Aging : Longevity Genes

by National Institute on Aging

(Page 4 of 15)

In C. elegans, a nematode (roundworm), researchers have found yet another treasure trove of genetic clues about the aging process. By altering certain genes, researchers can substantially extend the normal 2-to-3-week lifespan of these tiny worms. One of these genes, called daf-2, controls a special stage in the worm's development called dauer formation. A dauer forms, if, in the first few hours of its brief life, a worm finds food scarce. In this state, C. elegans grows a cuticle for protection and can go into hibernation for several months. When the food supply is ample again, the worm emerges from this metabolically slowed, non-aging state and continues its normal life cycle. The protein produced by the daf-2 gene drives the worm's development past or out of the dauer state. But Cynthia Kenyon, Ph.D., and her colleagues at the University of California, San Francisco, found that daf-2 does much more. It also can regulate the lifespan of normal, fertile adults. By altering this gene so that its activity is reduced, Kenyon's team found lifespan of well-fed worms, which did not form a dauer, could be doubled. Other investigators have detected mutations in similar daf genes that increase nematode lifespan three or even four-fold.

The genes isolated so far are only a few of what scientists think may be dozens, perhaps hundreds, of longevity- and agingrelated genes. But tracking them down in organisms like nematodes and fruit flies is just the beginning. The next big question for many gerontologists is whether counterparts in people - human homologs - of the genes found in laboratory animals have similar effects. The daf-2 gene in C. elegans, for instance, is similar to a gene found in humans that functions in hormone control.

In the worm, this gene makes a protein that looks much like the receptor for the hormone insulin. In humans, this hormone controls functions including food utilization pathways, glucose metabolism, and cell growth. These and other genetic linkages are under intense scrutiny, and ultimately could yield clues about how genes interact with environmental factors to influence longevity in humans and other species. Caloric restriction, for example, is the only known intervention shown to prolong life in species ranging from yeast to rodents. Scientists suspect this intervention works in yeast, worms, and other species, in part, because it triggers alterations of genetic activity. Caloric restriction also may work, partially, by altering metabolic pathways involved in energy utilization.

Many investigators, however, interpret these findings cautiously because there are important differences between human genes and those of lower animals. In fact, the structural similarity is only about 30 percent, which means that comparing yeast genes to human genes, for instance, is like comparing a go-cart to a high-performance racing car. The basic machinery may be similar, but one is far less complex than the other. So while yeast, worms, and other simple organisms are helpful models of aging, they probably don't completely mimic the process that occurs in humans. For this reason, gerontologists study the genetics of mice, primates, and other mammals that are more closely related to us. Some researchers are also studying human cells for more precise clues about how genes regulate human longevity and aging.

Other unanswered questions concern the roles played by these genes. What exactly do they do? How and when are they activated? On one level, all genes function by transcribing their "codes" - actually DNA base sequences - into another nucleic acid called messenger ribonucleic acid or mRNA. Messenger RNA is then translated into proteins. Transcription and translation together constitute the process known as gene expression.

The proteins expressed by genes carry out a multitude of functions in each cell and tissue in the body, and some of these functions are related to aging. So, when we ask what longevity or aging-related genes do, we are actually asking what their protein products do at the cellular and tissue levels. Increasingly, gerontologists also are asking how alterations in the process of gene expression itself may affect aging. Technological advances, which allow researchers to observe the expression of thousands of genes at once, are speeding the investigation of this process. In time, this emerging technology could help clarify what changes are occurring simultaneously in diverse cells, as they get older.

For now, investigators have found evidence that some proteins, such as antioxidant enzymes, prevent damage to cells, while others may repair damaged DNA, regulate glucose metabolism, or help cells respond to stress. Other gene products are thought to influence replicative senescence.

Age-related Traits Are All in the Family

Finding longevity genes is only one of many goals for gerontologists. An equally important mission is unraveling the genetic processes involved in age-related traits and diseases.

NIA and Italian investigators are focusing their attention on Sardinia, a secluded Mediterranean island. Since settlers first occupied the island thousands of years ago, the population has grown without much immigration from the outside world. Because they are more closely related than people living in other societies, Sardinians share much of the same genetic information, which makes it easier to track genetic effects through generations.

When a particular trait exists in a genetically isolated "founder" population such as Sardinia, it is likely that the same few genes are responsible for the trait in most or all affected individuals. Once the genes for a certain complex trait are identified within the founder population, researchers can use this information to isolate interacting genes and assess their importance in more genetically diverse cultures, like the United States. Other large founder populations exist in Finland, Iceland, and French-speaking Quebec.

In a study called the Progenia project, gerontologists are studying Sardinians for evidence of genetic influences on two traits: severe arterial stiffness and frequent positive emotions. Vascular stiffness may be an important predictor of heart disease mortality. Reports also suggest that joyfulness and other positive emotions can have profound impact on life satisfaction and health as we age. Gerontologists suspect these traits have strong genetic components. As the project progresses, investigators plan to conduct genetic analysis on individuals who share extreme values of these traits and will attempt to identify the underlying genes.

About the Author

www.nia.nih.gov
NIA, one of the 27 Institutes and Centers of NIH, leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life. In 1974, Congress granted authority to form NIA to provide leadership in aging research, training, health information dissemination, and other programs relevant to aging and older people.