| LE Magazine November 1998
SECOND OF 2 PARTS
Companies and academic researchers are racing to find the control
mechanism for aging, in order to block aging itself. In this second
installment, covering an important conference on the topic, Dr.
Gregory M. Fahy updates us on longevity genes, calorie restriction
and telomeres.
A Dynamic
Partnership in The Fight Against
Aging
Powerful forces are being unleashed in the war
against aging. The genes that control aging are rapidly being
identified, drugs have been found that appear to be effective
in reversing age-related changes without toxicity, and links to
aging phenomena observed in widely divergent species, such as
worms, yeast and humans, are becoming apparent.
Significantly, the economic implications of successful aging intervention
are becoming real, meaning that more interest from Wall Street
and other investors is forthcoming to bring products and techniques
to market. Anti-aging research is no longer solely in the realm
of "pure science," but is nearing a practical stage to be of benefit
to most people living today.
Perhaps the most spectacular presentation at the Conference on
Age-Related Diseases, held in Las Vegas in December, was given
by Cynthia Kenyon, the Herbert Boyer Distinguished Professor of
Biochemistry and Biophysics at the University of California, San
Francisco. Describing the elements of a general scientific tour
de force, she revealed that a special longevity gene in a nematode
worm called Caenorhabditis elegans is normally triggered
by calorie restriction, but can also be unleashed to double the
life span of the normal adult. Further, the gene acts through
a central signaling mechanism, and may function in a manner analogous
to similar established mechanisms in human beings.
As detailed in previous issues of Life Extension, the
basic way C. elegans usually balloons its life span under natural
conditions is by blocking its own development. The worm usually
goes through four larval stages prior to becoming an adult, but
if its calorie intake is reduced or if overcrowding takes place,
the worms go from the second larval stage into a state of arrested
development, called the dauer stage. Worms in the dauer state
live far longer than normal worms, allowing them to survive until
food becomes more available or until crowding subsides, whereupon
they complete development, become adults, and live out their 15-day
life spans. (Aging postponement through developmental arrest has
also been reported in insects, molluscs and mammals.)
Cynthia Kenyon of the University of California,
San Francisco, described the elements of a general scientific
tour de force: That a special longevity gene in the worm Caenorhabditis
elegans, normally triggered by calorie restriction, can also be
unleashed to double the life span of the normal adult. Further,
the gene acts through a central signaling mechanism, and may function
in a manner analogous to similar established mechanisms in human
beings.
Kenyon explained that the genes called daf-2 and daf-16 (daf refers
to "dauer formation") jointly govern life span in C. elegans.
Daf-2 action normally causes maturation to adulthood and a normal
life span, while daf-16 action tends to produce the dauer state
and a long life span (causing Kenyon and her colleagues to affectionately
call it "sweet 16"). Unless calorie restriction or crowding is
imposed, daf-16 is silent and daf-2 imparts a normal life span.
However, if mutations knock out daf-2, the result is a greatly
extended life span or a permanent dauer state.
If the technology can ever be applied to humans, it conjures up
images of people being six years old forever. The really interesting
observation was that merely weakening daf-2 activity,
rather than entirely knocking it out, allows daf-2 to facilitate
the maturation of the worm, while also permitting daf-16 to produce
long life spans-without arresting the worms in a pre-adult state.
Daf-2 activity is weakened by using a temperature-sensitive daf-2
mutant that permits maturation at low temperature, but then becomes
inactive when the worms are warmed. When daf-2 becomes inactive,
daf-16 is allowed to act in the adults, a very unusual situation.
These adult worms appear normal, and do not exhibit most of the
characteristics of dauer larvae.
Also of great importance is the fact that the metabolic rate of
these super long-lived adults is the same as that of non calorie-restricted,
normal adults, so the observed life span extension is not due
to "living slower" or producing fewer free radicals. Something
much more intriguing is involved. Daf-2 is a member of the insulin
receptor and insulin-like growth factor-I receptor family. Therefore,
the "death signal"-that is, the signal to mature and age at a
normal rate-presumably is induced by the binding of the worm version
of insulin to the daf-2 protein in response to increasing sugar
levels following feeding. (Worm insulin-like molecules are known
to exist.)
But daf-2 is no ordinary insulin receptor. Kenyon believes that
daf-2, rather than acting locally, serves a signaling role mediated
by neurons and endocrine cells. Using a special technique in which
chromosome fragments that contain daf-2 are distributed at random
throughout the cells of a daf-2-deficient worm as it develops,
Kenyon tried to find out whether daf-2 acts only locally, or at
a distance. What she found is that daf-2 in neurons and endocrine
cells blocked dauer formation in cells elsewhere in the body,
even though those cells lacked daf-2. Conversely, when daf-2 was
missing in neurons and endocrine cells, the other cells went into
a dauer state even when they had daf-2.
This means there must be a signal created by the daf-2 in neurons
or endocrine cells that travels throughout the body and controls
whether the animal as a whole goes into a dauer state or not.
This signal is a kind of master anti-youth hormone, and it no
doubt will be found soon.
But daf-16 is the more interesting gene. Kenyon's search for other
genes that act like daf-16 failed, indicating that this is a unique
master gene for life-span extension. In fact, when daf-16 was
essentially deleted from otherwise normal worms, they matured
normally and had a normal life span. This means that the only
thing daf-16 is naturally used for is increasing life span, in
association with producing the dauer state. Kenyon is now investigating
whether the effect of calorie restriction on life span requires
daf-16.
Daf-16 is a member of the HNF3, or forkhead, family of transcription
factor proteins. Therefore, the main function of daf-16 is to
turn on other genes, something that is required for life span
extension in the C. elegans worm. Finding which youth-preserving
genes are turned on by daf-16 will obviously be of great interest.
The daf-16 gene resembles analogous mammalian HNF3 genes, including
genes that affect the risk of cancer. Particularly tantalizing
is the fact that there are examples in mammals in which insulin
completely blocks the function of HNF3 forkhead proteins.
The obvious implication: The worm mechanisms also
may apply to humans, and might directly lead to human life span-extension
therapies, probably without the need for calorie restriction.
The thrust of almost all calorie-restriction research is to find
the mechanisms by which calorie restriction works to extend life
span, and then find ways for humans to do the same thing without
having to undergo the discomfort of excessively reducing their
food intake. Kenyon's worms seem especially close to showing us
how this might be accomplished.
Underscoring such possibilities, Kenyon notes that human cells
can use C. elegans genes and vice versa, including genes
that govern many vital functions such as cell division, programmed
cell death, cell migration, cell differentiation, and tissue pattern
formation, with the "transplanted" genes working just fine in
the radically alien host cells. This implies that a human analogue
of daf-16 could have an active role in humans.
It is hard not to conclude from Kenyon's talk that gerontology
is converging rapidly on some of the core mechanisms of both human
aging and human life-span extension.
This is, of course, provided that calorie restriction actually
does work in humans and other primates. This was addressed by
Mark Lane, a senior staff fellow at the National Institute on
Aging's Gerontology Research Center in Baltimore, Md. The NIA
study on primate calorie restriction was started about 11 years
ago and involves 200 rhesus monkeys (see "Calorie
Restriction in Monkeys," July 1998, of which Dr. Lane was
a co-author). Calories are restricted by 30 percent, a process
phased in by reducing the calorie intake 10 percent per month
over three months.
It is still too soon to know what is happening to aging per se,
but the following observations have been made: First, the restricted
animals are not emaciated, but are simply smaller. Secondly, restricted
animals have lower cholesterol, triglycerides, blood pressure
and fasting insulin (enhanced insulin sensitivity). Further, serum
DHEA sulfate has fallen noticeably in the control monkeys, but
not in the restricted ones.
In summary, 16 changes that have been induced by calorie restriction
in rodents also have been replicated in these primates. Similar
studies underway at the University of Wisconsin and at the University
of Maryland are showing results consistent with those found in
the NIA study. Lane concluded that calorie restriction appears
to be reducing risk factors for aging and disease, and that obese
animals respond in a manner similar to non-obese animals.
Previous studies have indicated that a common denominator is improvement
in insulin sensitivity (glucose control). Lane further linked
glucose metabolism to the calorie restriction effect by citing
the link between insulin signaling and aging in models such as
C. elegans. He also mentioned that the glucose analogue
2-deoxyglucose, which can't give rise to useful energy for the
cell, mimics calorie restriction in that it reduces tumor growth,
body temperature (even producing torpor) and cell cycling, and
facilitates necessary programmed cell death (apoptosis).
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Presentations were given
by Mike West, previously
of Geron Corp., left, Jan Vijg
of the Harvard Medical School,
and Minori Sugawara, of Agene
Research Institute Co., bottom
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In a pilot study, the diets of rodents were spiked
with three doses of 2-deoxyglucose (0.2, 0.4, and 0.6 percent
of food weight). These animals gained almost as much weight, and
ate almost as much food, as did control animals, yet their insulin
sensitivity was improved after three and six months of treatment.
Other candidate glucose analogues also are under study.
At the end of the first morning of the IBC meeting, there was a
panel discussion focused on central questions, including: If a
gene is identified in a model system of aging, will it tell us
anything about human disease? Are there universal mechanisms of
aging? Is there a correlation between "in vitro aging" and other
models of aging? Jack Egan, the senior director of pre-clinical
research for Alteon Inc., a Ramsey, N.J.-based publically traded
company, felt genes governing the ATP/ADP ratio and insulin resistance
would be relevant to human disease, and he believes in the usefulness
of in vitro models. Egan also said aging is a disease.
Kenyon said she felt her worms are not unique, that universal aging
mechanisms do exist, and that random damage might be an effect
of aging rather than a cause. Dr. Jan Vijg of the Harvard Medical
School felt that aging was nothing more than pathology, and that
in-vitro aging is not the cause of organismal aging.
Continuation
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