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Aging Arteriosclerosis

VIEWS: 5 PAGES: 8

									      Premature Aging




          Medical Genetics

R. Ostrowski, PhD. & L. McNally, M.S.

           Robert Qi Peng

           July 12th, 2001
                                          Abstract

        The purpose of this report is to determine the definition and reasons of aging, to
investigate the close relationship between aging and genetics, to describe the ways to
decelerate and accelerate aging, and to address concerns regarding premature aging
caused by genetic disease. The efforts of past researchers revealed that aging is a
complicated biological process determined by both environmental factors and genetic
factors. This process may have caused by somatic mutation or/and limit of cell
compensation. In the future, it may be possible to decelerate aging process as some
genetic diseases accelerate it. From one specific case study of Werner Syndrome and
research about the aging process, this paper explains the molecular bases of premature
aging caused by genetic disorder and addresses how to detect it with genetic counseling.

                                        Background


       Nobody is able to escape aging. In the year 2,000, one out of four Americans is 50

years old or older (biorap). As in most biological processes, the aging process is the

composite of both environmental and genetic determinants. In contrast to the relative

clarity of some environmental factors, the genetic basis for aging is both complex and

poorly understood. The existence of a genetic basis for aging, however, is

uncontroversial. The most convincing evidence for the genetic determination of aging is

the variation in life span among members of the animal kingdom. Even within

superfamilies, considerable variation is observed. The deer mouse, Peromyscus leucopus,

has a life span two to three times longer than the common laboratory mouse,

Musmusculus (Schneider, 1978).

       According to past research, genetic factors account for about 30 percent of the

variance in life expectancy. Scientists believe there are specific genes, that control aging.

In fact, they have discovered genetic mechanisms that possibly trigger aging and

determine the rate at which we age. Furthermore, researchers have already identified the

genes that make skin age (biorap).
       News from the molecular biology field is reinforcing the idea that deceleration of

the aging process could be achieved by genetic means.

               Scientists believe that free radicals (by-products of cells using oxygen to

               generate energy) damage cell membranes, which possibly opens the door

               to pathogens. To reduce damage by free radicals, researchers inserted

               extra copies of genes for antioxidant enzymes into fruit flies. The extra

               genes enabled the flies to produce more enzymes, reducing oxidative

               damage and increasing their life span by 30 percent. (Biorap,)

       Genetic mutations in the sperm or egg cells can cause diseases that pass on to the

next generation. In some cases, these mutations could accelerate the human aging

process, and result in premature aging abnormalities like Progeria syndrome, Cockayne

syndrome and Werner syndrome.

       The Werner Syndrome is the typical form of premature aging (progeria), which

was first characterized in 1904 by Otto Werner (University of Waterloo, Ca.). This

syndrome begins in adolescence or early adulthood and results in the appearance of old

age by 30- 40 years of age (genes and disease). Physical characteristics may include short

stature (common from childhood on) and other features that usually develop during

adulthood: wrinkled skin, baldness, cataracts, muscular atrophy, and a tendency to

diabetes mellitus, among others (See figure 1).

       This abnormality is a rare autosomal recessive disorder caused by the mutation of

WRN gene. There is characteristic chromosomal instability seen in Werner Syndrome

cells. This instability differs from the instability seen in other disorders and therefore has
been termed Variegated Translation Mosaicism. These instabilities include reciprocal

translocations, deletions and inversions (University of Waterloo Ca.).

                               Research Question/Problem

       The question this paper investigates is what is aging, what factors cause human

aging, how are they related to genetics, and in what ways could the aging process being

decelerated and accelerated. In the acceleration of the aging process, this paper

investigates a specific abnormality called Werner Syndrome. The further research of this

abnormality targets questions such as what is Werner Syndrome, what causes this

abnormality, how and when could it being detected and what is the current risk to pass it

to the next generation.

                                     Methods & Result

       What is aging? Aging is more than just getting wrinkles and not understanding

today's teenagers. A complicated system of many genes and proteins work together to

gradually lead us all down the path to our later years.

        One theory of aging involves somatic mutations. Szilard (1959) proposed that

somatic mutations accumulated in the genomes of somatic cells, gradually inactivating

the chromosome until ultimately the functional capability of the chromosome was

destroyed and the cell died (Schneider 1978).

       Another genetic aspect of aging is the gradual degradation of our telomeres, the

repeating sequences of DNA that cap the ends of each chromosome. There is no question

that cells are capable of repairing damage to DNA; moreover, accumulated evidence

suggested that this repair capability might decline with the advancement of time.

(Schneider 18) With each division of a cell, its telomeres become shorter and shorter --
until they are so short that the cell can no longer divide to reproduce or repair itself

(Biorap).

       If this theory is correct, it may be possible to decelerate aging process. As

researchers have found out, telomeres are the tips of the chromosomes, composed of

repeated sequences of DNA. The tips are shortened at each division causing genetic

imbalances and making the telomeres good biomarkers of senescence. Short telomeres

cause growth arrest. It is known that cancer cells, germ cells, and some eukaryotic

microorganisms have the ability to correct this defect with an enzyme called telomerase.

Normal human cells modified to express telomerase are immortal in culture. Old cells

treated with telomerase regain function, reversing the Hay flick limit (Magalhães).

       The human aging process is polygenic and multifactoria. However, sometimes the

mutation of one or more genes can accelerate the aging process at an astonishing rate.

These mutations result in genetic disorders, including Werner’s syndrome, Progeria

Syndrome, and Cockayne's syndrome. In the case of Werner Syndrome, a rare recessive

disorder, the abnormality is caused by the mutation of a large Rec Q type DNA helicase,

encoded by the WRN gene located on chromosome 8. (See figure 2.) (University of

Waterloo Ca.) Cells from Werner Syndrome patients have a shorter lifespan in culture

than do normal cells. The gene for Werner disease (WRN) was mapped to chromosome 8

and cloned; by comparing its sequence to existing sequences in GenBank, it is a predicted

helicase belonging to the Rec Q family. However, it has yet to be shown to have real

helicase activity (as a DNA unwinder important for DNA replication). The molecular role

of WRN in Werner syndrome therefore remains to be proven, as does any role it might

have in the aging process in general (Genes and diseases).
        Most of the visible characteristics of Werner Syndrome do not show up until

adolescence or early adulthood. The first evidence of the problem is the failure of Werner

Syndrome patients to undergo the usual adolescent growth spurt. Following this is

premature graying and loss of hair and development of bilateral cataracts in the twenties.

After this, osteoporosis, diabetes mellitus type II, accelerated arteriosclerosis and cancer

occur on the thirties and forties. Eventually, the Werner Syndrome patient succumbs to

cardiovascular disease or cancer in their forties or fifties (University of Waterloo) (see

figure 3).

        Werner syndrome is either caused by fresh mutation or parental inheritance. Since

the disorder is inherited and transmitted as an autosomal recessive trait; it is theoretically

possible to analyze the carrier type of the embryo and family tree to detect Werner

Syndrome and the possibility to pass it to the next generation.

                                         Conclusion

        Human aging is a polygenic and multifactorial process that leads to the end of

his/her life. It is determined by both environmental and genetic factors, and genetic

factors can play key roles in decelerating or accelerating aging. The genetic acceleration

of aging process often represents some sort of abnormality, such as Werner Syndrome.

Werner Syndrome is a premature aging disease that begins in adolescence or early

adulthood and results in the appearance of old age by 30-40 years of age. This disorder is

caused by a gene mutation in Chromosome 8. Theoretically, it could be detected by

carrier type analysis of embryo and family tree analysis. If both parents are carriers, the

possibility of having a WS child is 25%, theoretically. If both parents are WS patients,
the possibility is 100%. If one of them is a patient and the other is a carrier, the possibility

is 50%.

                                         Appendices

Fig 1. Images of Werner Syndrome Patient (Adoue, 1997)




          Fig. 2. The WRN (Werner Syndrome) gene maps to chromosome 8




                                 figure 2
Fig. 3 The comparison of a Werner Syndrome


patient in her teenager years and at age 48.




                                       Reference

Biorap, Biological Research for Animal and People world wide web

       http://www.biorap.org/tg/tgagecontents.html, July 9th, 2001


Genes and disease NCBI http://www.ncbi.nlm.nih.gov/disease/, July 6th, 2001


Magalhães, J. P. D. the Cellular Clock, World Wide Web

       http://users.compaqnet.be/jpnitya/science/clock.htm, July 6th, 2001



Schneider E. L. 1978 p1, p16, p18 The Genetics of Aging, Plenum Publishing

       Corporation New York N.Y.

University of Waterloo, Ca, Positional Cloning of the Werner Syndrome Gene, World

       Wide Web

       http://www.science.uwaterloo.ca/~bepillon/werner.htm#Clinical, July 12th, 2001

								
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