Zvarinograd
29-02-2004, 04:03
Most normal human cells can divide only a finite number of times. Cells from various tissues in the body, such as osteoblasts in the bone, endothelial cells in the blood vessels, retinal pigment epithelial cells in the eye, fibroblasts in the skin, and lymphocytes in the blood are mortal, that is to say, they divide 20-100 times (depending on the tissue and age of the donor) and then cease dividing in a process called cell senescence. This phenomenon of cell aging was first described by Leonard Hayflick in 1961, and therefore the limit of cell proliferation is often called the "Hayflick Limit". Since, it is widely believed that we age in large part because our cells age, the National Institute on Aging has sponsored a significant amount of research into the biological mechanisms of cell aging.
In the decades that followed Hayflick's discovery that human cells are mortal and age in the laboratory dish, a theory for the mechanism of a cellular clock that counts how many times a cell has divided has emerged, called the telomere hypothesis.
According to this theory, the clock of cellular aging resides at the linear ends of the DNA molecule, a region called the telomere (tea'-low-meer). The linear end of each DNA strand ends with a sequence of DNA (TTAGGG) that repeats hundreds of times, effectively "capping" the ends of chromosomes in a manner similar to the way the plastic on the ends of shoelaces "caps" and protects the shoelaces from unraveling.
The telomere hypothesis proposes that as mortal cells divide, terminal DNA or telomeres are progressively lost with each cell division, shortening like a burning fuse. When a critical amount of telomere shortening has occurred, the genetic program of cell senescence, or cell aging, is triggered.
Among normal cells, only the reproductive cells do not senesce; the telomere clock does not "tick", telomeres do not shorten, and the cells can apparently divide indefinitely, a characteristic referred to as immortality. Cellular immortality does not mean that the cells cannot die; like all cells, they must be carefully nourished to remain viable. Instead, immortality refers to the fact that these cells are not limited to a finite number of doublings. Immortal cells, provided they are properly fed and maintained, can divide indefinitely.
Senescent cells are not only incapable of dividing, they also exhibit an altered pattern of gene expression, leading to a number of changes in their structure and function. The effects of senescence on cell function can damage the surrounding tissues, contributing to age-related pathologies. For example, senescent skin fibroblasts produce lesser amounts of important skin matrix elements such as collagen and elastin and elevated levels of enzymes such as collagenase that break down the skin matrix. These changes contribute to atrophy of the skin and, ultimately, age-related skin disorders. Similarly, metabolic changes in senescent retinal pigmented epithelium cells, and the loss of proliferative capacity and overexpression of hypertensive and thrombotic factors in endothelial cells are considered contributors to the pathologies of age-related macular degeneration (AMD) and atherosclerosis, respectively.
Skin disorders, AMD, and atherosclerosis are major diseases in the aging population. Skin atrophy, for example, affects virtually all aging individuals, with 40 percent of the population over 75 years of age seeking treatment for at least one skin disorder. These disorders range from photoaging and wrinkling to increased wounding and, ultimately, skin ulceration. The latter disease can be life-threatening. The major class of drugs for treating age-related skin disorders, the retinoids, produces mainly palliative or "cosmeceutical" effects. In the case of AMD, one third of the population at age 70 is affected and, in most patients, the disease is currently untreatable.
The delay or prevention of cell senescence through the extension of cell life-span is expected to have important beneficial effects in diseases to which cell senescence contributes. In addition to skin disorders, AMD and atherosclerosis, this group is thought to include osteoporosis, immune dysfunction, arthritis, and neurodegenerative disorders. The improvement in the health of the elderly through the more effective treatment of age-related diseases is expected to increase the length of healthy life. There is no evidence that this will translate into an extension of the maximum human life-span, which is now believed to be about 120 years but with this research, the probability of extending human life or even immortality being possible is increasing with every passing year.
Regardless of the promise of immortality (because the government finds that it may offend religious nations and thus banned research for it), the United Communist States of Zvarinograd has begun research on Telomerase and Telomase with hopes for curing many diseases associated with aging as well as immortalized cancer cells.
OOC:
Bibliography
Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C.-P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S. and Wright, W. E. (1998). Extension of life-span by introduction of telomerase into normal human cells. Science 279: 349-352.
Boulme, F., Freund, F., Moreau, S., Nielsen, P. E., Gryaznov, S., Toulme, J. J. and Litvak, S. (1998). Modified (PNA, 2'-O-methyl and phosophoramidate) anti-TAR antisense oligonucleotide as strong and specific inhibitors of in vitro HIV-1 reverse transcriptase. Nucleic Acids Res., 26: 5492-5500.
Chambers, K. J., Tonkin, L. A., Chang, E., Shelton, D. N., Linskens, M. H. and Funk, W. D. (1998). Identification and cloning of a sequence homologue of dopamine beta-hydroxylase. Gene. 218: 111-120.
Greenberg, R., Allsopp, R.C., Chin, L., Morin, G.B. and DePinho, R. A. (1998). Expression of mouse telomerase reverse transcriptase during development, differentiation, and proliferation. Oncogene 16: 1723-1730.
Gryaznov, S.M., Winter, H., (1998). RNA mimetics: oligoribonucleotide N3'-->P5' phosphoramidates. Nucleic Acids Res., 26: 4160-7.
Harley, C. B., (1998). Telomeres and chromosome stability. In G. M. Attardi and F. Amaldi (eds.). The Genetic Language , Istituto della Enciclopedia Italiana Tressani.
Hinkley, C. B., Blasco, M. A., Funk, W. D., Feng, J., Villeponteau, B., Greider, C. W. and Herr, W. (1998). The mouse telomerase RNA 5' end lies just upstream of the telomerase template sequence. Nucleic Acids Res. 26: 532-536.
Testa, S. M., Gryaznov, S. M. and Turner, D. H. (1998 ). Antisense binding enhanced by tertiary interactions: binding of phosphorothioate and N3'-->P5' phosphoramidate hexanucleotides to the catalytic core of a group I ribozyme from the mammalian pathogen Pneumocystis carinii. Biochemistry, Jun 30;37: 9379-85.
Yui, J., Chiu, C.-P. and Lansdorp, P. M. (1998). Telomerase activity in candidate stem cells from fetal liver and adult bone marrow. Blood. 91: 3255-3262.
In the decades that followed Hayflick's discovery that human cells are mortal and age in the laboratory dish, a theory for the mechanism of a cellular clock that counts how many times a cell has divided has emerged, called the telomere hypothesis.
According to this theory, the clock of cellular aging resides at the linear ends of the DNA molecule, a region called the telomere (tea'-low-meer). The linear end of each DNA strand ends with a sequence of DNA (TTAGGG) that repeats hundreds of times, effectively "capping" the ends of chromosomes in a manner similar to the way the plastic on the ends of shoelaces "caps" and protects the shoelaces from unraveling.
The telomere hypothesis proposes that as mortal cells divide, terminal DNA or telomeres are progressively lost with each cell division, shortening like a burning fuse. When a critical amount of telomere shortening has occurred, the genetic program of cell senescence, or cell aging, is triggered.
Among normal cells, only the reproductive cells do not senesce; the telomere clock does not "tick", telomeres do not shorten, and the cells can apparently divide indefinitely, a characteristic referred to as immortality. Cellular immortality does not mean that the cells cannot die; like all cells, they must be carefully nourished to remain viable. Instead, immortality refers to the fact that these cells are not limited to a finite number of doublings. Immortal cells, provided they are properly fed and maintained, can divide indefinitely.
Senescent cells are not only incapable of dividing, they also exhibit an altered pattern of gene expression, leading to a number of changes in their structure and function. The effects of senescence on cell function can damage the surrounding tissues, contributing to age-related pathologies. For example, senescent skin fibroblasts produce lesser amounts of important skin matrix elements such as collagen and elastin and elevated levels of enzymes such as collagenase that break down the skin matrix. These changes contribute to atrophy of the skin and, ultimately, age-related skin disorders. Similarly, metabolic changes in senescent retinal pigmented epithelium cells, and the loss of proliferative capacity and overexpression of hypertensive and thrombotic factors in endothelial cells are considered contributors to the pathologies of age-related macular degeneration (AMD) and atherosclerosis, respectively.
Skin disorders, AMD, and atherosclerosis are major diseases in the aging population. Skin atrophy, for example, affects virtually all aging individuals, with 40 percent of the population over 75 years of age seeking treatment for at least one skin disorder. These disorders range from photoaging and wrinkling to increased wounding and, ultimately, skin ulceration. The latter disease can be life-threatening. The major class of drugs for treating age-related skin disorders, the retinoids, produces mainly palliative or "cosmeceutical" effects. In the case of AMD, one third of the population at age 70 is affected and, in most patients, the disease is currently untreatable.
The delay or prevention of cell senescence through the extension of cell life-span is expected to have important beneficial effects in diseases to which cell senescence contributes. In addition to skin disorders, AMD and atherosclerosis, this group is thought to include osteoporosis, immune dysfunction, arthritis, and neurodegenerative disorders. The improvement in the health of the elderly through the more effective treatment of age-related diseases is expected to increase the length of healthy life. There is no evidence that this will translate into an extension of the maximum human life-span, which is now believed to be about 120 years but with this research, the probability of extending human life or even immortality being possible is increasing with every passing year.
Regardless of the promise of immortality (because the government finds that it may offend religious nations and thus banned research for it), the United Communist States of Zvarinograd has begun research on Telomerase and Telomase with hopes for curing many diseases associated with aging as well as immortalized cancer cells.
OOC:
Bibliography
Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C.-P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S. and Wright, W. E. (1998). Extension of life-span by introduction of telomerase into normal human cells. Science 279: 349-352.
Boulme, F., Freund, F., Moreau, S., Nielsen, P. E., Gryaznov, S., Toulme, J. J. and Litvak, S. (1998). Modified (PNA, 2'-O-methyl and phosophoramidate) anti-TAR antisense oligonucleotide as strong and specific inhibitors of in vitro HIV-1 reverse transcriptase. Nucleic Acids Res., 26: 5492-5500.
Chambers, K. J., Tonkin, L. A., Chang, E., Shelton, D. N., Linskens, M. H. and Funk, W. D. (1998). Identification and cloning of a sequence homologue of dopamine beta-hydroxylase. Gene. 218: 111-120.
Greenberg, R., Allsopp, R.C., Chin, L., Morin, G.B. and DePinho, R. A. (1998). Expression of mouse telomerase reverse transcriptase during development, differentiation, and proliferation. Oncogene 16: 1723-1730.
Gryaznov, S.M., Winter, H., (1998). RNA mimetics: oligoribonucleotide N3'-->P5' phosphoramidates. Nucleic Acids Res., 26: 4160-7.
Harley, C. B., (1998). Telomeres and chromosome stability. In G. M. Attardi and F. Amaldi (eds.). The Genetic Language , Istituto della Enciclopedia Italiana Tressani.
Hinkley, C. B., Blasco, M. A., Funk, W. D., Feng, J., Villeponteau, B., Greider, C. W. and Herr, W. (1998). The mouse telomerase RNA 5' end lies just upstream of the telomerase template sequence. Nucleic Acids Res. 26: 532-536.
Testa, S. M., Gryaznov, S. M. and Turner, D. H. (1998 ). Antisense binding enhanced by tertiary interactions: binding of phosphorothioate and N3'-->P5' phosphoramidate hexanucleotides to the catalytic core of a group I ribozyme from the mammalian pathogen Pneumocystis carinii. Biochemistry, Jun 30;37: 9379-85.
Yui, J., Chiu, C.-P. and Lansdorp, P. M. (1998). Telomerase activity in candidate stem cells from fetal liver and adult bone marrow. Blood. 91: 3255-3262.