Scientists Find Way to Stimulate Anti-Aging Enzyme

Washington Post ^ | 24 August 2003 | Rick Weiss

[demlosers]

Scientists have found for the first time a way to rev up a potent "anti-aging" enzyme in living cells, an advance they said could speed the development of drugs to extend human life span and prevent a wide range of geriatric diseases.

The novel approach has significantly increased the life spans of yeast and human cells in laboratory dishes and extended the lives of flies and worms -- organisms that, on the level of molecular biology, age very much as humans do. Indeed, said the researchers, the compounds seem to have the same anti-aging effect as a drastic reduction in calories, the only strategy ever proven to extend life in mammals but one that most people find difficult to stick to.

It is too soon to say whether the latest findings will ever make the leap from the lab bench to the geriatrics clinic -- though some may choose not to wait: Of all the compounds the researchers tested, the one that boosted the anti-aging enzyme the most was resveratrol, an ingredient in red wine that's been credited with that beverage's ability to lower the risk of heart disease.

But the findings strengthen an increasingly popular notion among many scientists that the cellular enzymes at the core of the experiments -- called sirtuins -- are universal regulators of aging in virtually all living organisms and represent a prime target for new anti-aging drugs.

[demlosers]

Molecules discovered that extend life in yeast, human cells

Group of compounds found in red wine, vegetables simulate benefit of low-calorie diet

BOSTON, MA – Mice, rats, worms, flies, and yeast all live longer on a low-calorie diet, which also seems to protect mammals against cancer and other aging-related diseases. Now, in yeast cells, researchers at Harvard Medical School and BIOMOL Research Laboratories have for the first time found a way to duplicate the benefits of restricted calories in yeast with a group of compounds found in red wine and vegetables. One compound extended yeast life span by up to 80 percent. The molecules are also active in human cells cultured in the laboratory.
The findings are reported in the August 24 Nature advanced online edition. The research suggests a promising route to find and develop drugs to lengthen life and prevent or treat aging-related diseases.

The molecules belong to a familiar group of compounds known as polyphenols, such as the resveratrol found in red wine and the flavones found in olive oil. For these particular polyphenols, the beneficial effects seem to be independent of their famed antioxidant properties. Instead, the molecules activate sirtuins, a family of enzymes known to extend the life span of yeast and tiny lab round worms. In screening tests, the researchers found 17 molecules that stimulated SIRT1, one of seven human sirtuins, and the yeast sirtuin SIR2.

"We think sirtuins buy cells time to repair damage," said molecular biologist David Sinclair, assistant professor of pathology at Harvard Medical School and co-author of the new study. "There is a growing realization from the aging field that blocking cell death -- as long as it doesn't lead to cancer -- extends life span."

"The sirtuin stimulation provided by certain, but not all, polyphenols may be a far more important biological effect than their antioxidant action," said co-author Konrad Howitz, director of molecular biology at BIOMOL, a biochemical reagents company in Pennsylvania.

Calorie restriction (in mammals, reducing intake to 60 or 70 percent of the normal daily calories) may be one of many mild stresses that trigger beneficial effects, a phenomenon called hormesis. To explain their new findings, the researchers propose that plant polyphenols, which increase in response to stressful conditions, cue organisms to prepare for impending harsh conditions by switching to a more beneficial survival program. They call their hypothesis "xenohormesis."

The most potent molecule in the study, resveratrol, helped yeast cells live as much as 60 to 80 percent longer, as measured by the number of generations. Other studies have linked resveratrol to health benefits in mitigating age-related diseases, including neurodegeneration, cancer and clogged arteries. In this study, researchers were surprised to find that yeast cells treated with small doses of resveratrol lived for an average of 38 generations, compared to 19 for the untreated yeast. The polyphenol worked through a known sirtuin molecular pathway to help yeast and human cells survive environmental stresses.

In experiments with human cells, resveratrol activated a similar pathway requiring SIRT1. This enabled 30 percent of the treated human cells to survive gamma radiation compared to 10 percent of untreated cells. Little is known about the human sirtuin SIRT1, except that it turns off the tumor suppressor gene p53. This raises the concern that any promotion of this pathway might promote cancer even as it switches on a longevity program. But Sinclair said that calorie-restricted animals in experiments by others have lower, not higher rates of cancer.

In the paper, the researchers report that preliminary experiments in flies and worms are encouraging. Mouse studies are in the works. They are exploring synthetic variations on the molecules, which they call sirtuin activating compounds or "STACs," to improve the sirtuin activity. They are also searching for endogenous activators that may naturally exist in human cells.

In the May 8 Nature, Sinclair's research group reported the first known genetic link between environmental stresses and longer life in yeast. Triggered by low salt, heat, or calorie restriction (to as low as 25 percent of normal), a yeast "longevity gene" stimulated Sir2 activity. Sinclair and his colleagues are testing equivalent genes in humans to see if they similarly speed up human sirtuin activity.

The work was supported by the National Institute on Aging and the Harvard-Armenise Foundation. Researchers were further supported by fellowships and training grants from the Ellison Medical Research Foundation, the American Federation for Aging Research, the National Eye Institute, and the National Science Foundation. A provisional patent has been filed for refined versions of the natural molecules.

http://www.eurekalert.org/pub_releases/2003-08/hms-mdt081903.php

[At _War_With_Liberals]

anti-aging drugs=cash cow

[deroberst]

Well, until these jokers get their act together I'll just sit here drinking my Chateau Plonk de Plonk and wait for them to market the stuff using email spam as they do now with Viagara and various processes to enhance body parts.

[annyokie]

Ping!

[KellyAdmirer]

If they are testing at the fish and yeast cell stage, that means that, if it works in humans at all, it will be out after we are all dead anyway.

[Grut]

...if it works in humans at all, it will be out after we are all dead anyway.

How can you say that? With all the advances in medical technology, if we can just hang in there for another five years we'll never die!

Been that way for the last forty years, too....

[Gunslingr3]

If they are testing at the fish and yeast cell stage, that means that, if it works in humans at all, it will be out after we are all dead anyway.

The first powered flight was in 1903, by 1969 man was on the moon. The pace of technological advance is only quickening. Not only are anti-aging drugs being tested, but even efforts to reverse aging. The advent of these discoveries should blow the lid off the current welfare state arrangement of most Western governments. HALF of the federal budget is taking money from working people and giving it to the elderly (who vote).

[aimhigh]

A prediction:

Near immortality! What a discovery! Even the fruit flies and mice involved in the experiments became famous. Movies began to focus on the subject of eternal life, with subjects such as the "fountain of youth", and the ever living "wandering Jew".

Social institutions became occupied discussing the ethics of the discovery. Churches wrestled with contrast between the potential eternal physical life, and spiritual eternity. Many churches protested that it was not God's will for man beyond 80+ years. Others preached the benefits of serving the Lord for 800 years, like Methuselah. Most congregations chose the latter.

Zero Population groups went absolutely ballistic. They protested the potential overpopulation, and attempted to rally legislation against "long life", and for restrictions in childbirth. They were ignored, but eventually, some of their predictions become reality. The elderly wrestled with the ultimate decision. The middle aged wrestled with the loss of expected inheritances. The young always feel they will live forever, so they had no problem with it.

For the young, the decision to undergo "long life" enhancement was a "no brainer". The optimum age for "long life" treatment was found to be 19. For the elderly, the decision was more difficult. "Long life" enhancement was not cure for aging, but a prevention. For the old and infirm, "long life" merely allowed them to continue in their present condition for another 200+ years. Due to mankind's innate fear of death, many elderly took "long life" enhancement with false hopes. Eventually, most ceased their annual treatments, and allowed nature to complete its course. 300 years in a walker just wasn't living. Bionic joints, eyes and ears became common.

Social Transitions

The first social problem to occur was a skyrocketing divorce rate. In the "dying days", spouses remained in unhappy marriages due the near impossibility of finding a new partner in their declining years. Once people were given another 600 years to enjoy, the prospect of remaining unhappily yoked didn't sit well. In fact, the concept of marriage nearly disappeared.

Genealogy became more attractive. Grandparents lived to see the next 25 generations of descendants. For the offspring, tracing their ancestors became more interesting since they could actually meet them. Research became more difficult due to the multitudes of partners. Once found, the most unnerving aspect for a descendent was talking to a great grandparent (to the 10th generation) that didn't look much older then they did.

Crime rates mushroomed for a while, as murderers outlived their 99 year life sentences. With lesser crimes, prison terms of 5 to 10 years were no longer a deterrent. In the end Congress finally outlawed "long life" enhancement for anyone in prison. The ACLU fought this, arguing that denying "long life" was the equivalent of giving minor criminals a death sentence.

The working environment changed dramatically. In the "dying days", people worked 30 to 40 years and retired. Colleges blossomed as job retraining became the rage. People became more serious about pursuing their dreams. Eventually, even the successful met with boredom. Great ball players continued in the same line ups for over 100 years, until mandatory rotations were instituted. Broken dreams resulted in many suicides, which was legalized for anyone over 150.

With more time, people also pursued their talents. Nearly everyone became an artist, author or musician. Television became pretty boring after 90 years. Concerts and readings returned to society. Travel blossomed, then space travel. Eventually, philosophy flourished as the new elderly (500+) looked for meaning in their lives. Religion, on the other hand, was nearly outlawed due to its intolerance of the multitudes of lifestyle choices.

Politicians focused on the "long life" issues for decades. The primary problem involved the tax burden caused by millions of retirees. People expected to draw retirement and social security benefits after 40 years on the job. With long life, they looked forward to the "easy life" for the next 400 to 500 years. After only 50 years, senior citizens comprised the majority of the population, and the young were being taxed to ruin.

The youngsters (those under 65) fought a losing battle. They were the smaller voting block. The average politician was 120 years old, and knew their constituency. The youngsters finally staged prolonged work stoppages, crippling the economy. Congress finally eliminated social security and pensions. Howls of protests followed, but everyone knew there were no other options. By compromise, Congress finally approved tax paid, year long sabbaticals every 15 years. That satisfied most. The other problem was accumulation of wealth. This was resolved through a 20 percent assets tax every fifty years.

Wars became more prevalent as tyrants lived longer, and felt invulnerable. Wars also became scarier to the common people, since there seemed to be so much more to lose. Time didn't become civilization's friend.

[Dark Wing]

Effective anti-aging drugs seem to be less than 10 years away.

[NoControllingLegalAuthority]

The challenge is to extend the youthful years of our lives, not the old and decrepit years. Who wants to spend an extra thirty years drooling on yourself in a nursing home?

Oh boy, forty more years of incontinence, impotence and dementia!

[Mrs Zip]

ping

[dogbyte12]

It would be terrible for society if this were to happen. People would be required to work til 100. Who wants to do that even if you live longer? You certainly don't have that perspective. Often, it's not so much your body going, but at 65, you would rather play with your grandkids than assemble a widget or push paper.

The economy would be devastated with the demands of the elderly. We have a bunch of baby boomers nearing retirement age right now. Picture all the boomers living to 120 demanding services, and voting it in through sheer numbers.

Population control would be instituted. If our lifespan doubled, we would also have a large chunk of people here. Just picture 50 percent of all people born in 1865 still alive. It would be a mess. We would probably be limited by the government to 2 kids max per person. If ya wanted to become rich, you could sell your child credit to a wealthy person, in exchange for them having more.

I am all for people living healthy happy lives to 90... and then they can kick the bucket. If we extend life too much further, I don't think we can deal with the consequences very well.

One quick last point. If you like social security or not, there was a logic to it, when it was introduced. They had actuaries go over life expectancy tables and then they introduced the age of 65. They chose that number for a bit of a cushion. The median age of death was 63 at the time. Over half of all people wouldn't live to see it, so it was a cushion for those who did. Sort of a lottery in a sense. More likely than not, you wouldn't see dime 1, but in case you did live that long, here ya go, a little money so you don't starve. The program paid for itself easily, because a good 60% of people never got a penny back. Flash forward to now, where we are going to hit a life expectancy of 80 fairly soon... and we have a problem. If we extend age out to 100 even, and we don't totally realign the way our society is set up, we will have big issues.

[gcruse]

I would have thought the key was telomerase.  There may be several avenues to life extension.

[Mrs Zip]

ping

[qam1]

It's the Mitochrondria that's the key,

If we could just keep them from mutating or fix them as they mutate we would return and stay 18 forever.

I personally hope they take all these life extention drugs coming down the pike and hide them away until the last of the baby boomers drops dead. They are in power now screwing everything up and I figure we are already stuck with them ruling for another 15-20 years until the Xs and Ys take over. America will be lucky to survive the next 20 years with this loser generation in control, We most certainly would be utterly destroyed if they were able to live and stay in power longer.

[Cyclops08]

Long extended life. I see people working 20 to 40 years, and saving for a sabatical/"retirement" for 10 to 20 years, after wich they will be forced to retrain in a college, and reenter the working world for another 20 to 40 years.

[Doctor Stochastic]

The marketing people should rename resveratrol as "reversatrol"!

[nmh]

Anti-aging drug$? Only for those naieve enough to buy into it.

My Grandmother turned 100 this past June. She's in and out and must have liquidfied food, can't walk well but other than that as healthy as a horse. When she was more "with us" or even now in a "clear moment" she will tell you "it's time for me to go home". She doesn't identify with this world. Her husband died in 62'. She misses him. Her children and grandchildren are doing well and all healthy. Nearly all her friends are gone. My point is this, even if you had "great health" there are other factors that make living longer less satisfying.

Speaking for myself I don't want to live forever on this earth. When it's time to go, no matter what "anti-aging" drugs etc. they come up with, you won't cheat God. It is He who decides how long anyone lives.

[WOSG]

This is WOW stuff ...

Telomerase: What it is saying is you can potentially fix the limits on cell division, which means regeneration can continue without limit.

Sirtuin: This pass is different because it is regulating and helping extend the life of an individual cell.

A third avenue would be cell replacement therapies (eg take a stem cell cultivate it to be brain glial cells or liver cells or heart cells, then insert to help out the 'tired' existing cells).

Several avenues. Put them together and it is possible to imagine 2X, 4X ...???X ... life spans, with same quality of life, just 'stretched out'.

I think if you get down to it and are able to manipulate and fix things on cell level, there is not a natural limit to human life, any more than there is a 'natural limit' to life of say a car. It can go for 500,000 with proper upkeep and replacement of key parts.

Eventually it breaks down too much and has to get junked.

I am all for repealing Soc Security before this gets out of hand! :-)