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LE Magazine June 2002

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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,

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.

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.

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

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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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