R. Ostrowski, PhD. & L. McNally, M.S.
Robert Qi Peng
July 12th, 2001
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.
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.).
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
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
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.
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%.
Fig 1. Images of Werner Syndrome Patient (Adoue, 1997)
Fig. 2. The WRN (Werner Syndrome) gene maps to chromosome 8
Fig. 3 The comparison of a Werner
Syndrome patient in her teenager years
and at age 48.
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 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
http://www.science.uwaterloo.ca/~bepillon/werner.htm#Clinical, July 12th, 2001