Discovering The Genetic Controls That Dictate Life Span
Profile of Cynthia Kenyon, Ph.D.June 2002
By Melissa Block
Gene expression and longevity
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. Kenyons work has also focused on gene expressionthe process by which genes program for the production of body tissues.5,6 Genes arent simply inert blueprints that code for the structure of our cells; their expression is variable and complex. Each organisms 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 cellsand how those cells then assemble themselves into the requisite arrangements for building entire organismsDr. Kenyons 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. Kenyons research has to do with the effects of the hormone insulin and the growth factor IGF-1 on the aging process. Insulins role in agingin particular, in the acceleration of agingis 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.
In humans and many other animals, restricting caloric intake while ensuring adequate micronutrient intakeundernutrition without malnutritionhas 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 gene9one 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. Kenyons 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. Kenyons 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 Kenyons 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 studys 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 animals 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 spansfurther evidence that environmental cues have much to do with the genetic regulation of life span.
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.
- Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature 2000 Nov 9;408(6809):255-62.
- 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.
- 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.
- 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.
- 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.
- Salser SJ, Kenyon C. Patterning C. elegans: homeotic cluster genes, cell fates and cell migrations. Trends Genet 1994 May;10(5):159-64.
- 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.
- Hsin H, Kenyon C. Signals from the reproductive system regulate the life span of C. elegans. Development 1999 Feb;126(5):1055-64.
- 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.
- 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.
- 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.