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

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