrons" in the
mitochondria, you are making all these powerful oxidants ? superoxide, hydrogen
peroxide, and hydroxyl radical ? which are the very substances you get from
radiation. So living is like getting irradiated, in a fundamental sense.
Oxidants can
react with and damage DNA. When you add electrons to oxygen, you are reducing
the oxygen to water. When you burn something you are oxidizing it, which means
taking away electrons.
BSJ: What is the free radical theory of aging?
Ames: That oxidants are a major contributor to aging. A
scientist named Denham Harman, who worked at the Lawrence Berkeley National
Laboratory many years ago, was a physicist and biologist. He was intrigued that
getting irradiated was in some ways like aging. So he wondered if oxidants,
produced in normal metabolism, were doing the same thing as normal aging. And,
in fact, it looks like it is a major contributor.
BSJ: If you could stop oxidative damage to DNA, would that
prevent aging?
Ames: We think, it is not just DNA damage; it is your
proteins oxidizing, your lipids oxidizing. You are constantly repairing or
getting rid of all of these damaged molecules, but your defenses never quite
keep up ? because you want to put a lot of energy into reproduction. It does
not pay, from an evolutionary standpoint, to have 100% defenses. It is a major
tradeoff of life.
BSJ: So what about antioxidant supplements?
Ames: We need a certain amount of vitamin C and vitamin E.
If you do not get enough, it is like getting irradiated. But you do not need a
huge amount, and too much of some things can be toxic. Everybody should be
getting maybe 100 or 120 milligrams of vitamin C a day. Now the recommended
daily allowance is 60 milligrams, but I suspect they should raise that a bit,
because you do not saturate your tissues until you get to a 100 or so
milligrams: a couple of oranges. If you eat your two fruits and three
vegetables a day, which is what we should be doing, then you should be fine. Or
you can take a multivitamin pill as insurance.
Same thing with
vitamin E: perhaps 200 mg is sufficient. With both of these vitamins, I do not
believe people should be taking grams of them. But mostly, you do not see much
toxicity.
Cigarette smoke
is full of nitrogen oxide, a powerful oxidant, and that depletes your vitamin C
and E. So a smoker really ought to be eating up a better diet than a
non-smoker, but most smokers do not.
BSJ: Do you take multivitamin supplements?
Ames: I have an Italian wife, who is also a professor in
this department, so I eat a very good Mediterranean diet, with lots of fruits,
and vegetables. But I take a multivitamin pill as insurance. I think everybody should.
BSJ: Which kind do you take?
Ames: It does not matter. They are all pretty much the same
? they all have the same minimum daily requirements. I take one without
iron. Women need lots of iron and men
may be getting too much.
BSJ: Could you explain your research on micronutrients, such
as folate, B12, B6, etc.?
Ames: It is known that the quarter of the population eating
the fewest fruits and vegetables has double the cancer rate for practically
every type of cancer of the quarter of the population eating the most. If you
divide the population into quarters, which epidemiologists do, and study fruit
and vegetable intake versus cancer. There are over 200 studies, and they are
amazingly consistent: the lowest intake quarter of the population has double
the cancer rate of this type of cancer, or that type of cancer, of the quarter
eating the most.
So we should be
eating at least five portions of fruits and vegetables a day; 80% of U.S.
children do not. If you are not, you are in trouble. The bottom quarter is
eating two portions of fruits and vegetables a day on down, and the top quarter
is eating four or five on up. So we are not talking about a big difference.
One can discuss why
fruits and vegetables protect against cancer: I think that micronutrients are a
good part of it. It may not be the whole story. There are other things in
fruits and vegetables, but if you don?t get your micronutrients, you are in
trouble.
We have been
working on vitamin C, vitamin E, folic acid, B12, and B6. For all of these, if
you do not get enough, it is like being irradiated. One of my graduate students
worked out the mechanism of why folate deficiency breaks your chromosomes. And
when we looked at what percent of the American population was at a level where
they are breaking their chromosomes, it was 10% of the population who was
folate-deficient at that level. And in 2 small studies done 20 years ago, which
should be repeated, it was half the people in the inner-cities. So poor people
are eating terrible diets ? they are not getting their fruits and vegetables,
and they are their chromosomes which
gives them cancer and heart disease and some evidence suggests perhaps
cognitive dysfunction as well.
BSJ: So conceivably, children who live in these poor areas
and do not get as much nutrients could age faster?
Ames: I think they are aging faster. They are getting all
these degenerative diseases and may even damage their mental functions, that is
more controversial, but all these nasty things are happening if you do not get
your fruits and vegetables.
Folic acid is named
from the word leaf. "Folia" is the Latin word for leaf. Foliage means
leaves. You get folic acid from spinach. If you do not eat enough greens, you
become folate-deficient and chromosomes break.
If you do not
get your vitamin B12, which comes from meat, the same thing happens. It works
in the exact same way. You break your chromosomes. Elderly vegetarians and kids
on microbiotic diets, who are short on B12, are breaking their chromosomes; 14%
of the elderly are low in B12.
And vitamin B6,
which you get through peas and beans and things like that, works in the exactly
same way. So all three of those vitamins work in the same way biochemically.
They are all radiation mimics. It is just like getting irradiated. 10% of the
population is low on vitamin B6.
The public is
being scared about cancer from a hundred, miniscule hypothetical risks like
pesticide residues, which I think is all completely implausible and based on
wrong assumptions. They do not know what is important anymore. It is the worst
thing you could do to people, distract them with a hundred, hypothetical
miniscule risks, because what you want to do is go after the major risks and
hammer on those, so people understand them. People know about smoking, but you
ask the average person how many fruits and vegetables they should be eating per
day, they say maybe two. Does it have anything to do with cancer? Half of them
do not know that it does.
Did you know
that fruits and vegetables were so important in protecting against cancer? You
all know, however, that pesticide resins are damaging you, but they are not
really. Pesticides are a major public advance because they lower the price of
fruits and vegetables. So by the time EPA bans all the pesticides because of
all of the confused activists, all they are going to do is give the poor
cancer, because they are making fruits and vegetables more expensive. Organic
foods are a lot more expensive and probably more dangerous than ordinary foods.
E. Coli 0157H7 is a very toxic E. Coli strain. Where does it come from? From
horse or cow manure. You are likely to get more toxic E. Coli from organic food
than your other food.
It is all kind
of a mass hysteria spun up by people who have a self-interest in keeping all
this going, but it is not helping the poor, and it is not helping the
environment. Pesticides are good for the environment. What they do is give you
better yields on the same amount of land. So all the marginal farmland can go
back to being wild and the birds and the beasts can frolic. That is what you
want to do. You want genetically-engineered food and pesticides to get higher
yields in agriculture.
The U.S. has the
money to set aside national parks, and we should, so that we have birds and
trees, etc. It is a matter of putting
the money where it does the most good for the environment. All this fuss about
traces of DDT, or little traces of pesticides, or genetically engineered foods,
is all a distraction, and it is really all counter-productive because those
things help wealth creation and help get more food out of less land and do not
hurt people. People have been breeding crops for thousands of years to create
better yield, in all sense. Genetic engineering is just a faster way of doing
it. Why should we not use genetic engineering to make crops more insect
resistant? Then you will use less pesticides, and get better yields and tastier
produce.
People are
spreading this anti-technology fear, and I just think it is all perverse. The
newspapers have one scary story after another about some miniscule hypothetical
risk. You do not get a balanced view out of the newspapers on what is really
giving you cancer and what is good for your health. In the end, it is all your
own choices.
BSJ: What is uracil incorporation into DNA?
Ames: Folate, or folic acid, moves one-carbon units (methyl
groups) around in biochemistry. A methyl group is added to uracil, which is
used in RNA, to make thymine which is used in DNA. If there is not enough
folate, that methyl group is not added, and the uracil pool (dUNP) goes up, and
the thymine pool (dTNP) goes down, and uracil is just in DNA.
We found 4
million uracils per cell in human DNA, even though DNA repair mechanisms are
constantly removing the uracil. Everytime you remove a uracil, you make a
transient nick (a cut) in the DNA. When you have a nick on one strand across
from a nick on the other strand, there is a chance that you sever the DNA and
break the chromosome.
The reason
radiation is dangerous is that it gives you a shower of electrons and you hit
both strands at once. So you get an oxidant-damaged base on one strand and an
oxidant-damaged base on the opposite strand. If there is just one damage, you
can repair by making a nick in the DNA and sewing it up as the other strand is
holding it. But if you have two damages, then some percent of the time, you get
a nick on one strand and a nick nearby on the opposite strand and the
chromosome falls apart. That is hard to repair. The dangerous part of radiation
is when you get chromosome breaks.
Folate
deficiency gives you 4 million uracils per cell in the DNA. They are mostly in
one strand but then there is an occasional oxidant-damaged cell in the other
strand as well, and then the chromosome breaks. So, it is an exact mimic of radiation.
It works the same way mechanistically.
So my passion
now is to get vitamins into the poor. A quarter of the U.S. population take
multivitamin pills, but it is the quarter of the population who are eating good
diets who are taking the pills. And the people who need them, particularly the
Hispanics and blacks in the U.S. are eating really terrible diets, partly
because it is a poverty and education thing. Poor people are thinking
short-term instead of long-term, and are eating bad diets. In fact, 30% of the
vegetables that Americans are eating are potato chips and French fries; a much
better source of fat than vitamins.
BSJ: What foods are high in folate and all these other
micronutrients?
Ames: Each micronutrient comes from a different source.
Calcium comes from milk and cheese. Vitamin D from ultraviolet light: you need
a certain amount of sunshine to make vitamin D in your skin, unless you drink
vitamin D fortified milk. Folate comes from green leaves, vitamin C comes from
fruits like oranges, B12 and zinc come from meat, and Vitamin B6 comes from
peas and beans.
If you eat a
good, balanced diet, with not too much fat, not too much carbohydrate, not too
much meat (some fish, some meat), some whole-wheat grains, and lots of fruits
and vegetables, it can be a wonderfully good diet. The people with the longest
lives in Europe are the Greeks and the Southern Italians, who are on this
Mediterranean diet. First, they are getting lots of exercise, and second, they
are eating enough fish, some meat but not too much, lots of fruits and
vegetables, and olive oil. And that is a wonderful diet. The Japanese have a
long life span, and they are eating a completely different diet. Yet, they are
eating a good diet too.
BSJ: How did you first become interested in the science of
aging, or science in general?
Ames: My father was a schoolteacher. He taught chemistry in
high school. So I was always a little bit interested in science.
I collected
animals as a kid, up in the mountains. Frogs and snakes and such, what kids do.
So, I was always interested in science. I went to the Bronx High School of
Science, then went to Cornell, and did my Ph.D. at the California Institute of
Technology.
BSJ: What do you remember the most about your college years?
Ames: I had a wonderful time at Cornell. I was doing
everything. I was never a terribly good
student because I was always going to the library and checking out four or five
books about an area of interest, and reading about everything. Instead of
studying for some exam I would be reading Tolstoy. I was a little
undisciplined, and not a very good student, but I was always going my own way.
I was a graduate
student at Caltech in the early 1950s. I did my postdoctoral at the National
Institutes of Health, and stayed on for 15 years before coming to Berkeley.
BSJ: What advice would you give to undergraduates who wish
to pursue a career in science?
Ames: Do something you are passionate about. That is one
thing I feel strongly about in life. If you do something you are passionate
about, then it works out. If you are at all talented and have the ambition, and
you really want to do it, then you will do well.
Science is very
competitive, but running a business is very competitive. Being a lawyer is
competitive, and being a doctor is competitive, so whatever you go into, there
is competition. But science is a real meritocracy. It does not matter who you
are or what you look like, people judge you by what you do. If you do not run
controls and cut too many corners, soon everyone knows you are a slob, and
nobody pays any attention to you.
Everybody makes
some mistakes, but a good scientist really wants to get it right. If you shoot
down your own work, it is better than having someone else shoot you down. You can
be put into any city in the world that does science, and you know people, and
they know you. So it is really a fun field, a meritocracy without too much
politics, competitive but also cooperative.
BSJ: How does it feel to work alongside your wife in the
same building?
Ames: She is a professor in the department too, but she has
her own field. She works on cellular transport mechanisms. We have not
collaborated very much over our careers. Occasionally, we have one or two
papers together, but that is about all. She has her thing, and I do my thing.
We walk to work together, but that is it, though we enjoy discussing science
BSJ: Do you have any children?
Ames: Yes, two children.
BSJ: What do they do?
Ames: My daughter is an architect, and my son is a computer
consultant.
BSJ: And what do you like to do in your spare time?
Ames: I read an enormous amount and I garden. I never have
time to watch television, I may turn it on once every six months. Our kids
insisted on buying us a VCR and a proper color television, which we never had.
We hardly ever use it unless there is a war or an earthquake. My hobby is
reading economics and all sorts of other things. I am trying to be a wise man,
but that is hard.
BSJ: Where do you hope for your research to go?
Ames: Well, right now we are making progress in rejuvenating
old rats. By feeding the rats high levels of some normal mitochondrial
metabolites, we can apparently reverse the decay of mitochondria in the rats.
These rats get up and do the Macarena. They are the liveliest old rats you are
going to see.
To measure their
levels of activity, we have a video camera watching the rats at night. The
young ones are very frisky and the old ones are lethargic. When we feed the old
rats these compounds they become frisky. They also seem to run better in a
maze. Now we are trying to do longevity studies on these animals, and we are
trying to extend it to people.
In a fit of
enthusiasm, I called up my son in New York and said, "One of my students
seems to be changing old rats into young rats." My son was silent for a
minute, and then he said, "Oh, that is very well and good, but you let me
know when you do the next step: changing old people to young rats." My son
has a quick tongue, and my children keep me anchored to the ground.
BSJ: How would you like your work applied to society?
Ames: Well, I am really passionate now about getting
vitamins into the poor. The people in nutrition do not like the idea of
vitamins because they say, "You should eat a good diet, and we do not
understand all the reasons fruits and vegetables are good for you."
But, I know
micronutrients are important. Vitamin supplements may not provide all of the
good things in whole fruits and vegetables, but why not tell people to take one
as insurance. A multivitamin pill is not going to hurt anybody, it is cheap and
would help the poor. You can still try to get the poor to eat five portions of
fruits and vegetables.
I want to pin
down the science. I want to try to see: if vitamin deficiency causes cognitive
dysfunction? If it affects your brain, it is a big thing because the poor,
again, are eating terrible diets.
BSJ: How many kids do you think there should be per
couple?
Ames: Well, that depends on the circumstances ? the number you
can afford to take care of. You do not want the world to fill up with a person
standing everywhere, but that is not going to happen. Holland is enormously
more crowded than other places, and it is a wonderful country.
The best thing
for the environment is to make people rich, because then they stop having
children. It is the only thing that works.
What we owe to poor countries is to drop our protective economic
barriers ? the U.S. is the engine of the world because we have very little
protection ? and buy the goods of China and all these poor countries. They get
rich, and the first thing that happens is that they stop having children.
The best thing
for the environment is wealth and technology, and the worst thing for the
environment is poverty. You go into poor countries and you see that they ruin
the environment compared to rich countries. Rich countries can afford to set
aside all this land. The U.S. sets aside land as national parks ? we can afford
to do that. Poor countries are burning down the rain forests because they need
food to eat.
So I think
environmentalists are confused because they do not understand what works and
what does not. It is technology and wealth that you want, not poverty,
bureaucracies, and lack of technology. The world in the 1900s was a horrible
place. The streets were full of horse manure, people were dying in their 40s.
It is technology that brings us wealth, health, and control over the world?s
population.
BSJ: So you are only working on your research?
Ames: Yes, I usually work on Saturdays also. I come in, and
it is nice and quiet. And I am behind on everything as usual.
I get wonderful
people in my lab. I have a very international group, from all over, and they
are just great people. I give them a lot of freedom, and they are
cross-collaborating and generating all this research, and it is going very
well.
I also get
wonderful undergraduates. I have about eight undergraduates doing honors
research, and I let them interview post-docs and choose who they would like to
work with. It is fun having these bright young people around.
BSJ: How old do you think people should live? Is your goal to increase longevity
indefinitely in humans, or merely to improve health as we get older?
Ames: I really want to understand what is happening. And when you understand something, there are
hundreds of ways to intervene. Out of
that understanding, my student, Tory Hagen, stumbled upon a way to rejuvenate
the mitochondria in old rats. That came
out of understanding how mitochondria might be decaying, and how one could
intervene in the decay process.
I am not wise
enough to say how long people should live. But scientists are extending life in
all these little increments. There is progress on treating tumors through
chemotherapy. I am interested in preventing cancer, and that knowledge is
coming along very quickly.
But it is one
thing knowing that you should not smoke and that you should eat your fruits and
vegetables. The next thing is convincing people that it is eight years off your
life if you are a smoker and another big chunk off your life if you do not eat
enough fruits and vegetables. You probably all have friends that smoke, and I
am sure there is pleasure in doing that, but it can take years off your life.
It may be good for the country ? you die at 65 and do not collect your pension
? but it is not good for the individual.
BSJ: Why do you suppose that humans, as a whole, constantly
search for this fountain of youth?
Ames: Well, nobody likes the thought of dying, or even
decaying. Hopefully, in the future, not only will we live longer, but our
brains will function longer. Who wants to live longer with a brain that is not
working properly?
As we extend
life span, I think that we will affect not only mortality but also morbidity. I
am almost 71, and I feel young and energetic. I do not know how long that will
go on, but it is better than some people who mentally retires at 40. And now
that the university has taken the retirement age off, I am happy to keep my lab
running.
BSJ: In your opinion, how does one age gracefully?
Ames: I think you accept life for what it is, including the
tradeoffs ? you cannot have it all. I have had a wonderfully happy life, a
happy marriage, kids I like, and work that I like, so I feel very privileged. I
was never really interested in money, but the money somehow came along with
doing what I enjoyed.
BSJ: Do you believe that aging, cancer, and degenerative
diseases are related closely enough such that to find a solution to one would
be the key to bringing about the solution to all of these conditions?
Ames: To some extent, what we are trying to do is tune up
the body, just the way you tune up a car. We have forty micronutrients that we
need, and I want to make sure we get the optimum amount of each of them. The
amount of oil you want in your car is not the amount you need to get out of the
garage, it is the amount you need for the longest life span for that engine.
The same goes with people. The amount of vitamins that we need is the amount
that keeps our DNA damage to a minimum and gives us a long life span.
And that is
still being worked out. Biology is going like a rocket now with help from the
genomics revolution and computers. These new DNA chips will help in aging and
micronutrient research. Women after menopause take hormone replacement therapy,
and that may add a few years to their lives. We are going to be tuning up
people, tuning up their biochemistry. With some metabolites that we normally
make in our bodies, but do not think of as vitamins, we may need more of them
when we are old, or at least rats do. So in a sense, they are
"conditional" micronutrients. There may be micronutrients you need
only when you are old.
Nutrition is a
wonderful field. Every time I turn around, there is a "golden apple"
to pick. Some people think it is a fuzzy field. Same thing with aging.
Relatively few people work on aging, mostly elderly scientists like myself,
whose neurons are going rancid. I think it is time for the younger people to
come into the field.
Science is
moving so fast now. As long as we can keep the global economy going well, then
science will flourish.
BSJ: Which area of study do you believe is progressing the
most in terms of aging and promoting longevity?
Ames: All of science is progressing quickly. People are
understanding more about genetics. A DNA chip soon will have all 100,000 human
genes on a glass slide. We will be able to take some blood from a person and
see every gene ? which ones are turned off and which ones are not turned off.
And we will even be able to distinguish single nucleotide polymorphisms, the
differences between one of my genes and one of your genes. And how you
metabolize drugs, and what nutrients you need ? all that is going to be worked
out in the years to come.
So it is a good
time for science, for humanity, and for the world. There are so many
interesting problems to solve.
BSJ: If you could live forever, would you? Why or why not?
Ames: If your mind is functioning and your body is
functioning, why not enjoy life. I look forward to every year. But, I have a
happy marriage and work I enjoy. Without that, it might be different.
You know, single
men have about an eight year shorter life expectancy than married men. Women
know why: because single men self-destruct. They smoke too much, they drink too
much, and they don?t eat any vegetables. It is the wives that civilize them.
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