The Meaning of Anti-Aging
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There is a war being fought over the meaning of "anti-aging" and (to a lesser extent) "life extension." It's fought with words and funding between and within a number of different factions within the business and scientific community. You can see views from the scientific community expressed in a recent SAGE Crossroads webcast.

A recent skirmish in this war - in the context of the Silver Fleece award made by Jay Olshansky to A4M at International Conference on Longevity - was mentioned at the Longevity Meme, complete with further links for your perusal. This was a fairly typical exchange of views, but involved some of the players in the wider war who are of more interest to advocates for serious research into understanding and curing aging.

On the one side, we have Jay Olshansky, regarded as one of the more conservative gerontologists. He has said that radical extension of the healthy human life span is impossible in the near term, and maybe also in the long term. This is an extreme position that Jay Olshansky must defend within his own field. Moderate gerontologists like Stephen Austad (with whom Oleshansky has a well-known public bet on healthy life extension) and forward-looking biogerontologists like our own Aubrey de Grey hold that large gains in healthy longevity are possible within our lifetimes.

On the other side, we have the American Academy of Anti-Aging Medicine (A4M), often represented in the media by Ronald Klatz. I will admit to being confused by the actions of A4M; they seem to straddle the new school and old school worlds in the community. For example, A4M was an early donor to the Methuselah Mouse Prize and Ronald Klatz speaks out in support of therapeutic cloning, stem cell research and regenerative medicine as tools that will extend the healthy human life span. On the other hand, A4M runs anti-aging conferences that are widely reviled in the scientific community due to the presence of vendors from the fraudulent and adventurous marketing school of "anti-aging" pills, potions and crystals. At the same time, Ronald Klatz has expressed the desire to see the "marketeers" vanish from the industry, and recognizes the great harm they are doing to scientific progress.

Olshansky views A4M as doing great damage to legitimate research and science. The founders of A4M view Olshansky as an entrenched member of an establishment unwilling to grant legitimacy to any of the "anti-aging" industry, no matter what evidence is offered or views espoused.

This war is being fought over money, but money takes second place to the perception of legitimacy. It is this perception of legitimacy that determines funding for scientific research and revenues for businesses. Scientists feel, quite rightly, that the noise and nonsense coming from the "anti-aging" marketplace is damaging the prospects for serious, scientific anti-aging research. If everyone knows that anti-aging means high-priced cream from Revlon marketed to the gullible and brand-aware, no scientist is going to get funding for a proposal that uses the word "anti-aging." Worse than that, people start to assume that real efforts to reverse aging must be impossible.

Businesses in the "anti-aging" marketplace make money from the aura of legitimacy whether or not their products perform as advertised, and so a lot of effort is expended to create and maintain this perception of legitimacy. Those businesspeople who do feel they have working problems carry out their own fight aginst opportunists, frauds and "marketeers" who they feel are damaging their own market. Ironically, this is much the same argument used against these businesses by scientists like Jay Olshansky. The vast amount of money spent on products that claim to turn back the clock demonstrates that people want real anti-aging medicines. The trouble is that these real anti-aging therapies simply don't exist. Or do they? It all depends on how you define "anti-aging."

I've spoken before about "optimizing natural longevity" in the context of trying to draw a distinct line between what you can do now to lead a longer, healthier life, and what will be possible in the future. We can presume that there exists, for each person, some maximum life span that you can reach using the technologies and understanding of today. You can adopt calorie restriction, exercise, keep a good relationship with a physician, and spend an appropriate amount on supplements and healthcare. Each of these items will help you to live longer and in better health than you would otherwise have done. Does this make them "anti-aging," preventative medicine, good maintenance, or merely not damaging yourself quite so much?

If an improved supplement comes onto the market that adds a few years of life through some biochemical mechanism, is that "anti-aging?" How about improvements in general healthcare for the elderly that have the same effect? Or a way to cure heart disease? All of these things are clearly going to extend healthy life span by some amount. We could spend a lot of time arguing one way or another (and proposing further, more ambiguous examples). When Ronald Klatz says "anti-aging," however, I'm fairly sure he doesn't mean the same thing as Jay Olshansky's definition.

One problem is that we don't have any way of measuring effectiveness for a proposed anti-aging treatment, short of waiting for the subject to keel over. This is clearly not the desired experimental approach for those of us who want to see radical life extension in our lifetimes. We need biomarkers for aging: ways of measuring the progression of the aging process in our bodies. Even if we do find aging biomarkers, however, it isn't clear that they will allow accuracy to the point of being able to say "this treatment is giving you an extra two years of healthy life." Car enthusiasts can tell when they're getting that last 10% out of the engine, but you can't determine that sort of thing when examining health and life span.

I'll leave you with this thought to mull over: if we possessed medical technologies that could extend the healthy human life span to 150 years (or more), I think it's a fair bet that we wouldn't be arguing about the semantics of anti-aging and life extension. In large part, this money-fueled argument is entirely due to the absence of working anti-aging medicine that can greatly extend our healthy life span.

This is - once again, not to be repeating myself too much here - why a focus on medical research and funding is vital to healthy life extension. If a tenth of the effort spent on redefining "anti-aging," selling junk, or trying to optimize natural longevity was spent on the medicine of the future, just imagine where we could be by now! The medicine (and lifestyle choices like calorie restriction) that we have access to in the here and now are largely ineffective in the grand scheme of what is possible. Science can do far, far better in the long run, but getting there is going to take work, activism and support. What are you waiting for?

Comments

Excellent and (from my opinion) balanced overview of the current situation.

Thanks Reason

Posted by: Bruce Klein at March 10, 2004 11:30 PM

Effective biomarkers for aging would be a very important milestone. There could be advances in life extension before a standard system of aging biomarkers is developed and accepted. But I don't believe that anti-aging medicine will be fully accepted until such biomarkers are established practice. If the effectiveness of a treatment can't be readily measured within a reasonable time frame and within humans, it will remain suspect.

If biomarkers were available the doctor and patient could see how well anti-aging therapy was working. I can imagine a patient being happy that his biomarkers showed 45 when he is 65. The doctor would then say that yes, this was good for five years ago, but now we expect people your age to have a mean biomarker score no higher than 40.

I agree that if we had treatments that extended life to 150 years there would be no semantical argument over life extension. This reminds me of the state of impotence treatment a few years back.

Treatment for impotence was something that the medical community was slow to, er, touch. That was a field dominated by quacks and witch doctors: "Stir this rhino horn powder into your coffee and think about trains going into tunnels." Viagra was discovered by researchers who were investigating drugs to improve circulation. Had they set out to find an impotence drug they may have had trouble getting the funding.

Today there is no lack of funding for impotence drugs. The same will be true I suspect once we have a treatment that is as obviously effective for aging as Viagra is for impotence. This brings me back to the biomarkers. Humans age so slowly that without biomarkers it will be very hard to make speedy scientific progress. "It works in the mouse models, but what efficacy" the FDA will ask, "can you show for humans? Come back to us when your test subjects pass the 100 year mark."

Posted by: Stephen Gordon at March 11, 2004 6:15 PM

Comparison with the recent evolution of the erectile dysfunction industry is an interesting one - thanks for bringing that to my attention. I'll have to add it to my list of analogies.

Posted by: Reason at March 11, 2004 10:12 PM

The idea that we need biomarkers for aging deserves a bit of scrutiny: it is widely stated, but actually it isn't all that cogent. It's not just that such markers are unlikely ever to be all that accurate (as Reason notes). Worse is that such markers will not be establishable to **be** markers except by ... waiting for a bunch of subjects to keel over. If the subjects are monkeys then this validation will be nearly as good as if they are humans, but that still takes a very long time.

Worse yet, a biomarker of normal aging (i.e. a measure of how long it will be before a person dies of age-related cause in the absence of any intervention) may or may not be retarded by an effective therapy to extend healthy lifespan a lot, because that therapy may not work by slowing the process measured by the biomarker -- it may work by making people more tolerant of the process. A simple example is accumulation of mutant mitochondrial DNA: the likeliest good solution to that is to introduce modified copies of the 13 protein-coding genes from that DNA into the nucleus, so that any mutations in the mitochondrion will be harmless because the same proteins are being synthesised from the new nuclear genes. So the level of mitochondrial mutations ceases to be a biomarker of aging in any useful sense. A different sort of case is when a range of types of change cause (additively) the same types
of problem, and some of the changes can be reversed more easily than others. A case is the accumulation of protein/protein crosslinks in long-lived material such as the artery wall. It turns out that some of these crosslinks are pretty easy to break with drugs -- that's why ALT-711 is in clinical trials -- but others will be much harder to break because they're chemically more stable. That means that in the first generation of life extension therapies we can get away with breaking the easy ones and letting the others carry on accumulating, because it's the total amount of all types of link that makes the artery less elastic and causes hypertension. So again, the level of the hard-to-break links will cease to be a good biomarker of aging.

This is actually extremely good news for curing aging soon, however. When you have a pretty good idea of what progressive processes end up causing a machine to fail, and if you have a way to reverse all those processes, you will be confident that doing so will extend the life of the machine even before it duly exceeds the default lifetime. That is where we are with aging today. We have a very good idea of all the types of molecular and cellular change that accumulate over time as side-effects of metabolism and eventually cause age-related losses of function and eventually death. And we know the fundamentals of how to fix all those things. Sure, it'll be a nice relief when people who've received all these treatments actually do live a long time, but we'll already be confident of that result well before then.

A fair retort to the above is "hang on though, surely you needed some biomarkers in order to gain the initial good idea of what progressive processes end up causing a machine to fail?". But really that's just another way of saying that we do indeed have good biomarkers -- they are just hard to measure accurately and non-invasively. We know that mutations accumulate and cause cancer; we know that fatty deposits in arteries accumulate and cause heart disease; etc etc. So actually what we need is better assays for biomarkers, not better biomarkers.

Posted by: Aubrey de Grey at March 12, 2004 10:11 AM

The NIA has spent a fair amount of effort over the last 20-30 years trying to develop biomarkers for aging without much success. Aubrey has done a good job promoting some of the specific failures that contribute to aging and proposing solutions for some of those problems.

It is reasonable to assume that aging is a complex set of problems. It has taken 30+ years (since the war on cancer first began) to understand there are ~20 tumor suppressor genes and perhaps a hundred or more tumor promoter genes as well as many genes involved in controlling gene mutation rate, angiogenesis, metastasis, and other factors that contribute to whether one dies of cancer. We can expect aging to be as complex or even more complex than cancer. So it is reasonable to assume that until the funding devoted to aging studies (NIA) are equal to that that have been devoted to cancer (NCI) and heart disease (some subset of NHBLI funding) that we should not expect equivalent progress.

Now if, as I believe, somatic mutation is going to be an essential component of the aging process (as Aubrey might cite mitochondrial DNA mutations or the accumulation of undigestable protein fragments) then it is going to be *very* hard to develop useful biomarkers. This is because each and every cell in the body may, over time, be accumulating a different mutation set and may thus be failing in completely different ways. It will likely be very difficult to develop biomarkers for aging when one can have failures in a few dozen of 30,000+ genes or mutations of hundreds in billions of base pairs of DNA. It can be done but it is going to require much larger sample sets than a few dozen monkeys in calorie restriction studies. (It probably requires hundreds to thousands of biopsies to provide gene expression and mutation information from hundreds to thousands of individuals as they age to get sufficient statistical information to determine whether or not specific therapies are making a difference in the "rate of aging").

It is because it is so hard to prove that an anti-aging therapy is working that there is a large amount of space for "solution" providers to claim that their therapies actually work. All one has to go on is arguments that "appear" to make sense. Anti-oxidants are a classic case. They probably help some people some of the time. But the more we learn the more we begin to understand that there is internal cellular control over the oxidative state of cells, the amount of pro-oxidative molecules they generate or eliminate, the degree of oxidative stress that cells will tolerate before they execute an apoptosis program, etc. So there are limits on how effective anti-oxidant supplements may be and they may vary from individual to individual. Given that situation there are no solutions that will work for everyone. There are only solutions that will work for some of the people some of the time. What is needed is to learn to weigh therapies in a context. Anti-oxidants may be quite helpful to some people. Crystal therapies may be quite useful to people who believe they are helpful who in using them have lowered stress hormone levels which in turn raises the capacity of the immune system allowing it greater capacity to deal with the SARS, influenza, pneumonia, septicemia, etc. But a drug or meditation that lowers stress hormone levels could be just as effective in reducing these as causes of death.

So exactly what is an "anti-aging" therapy and how one would measure it is a very very difficult question.

Robert

Posted by: Robert Bradbury at March 13, 2004 11:44 PM
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