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LE Magazine June 2002
Page 2 of 2
Gene expression and longevity
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| Genes aren't simply
inert blueprints that code for the structure of our cells; their
expression is variable and complex. Each organism's specific
genetic code tells only a small part of the story of its physiology, |
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Dr. Kenyon’s work has also focused on gene expression—the process by
which genes “program” for the production of body tissues.[5,6]
Genes aren’t simply inert blueprints that code for the structure of our
cells; their expression is variable and complex. Each organism’s specific
genetic code tells only a small part of the story of its physiology, as
you well know if you have ever been acquainted with a set of identical
twins. Although they have exactly the same genes, the environment shapes
the expression of those genes into individuals that may be as different
as night and day.
By studying the ways in which the genetic code is transformed into living
cells—and how those cells then assemble themselves into the requisite
arrangements for building entire organisms—Dr. Kenyon’s team has gained
important insights into the mechanisms of cell division, cell differentiation,
cell behavior, neurotransmitter formation and cell death. Her research
has examined the similarities between the gene expression of C. elegans,
insects and vertebrates.[1] Such insights
are valuable tools for understanding the anti-aging action of daf-2, daf-16
and similar genes in various organisms.
The roles of insulin and IGF-1
One of the most fascinating findings of Dr. Kenyon’s research has to
do with the effects of the hormone insulin and the growth factor IGF-1
on the aging process. Insulin’s role in aging—in particular, in the acceleration
of aging—is becoming more apparent as the epidemic of type II diabetes
continues unabated in the American population. The chronically high insulin
levels seen in people with prediabetes (insulin resistance) and type II
diabetes have a potent age-accelerating effect throughout the body.
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The newest research
from the Kenyon lab
It has long been known that reproduction is intimately involved
in the aging process. Although the stresses of parenting could
well have something to do with this connection, there is far
more to the relationship between the bearing of progeny and
the onset of senescence than endless carpooling, discipline
problems, household chores or rising college tuitions. Nuno
Arantes-Oliveira, Javier Apfeld, and Andrew Dillin,
colleagues and students of Dr. Kenyon’s who perform nematode
research at her laboratory at UCSF, have come one step closer
to understanding how reproduction and longevity are linked
to one another. The results of their study—coauthored with
Dr. Kenyon—appear in the January 18, 2002 issue of the journal
Science.
Dr. Arantes-Oliveira’s research focuses on germ-line stem
cells, primitive cells continually made in the gonads throughout
adult development that eventually differentiate into either
sperm or egg. (These stem cells are not as versatile as embryonic
stem cells, which can be used to grow any type of tissue.)
With specific genetic manipulations, the researchers were
able to in essence remove these germ-line stem cells without
disturbing the somatic gonad cells—the cells that make up
the rest of the reproductive organs. The result: a life extension
of 60%, whether this change occurred in youth or adulthood.
Longevity could be increased even in adults who were already
actively reproducing; this suggests that the aging process
is plastic throughout life, not dictated by unchangeable factors
set in place before birth.
Other studies have shown that the elimination of the entire
reproductive system, including both germ-line cells and somatic
gonad cells, does not increase life span. Previous research
has shown that somatic gonad cells have a life-extending effect,
while germ-line stem cells have a life-shortening effect.
These two systems balance one another out, but when the latter
is removed, the life-extending effects of the somatic cells
prevail.
Dr. Arantes-Oliveira and colleagues believe that germ-line
stem cells send a hormonal message that reduces life span.
The ablation (removal) of germ-line cells affected the activity
of daf-12, a gene that regulates a life span-affecting steroid
hormone. The results of the study also suggest that germ-line
cells may act to decrease life span by downregulating the
activity of the daf-16 gene. Worms that had their germ-line
cells ablated showed increased resistance against oxidation,
heat and radiation. Hormonal cues sent out by the germ-line
cells could act to decrease life span by lowering resistance
to these stresses. According to Dr. Kenyon, the study shows
that “these proliferating stem cells are master control cells,
sitting at the top of paths that affect both reproduction
and aging. . . We’re now searching for the missing pieces.
We’re looking for other proteins that may be involved in this
surprising level of control over life span. . . we particularly
want to know more about this steroid hormone. What is it?
Do humans have it?”
What are the implications of this research for humans who
wish to live longer lives? It’s further proof of the price
higher animals pay for their complexity: because we reproduce,
we senesce and die. Once we’ve created our progeny, nature
sees us as obsolete. As we move towards a more comprehensive
understanding of the biochemical and genetic factors that
make this a reality, we can look forward to a day when those
factors can be controlled.
Nuno-Arantes N, Apfeld J, Dillin A, Regulation
of life span by germ-line stem cells in Caenorhabditis elegans,
Science 2002 Jan 18.
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In humans and many other animals, restricting caloric intake while ensuring
adequate micronutrient intake—undernutrition without malnutrition—has
been shown to consistently lengthen life span and postpone the onset of
aging, cancer and degenerative diseases. Caloric restriction rapidly leads
to a significant drop in insulin levels, and insulin stays low as long
as food is scarce. Lower insulin levels could be an important mechanism
for the life extension seen with dietary restriction.
Insulin-like growth factor-1 (IGF-1) is structurally similar to insulin,
and attaches to the same hormone receptor sites as insulin. (A hormone
or other biochemical exerts its effects by fitting into a receptor site
like a key into a lock, “turning on” certain cell functions in the process.)
IGF-1 and insulin have different functions in the body, however. Normally
secreted from the liver in response to growth hormone release from the
pituitary gland, IGF-1 is receiving much attention today because of its
youth-enhancing effects. In fact, it is responsible for most of the preservation
of lean body mass, fat loss and tissue-building properties once attributed
to growth hormone.
In studies published during the late 1990s, the laboratory of Gary Ruvkun
at Harvard, who had long been studying the role of daf-2 in the process
of dauer formation, discovered an interesting characteristic of the daf-2
gene9—one that makes its study extremely valuable for insights into human
aging. Dr. Ruvkun found that daf-2 encodes a protein that closely resembles
the insulin and IGF-1 receptor in the bodies of human beings. Dr. Kenyon’s
lab,[2,10] as well as the Ruvkun lab, showed
that daf-16 genes code for a regulatory biochemical called FKHR, and in
humans, insulin decreases the expression of certain genes by antagonizing
FKHR activity. When insulin levels drop due to caloric restriction, FKHR
levels rise, and this could also help to explain why this practice increases
life span.
Parallels between daf-2, daf-16, and human insulin/IGF-1 receptors are
good evidence that research into these genes in C. elegans will lead us
to life-extending gene therapies for humans. Dr. Kenyon’s research suggests
that the reduced activity of daf-2 that precedes nematodes’ entry into
dauer is analagous to this drop in insulin production. It could be that
the drop in daf-2 activity has similar physiological effects to those
of a drop in insulin levels; the human gene that triggers this change
may be activated by lack of food, just as it is in nematodes. According
to Dr. Kenyon, “…the signaling cascade prompted by daf-2 in certain cells
occurs in a similar way in the insulin and IGF family of receptors in
mammals in response to caloric restriction.” In time, we may be able to
use gene therapies that offer the benefits of caloric restriction without
having to be in a state of semistarvation throughout our lives.
Reproduction, sensory perception and life span
Studies from Cynthia Kenyon’s lab also examine the ways in which life
span is influenced by signals from the reproductive system and sense organs.[8,11]
Prepubescent nematodes can sense overcrowding and food scarcity, and their
bodies respond by altering genetic activity, which decreases fertility
and activity by sending them into dauer diapause. By gaining an understanding
of the ways in which genes affect this process, researchers hope to find
ways to alter those genes that will reap the benefits of genetically extended
life span without the liabilities of infertility or suspended animation.
In a nematode study published in Nature in 1999,[11]
Dr. Kenyon and a research associate destroyed the cells that give rise
to germ cells (sperm and eggs). They found that worms without the ability
to make germ cells lived significantly longer. The study’s authors conclude
that signals from the reproductive organs affect the activity of the daf-16
genes (without affecting daf-2), as well as another gene called daf-12.
The daf-12 gene encodes another hormone receptor, suggesting that the
germ cells regulate a hormone that affects life span. This study provides
evidence that the animal’s body coordinates its reproductive function
with its rate of aging, so that it can reproduce while still youthful.
Another study, published a few months later, showed that nematodes with
defects in certain sensory neurons had impaired sensory perception.[8]
Interestingly, those nematodes had longer life spans—further evidence
that environmental cues have much to do with the genetic regulation of
life span.
Future directions
With continuing research efforts, Dr. Kenyon, her colleagues and the
many other scientists delving into the mysteries of anti-aging genes hope
to someday discover how to adjust the aging clock in humans. If a drug
can be developed to trigger or suppress the activity of appropriate genes,
we could see the kind of life extension previously seen only in calorically
restricted laboratory animals. The human equivalent of such a life span
increase could add an additional 20 to 60 healthy, vital years to human
life.
Dr. Kenyon has also started a company called Elixir, based in Boston,
that will attempt to use the information we and others are learning about
the genes that control aging to develop ways of extending youthfulness
and improving the quality of old age.
References
1. Guarente L, Kenyon C. Genetic pathways that regulate
ageing in model organisms. Nature 2000
Nov 9;408(6809):255-62.
2. Lin K, Dorman JB, Rodan A, Kenyon C. daf-16: An HNF-3/forkhead family
member that can function to double the life span of Caenorhabditis elegans.
Science 1997 Nov 14;278(5341):1319-22; comment in: Science
1998 Feb 6;279(5352):787-8.
3. Kenyon C. Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant
that lives twice as long as wild type. Nature
1993 Dec 2;366(6454):461-4; comment in: Nature. 1993 Dec 2;366(6454):404-5.
4. Dorman JB, Albinder B, Shroyer T, Kenyon C. The age-1 and daf-2 genes
function in a common pathway to control the life span of Caenorhabditis
elegans. Genetics 1995 Dec;141(4):1399-406.
5. Salser SJ, Kenyon C. A C. elegans Hox gene switches on, off, on and
off again to regulate proliferation, differentiation and morphogenesis.
Development 1996 May;122(5):1651-61.
6. Salser SJ, Kenyon C. Patterning C. elegans: homeotic cluster genes,
cell fates and cell migrations. Trends Genet
1994 May;10(5):159-64.
7. Apfeld J, Kenyon C. Cell nonautonomy of C. elegans daf-2 function in
the regulation of diapause and life span. Cell
1998 Oct 16;95(2):199-210.
8. Hsin H, Kenyon C. Signals from the reproductive system regulate the
life span of C. elegans. Development
1999 Feb;126(5):1055-64.
9. Wolkow CA, Kimura KD, Lee MS, Ruvkun G. Regulation of C. elegans life
span by insulinlike signaling in the nervous system. Science
2000 Oct 6;290(5489):147-50.
10. Lin K, Hsin H, Libina N, Kenyon C. Regulation of the Caenorhabditis
elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling.
Nat Genet. 2001 Jun;28(2):139-45.
11. Apfeld J, Kenyon C. Regulation of life span by sensory perception
in Caenorhabditis elegans. Nature 1999
Dec 16;402(6763):804-9; Comment in: Nature
1999 Dec 16;402(6763):740-1.
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