杏吧原创

SO YOU think you lead a healthy lifestyle. You eat plenty of fruits and
vegetables, exercise regularly, and avoid smoking or overindulging in
alcohol鈥攁ll in the hope of adding a few years to your life. Well, good for
you. But perhaps you should be doing more. Some intriguing evidence suggests
that our bodies function best when they are exposed to small amounts of
poison鈥攑erhaps even a smidgen of radiation. Gentle physical stresses may
act as a kind of vaccination, some scientists reckon, stimulating the body鈥檚
defences to resist the accumulating damage that leads to ageing.

鈥淭he immune system is not the only system we have in our bodies to protect
against foreign organisms and foreign chemicals,鈥� says Thomas Johnson, a
geneticist at the University of Colorado in Boulder. There are other mechanisms
which are constantly dealing with the chemical and physical onslaught. But they
need to be kept ticking over, he argues. 鈥淭hese other systems also have to be
primed to continue to function normally.鈥�

Johnson has already shown that such priming can extend the lifespan of the
millimetre-long nematode worm Caenorhabditis elegans. Others have shown
similar effects in yeast, paramecia, fruit flies and mice. If the principle
applies to humans too, it could turn your ideas about what鈥檚 good for you
upside-down.

This isn鈥檛 the first time Johnson has been at the forefront of ageing
research. In 1988, he was the first to discover a mutation that increases
lifespan. Nematode worms with a mutant age-1 gene live five weeks,
compared with three weeks for normal worms. Since then, researchers have found
nearly 70 more longevity genes in worms, and a handful of others in mice and
fruit flies. Most recently, a gene dubbed Indy鈥斺�滻鈥檓 Not Dead
Yet鈥濃�攈as been found to nearly double fruit flies鈥� mean lifespan from 37 to 70 days
(New 杏吧原创, 23/30 December 2000, p 11).

When you look at all of those genes together, a striking pattern begins to
emerge. Most of the long-lived mutants are also more resistant to a wide range
of physical and chemical stresses. More specifically, they appear to share
increased resistance to heat and free radicals鈥攈ighly reactive molecules
with an unbound electron. The effect is seen not just in the nematode worms, but
in fruit flies and mice as well.

This pattern makes sense given what we know about ageing. One leading theory
attributes the ageing process to free radicals that are produced by our own
metabolism. These free radicals denature proteins and damage other cellular
components, leading to the gradual degeneration we call ageing. Radiation and
various pesticides also cause this kind of damage.

But cells have a mechanism for dealing with the harm done by free radicals.
Part of this response involves a group of proteins collectively known as
鈥渃haperones鈥�, or heat shock proteins. HSPs earned their name because a sudden
rise in temperature causes cells to produce more of them, though they are also
produced in response to other stresses such as free radicals or radiation
damage. HSPs help to prevent and repair the structural changes that occur to
proteins when they denature. They can also stop denatured proteins from clumping
into harmful aggregates
(see Inside Science, this issue). So could HSPs explain
the increased longevity of the mutant organisms?

Early indications are promising. Working in the lab of molecular biologist
Gordon Lithgow at the University of Manchester, doctoral student Glenda Walker
exposed normal worms and long-lived worms that had the mutant age-1
gene to heat, in order to induce production of a heat shock protein called
HSP-16. She found that the age-1 worms produced as much as eight times
as much HSP-16 as the normal worms. She then added extra copies of the gene
responsible for HSP-16 to the age-1 mutants, and found that the worms
lived up to 20 per cent longer than they would with the age-1 mutation
alone. The more HSP-16 the worms produced, the longer they lived.

鈥淲orms that over-express chaperones have an increased lifespan,鈥� says
Lithgow, who presented the results last summer at a conference on the genetics
of ageing. If engineering extra HSP genes into animals makes them live longer,
might it be possible to achieve the same effect using the HSP genes already
present, by activating them with appropriate stress stimuli?

The concept of 鈥渉ormesis鈥濃�攖he idea that low doses of physical stresses
might have a protective effect鈥攈as been around for decades, and over the
years various researchers had filled in little bits of the puzzle. It was known
that exposure to heat extended lifespan in yeast and fruit flies. Doses of
ultraviolet light lengthened the lifespan of paramecia, and radiation increased
longevity in mice, houseflies and fruit flies.

Johnson and his graduate student Jim Cypser set out to explore hormesis more
carefully. They exposed genetically normal C. elegans worms to various
environmental stresses. In experiments not yet published, they found that worms
that were heat-stressed for one hour at 35 掳C when 4 days old lived an
average of nearly 25 days, compared with 21 days for unstressed worms. Brief
exposure to an oxygen-rich atmosphere had the same effect. Curiously, exposure
to ultraviolet light and other ionising radiation did not make the worms live
longer. Cypser is now testing the effects of food restriction and chemicals that
cause oxidative damage.

For most types of stress, the life-extending effect appears at a dose roughly
one-tenth of the lethal dose, says Johnson. Most worms held at a high
temperature for 10 hours will die, but an hour or two of exposure yields an
increase in longevity.

鈥淣ow that we know it works,鈥� says Johnson, 鈥渨e can start trying to figure out
how.鈥� And that means going for the genes. He and Cypser have begun using 鈥済ene
chips鈥� to study which genes are switched on in response to heat and oxidative
stress. This allows them to monitor how the stresses alter the activity of each
of the worm鈥檚 18,000 genes. They鈥檝e already confirmed that the stresses induce
heat shock proteins, as well as activating antioxidant enzymes and about 80 more
genes. 鈥淔or a lot [of these genes], we have no idea what they do,鈥� says
Johnson.

So far, though, they are focusing most of their attention on the 鈥渄auer
formation (daf) pathway鈥�, the genes that cause the worms to assume a spore-like
resting state in harsh conditions when nutrients are scarce. The genes in this
pathway are known to be involved with making the worms more resistant to stress.
At least one also affects longevity鈥攚orms with a mutation in the
daf-2 gene live almost twice as long as normal, Johnson has found. Some
genes seem to control both processes. The gene daf-16, for example,
codes for a transcription factor that turns on many of the later switches in the
daf pathway. Worms with mutant daf-16 genes don鈥檛 respond well to
hormesis鈥攊ndeed, a small dose of stress may lead to a slightly earlier
demise. The same daf-16 mutation also blocks the effect of the
daf-2 longevity mutation鈥攚orms with both mutations live only their
allotted 21-day span.

So the genes in the daf pathway are critical to longevity. Some of them do
trigger the production of heat-shock proteins鈥攂ut that can鈥檛 be the whole
story, says Johnson. He and Cypser have already identified some gene mutations
in which heat stress makes worms live longer, yet they don鈥檛 produce HSPs, or
vice versa. He鈥檚 reluctant to talk further about these genes because of pending
patent applications.

So much for worms and flies, what about people? 鈥淚t certainly is a
controversial idea that low levels of xenobiotics in the environment might
actually be a good thing,鈥� says Huber Warner, associate director of the biology
of ageing programme at the US National Institute on Aging in Maryland.

Yet there is quite a bit of evidence that hormesis may work in people.
Numerous epidemiological studies indicate, for example, that low doses of
radiation may increase human lifespan and decrease cancer mortality. Thomas
Luckey of the University of Missouri in Columbia compared 37,000 nuclear workers
in Baltimore shipyards with the same number of unexposed controls. The exposed
workers lived 17 per cent longer and had half the incidence of cancer. Another
study looked at 150,000 nuclear workers who were exposed to roughly 10 times the
background level of radiation. It found that they had cancer rates barely half
those of a matched control sample. Luckey is so convinced of the benefits of
radiation that in a 1999 paper, he recommends that we 鈥渦se radionuclides as food
补诲诲颈迟颈惫别蝉鈥�.

Not everyone goes that far, of course, and the question of whether low levels
of radiation might be good for you is still highly controversial. The US
Environmental Protection Agency, for example, remains undecided about the risks
or benefits of low-level radiation. 鈥淭here鈥檚 a long way to go before we accept
the data as legitimate,鈥� says Frank Marcinowski, an EPA scientist. Last year the
EPA set up a task force to assess the health effects of very low doses of
radiation, but its results aren鈥檛 expected until 2003. In the meantime, however,
Warner concludes, 鈥淭he weight of accumulated evidence is that low-level
radiation is an advantage.鈥�

If so鈥攁nd if Johnson is right about physiological stress in general
making us live longer鈥攖hen this raises the possibility that our lives have
become too pampered for our own good. Johnson thinks so, for one. He says our
exposure to environmental stress is 鈥渄ramatically less than it鈥檚 ever been鈥�. We
didn鈥檛 evolve in climate-controlled surroundings with abundant high-quality
food. Our ancestors shivered in caves and ate scraggly wild plants loaded with
toxins that aren鈥檛 present in today鈥檚 crops. Just as many researchers now think
asthma and some other diseases may result from too little exposure to germs
(New 杏吧原创, 18 July 1998, p 26),
we may also suffer from not being knocked about more in life.

But most environmental and consumer watchdogs say there isn鈥檛 yet enough
evidence to warrant a rethink about what鈥檚 good for us and what鈥檚 not. 鈥淚t鈥檚
premature and unwise to use preliminary research to weaken current health
standards,鈥� says Gina Solomon of the Natural Resources Defense Council in San
Francisco. 鈥淭here鈥檚 too much unknown to extrapolate to people and then to policy
on the basis of a few suggestive lab studies,鈥� agrees Michael Hansen of the
Consumers Union in Yonkers, New York. 鈥淭here鈥檚 no evidence that in humans there
are life-prolonging effects.鈥�

Indeed, any hint that oxidants might be good for you would seem to fly in the
face of the prevailing wisdom that antioxidants鈥攚hether in the diet or as
vitamin pills鈥攃an lead to longer, healthier lives. But Johnson sees no
contradiction. The principle of Johnson and Cypser鈥檚 work on the worms was to
apply brief low doses of oxidants in order to trigger endogenous antioxidants.
鈥淵ou鈥檝e got either endogenous antioxidants or exogenous antioxidants,鈥� he says.
鈥淭hey have the same effect.鈥�

Johnson concedes that it鈥檚 unlikely we鈥檒l ever do the experiments to
determine what doses of oxidants would be safe and effective, but he does point
out several examples of the principle being applied for good, scientific
reasons. 鈥淒octors give people low-level, full-body radiation before tumour
therapy to increase their radiation resistance,鈥� he notes. And some hospitals
now heat-stress patients before surgery because they find it improves recovery
afterwards. The same mechanism may underlie the supposed healing effects which
people ascribe to naturally occurring radiation in places such as Bad Gastein in
Austria.

In fact, hormesis may also be involved in the one regime proved to extend
human lifespan鈥攃aloric restriction, or limiting how much you eat
(New 杏吧原创, 25 March 2000, p 20).
鈥淐aloric restriction chronically elevates
stress-inducible defence systems,鈥� says Steven Austad, an expert on ageing at
the University of Idaho in Moscow, Idaho. Edward Masoro of the University of
Texas Health Science Center in San Antonio agrees. He notes that starved animals
are more resistant to heat, surgical stress and toxic chemicals. No one knows
whether the caloric restriction induces HSP production or whether stress
hormones are directly responsible, Masoro says, but 鈥渆ither could really do the
箩辞产鈥�.

So does this mean that we should go out of our way to get more exposure to
extreme temperatures, chemicals, or even radiation? 鈥淭hat鈥檚 the leap not
everyone鈥檚 going to buy,鈥� says Warner. 鈥淲e can鈥檛 suggest to people that they
expose themselves to toxins,鈥� agrees Cypser. 鈥淲e don鈥檛 want to make
尘颈蝉迟补办别蝉.鈥�

Fortunately, there may be a way to get the gain without the pain. 鈥淔or me,
any environmental stress is exactly that,鈥� says Lithgow. 鈥淵ou鈥檝e got to incur
damage before you turn on these repair processes. If you can find a way to do
that without actually taking damage, that鈥檚 got to be an advantage. We really
want to get to the molecular heart of hormesis, and think in terms of
诲谤耻驳蝉.鈥�

Johnson agrees. He has begun collaborating with a biotech company in San
Diego to develop drugs designed to extend life without the need for physical
stress. It looks set to be a long battle, though鈥擩ohnson estimates that
results are at least 5 to 10 years off.

In any case, Johnson鈥檚 company won鈥檛 be the first to come up with a drug
proven to extend lifespan. That honour belongs to two synthetic antioxidants,
EUK-8 and EUK-134, developed by the biotech company Eukarion in Bedford,
Massachusetts.

Lithgow and Simon Melov at the Buck Institute for Aging Research in Novato,
California, tested these compounds on genetically normal worms and found that
they extended their lifespan by 54 per cent
(New 杏吧原创, 9 September 2000, p 23).

But Lithgow sees a bigger pay-off from the hormesis work鈥攁 whole new
view of the ageing process. 鈥淚f a stress factor can postpone ageing, that tells
you that ageing has something to do with the processes that chaperones are used
for, which is protein conformation and protein folding,鈥� he says. 鈥淚f we can
start thinking of ageing as a disease of protein folding, then we鈥檙e getting
蝉辞尘别飞丑别谤别.鈥�