Los telómeros en la investigación sobre envejecimiento
Hallmarks of telomeres in ageing research
JW Shay and WE Wright
University of Texas Southwestern Medical Center, Department of Cell Biology, Dallas, TX 75390-9039, USA
Journal of Pathology J Pathol 2007; 211: 114-123
Abstract
Telomeres are repetitive DNA sequences at the ends of linear chromosomes. Telomerase, a cellular reverse transcriptase, helps maintain telomere length in human stem cells, reproductive cells and cancer cells by adding TTAGGG repeats onto the telomeres. However, most normal human cells do not express telomerase and thus each time a cell divides some telomeric sequences are lost. When telomeres in a subset of cells become short (unprotected), cells enter an irreversible growth arrest state called replicative senescence. Cells in senescence produce a different constellation of proteins compared to normal quiescent cells. This may lead to a change in the homeostatic environment in a tissue-specific manner. In most instances cells become senescent before they can become cancerous; thus, the initial growth arrest induced by short telomeres may be thought of as a potent anti-cancer protection mechanism. When cells can be adequately cultured until they reach telomerebased replicative senescence, introduction of the telomerase catalytic protein component (hTERT) into telomerase-silent cells is sufficient to restore telomerase activity and extend cellular lifespan. Cells with introduced telomerase are not cancer cells, since they have not accumulated the other changes needed to become cancerous. This indicates that telomeraseinduced telomere length manipulations may have utility for tissue engineering and for dissecting the molecular mechanisms underlying genetic diseases, including cancer.
Keywords: ageing; cancer; telomeres; telomerase
http://www4.utsouthwestern.edu/cellbio/shay-wright/publications/J%20Pathology%202007.pdf
El envejecimiento biológico no es mas un problema sin resolver
Biological Aging Is No Longer an Unsolved Problem
LEONARD HAYFLICK
Department of Anatomy, University of California, San Francisco, School
of Medicine, The Sea Ranch, California 95497, USA
Ann. N.Y. Acad. Sci. 1100: 1-13 (2007). C 2007 New York Academy of Sciences. doi: 10.1196/annals.1395.001
ABSTRACT: The belief that aging is still an unsolved problem in biology is no longer true. Of the two major classes of theories, the one class that is tenable is derivative of a single common denominator that results in only one fundamental theory of aging. In order to address this complex subject, it is necessary to first define the four phenomena that characterize the finitude of life. These phenomena are aging, the determinants of longevity, age-associated diseases, and death. There are only two fundamental ways in which age changes can occur. Aging occurs either as the result of a purposeful program driven by genes or by events that are not guided by a program but are stochastic or random, accidental events. The weight of evidence indicates that genes do not drive the aging process but the general loss of molecular fidelity does. Potential longevity is determined by the energetics of all molecules present at and after the time of reproductive maturation. Thus, every molecule, including those that compose the machinery involved in turnover, replacement, and repair, becomes the substrate that experiences the thermodynamic instability characteristic of the aging process. However, the determinants of the fidelity of all molecules produced before and after reproductive maturity are the determinants of longevity. This process is governed by the genome. Aging does not happen in a vacuum. Aging must be the result of changes that occur in molecules that have existed at one time with no age changes. It is the state of these pre-existing molecules that governs longevity determination. The distinction between the aging process and age-associated disease is not only based on the molecular definition of aging described above but it is also rooted in several practical observations. Unlike any disease, age changes (a) occur in every multicellular animal that reaches a fixed size at reproductive maturity, (b) cross virtually all species barriers, (c) occur in all members of a species only after the age of reproductive maturation, (d) occur in all animals removed from the wild and protected by humans even when that species probably has not experienced aging for thousands or even millions of years, (e) occur in virtually all animate and inanimate matter, and (f) have the same universal molecular etiology, that is, thermodynamic instability. Unlike aging, there is no disease or pathology that shares these six qualities. Because this critical distinction is poorly understood, there is a continuing belief that the resolution of age-associated diseases will advance our understanding of the fundamental aging process. It will not. The distinction between disease and aging is also critical for establishing science policy because although policy makers understand that the funding of research on age-associated diseases is an unquestioned good, they also must understand that the resolution of age-associated diseases will not provide insights into understanding the fundamental biology of age changes. They often believe that it will and base decisions on that misunderstanding. The impact has been to fund research on age-associated diseases at several orders of magnitude greater than what is available for research on the biology of aging. There is an almost universal belief by geriatricians and others that the greatest risk factor for all of the leading causes of death is old age. Why then are we not devoting significantly greater resources to understanding more about the greatest risk factor for every age-associated pathology by attempting to answer this fundamental question-"What changes occur in biomolecules that lead to the manifestations of aging at higher orders of complexity and then increase vulnerability to all age-associated pathology?"
KEYWORDS: aging; age-associated disease; longevity
http://ibgwww.colorado.edu/pdf/hayflick_1.pdf
Atentamente
Anestesiología y Medicina del Dolor
www.anestesia-dolor.org
Hallmarks of telomeres in ageing research
JW Shay and WE Wright
University of Texas Southwestern Medical Center, Department of Cell Biology, Dallas, TX 75390-9039, USA
Journal of Pathology J Pathol 2007; 211: 114-123
Abstract
Telomeres are repetitive DNA sequences at the ends of linear chromosomes. Telomerase, a cellular reverse transcriptase, helps maintain telomere length in human stem cells, reproductive cells and cancer cells by adding TTAGGG repeats onto the telomeres. However, most normal human cells do not express telomerase and thus each time a cell divides some telomeric sequences are lost. When telomeres in a subset of cells become short (unprotected), cells enter an irreversible growth arrest state called replicative senescence. Cells in senescence produce a different constellation of proteins compared to normal quiescent cells. This may lead to a change in the homeostatic environment in a tissue-specific manner. In most instances cells become senescent before they can become cancerous; thus, the initial growth arrest induced by short telomeres may be thought of as a potent anti-cancer protection mechanism. When cells can be adequately cultured until they reach telomerebased replicative senescence, introduction of the telomerase catalytic protein component (hTERT) into telomerase-silent cells is sufficient to restore telomerase activity and extend cellular lifespan. Cells with introduced telomerase are not cancer cells, since they have not accumulated the other changes needed to become cancerous. This indicates that telomeraseinduced telomere length manipulations may have utility for tissue engineering and for dissecting the molecular mechanisms underlying genetic diseases, including cancer.
Keywords: ageing; cancer; telomeres; telomerase
http://www4.utsouthwestern.edu/cellbio/shay-wright/publications/J%20Pathology%202007.pdf
El envejecimiento biológico no es mas un problema sin resolver
Biological Aging Is No Longer an Unsolved Problem
LEONARD HAYFLICK
Department of Anatomy, University of California, San Francisco, School
of Medicine, The Sea Ranch, California 95497, USA
Ann. N.Y. Acad. Sci. 1100: 1-13 (2007). C 2007 New York Academy of Sciences. doi: 10.1196/annals.1395.001
ABSTRACT: The belief that aging is still an unsolved problem in biology is no longer true. Of the two major classes of theories, the one class that is tenable is derivative of a single common denominator that results in only one fundamental theory of aging. In order to address this complex subject, it is necessary to first define the four phenomena that characterize the finitude of life. These phenomena are aging, the determinants of longevity, age-associated diseases, and death. There are only two fundamental ways in which age changes can occur. Aging occurs either as the result of a purposeful program driven by genes or by events that are not guided by a program but are stochastic or random, accidental events. The weight of evidence indicates that genes do not drive the aging process but the general loss of molecular fidelity does. Potential longevity is determined by the energetics of all molecules present at and after the time of reproductive maturation. Thus, every molecule, including those that compose the machinery involved in turnover, replacement, and repair, becomes the substrate that experiences the thermodynamic instability characteristic of the aging process. However, the determinants of the fidelity of all molecules produced before and after reproductive maturity are the determinants of longevity. This process is governed by the genome. Aging does not happen in a vacuum. Aging must be the result of changes that occur in molecules that have existed at one time with no age changes. It is the state of these pre-existing molecules that governs longevity determination. The distinction between the aging process and age-associated disease is not only based on the molecular definition of aging described above but it is also rooted in several practical observations. Unlike any disease, age changes (a) occur in every multicellular animal that reaches a fixed size at reproductive maturity, (b) cross virtually all species barriers, (c) occur in all members of a species only after the age of reproductive maturation, (d) occur in all animals removed from the wild and protected by humans even when that species probably has not experienced aging for thousands or even millions of years, (e) occur in virtually all animate and inanimate matter, and (f) have the same universal molecular etiology, that is, thermodynamic instability. Unlike aging, there is no disease or pathology that shares these six qualities. Because this critical distinction is poorly understood, there is a continuing belief that the resolution of age-associated diseases will advance our understanding of the fundamental aging process. It will not. The distinction between disease and aging is also critical for establishing science policy because although policy makers understand that the funding of research on age-associated diseases is an unquestioned good, they also must understand that the resolution of age-associated diseases will not provide insights into understanding the fundamental biology of age changes. They often believe that it will and base decisions on that misunderstanding. The impact has been to fund research on age-associated diseases at several orders of magnitude greater than what is available for research on the biology of aging. There is an almost universal belief by geriatricians and others that the greatest risk factor for all of the leading causes of death is old age. Why then are we not devoting significantly greater resources to understanding more about the greatest risk factor for every age-associated pathology by attempting to answer this fundamental question-"What changes occur in biomolecules that lead to the manifestations of aging at higher orders of complexity and then increase vulnerability to all age-associated pathology?"
KEYWORDS: aging; age-associated disease; longevity
http://ibgwww.colorado.edu/pdf/hayflick_1.pdf
Atentamente
Anestesiología y Medicina del Dolor
www.anestesia-dolor.org
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