BIOL. 2402 - ANATOMY  & PHYSIOLOGY
RICHLAND COLLEGE
SPRING 2001
Class Project
Web project members:

• Ami Stovall
• Amanda Dean
• Helen Chen

   External agents
   Defects already present in the organism

One of the major theories of aging is that it results from the inability either to:

   Read
   Repair
   or replicate DNA

(Telomeres keep the DNA strand from unraveling [DO NOT code for traits], and Helicases are not directly involved in any of these functions, but they prepare the DNA for all of the above) (Human Genetic Diseases That Mimic the Aging Process, p. 1 & 8)

       Progeroid syndromes are rare genetic disorders that accelerate the aging process causing multiple effects on the body. The two main syndromes, Werner's syndrome and Hutchinson-Gilford syndrome differ in the age of onset. Werner's syndrome generally doesn't appear until the second to third decade of life whereas the Hutchinson-Gilford syndrome is evident within the first five to ten years of life. There are many facets to these diseases including genetics, symptoms, treatment, and how these disorders affect the body. In order to gain a better understanding of such conditions as Werner's syndrome and Hutchinson-Gilford syndrome, one must consider what is happening at the cellular level. This leads to theories of possible causes of these disorders which includes:

Mutant gene theory
Telomere theory
Free radical theory
Helicase theory

(Frequently Asked Questions On:  Progeria/Werner’s Syndrome, p.1)

        Ultimately, Progeria results from defects within the genetic makeup of a cell. Therefore, this page will focus on the Telomere theory, the Helicase theory, and their possible links in these syndromes.

Before proceeding, here are some helpful definitions to better understand the text:

Germ cells - sperm (spermatozoa) or eggs (ova); cells whose function is to reproduce the organism; haploid - single set of chromosomes
(Mechanisms of Aging, p. 3)

Stem cells - undifferentiated cells that can differentiate into functioning body cells; a cell capable of both differentiation and self-renewal
(Mechanisms of Aging, p.3)

Somatic cells - differentiated functioning body cells; have two sets of chromosomes, diploid and are represented by cells of many shapes and functions
(Mechanisms of Aging, p.3)

Hayflick’s limit- the number of cell divisions that will take place in human cell cultures prior to dying out; this is estimated to be about 50 cell divisions. Dr. Hayflick estimated that the limit of life of human beings could be more than 100 years.
(Taber 841)

Senescence- the process of growing old; the period of old age.
(Taber 1738)

Helicase - is an enzyme that untwists the double helix at the replication fork, separating the two old strands (unwind the parental double helix).
(Campbell, Reece, and Mitchell 289)

Telomere - the protective structure at each end of a eukaryotic chromosome. Specifically, the tandemly repetitive DNA at the end of the chromosome’s DNA molecule.
(Campbell, Reece, and Mitchell G-23)

Telomerase - an enzyme that catalyzes the lengthening of telomeres; the enzyme includes a molecule of RNA that serves as a template for new telomere segments.
(Campbell, Reece, and Mitchell G-22)

      Before learning the pathology of progeria, it's a good idea to start with the normal cellular mechanism of aging. Comprehending the normal function of telomeres is a critical part in understanding progeria. It plays an important role in cellular aging. The repeating DNA sequences at the end of chromosomes are called telomeres. Their main function in the human body is to maintain the base pair sequence on the tips of the chromosomes. Preventing chromosomes from fusing to each other is another function of telomeres. Telomere shortening over the life span is a process of normal aging. In normal cells, some telomere is lost each time the cell divides and grows. After many cell divisions, the chromosome reaches a "critical length" and can non-longer replicate. Eventually the aged cell dies. This cellular aging process of shortening of the telomeres may be one of the most important determinants of human life span.

http://www.swmed.edu/home_pages/cellbio/shay-wright/intro/facts/sw_facts.html
 
 

        Currently in the aging process, the role of telomeres hasn’t been fully established. At the end of a linear chromosome, these repetitive DNA sequences avoid DNA polymerase’s (an enzyme that catalyzes the elongation of a new DNA at a replication fork during DNA replication) inability to completely replicate the end of chromosomes. “In progeria cells, telomeres are short and prevent further replication at a critically reduced length. This allows DNA damage to occur unrepaired” (Dyer and Sinclair 9). “Genetically defective (shorter) telomeres could allow for cells that age, and die, drastically faster than in the average healthy person” (Theory Page:  Telomeres, p.1).

        As a result, this leads to the eventual variety of symptoms associated with progeria. For an excellent movie regarding telomeres and their processes in aging and to obtain a better general idea of their roles go to: http://web.centre.edu/~bmb/movies/Telomeres.html

        Keeping DNA strands from unraveling, telomeres don’t code for any traits. The daughter cell produced when a cell divides has a little less telomere at the end to work with. Further cell divisions and reaching it’s Hayflick limit of about 50 cell divisions, it is much shorter and when the cell stops replicating, the genes that were covered by the previously longer telomeres become exposed and active, which produced proteins that triggered deterioration of tissues associated with the aging process. It was found that sperm cells and cancer cells unlike most cells in the body, exhibit telomere loss.

“Research was done to explore those cells that were spared of the telomere loss. Telomerase (the telomere-preserving enzyme), was found in the precursor cells that give rise to:

   Human eggs
   Stem cells that give rise to blood cells
   Up to 95% of cancer cells”

(Time:  Can We Stay Young?, p.7).

        Through research, it was determined that telomerase keeps cells such as these going, preserving telomeres in the process. Further research is being done to look for the gene(s) that direct telomerase production. Through this process though, of concern is the fact that dosing cells with telomerase is to be considered unsafe currently due to this enzyme thus helps healthy cells turn cancerous. Locating the gene(s) is at present, the challenge considering that there are approximately 100,000 or so genes in each cell. Eventually, they are exploring manipulating this enzyme (telomerase) to help cells and the body to lengthen their programmed life span.

        Learning more about telomeres and telomerases that preserve telomeres and thus the length of chromosomes during the replication process and eventually lengthening life span would further contribute to figuring out how to attack diseases such as progeria and therefore preventing this premature aging process and it’s devastating effects on human.
 

* Of note in regards to telomeres and progeria:

Werner’s Syndrome - one form of progeria in which a symptom present is cancer.
Hutchinson-Gilford - another form in which the symptom of cancer is absent.
 
 

        To gain a better understanding of the possible role helicase plays in aging as well as in progeria, one should have a grasp of DNA replication and the normal functioning role helicase has in this process.

        First, deoxyribonucleic acid (DNA) is a complex nucleic acid of high molecular weight consisting of deoxyribose, phosphoric acid, and four bases (two purines, adenine and guanine, and two pyrimidines, thymine and cytosine). These are arranged as two long chains that twist around each other to form a double helix joined by bonds between the complementary complements. Nucleic acid, present in chromosomes of the nuclei of cells, is the chemical basis of heredity and the carrier of genetic information for all organisms…” (Taber 511)

        In the process of DNA replication, the parental DNA molecule serving as a template makes an exact copy of itself. “This replication of an enormous amount of information is achieved with very few errors—only about one per billion nucleotides” (Campbell, Reece, and Mitchell 286). DNA replication occurs with remarkable speed and accuracy. Many enzymes and proteins are involved in this process including:

Helicase – an enzyme that begins the process by unwinding the DNA double helix

Binding proteins – on the single-stranded DNA function to stabilize the unwound DNA

DNA polymerase - in the leading strand, it catalyzes the elongation, & continuous synthesis
         of the leading strand, in addition to replacing of DNA with RNA
         primer, and in the lagging strand, it functions in the extension of RNA
         primer to form a series of pieces called Okasaki Fragments

Primase – functions in the synthesis of an RNA primer

DNA ligase – is then required to join the Okasaki Fragments into a single DNA strand

   Helicase is important in the DNA replication because it prepares it for replication by unwinding the complex molecule.  As a result, any malfunction with this enzyme would have devastating consequences. In regards to the theories of aging and progeria, any malfunctions in the processes of reading, repairing, or replicating DNA for which helicase among others are involved results in the devastating manifestations of such diseases as progeria.
 

        The differences between normal human chromosomes and those in patients with progeroid syndromes, such as Werner’s syndrome or Hutchinson-Gilford, are numerous. There have been links found in the DNA of the chromosomes and the enzymes involved. Though many of them remain to be clarified, the implication that DNA helicases have a role in chromosomal stability and the lack there of, has been studied as a possible link to progeroid syndromes.

        DNA helicases have been known to play a role in many molecular processes. Mainly, this enzyme is responsible for unwinding the DNA during replication, DNA repair, and separation of the chromosomes. Basically, they pry apart the two strands of the double helix.

        In Werner’s syndrome, gene mutations suggest that somehow helicase is disrupted. Though the mutations themselves are a possible cause of the disease, some of the mutations studied showed either a defect in the helicase domain region, or an absence of the region altogether. This causes a chromosome to “malfunction” and not work properly.

        It was also suggested that the helicase defective in Werner’s syndrome is missing, a signal called the nuclear localization signal (NLS). This is a potential factor contributing to molecular inactivity in this disorder.

       Though the definitive causes of progeroid syndromes remain to be found, it is known that the DNA in these syndromes is different from those in normal humans. The proteins and enzymes that play such a vital role in our chromosomes are somehow defective, leading to potential disorders, such as Werner’s syndrome, or Hutchinson-Gilford.
 

       In conclusion, there are several theories in progeroid syndromes. The main theories discussed detail the cellular mechanisms in regards to the genetic makeup of a cell and possible malfunctions, which in turn produce such symptoms of these diseases. Although a definitive cause has not yet been identified, we do know that if such alterations as those discussed in this website occur, there is a direct correlation to the symptomology of Werner's syndrome and Hutchinson-Gilford syndrome.

INTRODUCTION TO PROGERIA

HUTCHINSON-GILFORD SYNDROME

WERNER SYNDROME

CAUSES OF DEATH

Best, Ben. “Mechanisms of Aging.” World Wide Web. 27 January 2001
<http://www.benbest.com/lifeext/aging.html>.

Campbell, Reece, and Lawrence Mitchell. Biology. 5th ed. Menlo Park:  Benjamin/Cummings, 1999.

“Can We Stay Young?” Time Magazine 25 November 1996. World Wide Web. 25 January 2001
<http://www.time.com/time/magazine/archive/1996/dom/961125/medicine.can_we_stay_you8.html1/25/01>.

Dyer, and Alan Sinclair. “The Premature Aging Syndromes:  Insights into the Aging Process.” Age and Aging 27.1 (1998):  73-78.

“Facts about Telomeres and Telomerase.” 20 August 2000. World Wide Web. 27 January 2001
<http://www.swmed.edu/home_pages/cellbio/shay-wright/intro/facts/sw_facts.html>.

”Human Genetic Diseases That Mimic the Aging Process.” World Wide Web. 25 January 2001
<http://www.wrclarkbooks.com/downloads/means_chapter.html>.

Kaku, Michio. “Visions:  How Science Will Revolutionize the 21st Century.” 1997. World Wide Web. 7 March 2001 <http:www.dorsai.org/~mkaku/mk-vbook.html>.

“National Center for Biotechnology Information.” 18 April 2001. World Wide Web. 5 March 2001
<http://www.ncbi.nlm.nih.gov.>.

Roddy, Robin. “Frequently Asked Questions On Progeria/Werner’s Syndrome.” March 2000. World Wide Web. 7 March 2001 <http://www.1freespace.com/health/progeria/faq.htm>.

“Theory Page:  Telomeres.” World Wide Web. 7 March 2001
<wwysiwyg://11/http://www.1freespace.com/health/progeria/telomere.htm>.

Thomas, Clayton L.,Taber’s Cyclopedic Medical Dicitonary. 18th ed. Philadelphia:  F.A. Davis Co., 1997.
 

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