This old monkey can keep us young


Methuselah monkeys are among the creatures that are shedding light on the ageing process, and ways of arresting it, says Roger Highfield

The more we know about the way the body ages, the greater the chance that we can do something about it.

In the past few weeks, yeast, worms and monkeys have helped to give new insights into how cellular machinery runs down as we grow older, suggesting novel ways to lengthen lifespan.





Old brain: Rhesus monkeys like those used in a University of Utah study include (A) 4-year-old Ding-Ding , (B) 7-year-old Miki , [C] 14-year-old Yi-Yi and (D) 26-year-old Grandpa Solomon

One reason that a body slows down has been revealed by aged macaques in the Far East. Thought to be the oldest monkeys in the world, the colony was established as part of a Chinese and Russian experimental programme in the 1950s in Kunming, China. At 30 years old - around 90 in human years - these animals have lived twice as long as they would have in the wild.

"They really do sort of look like grandpa. They have thinning hair and wrinkles," says Dr Audie Leventhal of the University of Utah School of Medicine, who studied the monkeys with colleagues and published their findings in the journal Science.

In monkeys, as well as humans, vision declines with age. While the eye itself does degenerate, this decline also involves the vision centres of the brain, found on the cerebral cortex, which handles higher-order brain functions.

The researchers studied the activity of individual brain cells in the visual cortex of old and young macaque monkeys as they were shown various images on a computer screen. The devices that monitored the brain cells could also release a messenger chemical found in the brain called Gaba, a Gaba-enhancing compound called muscimol, and a Gaba-blocking compound called bicuculline.

The Gaba blocker made the brain cells less selective in the young monkeys, but had no significant effect in old monkeys. Presumably, that's because the older cells had already lost much of their selectivity.

Gaba and the Gaba-enhancer had a relatively small effect in the young monkeys. But in the old monkeys Gaba and the Gaba-enhancer had a much stronger effect, significantly increasing the fraction of highly selective cells.

This suggests that Gaba production dwindles in older brains. And the researchers reason that what affects the visual system likely applies to age-related declines in other parts of the cerebral cortex.

Gaba helps nerve cells stay selective about which signals they respond to - a must for the brain to function at its peak. But certain nerve cells in ancient macaque monkeys - and, presumably, people - lose their pickiness, seemingly because they do not get enough Gaba.

The good news is that some existing drugs, such as anti-anxiety agents called benzodiazepines, increase Gaba production and may help prevent this mental decline. "There are a lot of drugs around that can facilitate Gaba-ergic function and maybe some of them will help," says Dr Leventhal.

"We actually have applied for patents dealing with enhancing brain function in the elderly using Gaba-increasing drugs.''

Another effect of ageing - a greater susceptibility to diabetes - has been studied by a team at Yale University. The scientists found that, compared with the young, older people appear to have lower levels of metabolic activity in their mitochondria, the tiny "factories" that power cells.

Their findings suggest that reduced mitochondrial activity underlies insulin resistance, a major contributor to type two diabetes. And they also found a way to combat this side effect of ageing, described in the Proceedings of the National Academy of Sciences: physical activity boosts the number of mitochondria in muscle by turning on an enzyme called AMP kinase.

"By staying active, the elderly might well be able to maintain mitochondrial content and head off such health problems," says author Prof Gerald Shulman.

In other research, a common cause that links ageing and age-related disease, such as cancer and the degenerative disorders Alzheimer's and Huntington's disease, has been revealed by the tiny worm C. Elegans.

A team at the University of California, San Francisco, have discovered that a class of molecules found in the worms - and in people - can both prolong life in the worm and prevent the harmful accumulation of abnormal proteins that cause a debilitating Huntington's-like disease. This finding appears to be the first evidence in an animal of a link between ageing and age-related disease.

The molecules, called "small heat-shock proteins", are known to prevent proteins from forming into harmful clumps. "We think we have found an important physiological explanation for both ageing and age-related disease," says Prof Cynthia Kenyon, senior author of a paper describing the work in the journal Science.

"The question of why older people are more susceptible to so many diseases has been a fundamental, unsolved problem in biology. Our findings suggest a beautiful molecular explanation, at least for this protein-aggregation disease," she says.

"By preventing damaged and unfolded proteins from aggregating, this one set of proteins may be able to stave off both ageing and age-related disease. The small heat-shock proteins are the molecular link between the two.'

The growing roster of diseases thought to be caused by protein aggregation - Alzheimer's, Huntington's, Parkinson's and vCJD - suggests that the small heat-shock proteins may influence the onset of many age-related ailments.

The pharmaceutical industry is now exploring ways to increase the activity of these heat-shock proteins. Prof Kenyon's work indicates that if these drugs work, they may not only protect protein function, but also extend life.

At present, the best known way to arrest ageing is to go on a diet. In recent decades, researchers have discovered that severe calorie restriction extends the lives of many organisms, from yeast and fruit flies to worms, rats and people.

But coping with this chronic drop in calories is so miserable that wags often joke that it only feels like you are living longer. To exploit this discovery scientists have to find an alternative way to tap this anti-ageing effect. But why less food helps organisms live longer has been puzzling.

Now a gene called PNC1 has been discovered, the first that has been shown to respond specifically to calorie restriction. The find was reported recently in the journal Nature by a team from Harvard Medical School, led by Prof David Sinclair, and sheds light on the fundamental mechanisms by which calorie restriction can extend life.

The investigations, made in yeast, imply that lifespan is not simply dependent on accumulated wear and tear, or metabolism, as some researchers have suggested, but is at least partly controlled by an active genetic programme in cells - one that could theoretically be boosted.

"We show that the lifespan extension from calorie restriction is the result of an active cellular defence involving the upregulation of a specific gene," Prof Sinclair says.

The gene is the recipe for a protein called PNC1, which regulates nicotinamide, a form of vitamin B3 that in turn inhibits Sir2, the founding member of a family of proteins that control cell survival and lifespan. PNC1 converts nicotinamide into nicotinic acid, a molecule that does not affect lifespan. In doing so, it keeps nicotinamide from inhibiting Sir2, allowing the yeast to live longer.

Prof Sinclair's team believes that the PNC1/nicotinamide pathway provides a genetic link between the environment of an organism and its lifespan, allowing an organism actively to change its survival strategies according to the level of environmental stress it senses. His group is now investigating human genes that may play the same role as PNC1, marking the first step towards developing anti-ageing drugs based on this new understanding.

11 June 2003