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Biology Articles » Neurobiology » Antiaging research, DAF-16 protein and neurodegeneration

Antiaging research, DAF-16 protein and neurodegeneration

Nezih OKTAR

Journal of Neurological Sciences (Turkish), 2006, Volume 23, Number 1, Page(s) 001-002. An Open Access Article.

When prosecutors are trying to reveal an underground conspiracy, they usually start with the inferior perpetrators and gradually lead to the bosses. However, researchers probing how a biochemical pathway controls worm aging are following the opposite course. They know that the protein DAF-16 extends survival, but they are still investigating the genes that undergo its bidding. A new study has revealed more than 100 genes receiving orders from DAF-16 (4).
"Gerontogenes" (genes that affect the rate of aging) are theoretically categorized as genes that can be altered such that a longer than normal maximum lifespan is the result. In order to define a gene as a “gerontogene”, one is experimentally to show that full or partial ablation, or overexpression of the gene will affect life expectancy. During the last two decades, researchers have overwhelmingly demonstrated that gerontogenes exist and modulate the rate of aging (5). The first direct demonstration that genes play a role in the aging process was carried out in the nematode Caenorhabditis elegans. These results lead to the important fact that the process of aging, just as other biological processes, is actually specified by the gene (2).

These evolutionary studies on C. elegans have shown that an insulinlike signaling pathway helps control the nematode's lifespan. A study led by Fred Ausubel, HMS professor of genetics at Massachusetts General Hospital, now suggests that a hardier immune system may account for part of the pathway's effect on longevity. Worms with mutations in the pathway are resistant to pathogenic bacteria and live much longer when fed a diet of these bad bugs than do wild type strains (3). The gerontogene mutants in C. elegans have increased the level of interest in the topic, but the definite answer to the question whether similar genes exist in mammals remains unresolved. Although it is believed that the contribution of genetic component in human longevity is small, there is reason to be optimistic that major gerontogenes exist in humans.

At this step research done on rodents, especially on mice, is significant as mice they provide a useful model system that has the value of a bridge between invertebrate and human. Hopefully, at least four distinct genes have been determined in which loss-of function mutations lead to drawfism and increasead mean and maximum longevity. The second significant act on human longevity gene research is to sort known genes into theoretical categories for a better understanding of their roles on human aging.

Generally they are studied in three groups. Most gerontologists believe that there must not be a group as “genes that cause aging”, since such a gene promoting aging would be likely to decrease reproductive fitness and thus would be subject to negative selection. On the other hand, there are statements by notable developmental biologists who say that aging must be programmed to avoid the competition with offsprings.

Perhaps, the group “genes that affect what kind of an individual you are” is more concrete. Not surprisingly, thousands of these genes (that fit to this definition) are found in mice and human. This group includes polymorphic differences that help to determine which and how soon the individuals will become bald or gray or even will develop certain pathologies such as osteoporosis, macular degenerationor cognitive impairment. However, this is not the same as to say that these genes have a direct control on the rate of aging.

The last group includes the “genes that extend life expectancy or maximum lifespan”. These genes are important in response mechanisms such as response to growth hormone, insulin-like signaling and response to stress. It is not hard to see that in doing so they affect life expectancy. First, they were found in model systems such as nematodes and fruit flies, but examples in mice are also identified. Alleles of this type predictably exist in humans; however, it is harder to demonstrate in such a long-lived species than in short lived ones.

The symptoms of many inherited human neurodegenerative diseases begin late in life. This observation suggests that, in these disorders, aged neurons are more susceptible to degeneration. At least eight hereditary neurodegenerative disorders, including Huntington's disease, are caused by a disease locus that encodes a protein containing an expanded glutamine tract. The mechanism by which these polyglutamine repeats cause late onset neurodegeneration and cell death is unknown (1).

Perhaps, these accelerated studies on longevity research lead us to a crucial reconsideration of the path of developing research. At the moment , it is observed that the research mainly concentrates on increasing the lifespan of humankind. However, this theoretical approach in fact will predictably be challenged by a realistic fact; neurodegeneration. Without sustaining the level of consciousness the study of longevity will lead nowhere. The ultimate challenge is to increase lifespan with the timespan of human specific abilities such as intellectual and cognitive functions. Thus, it can be predicted that after defining fundalmentals of longevity the concentration will shift to neurosystem.

References

1) Ailion M, Inoue T, Weaver CI, Holdcraft RW, Thomas JH. Neurosecretory control of aging in Caenorhabditis elegans.Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7394-7.

2) Barsyte D, Lovejoy DA, Lithgow GJ. Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans.FASEB J. 2001 Mar;15(3):627-34.

3) Gelman R, Watson A, Bronson R, Yunis E.: Murine Chromosomal Regions Correlated With Longevity. Genetics 118, 693-704 (1988).Science's SAGE KE (25 September 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/38/cp24

4) Leslie M.: Chain of Command. Sci. Aging Knowl. Environ. 2006 (2), nf2 (2006).

5) Longevity genes from primitive organism to humans International Longevity Center-USA ILC-Workshop Report2002


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