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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

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.