Premature Aging

432
-1

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
432
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
3
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Premature Aging

  1. 1. Premature Aging Medical Genetics R. Ostrowski, PhD. & L. McNally, M.S. Robert Qi Peng July 12th, 2001
  2. 2. 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).
  3. 3. 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
  4. 4. 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 --
  5. 5. 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).
  6. 6. 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%.
  7. 7. Appendices Fig 1. Images of Werner Syndrome Patient (Adoue, 1997)
  8. 8. 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.
  9. 9. Reference Biorap, Biological Research for Animal and People world wide web http://www.biorap.org/tg/tgagecontents.html, July 9th, 2001 th Genes and disease NCBI http://www.ncbi.nlm.nih.gov/disease/, July 6 , 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

×