- Email: [email protected]
Telomere length and mortality
CORRESPONDENCE
A war in Iraq might not be the greatest humanitarian disaster of all times as some critics argue. But it is surely one of the major opportunities to reduce potential humanitarian damage in the world. To date, the lack of open discussion to address these risks and reduce harm is in striking contrast to the very public dissemination of plans for war. The Lancet’s reporting should encourage us to do more, do it better, and do it now. Richard Garfield Columbia University, 630 West 168th Street, New York, NY 10032, USA (e-mail: [email protected])
Telomere length and mortality Sir—Richard Cawthon and colleagues (Feb 1, p 393)1 describe an association between telomere length and premature mortality. Many questions arise from this research. Do some individuals start life with shorter than average telomeres? Does the level of oxidative stress or infection during life affect telomere length in blood cells? Although the authors state the generally accepted explanation that loss of telomeric DNA in dividing somatic cells can lead to neoplastic transformation, they found no association with cancer in their study. We would like to propose a testable hypothesis on the basis of this paper. The mechanism whereby telomeres shorten in life as they are “used up” supports a hypothesis that there will be an upper limit to the number of divisions any particular somatic cell line can undergo in a typical lifespan for any one species. If the stem cells in a particular tissue were turning over at a higher rate than they were evolutionarily designed for, over a lifetime, then a premature decrease in telomeric length would be expected. Dysplastic tissues might provide a suitable model for chronically increased cellular proliferation. For example, undescended testes are regarded as a premalignant disorder, and subclinical testicular dysplasia has been associated This with malignant change.2 association could fit well with the theory of Sonnenschein and Soto,3–5 who have proposed a negative feedback paradigm whereby all cells in the body are in a default state of proliferation, which in normal tissues is suppressed by tonic juxtacrine signalling. They further posit that, if such signalling breaks down due to changes in local architecture of the tissue, the cells might revert to the default state of proliferation and
1224
migration—clinically cancer. In dysplastic architecturally disorganised tissues, any such negative feedback mechanism could be suboptimal, allowing increased rates of stem-cell proliferation. The relevance of the study by Cawthon and colleagues to these ideas is that, although telomere shortening could be associated with increased genetic damage through decreased repair capacity, it did not lead to increased cancer mortality, which is surprising. Could, therefore, the aneuploidy and genetic damage associated with cancers be a secondary result of telomere shortening through increased proliferation, rather than the primary cause of the cancer, which is assumed to be a sequel to the genetic damage under the single mutation hypothesis?
withstand illness, infection, or other stress. Deaths from heart disease in Cawthon and colleagues’ study were significantly more frequent in the short telomere population than in those with longer telomeres. There have been many reports of apparent recruitment by damaged heart muscle of bone-marrowderived stem cells. For example, Orlic and colleagues3 indicated that cardiac muscle function was significantly improved by treatment with mobilised bone-marrow stem cells. Infectionfighting capacity is highly dependent on the ability to bolster immune-system cell numbers. A depleted reservoir would again be expected to diminish the defences against this potential cause of death.
*C V Howard, G Staats de Yanés
Ken Campbell
Human Anatomy and Cell Biology, University of Liverpool, Liverpool L69 3BX, UK (e-mail: [email protected])
Leukaemia Research Fund, 43 Great Ormond Street, London WC1N 3JJ, UK (e-mail: [email protected])
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3
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5
Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003; 361: 393–95. Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common development disorder with environmental aspects. Hum Reprod 2001; 16: 972–78. Sonnenschein C, Soto AM. The society of cells: cancer and control of cell proliferation. Oxford: BIOS Scientific Publishers Ltd, 1999. Soto AM, Sonnenschein C. Regulation of cell proliferation: is the ultimate control positive or negative? In: Iversen OH, ed. New frontiers in cancer causation. Washington, DC: Taylor and Francis, 1993: 109–23. Howard CV. Review of ‘The society of cells’. J Pathol 2000; 190: 518–20.
Sir—Richard Cawthon and colleagues1 report an association between telomere length and mortality in people aged 60 years and older. They suggest that “telomere shortening might not affect mortality, but might be controlled by (and so serve as a useful indicator of) progression of a process of senescence that raises mortality rates by other mechanisms”. I have proposed that the presence of a population of pluripotent stem cells within the bone marrow might indicate a reservoir of cells responsible for postnatal somatic growth, repair, and regeneration (GRR cells).2 Within this model, telomere length could be a function, partly or wholly, of the adequacy of this reservoir. Additionally, as suggested by Cawthon and colleagues, the state at a given time would also reflect the extent of recruitment of GRR cells throughout life. Both of these factors might be expected to bear heavily on the ability to
Views expressed in this letter do not necessarily reflect those of the Leukaemia Research Fund.
2
3
Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003; 361: 393–95. Campbell K. Bone marrow as a reservoir of pluripotential stem cells for somatic growth, repair, and regeneration. http://www. bloodmed.com/400000/reviewarticle1.asp?id =43 (accessed March, 2003). Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001; 98: 10344–49.
The world’s forgotten children Sir—Your Editorial (Jan 4, p 1)1 appeared on the inaugural day of a paediatric conference at a five-star hotel in Mumbai, India, at which 5000 delegates attended to discuss such issues as malnutrition, sepsis, and HIV in Indian children. Although this event sounds encouraging, the administrators and ministers who draw up the various health policies at such meetings are residents of metropolitan areas and big cities, and are not aware of the real problems that exist in rural areas. 67 per 1000 children die from infectious diseases such as pneumonia, diarrhoea, tuberculosis, HIV-related diseases, and scabies. But susceptibility to such infections is caused by depressed immunity due to malnutrition and unhygienic conditions in rural and slum areas. Deaths attributed to infectious diseases are diverting the public’s attention away from the root cause:
THE LANCET • Vol 361 • April 5, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
A war in Iraq might not be the greatest humanitarian disaster of all times as some critics argue. But it is surely one of the major opportunities to reduce potential humanitarian damage in the world. To date, the lack of open discussion to address these risks and reduce harm is in striking contrast to the very public dissemination of plans for war. The Lancet’s reporting should encourage us to do more, do it better, and do it now. Richard Garfield Columbia University, 630 West 168th Street, New York, NY 10032, USA (e-mail: [email protected])
Telomere length and mortality Sir—Richard Cawthon and colleagues (Feb 1, p 393)1 describe an association between telomere length and premature mortality. Many questions arise from this research. Do some individuals start life with shorter than average telomeres? Does the level of oxidative stress or infection during life affect telomere length in blood cells? Although the authors state the generally accepted explanation that loss of telomeric DNA in dividing somatic cells can lead to neoplastic transformation, they found no association with cancer in their study. We would like to propose a testable hypothesis on the basis of this paper. The mechanism whereby telomeres shorten in life as they are “used up” supports a hypothesis that there will be an upper limit to the number of divisions any particular somatic cell line can undergo in a typical lifespan for any one species. If the stem cells in a particular tissue were turning over at a higher rate than they were evolutionarily designed for, over a lifetime, then a premature decrease in telomeric length would be expected. Dysplastic tissues might provide a suitable model for chronically increased cellular proliferation. For example, undescended testes are regarded as a premalignant disorder, and subclinical testicular dysplasia has been associated This with malignant change.2 association could fit well with the theory of Sonnenschein and Soto,3–5 who have proposed a negative feedback paradigm whereby all cells in the body are in a default state of proliferation, which in normal tissues is suppressed by tonic juxtacrine signalling. They further posit that, if such signalling breaks down due to changes in local architecture of the tissue, the cells might revert to the default state of proliferation and
1224
migration—clinically cancer. In dysplastic architecturally disorganised tissues, any such negative feedback mechanism could be suboptimal, allowing increased rates of stem-cell proliferation. The relevance of the study by Cawthon and colleagues to these ideas is that, although telomere shortening could be associated with increased genetic damage through decreased repair capacity, it did not lead to increased cancer mortality, which is surprising. Could, therefore, the aneuploidy and genetic damage associated with cancers be a secondary result of telomere shortening through increased proliferation, rather than the primary cause of the cancer, which is assumed to be a sequel to the genetic damage under the single mutation hypothesis?
withstand illness, infection, or other stress. Deaths from heart disease in Cawthon and colleagues’ study were significantly more frequent in the short telomere population than in those with longer telomeres. There have been many reports of apparent recruitment by damaged heart muscle of bone-marrowderived stem cells. For example, Orlic and colleagues3 indicated that cardiac muscle function was significantly improved by treatment with mobilised bone-marrow stem cells. Infectionfighting capacity is highly dependent on the ability to bolster immune-system cell numbers. A depleted reservoir would again be expected to diminish the defences against this potential cause of death.
*C V Howard, G Staats de Yanés
Ken Campbell
Human Anatomy and Cell Biology, University of Liverpool, Liverpool L69 3BX, UK (e-mail: [email protected])
Leukaemia Research Fund, 43 Great Ormond Street, London WC1N 3JJ, UK (e-mail: [email protected])
1
1
2
3
4
5
Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003; 361: 393–95. Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common development disorder with environmental aspects. Hum Reprod 2001; 16: 972–78. Sonnenschein C, Soto AM. The society of cells: cancer and control of cell proliferation. Oxford: BIOS Scientific Publishers Ltd, 1999. Soto AM, Sonnenschein C. Regulation of cell proliferation: is the ultimate control positive or negative? In: Iversen OH, ed. New frontiers in cancer causation. Washington, DC: Taylor and Francis, 1993: 109–23. Howard CV. Review of ‘The society of cells’. J Pathol 2000; 190: 518–20.
Sir—Richard Cawthon and colleagues1 report an association between telomere length and mortality in people aged 60 years and older. They suggest that “telomere shortening might not affect mortality, but might be controlled by (and so serve as a useful indicator of) progression of a process of senescence that raises mortality rates by other mechanisms”. I have proposed that the presence of a population of pluripotent stem cells within the bone marrow might indicate a reservoir of cells responsible for postnatal somatic growth, repair, and regeneration (GRR cells).2 Within this model, telomere length could be a function, partly or wholly, of the adequacy of this reservoir. Additionally, as suggested by Cawthon and colleagues, the state at a given time would also reflect the extent of recruitment of GRR cells throughout life. Both of these factors might be expected to bear heavily on the ability to
Views expressed in this letter do not necessarily reflect those of the Leukaemia Research Fund.
2
3
Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003; 361: 393–95. Campbell K. Bone marrow as a reservoir of pluripotential stem cells for somatic growth, repair, and regeneration. http://www. bloodmed.com/400000/reviewarticle1.asp?id =43 (accessed March, 2003). Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001; 98: 10344–49.
The world’s forgotten children Sir—Your Editorial (Jan 4, p 1)1 appeared on the inaugural day of a paediatric conference at a five-star hotel in Mumbai, India, at which 5000 delegates attended to discuss such issues as malnutrition, sepsis, and HIV in Indian children. Although this event sounds encouraging, the administrators and ministers who draw up the various health policies at such meetings are residents of metropolitan areas and big cities, and are not aware of the real problems that exist in rural areas. 67 per 1000 children die from infectious diseases such as pneumonia, diarrhoea, tuberculosis, HIV-related diseases, and scabies. But susceptibility to such infections is caused by depressed immunity due to malnutrition and unhygienic conditions in rural and slum areas. Deaths attributed to infectious diseases are diverting the public’s attention away from the root cause:
THE LANCET • Vol 361 • April 5, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.