A mutation in the gene daf-2 in the worm Caenorhabditis elegans (generallly referred to as C. elegans) doubles life expectancy by turning on a large number of other genes which serve a variety of functions.
Tracing all the genetic changes that flow from a single mutation, UCSF scientists have identified the kinds of genes and systems in the body that ultimately allow a doubling of life span in the roundworm, C. elegans. Humans share many of these genes, and the researchers think the new findings offer clues to increasing human youthfulness and longevity as well.
Using DNA microarray technology, the researchers found that the single life-extending mutation -- a change in the gene known as daf-2 -- exerts its influence through antimicrobial and metabolic genes, through genes controlling the cellular stress response, and by dampening the activity of specific life-shortening genes.
"This study tells us that there are many genes that affect life span, each on its own having only a small effect," said Cynthia Kenyon, PhD, UCSF professor of biochemistry and senior author on a paper in Nature reporting the research.. "The beauty of the daf-2 gene is that it can bring all of these genes together into a common regulatory circuit. This allows it to produce these enormous effects on lifespan." Kenyon is also director of the Hillblom Center for the Biology of Aging at UCSF's Mission Bay campus.
Lead author on the paper is Coleen Murphy, PhD, a postdoctoral scientist in Kenyon's lab.
By partially disabling one gene at a time, either in daf-2 mutants or in wild-type worms, through a technique known as RNA interference, the scientists were able to discover that no single gene by itself determines lifespan. Of the key genes, each can increase life span by 10 to 30 percent, the research shows. But when daf-2 engages the whole army of genes, they can produce huge changes in lifespan.
Because any individual gene appears to have a relatively small effect on life span, identifying the key players would have been difficult in a standard genetic screen, the scientists say, underscoring the power of DNA microarray analysis for teasing apart complex systems.
Kenyon's team discovered ten years ago that a single mutation in the daf-2 gene, which encodes a hormone receptor similar to the human receptors for the hormones insulin and IGF-1, doubled the worms' life span. The same or related hormone pathways have since been shown to affect life span in fruit flies and mice, and therefore are likely to control life span in humans as well. Her lab found that daf-2 affects lifespan through a second gene, known as daf-16, whose function was known to control the expression of other genes.
But the finding left unanswered just how longevity is achieved. What are the genes that daf-16 regulates? The new research shows that several key systems are involved. Many of the genes that affect lifespan code for antioxidant proteins, the researchers found; others code for proteins called chaperones that help repair or degrade damaged proteins. This is especially interesting, Kenyon says, because many diseases of aging involve oxidative damage or protein aggregation.
Other longevity genes found active in the long-lived mutants make proteins that help ward off bacterial infections, the researchers found. Kenyon's lab showed earlier that infections are the likely cause of death for the worm; recent research from others has shown that the long-lived animals are known to be resistant to bacterial infection. The current study shows that without these genes activated, the long-lived worms die sooner. In humans, too, infections pose a serious health problem for the aged.
"Maybe one day we will be able to tweak the insulin/IGF-1 systems in humans to produce many of the same benefits that we see in the worm," Kenyon says.
The scientists also found longevity genes affecting lipid transport and energy metabolism, as well as a host with unknown functions.
"The diversity of these life span gene functions is just remarkable" said Kenyon.
The long-lived worms, as well as mice with similar changes in the same genes, also are disease resistant, and the study suggests possible mechanisms for this finding. The antimicrobial response could protect against infections, and the antioxidant response can protect against diseases that involve oxidative damage. Many researchers suspect stroke and a number of neurological diseases in humans are hastened by oxidative damage.
Earlier this year, Kenyon's lab showed in C. elegans that the damage-repairing chaperone proteins not only increase lifespan, but also delay the onset of protein-aggregation diseases similar to Huntington's disease.
"The marvelous thing about this new study is that it provides an explanation not only for the remarkable longevity of these animals, but also for their ability to stay healthy so long," Kenyon says.
"They just turn up the expression of many, many different genes, each of which helps out in its own way. The consequences are stunning, and if we can figure out a way to copy these effects in humans, we might all be able to live very healthy long lives," she adds.
Co-authors on the Nature paper are Cornelia Bargmann, PhD, professor of anatomy and Howard Hughes Medical Institute investigator at UCSF; Steven McCaroll, a graduate student; Hao Li, PhD, UCSF assistant professor of biochemistry; and Andrew Fraser and Ravi Kamath at the Welcome CRC Institute and Department of Genetics, University of Cambridge.
You might be thinking, if a single mutation in a single gene can increase life expectancy why doesn't this mutation exist naturally? The most likely explanation is that the mutation in daf-2 somehow decreases reproductive fitness. In other words, it exerts some effect that decreases the number of viable offspring that a C. elegans organism will produce in at least some environments.
One reason why upregulation of repair and other systems might be selected against is that there are energy costs and other costs to making and operating enzymes. Just increasing the amount of a particular type enzyme in a cell has the effect of taking up room that would otherwise be used for other enzymes that serve other purposes. A cell that has more repair enzymes floating around in it can do a better job of repairing itself but at the cost of not being able to do some other functions as well.
An organism has to first survive in the short term in order to even be around to grow old in the long term. If a mutation helps short term early life survival enough to allow the organism to reproduce where it otherwise wouldn't have lived long enough to reproduce then that mutation will tend to be selected for. We can see in a large number of design trade-offs in cells that natural selection has acted to put limits to how much of a cell's metabolism is dedicated to dealing with longer term threats.
Research into genetic variations that influence life expectancy is certainly valuable because it produces a better understanding of the aging process and may point the way toward therapies that will slow or, in some cases, even reverse some changes that cause aging. Drugs will eventually be developed that will intervene in gene expression regulatory mechanism to turn up expression of genes for repair, antioxidant, immune, and other systems related to longevity. But keep in mind that there are limits to how much can be accomplished by turning up existing biological subsystems that extend because all of these systems have the effect of only slowing the process of aging. They do not reverse the process of aging.
The really radical anti-aging therapies of the future will use Strategies for Engineered Negligible Senescence (SENS) to rejuvenate cells and whole organisms by repairing and replacing cells and organs that existing human genes do not know how to repair or replace.
|Share |||Randall Parker, 2003 June 30 05:05 PM Aging Reversal|