Testing Begins on Drugs that May Slow Aging.

[stephendare]

http://www.nytimes.com/2009/08/18/science/18aging.html?_r=1&8dpc

It may be the ultimate free lunch â€" how to reap all the advantages of a calorically restricted diet, including freedom from disease and an extended healthy life span, without eating one fewer calorie. Just take a drug that tricks the body into thinking it’s on such a diet.

It sounds too good to be true, and maybe it is. Yet such drugs are now in clinical trials. Even if they should fail, as most candidate drugs do, their development represents a new optimism among research biologists that aging is not immutable, that the body has resources that can be mobilized into resisting disease and averting the adversities of old age.

This optimism, however, is not fully shared. Evolutionary biologists, the experts on the theory of aging, have strong reasons to suppose that human life span cannot be altered in any quick and easy way. But they have been confounded by experiments with small laboratory animals, like roundworms, fruit flies and mice. In all these species, the change of single genes has brought noticeable increases in life span.

With theorists’ and their gloomy predictions cast in the shade, at least for the time being, experimental biologists are pushing confidently into the tangle of linkages that evolution has woven among food intake, fertility and life span. “My rule of thumb is to ignore the evolutionary biologists â€" they’re constantly telling you what you can’t think,” Gary Ruvkun of the Massachusetts General Hospital remarked this June after making an unusual discovery about longevity.

Excitement among researchers on aging has picked up in the last few years with the apparent convergence of two lines of inquiry: single gene changes and the diet known as caloric restriction.

In caloric restriction, mice are kept on a diet that is healthy but has 30 percent fewer calories than a normal diet. The mice live 30 or 40 percent longer than usual with the only evident penalty being that they are less fertile.

People find it almost impossible to maintain such a diet, so this recipe for longevity remained a scientific curiosity for many decades. Then came the discovery of the single gene changes, many of which are involved in the body’s regulation of growth, energy metabolism and reproduction. The single gene changes thus seem to be pointing to the same biochemical pathways through which caloric restriction extends life span.

If biologists could only identify these pathways, it might be possible to develop drugs that would trigger them. Such drugs could in principle have far-reaching effects. Mice on caloric restriction seem protected from degenerative disease, which may be why they live longer. A single drug that protected against some or all the degenerative diseases of aging would enable people to enjoy more healthy years, a great benefit in itself, even if it did not extend life span.

The leading candidates for such a role are drugs called sirtuin activators, which may well be mimicking caloric restriction, in whole or in part. The chief such drug is resveratrol, a minor ingredient of grapes and red wine. Sirtris Pharmaceuticals, of Cambridge, Mass., is now conducting clinical trials of resveratrol, in a special formulation, and of small-molecule drugs that also activate sirtuin but can be given in much lower doses. The resveratrol formulation and one of the small chemicals have passed safety tests and are now being tested against diabetes and other diseases. The Food and Drug Administration does not approve drugs to delay aging, because aging in its view is not a disease.

The sirtuin activators have a strong scientific pedigree. They emerged as the surprising outcome of a quest begun in 1991 by Leonard P. Guarente of M.I.T. to look for genes that might prolong life span in yeast, a single-cell organism. Working with David A. Sinclair, now at Harvard Medical School, he discovered such a gene, one called sir-2. People and mice turned out to have equivalent genes, called sirt genes, that produce proteins called sirtuins.

Dr. Guarente then found that the sirtuins can detect the energy reserves in a cell and are activated when reserves are low, just what would be needed for a protein that mediates the effects of caloric restriction. Dr. Sinclair and colleagues screened a number of chemicals for their ability to activate sirtuin, and resveratrol landed at the top of the list. The chemical was already known as the suspected cause of the French paradox, the fact that the French eat a high fat diet without penalty to their longevity.

The two researchers and their colleagues thus argued that caloric restriction works by activating sirtuins, and so drugs that activate sirtuins should offer the same health benefits.

In 2004 Dr. Sinclair co-founded Sirtris with Christoph Westphal, a scientific entrepreneur. Helped by growing interest in the sirtuin story, Dr. Westphal was able to sell the company last year to GlaxoSmithKline for $720 million.

Dr. Sinclair says that “the results from the Sirtris compounds are promising and will be submitted for publication in coming months.”

But despite the high promise and strong scientific foundation of the sirtuin approach, it has yet to be proved that Sirtris’s drugs will work. The first of many questions is that of whether caloric restriction applies at all to people.

Two experts on aging, Jan Vijg of the Albert Einstein College of Medicine and Judith Campisi of the Lawrence Berkeley National Laboratory, argued recently in Nature that the whole phenomenon of caloric restriction may be a misleading result unwittingly produced in laboratory mice. The mice are selected for quick breeding and fed on rich diets. A low-calorie diet could be much closer to the diet that mice are adapted to in the wild, and therefore it could extend life simply because it is much healthier for them.

“Life extension in model organisms may be an artifact to some extent,” they wrote. To the extent caloric restriction works at all, it may have a bigger impact in short-lived organisms that do not have to worry about cancer than in humans. Thus the hope of mimicking caloric restriction with drugs “may be an illusion,” they write.

To decide whether life extension by caloric restriction is an artifact of mice in captivity, why not try it on wild mice? Just such an experiment has been done by Steven N. Austad of the University of Texas Health Science Center. Dr. Austad reported that caloric restriction did not extend the average life span of wild mice, suggesting the diet’s benefits are indeed an artifact of mice in captivity. But others interpret his results differently. Richard A. Miller of the University of Michigan, says the maximum life span of the wild mice was extended, and so the experiment was a success for caloric restriction.

Laboratory mice are very inbred, and researchers can get different results depending on the breed they use. To put the mouse data on a firmer footing, the National Institute on Aging has set up a program to test substances in three labs simultaneously. Its first round of candidate agents for reversing aging include green tea extract and two doses of resveratrol.

The resveratrol tests are still under way, but last month the results with another substance, the antifungal drug rapamycin, were published. Rapamycin was found to extend mice’s lives significantly even though by accident the mice were already the equivalent of 60 years old when the experiment started.

Rapamycin has nothing to do with caloric restriction, so far as is known, but the study provided striking proof that a chemical can extend life span.

Another result, directly related to the caloric restriction approach, emerged last month from a long-awaited study of rhesus monkeys kept on such a diet. The research was led by Richard Weindruch of the University of Wisconsin. As fellow primates, the monkeys are the best possible guide to whether the mouse results will apply in people. And the answer they gave was ambiguous.

[Jason]

Wow, amazing stuff.

I can't help but think of how this will affect the worldwide economic and political engine.  We humans have a specific lifespan that affects everything we do and do not do.  To further extend the lifespan of an already over populated species sounds like a bad idea to me.  Unless birth control methods are implemented to maintain some level of control.

[Captain Zissou]

Jason, that was the first thing that came to mind.  Our political system is designed around folks kicking the bucket at around 80 years old.  People living to be 110+ could be catastrophic.

[Deuce]

To further extend the lifespan of an already over populated species sounds like a bad idea to me.  Unless birth control methods are implemented to maintain some level of control.

Agreed. It confounds me that people continue to have multiple kids. How can society & the Earth support all these people especially if we all start living much longer. With continued advances in computers, robotics, and automation this problem is just compounded.

Should be required reading for everyone:
http://www.wired.com/wired/archive/8.04/joy.html

Still, I want my reverseitall or whatever they're going to call it!

[JeffreyS]

My guess is the biggest factor in life extension will be lab grown replacement organs. Duke university has already grown all of the major organs other than the brain including skin and have begun transplanting them.  More the keeping you alive approach than slowing your aging. That same report mentioned the work of trying to mimic caloric restriction as having promise.  As we begin to repair the body at a cellular level you might see Sci fi results.

[Jason]

Honestly, I think the slowed aging approach will be more beneficial than the "keep you alive" approach when talking about our current economil engine.  If people are younger for longer they can therefore effectively work longer and pay into programs such as social security, medicare/medicare, and other retirement related programs.  As it stands now, if someone retires at 65 and is expected to live until their 80's but are "kept alive" until their 100's they will be draining the system.  It would surely collapse.

But if the same person could work until they're 70 or 80 then their pay-in would better support their lifestyle well into their 100's.

[Captain Zissou]

Deuce, I read 8 pages of that article and I think my brain is fried.  Intense stuff.

[Deuce]

But if the same person could work until they're 70 or 80 then their pay-in would better support their lifestyle well into their 100's.

Work until I'm 80. Uugh! I hope to retire by 56 and the SS age for my generation is about 68. Lab grown replacement organs is definitely a future to extending life. Imagine what that could do for those awaiting an organ transplant right now, in terms of lifespan.

Sorry cap, didn't mean to blow your mind. As a Wired subscriber and someone who's read the books by Moravec and Kurzweil mentioned, I didn't find it as intense and heavy. For years, I have been talking up the points from the article and the work of those other guys. Most people look at me like I'm some crazy technologist (see avatar) but advances since then have continued to support the notion that, the future doesn't need us.

One of my favorite examples is the self-check out lane. An innocuous technology on the surface. Some people hate them, some love them. Once you master the vagaries of the machine, I think it's much faster than the regular lines. There are still some improvements to be made, for example they are horrible at detecting low-weight items in the bagging area and often require the clerk to come over and override the warning message. Although I've got an idea that might fix that, and I'm sure that they will.

Point is, you've got four checkout lines that require only one clerk to run them. That's more or less equivalent to having 4 lines with 4 clerks. A reduction of staffing needs to a quarter of what was required before. If the technology continues to improve, then one day one clerk may assist with 8 machines. Imagine if all retailers started to replace their checkout lines with these exclusively. That's a huge elimination of jobs by technology. And there are no robots or AI androids in this scenario, just a simple machine that allows you to scan, bag, and pay for your items.

[Sportmotor]

Unless birth control methods are implemented to maintain some level of control.

Yea, thought that was called war?

[Deuce]

^ Funny but true. Throughout history, war and disease have had large impacts on population growth. Modern science and warfare methods eliminated this impact at least for modernized countries.

[Sigma]

^ Funny but true. Throughout history, war and disease have had large impacts on population growth. Modern science and warfare methods eliminated this impact at least for modernized countries.

Hey Deuce, back in college I read a book titled "Cows, Pigs, Wars, and Witches" that talks directly to your point (among others).  Have you read that?  Your comment brought that from my memory.  Think I'll reread that one.

Great article.

[Deuce]

I haven't but what an attention-grabbing title.

[Ocklawaha]

We already have a 100% effective cure for old age, it's called the afterlife. Those who believe in God don't have to worry about it, and those who don't... well... you can always take a pill.

Besides this, I think the earth has a "TILT" factor built in, when the population hits a certain mark, we all blow eachother into atoms. Whoever is left after the next big one, wins the brass ring and gets to play Adam and Eve for a generation or two.

OCKLAWAHA

[Ocklawaha]

Is it really death we try so hard to avoid, or is it the perceived pain and suffering we assign to it that we try to avoid?

OCKLAWAHA