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Life Extension Magazine

LE Magazine June 2002

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Discovering The Genetic Controls
That Dictate Life Span

Profile of Cynthia Kenyon, Ph.D.

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Single-celled organisms don't ever really die of old age; they divide to produce offspring, making the dividing organism both parent and child. Barring external events that might squelch out a line of these microscopic creatures, they can renew themselves indefinitely. More complex organisms-including humans-pay a dear price for their complexity: they age and die. It seems that passing our genes on to our progeny via germ cells (sperm and egg) essentially makes the rest of the cells that comprise us obsolete. It follows that we age and die once we lose our capacity to reproduce.

By Melissa Block

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Cynthia Kenyon, Ph.D. Professor of Biochemistry and Biophysics, University of California, San Francisco

The question remains, What exactly causes cells to age? What causes the loss of organ function that eventually leads to breakdown and demise, often with a period of chronic degenerative illness in between? Scientists have identified several possible mechanisms. Some are based on the concept that aging is caused by cellular wear and tear, while others focus on genetically programmed “aging clocks” that kick in at a predetermined point of an organism’s life span. Theories involving wear and tear include free radical stress, the accumulation of cellular wastes, the binding of sugars to proteins (glycation), the shortening of chromosomes with each cellular division (eventually leading to the activation of an as yet unexplained self-destruct mechanism), or the deterioration of the tiny ‘engines’ that power each cell (mitochondria). Although there is substantial evidence that all of these factors come into play during the aging process, are these factors causes of aging, or are they effects of a pre-programmed genetic code designed to limit life span?

It is becoming ever more apparent that the manipulation of specific genes may be our ticket to immortality. It has long been suspected that the DNA within the cells of complex organisms is designed to senesce and die once reproductive viability is past.[1] Genetic theories of aging imply that by changing the activity of certain genes, we might be able to alter the body’s inherent aging clock. With gene therapy, it may be possible to program our cells to circumvent or control the processes of wear and tear—or, at the very least, to slow them down.

Biochemist Cynthia Kenyon, Ph.D. has devoted her research efforts to identifying life-extending genes within the genome of a tiny worm called Caehorhabditis elegans, or C. elegans for short.[2] These efforts have revealed the existence of specific genes that, when mutated or manipulated, double the life span of these worms. These genetically modified nematodes don’t spend more time in old age; they stay young and active longer than “wild-type” (unmodified) nematodes do.

This research has caused quite a stir in anti-aging circles. It provides strong support for the notion that the aging process is under genetic control, and offers hope for a future where such genes could be manipulated to extend youthful, healthy life span. The problem, of course, is that a one-millimeter-long worm that feeds on bacteria bears only the most negligible resemblance to the complex, cognizant hominid that is man. Or does it?

An introduction to C. elegans

The similarities between nematodes and human beings are far from obvious to the naked eye, but they have inspired hundreds of scientists worldwide to investigate the biology of this diminutive worm. An effort to sequence the entire 100,000,000 bases of DNA in its genome is currently underway.

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It has been known for several years that nematodes with certain mutations in a gene known as daf-2 live longer than their normal counterparts. Dr. Kenyon's research team found that this mutation more than doubled the worms' life spans-the most significant life extension that had been reported in any organism up to that point.

Nematodes—smooth-skinned, unsegmented worms with cylindrical bodies tapered at each end—are conceived from sperm and egg during the process of mating, just as we are. They measure only eight microns in length at birth and a millimeter in length at adulthood, but they possess a nervous system and a rudimentary brain, as well as the senses of taste, smell and touch. Nematodes are among the most primitive organisms known to exist today, and yet they are sensitive to temperature and light, exhibit behaviors, and are capable of learning. A nematode starts out as an embryo, undergoes the process of cell differentiation (the development of various cell types with differing functions), hatches from one of about 200 eggs laid by the parent, and grows to adulthood and sexual maturity within the first four days of life. They reproduce, age and die just as we do, but their life spans average two to three weeks rather than seven to eight decades.

In short, many of the processes modern biologists seek to understand go on within both C. elegans and Homo sapiens. Similar genes are thought to prompt development, cell differentiation and aging in both species. Because of the nematode’s short life span; because its body contains only 959 distinct cells based on the code within its 17,800 genes; and because its transparent body provides for easy visualization of these cells under a microscope, the nematode provides us with an ideal organism in which to study the activity of genes with anti-aging potential. In fact, the nematode genome is thought to contain copies of about 70% of the genes in the human genome! Dr. Kenyon’s award-winning research will lead to a better understanding of how those genes operate in more complex organisms such as fruit flies, rodents and—eventually—human beings.

Cynthia Kenyon, Ph.D. A brief biography

Cynthia Kenyon, Ph.D. was born in Chicago, Illinois. In 1976 she graduated from the University of Georgia with a degree in chemistry and biochemistry. At the prestigious Massachusetts Institute of Technology, she earned a Ph.D. with research focused on gene regulation in E. coli bacteria. She further refined her skills with a postdoctoral fellowship at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England. In 1986 she became an assistant professor at UCSF and was promoted to Professor in the Department of Biochemistry and Biophysics in 1992.

Her work with C. elegans earned her a Herbert Boyer Distinguished Professorship in 1997 and an award from the Ellison Medical Foundation in 1998. She also was awarded the King Faisal International Prize for Medicine, given by the Saudi Arabian King Faisal Foundation for excellence in medical research—for which she received a 240-carat, 200-gram gold medal and a $200,000 cash award.

The research and its implications

It has been known for several years that nematodes with certain mutations in a gene known as daf-2 live longer than their normal counterparts. In 1993, Dr. Kenyon and colleagues published a study in Nature that describes this life-extending genetic mutation.[3] Her research team found that this mutation more than doubled the worms’ life spans—the most significant life extension that had been reported in any organism up to that point. They found that this mutation of daf-2 also required the activity of a second gene called daf-16. These changes in the daf-2 gene trigger changes in the “fountain of youth” gene, daf-16; the daf-16 gene then attaches to DNA within cell nuclei, controlling gene activity in a manner that leads to the formation of new proteins that guide growth and development.

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The activities of the daf-2 and daf-16 genes change in normal, “wild-type” nematodes during times of food shortage or overpopulation. As a result, they enter a state of suspended animation called dauer diapause. This can only happen in prepubescent nematodes; once they have been through puberty and reached adulthood, they no longer have the ability to make this transformation. While in dauer, they don’t eat or reproduce, but can remain in this state for up to five months. Once the food shortage ends or the population thins out, the genes switch back off and dauer ends, bringing the nematode back into its normal life cycle.

In Dr. Kenyon’s 1993 study, the mutant nematodes didn’t enter dauer, but a slightly different action of the daf-2 gene—caused by a “weak mutation” of that gene—caused them to live twice as long as normal, and to remain more youthful throughout much of their extended life span. This early study showed Dr. Kenyon and her colleagues that the life-extending qualities of these genes could be activated without sending the nematode into dauer. The long-lived nematodes were active and could reproduce normally.

In other experiments, organisms with lengthened life spans have appeared to incur less wear and tear because of slowed metabolisms and decreased activity. Fruitflies with a similar longevity gene were infertile. While the mutant Dr. Kenyon’s lab examined for this study may have had a slower metabolic rate than normal nematodes, it has since been shown that mutations that affect the same body functions yield worms with normal metabolic rates. Some daf-2 mutations reduce fertility; others do not. “Gene activity effects on reproduction and aging can be uncoupled from one another,” Dr. Kenyon concludes. This means that with specific genetic manipulation, we may be able to extend life span without altering metabolism or reproductive capacity—a new and very exciting finding in life extension research.

In her research, Dr. Kenyon has sought to discover how daf-2 and daf-16 work together to alter the life span of C. elegans. Her team has published a series of papers describing the complex interplay between the daf-16 gene and the resulting cascade of other responses in the cells throughout the body.[4-6] These responses serve as secondary signals that control the growth and longevity of the individual tissues that make up the organism. Further studies[7,8] showed that the daf-2 gene’s activity is not isolated to the cell within which it resides; altered daf-2 activity in a small group of cells affects many other cells, even those without the altered gene, extending their healthy life span. This could explain how the activation of these genes within a few cells can coordinate the rate at which the entire organism ages.


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