Future Current

To be practically useful, the measurement of aging rate (by monitoring the decline of a global index of functional capacity, expressed as a rate function) must be relatively easy and inexpensive. Measured aging rate should enable empirical testing of purported anti-aging interventions in relatively short-term human clinical trials. This is the primary objective of the Kronos Longitudinal Aging Study. Chris Heward, President of Kronos Science Laboratory, presented on strategies aimed at intervening in the aging process at the 2007 Foresight Vision Weekend, including a brief overview of the study and its intentions.

The following transcript of Chris Heward’s Foresight Vision Weekend presentation has not been approved by the speaker. Video is also available.

I like to start all of my talks with the same joke.  It’s a good joke, and it’s important to tell this joke because it fits right in with the philosophy of the way we practice medicine at Kronos.

This old guy goes into the doctor’s office, he’s obviously in pain.  The doc says, “Sit down, sir, and tell me what your problem is.”  The gentleman says,” Doc, my problem is I can’t pee.”  The doc says, “What do you mean you can’t pee?”  The man says, “Well, I’ve been noticing for years every morning the stream gets smaller and smaller and it takes me longer and longer.  Finally, when I went to the bathroom this morning and tried to pee, nothing would come out.  You’ve got to help me—it’s starting to really hurt me!”  The doc looks at him and says, “Do you mind telling me how old you are?”  The guy kind of straightens up and says, “I’m 99 years-old!”  The doc thinks for a minute and says, “Well then, you’ve peed enough.”

I like that joke because it illustrates a couple of very important points when thinking about your health.  The first one, the most important thing I want to drive home, you don’t wait until you’ve got a serious health problem before you go do something about it.  You go and find a professional to give you advice on how to prevent a real serious problem, like not being able to pee, or a lot of other problems, like heart disease and stroke, diabetes and so forth.  The other thing I like about it is, operating in an arena of constantly trying to practice our version of anti-aging medicine, we encounter people who think it may not be a good idea to help people live longer.  We’re supposed to die on time and get out of the way for the next generation.  I think that’s as ridiculous an idea as telling somebody when they’ve peed enough.

There is a lot of stuff I want to share with you all, and I really enjoy the opportunity to talk to a group of people who are smart and with whom I can share this much in this short a period of time and still count on them tracking what it is I’m saying.  What we practice at Kronos is optimal health medicine, not “anti-aging medicine.”  What we mean by that is we help people live as healthy as possible for as long as possible, and we use conventional technology to do that.  That is what I’m going to describe today.

Part of the driving question behind the research that we do at Kronos is to ask, “What is aging?”  Sadly, I don’t have a good answer for that.  Aging is a very difficult, complex problem.  We all recognize it when we see it—it’s kind of like pornography in that way.  You know it when you see it, but it’s hard to define.  The symptoms of aging are familiar to all of us.  When those symptoms are allowed to progress for a very, very long time, this is what you end up looking like.

This is the world record holder: the oldest woman who’s ever lived.  She died at the age of 122.  She is in the minds of many gerontologists the most successful ager, but if you look at her, she does not look very good.  The problem is, this is what it’s like to be old. I’ll talk to you at some length about what it means to age successfully in this day and age, because we don’t have true anti-aging interventions.

The major causes of death these days, things that are going to kill three out of four people in this room, are age-related diseases.  This aging thing is a big problem.  Gerontologists have pointed at charts like this to brag about the improvements that we’ve achieved over the past 1,000 years in terms of human lifespan.  However, if you look closely at what we have really done, particularly in this most dramatic period of improvement, and spread it out a little bit, it does not look quite so good.  The important thing to remember about this chart is life expectancy at birth.  The bulk of this improvement is due to improvement in things like hygiene and reduction in infant mortality.  It isn’t that older people are living longer.   In fact, it’s now beginning to slow down because we aren’t making those kinds of improvements at the same pace.

If you look at life expectancy at age fifty, the improvement in the last fifty years is not nearly all that great.  If you look at life expectancy at age 65, it’s even flatter.  Living older is still pretty tough.  If you are going to make it past the age of 85, you have to do it with some intention—it does not happen accidentally very often.

What can we do about it?  What is the status of anti-aging medicine in 2007?  It’s still hope in a bottle.  We don’t know how to do it.  Aging is still a hard problem, and we still don’t understand exactly what it is.

What we do at Kronos is we take a Western scientific approach.  Anybody who knows me well will tell you I’m a skeptic.  I have a hard time believing almost anything unless I see the data.  We apply that approach at Kronos throughout.  There’s a lot of what we do that is just testing what happens to people as they grow older.  There is a huge battery of clinical tests that we put our patients through that measure physiological changes as we age and a huge battery of biochemical tests that we do on blood and urine samples to get a good snapshot of an individual’s health status and functional capacity at that point in time.

Our objectives in this process are to measure that health status, looking at two things: biomarkers of functional capacity and health risk factors.  The purpose is to reduce disease.  We don’t start out trying to diagnose diseases.  That’s not our role—that’s what most doctors do.  Our focus is really on trying to evaluate where you are in the process of developing diseases.  Everybody in this room has a number of disease processes underway right now, and one of them is going to kill you.  We’re trying to figure out which one that is, or which one of your problems is likely to be your biggest one.

Once we have identified those risks we try to mitigate those with appropriate interventions.  The goal ultimately is not to live forever—actually, it is, but we don’t know how to do that—at the very least we think we know how to preserve functional capacity, improve your quality of life, and maybe live a little longer.  We do this with the health risk assessment, as I mentioned, and the interventions that are in our quiver of arrows are very extensive.  The reason we have physicians on our staff is so that we can prescribe drugs if necessary, and do anything we can do that makes sense to do to make you live healthier and longer.  We are as open-minded as we can possibly be and very skeptical.

Neutraceuticals and hormone replacement therapy are elements of the set.  The two biggies, I’m sad to tell you, are still diet and exercise.  That brings me to the Kronos Longitudinal Aging Study.  This is really the reason I went to Kronos.  I started out as a research endocrinologist, and when I went to Kronos my colleagues said, “What are you getting into anti-aging for?”  The answer is that it’s really a hard problem and really interesting.  This is really the study I came to Kronos to do.  It’s basically to try to follow the trajectory of people’s lives over time.  Our definition is an operational definition of aging that gives us the ability to measure it and to test interventions. By defining aging that way operationally based on a measurement of a wide variety of biomarkers, we can define it as the progressive degenerative decline in function with time, and it gives us the ability to quantify it.  You can actually measure aging as a rate.

Gerontologists have been studying aging for years and years, and yet, what are the units of aging?  How do you measure it?  Without a tool to actually measure something, an endocrinologist would be helpless.  You have to be able to measure those hormones to say anything about them.  For gerontologists, it’s no different.

This is the philosophy really that underpins our approach to the aging process and the research that we do at Kronos.  It’s based on the Baltimore Longitudinal Study on Aging. If you follow that trajectory that follows development, it looks as if everybody ought to live to about a hundred.  We don’t.  Why not? The reason people don’t make it to a hundred is because we don’t age in our own bodies uniformly.  You have different processes that are declining at different paces.  In this case, this gentleman’s cardiovascular system declined prematurely (this happens quite often) and hit the threshold for the viability of his cardiovascular system with a heart attack and died at age 65.  He might have had perfectly good bones and perfectly good muscle, but he is just as dead at 65 and was cheated out of an extra thirty years of lifespan because his weakest link bumped him off early.

Traditional medicine identifies those problems late in the game and intervenes in targeted ways to address the symptoms of the disease.  If they are successful they can buy a few additional years.  What we suggest as a better approach is to identify those degenerative processes as early as possible and use targeted interventions as early as possible to head it off at the pass, offering the individual many more years of healthy life expectancy.

That brings us to the future of anti-aging medicine.  Maybe someday in the future somebody will come up with an anti-aging elixir that will increase the lifespans of worms, flies, mice and monkeys, until we’re ready to try it in humans.  The idea there is that we have this population of people that we have been following for many years, and we have lots of data on their biochemistry and physiology.  We know the trajectory of decline that we’ve been monitoring over time.  We now have a population of people that we can use as subjects, and they don’t have to wait fifty or sixty years for the completion of a lifespan study.  You can look for a change in slope in this battery of biomarkers, and that change of slope if it happens is an indication of an anti-aging effect of this magic elixir.

That is basically the bulk of the Kronos Longitudinal Study on Aging.  You are all invited to participate in that study as subjects.  We need as many people as possible committed to being in this study for the rest of their lives.  We have thousands of people who have been in the study so far, on whom we have one single data point.  We have hundreds of people on whom we have two or more data points.  We really need thousands of people who will come in, being committed to coming back every two or three years to be retested so that we can get that longitudinal data.

I wanted to give you a better picture of the depth and breadth of what Kronos is about.  We are interested in aging research in general and are studying all kinds of things related to aging.  The KLAS is just one aspect of what we’re studying.  The first of these that I wanted to talk about is a study we’ve almost finished on Alzheimer’s disease.  Suffice it to say, Alzheimer’s is a big problem.  The United States spends $100 billion a year dealing with people in this country with Alzheimer’s disease.  We think it is a disease that would lend itself well to early interventions, like lifestyle interventions that have already been demonstrated to slow the progression of the disease.  The problem is in identifying individuals who are susceptible to the disease early enough so that you can target those individuals with appropriate interventions.  We have been working for some time trying to do that.

The thing about Alzheimer’s that you need to know is that it is essentially senile dementia with plaques and tangles.  You really cannot definitively diagnose AD, except after death.  We have attempted to come up with a genetic test for Alzheimer’s disease that is an improvement on the existing APOE test for AD that does not diagnose the disease but tells us your genetic susceptibility.  The test is based on Affymetrix’s 500,000 single nucleotide polymorphism chip.  We took a thousand Alzheimer’s patients post-mortem and a thousand matched controls and used both the Affy 100k and 500k chips.  With the 100k, we tested to see if any of those SNPs were predictive of Alzheimer’s disease risk.  We came up with a number of those SNPs which can be integrated into a global score that is predictive of Alzheimer’s disease in both APOE4 carriers and non-carriers.  We are now taking a look at the process of commercializing that. The value in the short-term is not clinically, but in researching, to help drug companies that have drug that may be helpful if given early in the process.

That is one study that we are just about finished with.  Another area that we focus on at Kronos is oxidative stress.  We probably have the best oxidative stress lab in the world.  We measure more free radical generators and enzymes—anything that has to do with oxidative stress, we do it.  The idea was to evaluate an individual’s level of oxidative stress, looking at protection factors and damage factors.  The idea was that you find a guy who is in the above average damage quadrant and below average protection quadrant.  We then give him protection factors and move him into the low damage quadrant.  It’s a nice story, but we have not bee able to do that.  We have been working on this for nine years and we still don’t know how to measure oxidative stress in a whole living, breathing individual.

We’re still working on it.  There are a lot of interesting studies that have been done and circumstances where we know oxidative stress goes up, like smoking.  We publish on that, but to actually do something about individuals’ oxidative stress levels in a day-to-day way, we don’t know how to do it.

Since I’m an endocrinologist, we also take a look at what happens to hormones as we age.  The endocrine system suffers the same sorts of functional decline as the rest of the body.  The big message that I want to drive home for those of you in the audience who are women, or know women, there is this gigantic misinformation machine out there in my opinion regarding hormone replacement therapy in menopausal women.  How many of you know what the Women’s Health Initiative is?  This is a big study that was done recently to study the effects of hormone replacement therapy in post-menopausal women.  The study cost the government half a billion dollars and the conclusion was that “hormones are bad.”  They terminated the trial early and millions of women stopped taking hormones as a result of the publicity surrounding that study.

Basically, what hormone replacement does is recognize that higher estrogen levels are associated with healthy useful function.  When those estrogen levels drop at menopause, there are consequences associates with that drop, largely because estrogen has receptors on virtually every important tissue in the body.  You take away that estrogen and there are serious health consequences.  We knew that before the WHI.  When I first got into gerontology, one of things that struck me first as an endocrinologist was that there was one true longevity drug, where risk of death from all causes was actually reduced if they took this drug.  It’s estrogen.

The data were compelling.  We just needed a study that wasn’t epidemiological—a double-blind, placebo controlled, prospective clinical study to get us past the worry that maybe the reason we are seeing all these women on hormones live longer and do better is healthy user bias.  (Healthier women tend to be the ones who would use the hormones, and so we’re seeing a spurious result).  So they spent a half billion dollars to do this study.  The problem is, the important issue being addressed by that study was cardioprotection.  The epidemiological data suggested that women on hormones didn’t get as many heart attacks, but it could be healthy user bias.  They needed to measure cardiac events.  It had to be a big trial, which is why it cost so much.

If you study the women who normally get hormones, around age fifty, you are going to have to study them for a long time before enough of them have heart attacks that you can draw any conclusions.  Women in their fifties don’t get a lot of heart attacks—so what did they do?  They found a bunch of old ladies and recruited them into this study.  The average age of the women in the WHI was 63.  Some of these women were smokers in their 70′s.  They’ve never been on hormones, but let’s give them hormones now!  What hormones did they give them?  Oral estrogens.  Well, I can tell you as an endocrinologist that there is one effect you can be certain of with oral estrogens, they have an effect on the liver.  When you take something in your mouth, the first thing that happens is that the blood absorbing those chemicals goes straight to the liver for detox.  The liver is exposed to this huge dose of estrogens that are not physiological and it produces clotting factors.  We know women in their 60′s have atheriosclerosis—let’s give them a clotting agent.  That’ll fix ‘em up.  Then we’re all surprised why we didn’t see a cardioprotective benefit in this population.

Eliezer Yudkowsky: Did you predict that in advance, or did you notice that after the study was concluded?

Sadly, I didn’t predict it in advance.  It took us awhile to figure it out, because we were all astounded by those results when they were released.  Should I have predicted it in advance?  Could I, if I had thought about it?  Absolutely.  We just didn’t.  It was a big, stupid, expensive mistake.

Look at what happens to cardiovascular events as a function of age to ordinary women.  Something magic happens at about age 50—I wonder what that could be?  It’s menopause.  We saw the protective benefits of the hormones in terms of fractures.  We have done extensive follow-ups on this research. The younger cohort who continued taking hormones after they terminated this study are beginning to show the cardioprotective benefit.   The women who would normally get hormones at menopause and stay on them, when you look at them in the study, there was a cardioprotective benefit that they should have picked up early on.  However, that was not even looked at until after the study was terminated.

I want to make this other point for those of you who are not on hormones because you’re afraid of breast cancer.  It is true that hormones in studies do show an increased risk of breast cancer diagnosis because estrogen does take cancer cells and stimulate them to grow faster.  There is no evidence that estrogen takes a normal cell and converts it to a cancer cell.  It is a Trophic hormone and it does stimulate cell division, so if you have cancer it is going to make the tumors grow faster.  Within the timeframe of the study, you are likely going to diagnose more cancers in that population where the cancer is growing faster.  The risk of dying of breast cancer as a function of estrogen use does not go up.  The risk of dying of heart disease is vastly higher than that.

Men have not been left out at Kronos.  We did a study on what happens to men as they age.  Hormones work in concert, so one of the things we are doing that is a little novel is studying, rather than just one hormone or compound at a time, we are trying to look at combinations of things.  There are examples in our biochemistry of synergistic effects.  Guys, we are hopefully going to come up with ways of addressing your problems as well.  The problem with most of the hormone replacement therapies, including estrogen, is the delivery system.  If we could find ways of delivering the hormones in the same fashion that the body does in youth, the vast majority of the negative side effects of hormone replacement therapy of whatever type would probably go away.  That’s going to require some technology and further research, and that’s what we’re doing.

Here, I’m going to address what you can do now.  I’m a here and now kind of guy.  I’m studying stuff to try and learn about the future, but I’m interested in helping people live healthier, longer today.

Here is the biggest health problem facing us today.  This is supposed to be a funny slide, but nobody ever laughs, and I think that’s probably a good thing.  The reality is that not just Americans now but all over the world this problem of obesity is becoming increasingly epidemic.  We’ve known about it for a long time.  The old food pyramid that we all memorized demonized fat, exhorting the American people in the literature and in the press to eat less fat.  We have known for forty years that we were too fat and it was not good for our health.  People have been dying of heart disease for a long time.

The amazing thing about the publicity campaign around that pyramid is that it worked.  In the United States we actually reduced the percent of calories in the diet from fat.  That’s an amazing accomplishment!  It’s unprecedented to budge people’s eating habits en masse like that, and yet they did.

Hooray for us, right?  We’re making progress. Well, what happened to the obesity rate during the same period?   The percentage of the population that is clinically obese, and by that we mean they have sufficiently excess body mass index to the point where we know there is a health consequence—it’s hurting them. What that means, just so you can guage it in your head, is a five foot four inch woman who is thirty pounds overweight—that is the point at which there are health consequences we can measure.  Are we solving this problem?  In 2005 we have some states that are almost one-third clinically obese.

What does that mean?  Does that mean you should go on a “diet”?  If there is anything we have learned over the past 40 years, it’s that the diets don’t work.  There are a zillion diet books and a zillion diet programs, but we are still getting fatter.  When I first began to address the issue  at Kronos of helping people control their weight, I spent months and months at the UCLA library trying to figure this stuff out.  The upshot is that eating certain foods trigger primitive genes.  The advice for our patients is to stop eating so much garbage.  If you are going to eat garbage, you are going to trigger those primitive genes and pay the health consequences.

I know there are those who are on caloric restriction and think it is really the end-all for longevity.  The results of human studies do not support that view.  I’m a data guy—until I see data to the contrary, I’ve got to go with the data we have.  The important thing about nutrition is to eat good things.  Everybody in this room knows pretty well when they are eating garbage.  If you are going to cut your calories back somewhere and you don’t want to risk lowering your nutrition, cut back those calories that don’t carry nutritional components.  What that means is most things that are white: rice, pasta, white bread, potatoes, that sort of thing.  If you are going to take in carbs, make sure they are brightly colored fruits and vegetables—there is good stuff that comes along with those calories.

Here is another problem we have today: portion distortion.   A turkey sandwich has five hundred calories more today than it did while back, and we eat it anyway.  If a pound of fat is 3,500 calories and you eat a turkey sandwich with an extra 500 calories in it each day, that’s a pound a week and fifty pounds a year.  That’s 500 pounds in ten years.  When you think about, you have really been restraining yourselves quite well because you’re not that heavy.  Just a little bit more restraint and you can really get your weight under control.

It’s really about calories in, calories out.  That is the first law of thermodynamics.  There are no tricks.  This is all about how many calories you take in and how many calories you burn.  That brings us to exercise.  There are a lot of things associated with exercise that change as a function of age.  If you look at what happens to athletes, people who exercise quite heavily function at a much younger level. The sad thing is that the slope is the same.  Even these exercisers are declining at the same rate as the sedentary people.  Exercise is not an anti-aging intervention.  The really bad news is that at about the late 70s, early 80s, they accelerate into decline. When I first saw an example of this, I argued and argued with the guy.  Then I saw another data set and another one.  What we think is going on is pain.  People are not able to maintain any level of exercise like they used to, and at those ages pain starts impacting the intensity of the exercise.  The training effect declines.

Here is the important thing.  If you don’t care about being fat, then you can get all the health benefits of being thin if you are fit.  I’ll never forget, I ran a race in Redondo Beach called the Sand and Strand–two and a half miles on the sand, and two and a half miles on the strand.  It’s co-ed and there’s not much room, everyone is mixed in there together.  I got there, and there’s this fat lady in front of me, and I wondered how I was going to get around this lady.  I followed her for five miles, because I couldn’t catch her.  She was fit.  If you look at unfit people, regardless of their level of obesity, their risk of death is higher than fit people.  This same sort of thing applies to smokers as well.   If you can be a fit smoker, then the consequences of smoking are not nearly as dire.

I could spend three hours talking about supplements.  We spend a lot of time researching and studying supplements.   Again, I’ll cut to the chase and give you the bottom line.  Fish oil is magic, and I don’t say that lightly.  It’s probably only magic because our diet is so completely lopsided these days in terms of the amount of Omega-6 fatty acids that we take in our diet because of the nutritional changes that were introduced into our diets in the latter half of the last century.  We take in all these vegetable oils, which are rich in Omega-6, and that produces an imbalance between Omega-3 and Omega-6 that has health consequences.  When you take Omega-3s as a supplement, it helps reestablish that balance, and the health benefits are pretty impressive.  In a small human trial we showed that fish oil actually improves insulin sensitivity in older people. Loss of insulin sensitivity is a well known and serious age-related process.

This is the proof.  Those cultures that have lots of fish in their diet do not have heart disease.  Heart disease is the biggest threat coming at most of us.

One of our biggest challenges is that it’s expensive to do the testing that we do.  We get a snapshot on you today, and we don’t know how that really compares to the snapshot next month.  You usually do not come back for at least a year to three years, and we have to draw our conclusions not based on a small data set, but based on a very large data set because of that biological variation that occurs from day to day.  If we had those kinds of things, that would be great.

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