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Telomere attrition: a potential limit to longevity?
Telomere shortening is itself a cause of aging, but telomeres also shorten in response to stresses and diseases. Extending telomeres in animals prolongs their lifespan, albeit modestly.
Highlights:
- Telomeres are the protective caps on the end of chromosomes in cells, which get shorter with aging despite being elongated by the enzyme telomerase
- Telomere shortening is itself a cause of aging, but telomeres also shorten in response to stresses and diseases
- Multiple studies show that extending telomeres in animals prolongs their lifespan, albeit modestly
Introduction
Nine hallmarks of aging have become an accepted consensus in the research community. Among them, telomere attrition (too short telomeres) has been perhaps the one most often mentioned in popular science. The telomeres are the ends of the chromosomes in the cells of organisms that protect the genomes of cells. This article covers the facts vs. fiction surrounding how this particular hallmark is a factor in the aging process and can be modulated.
Telomere attrition as a hallmark of aging
Among the earliest published discoveries on cellular aging was Leonard Hayflick's observation that cells divided a finite number of times in a Petri dish and then died after not proliferating anymore (1). This number was recorded as being between 40 to 60 times, and it was assumed it would occur in vivo as well. During the 20th century, this finding led to early researchers on aging (gerontologists) thinking that the shortening of telomeres would be a major causative factor in aging. Human lifespan typically extends to 80-90 years, and no one has lived beyond 122, which would mathematically add up to some limiting factor found in cellular aging. Also, there is a loss of proliferative capacity in cells with age. The wounds in advanced age tend to heal slower; also turnover rates of cells in organs are longer, which is interlinked with another hallmark of aging, stem cell exhaustion (2).
However, the processes in complex organisms like humans are not as straightforward as in a Petri dish. While it is true that the telomeres do shorten, they can also be replenished by the enzyme telomerase that lengthens them (although activity in somatic cells is very low). Aging has generally been associated with shorter telomeres. However, many studies indicate a correlation but do not prove that it is simply a reduced telomere length that is causative.
How do telomeres and telomerase function?
Cells have telomeres that are structures of up to 15000 bases (humans) at the end of chromosomes that are made up of the same repeating DNA sequences. Telomeres have multiple functions, such as protecting chromosomes from attaching to each other. Also, they allow for replication without DNA getting lost in the process since some base pairs are lost during replication. When telomeres get too short, this can cause the cells to die or become damaged (senescent) cells that linger around and harm surrounding tissues (3).
Telomeres are prolonged by the enzyme telomerase that adds sequences of DNA and subsequently prevents them from getting too short during life. Subsequently, telomerase could be described as an anti-aging enzyme, but to a limited extent since telomere shortening is only a part of the aging process, and also too much telomerase could, in theory, increase the risk of cancer due to allowing replication of damaged cells. There are several drugs to prevent telomerase from prolonging telomeres which inhibit cell replication. Since cell division can be dangerous when it is “hijacked” by cancer cells, several drugs inhibiting telomerase are used in oncology, for example, Imetelstat.
Experimental evidence of the role of telomeres in aging
Many studies have been done showing the impact of shortened telomeres on aging. However, numerous initial studies were conducted on premature aging phenotypes in mice. These mice had critically short telomeres, died prematurely, and displayed many markers of dysfunction that are similar to normal aging.
A study performed by the lab of telomere researcher Maria Blasco showed that breeding mice with exceptionally long telomeres extended their lifespan. It also improved multiple markers of aging at once. The results confirmed earlier show that telomeres do play a role in aging. However, lifespan was increased by 13 %, which is modest compared to the gold standards in mice lifespan interventions such as calorie restriction. The mice with long telomeres were thinner and had a lower cancer rate than their controls; they also had an improved mitochondrial function compared to normal mice (4).
Furthermore, studies have shown that treating normal mice with telomere-extending gene therapy prolonged their lives. Like in the case of the mice bred with hyper-long telomeres, they retained a better healthspan than the controls, and their lifespan increased by 10%. Many physiological function markers improved at once indicate the role of telomere shortening across tissues systemically in the body (5). Both of these therapies worked to extend lifespan and healthspan slightly. Still, the dramatic lifespan extension and aging reversal are not likely to occur simply by targeting the telomere attrition hallmark.
Evidence for the importance of telomeres in lifespan also comes from premature aging disorders that mimic aspects of normal senescence. An example is dyskeratosis congenita, a range of diseases that manifests as bone marrow failure and skin dysfunction, among other symptoms. It results from too short telomeres secondary to genetic defects in the telomere elongation machinery, the Telomerase RNA component (TERC) complex, which is a template for telomeres to get elongated. This disease can also come from defects in dyskerin, a protein that provides instructions on how to make telomerase. Hence, the more dramatic results may be observed if the therapy is deployed for particular premature aging conditions, such as dyskeratosis congenita where short telomeres are the defining feature causing the clinical pathology (6).
Cause or effect?
The hallmarks of aging are interlinked, and when one falters, it subsequently affects the others. From the evolutionary perspective, the repair systems in organisms fail at roughly the same rates, which causes different species to have considerably variable lifespans.
In the case of telomere attrition, it is well known that many diseases, such as irritable bowel syndrome and kidney fibrosis, lead to short telomeres, which means it is a marker for tissue damage and pathological conditions in general. In conclusion, an old organism may display shortened telomeres as part of its frailty phenotype, but that does not mean that its lifespan can be extended significantly by targeting this hallmark.
Many interventions improve general health, leading to longer telomeres, such as exercise and healthy eating. This indicates that longer telomeres in themselves are associated with good health and that a variety of stressors such as aging and disease cause them to shorten (7,8). Subsequently, it can be argued that telomere attrition is both a cause in itself, as evidenced by specific telomere-related premature aging diseases, and a secondary effect from other hallmarks.
Summary
The role of telomeres in disease and aging for humans is still unclear except in premature aging disorders. There is evidence that mice in which telomere shortening is prevented with age, either through breeding or gene therapy, live somewhat longer and in better health. By addressing other hallmarks of aging, one could expect an improvement in telomere length secondary to addressing aspects making telomeres age faster.
A telomere extending therapy in humans would likely have more impact if used for a particular premature aging disorder related to telomere dysfunction rather than a single bullet toward generalized aging.
References
- Shay JW, Wright WE. Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol. 2000 Oct;1(1):72-6. doi: 10.1038/35036093. PMID: 11413492.
- Kirschner K, Chandra T, Kiselev V, et al. Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment. Cell Rep. 2017;19(8):1503-1511. doi:10.1016/j.celrep.2017.04.074
- van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509(7501):439-446. doi:10.1038/nature13193
- Mice with hyper-long telomeres show less metabolic aging and longer lifespans. Miguel A. Muñoz-Lorente, Alba C. Cano-Martin, Maria A. Blasco (Nature Communications, 2019)
- Bernardes de Jesus B, Vera E, Schneeberger K, Tejera AM, Ayuso E, Bosch F, Blasco MA. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med. 2012 Aug;4(8):691-704. doi: 10.1002/emmm.201200245. Epub 2012 May 15. PMID: 22585399; PMCID: PMC3494070.
- Savage SA, Alter BP. Dyskeratosis congenita. Hematol Oncol Clin North Am. 2009;23(2):215-231. doi:10.1016/j.hoc.2009.01.003
- Arsenis NC, You T, Ogawa EF, Tinsley GM, Zuo L. Physical activity and telomere length: Impact of aging and potential mechanisms of action. Oncotarget. 2017;8(27):45008-45019. doi:10.18632/oncotarget.16726
- Serena Galiè, Silvia Canudas, Jananee Muralidharan, Jesús García-Gavilán, Mònica Bulló, Jordi Salas-Salvadó, Impact of Nutrition on Telomere Health: Systematic Review of Observational Cohort Studies and Randomized Clinical Trials, Advances in Nutrition, Volume 11, Issue 3, May 2020, Pages 576–601,
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Highlights:
- Telomeres are the protective caps on the end of chromosomes in cells, which get shorter with aging despite being elongated by the enzyme telomerase
- Telomere shortening is itself a cause of aging, but telomeres also shorten in response to stresses and diseases
- Multiple studies show that extending telomeres in animals prolongs their lifespan, albeit modestly
Introduction
Nine hallmarks of aging have become an accepted consensus in the research community. Among them, telomere attrition (too short telomeres) has been perhaps the one most often mentioned in popular science. The telomeres are the ends of the chromosomes in the cells of organisms that protect the genomes of cells. This article covers the facts vs. fiction surrounding how this particular hallmark is a factor in the aging process and can be modulated.
Telomere attrition as a hallmark of aging
Among the earliest published discoveries on cellular aging was Leonard Hayflick's observation that cells divided a finite number of times in a Petri dish and then died after not proliferating anymore (1). This number was recorded as being between 40 to 60 times, and it was assumed it would occur in vivo as well. During the 20th century, this finding led to early researchers on aging (gerontologists) thinking that the shortening of telomeres would be a major causative factor in aging. Human lifespan typically extends to 80-90 years, and no one has lived beyond 122, which would mathematically add up to some limiting factor found in cellular aging. Also, there is a loss of proliferative capacity in cells with age. The wounds in advanced age tend to heal slower; also turnover rates of cells in organs are longer, which is interlinked with another hallmark of aging, stem cell exhaustion (2).
However, the processes in complex organisms like humans are not as straightforward as in a Petri dish. While it is true that the telomeres do shorten, they can also be replenished by the enzyme telomerase that lengthens them (although activity in somatic cells is very low). Aging has generally been associated with shorter telomeres. However, many studies indicate a correlation but do not prove that it is simply a reduced telomere length that is causative.
How do telomeres and telomerase function?
Cells have telomeres that are structures of up to 15000 bases (humans) at the end of chromosomes that are made up of the same repeating DNA sequences. Telomeres have multiple functions, such as protecting chromosomes from attaching to each other. Also, they allow for replication without DNA getting lost in the process since some base pairs are lost during replication. When telomeres get too short, this can cause the cells to die or become damaged (senescent) cells that linger around and harm surrounding tissues (3).
Telomeres are prolonged by the enzyme telomerase that adds sequences of DNA and subsequently prevents them from getting too short during life. Subsequently, telomerase could be described as an anti-aging enzyme, but to a limited extent since telomere shortening is only a part of the aging process, and also too much telomerase could, in theory, increase the risk of cancer due to allowing replication of damaged cells. There are several drugs to prevent telomerase from prolonging telomeres which inhibit cell replication. Since cell division can be dangerous when it is “hijacked” by cancer cells, several drugs inhibiting telomerase are used in oncology, for example, Imetelstat.
Experimental evidence of the role of telomeres in aging
Many studies have been done showing the impact of shortened telomeres on aging. However, numerous initial studies were conducted on premature aging phenotypes in mice. These mice had critically short telomeres, died prematurely, and displayed many markers of dysfunction that are similar to normal aging.
A study performed by the lab of telomere researcher Maria Blasco showed that breeding mice with exceptionally long telomeres extended their lifespan. It also improved multiple markers of aging at once. The results confirmed earlier show that telomeres do play a role in aging. However, lifespan was increased by 13 %, which is modest compared to the gold standards in mice lifespan interventions such as calorie restriction. The mice with long telomeres were thinner and had a lower cancer rate than their controls; they also had an improved mitochondrial function compared to normal mice (4).
Furthermore, studies have shown that treating normal mice with telomere-extending gene therapy prolonged their lives. Like in the case of the mice bred with hyper-long telomeres, they retained a better healthspan than the controls, and their lifespan increased by 10%. Many physiological function markers improved at once indicate the role of telomere shortening across tissues systemically in the body (5). Both of these therapies worked to extend lifespan and healthspan slightly. Still, the dramatic lifespan extension and aging reversal are not likely to occur simply by targeting the telomere attrition hallmark.
Evidence for the importance of telomeres in lifespan also comes from premature aging disorders that mimic aspects of normal senescence. An example is dyskeratosis congenita, a range of diseases that manifests as bone marrow failure and skin dysfunction, among other symptoms. It results from too short telomeres secondary to genetic defects in the telomere elongation machinery, the Telomerase RNA component (TERC) complex, which is a template for telomeres to get elongated. This disease can also come from defects in dyskerin, a protein that provides instructions on how to make telomerase. Hence, the more dramatic results may be observed if the therapy is deployed for particular premature aging conditions, such as dyskeratosis congenita where short telomeres are the defining feature causing the clinical pathology (6).
Cause or effect?
The hallmarks of aging are interlinked, and when one falters, it subsequently affects the others. From the evolutionary perspective, the repair systems in organisms fail at roughly the same rates, which causes different species to have considerably variable lifespans.
In the case of telomere attrition, it is well known that many diseases, such as irritable bowel syndrome and kidney fibrosis, lead to short telomeres, which means it is a marker for tissue damage and pathological conditions in general. In conclusion, an old organism may display shortened telomeres as part of its frailty phenotype, but that does not mean that its lifespan can be extended significantly by targeting this hallmark.
Many interventions improve general health, leading to longer telomeres, such as exercise and healthy eating. This indicates that longer telomeres in themselves are associated with good health and that a variety of stressors such as aging and disease cause them to shorten (7,8). Subsequently, it can be argued that telomere attrition is both a cause in itself, as evidenced by specific telomere-related premature aging diseases, and a secondary effect from other hallmarks.
Summary
The role of telomeres in disease and aging for humans is still unclear except in premature aging disorders. There is evidence that mice in which telomere shortening is prevented with age, either through breeding or gene therapy, live somewhat longer and in better health. By addressing other hallmarks of aging, one could expect an improvement in telomere length secondary to addressing aspects making telomeres age faster.
A telomere extending therapy in humans would likely have more impact if used for a particular premature aging disorder related to telomere dysfunction rather than a single bullet toward generalized aging.
References
- Shay JW, Wright WE. Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol. 2000 Oct;1(1):72-6. doi: 10.1038/35036093. PMID: 11413492.
- Kirschner K, Chandra T, Kiselev V, et al. Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment. Cell Rep. 2017;19(8):1503-1511. doi:10.1016/j.celrep.2017.04.074
- van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509(7501):439-446. doi:10.1038/nature13193
- Mice with hyper-long telomeres show less metabolic aging and longer lifespans. Miguel A. Muñoz-Lorente, Alba C. Cano-Martin, Maria A. Blasco (Nature Communications, 2019)
- Bernardes de Jesus B, Vera E, Schneeberger K, Tejera AM, Ayuso E, Bosch F, Blasco MA. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med. 2012 Aug;4(8):691-704. doi: 10.1002/emmm.201200245. Epub 2012 May 15. PMID: 22585399; PMCID: PMC3494070.
- Savage SA, Alter BP. Dyskeratosis congenita. Hematol Oncol Clin North Am. 2009;23(2):215-231. doi:10.1016/j.hoc.2009.01.003
- Arsenis NC, You T, Ogawa EF, Tinsley GM, Zuo L. Physical activity and telomere length: Impact of aging and potential mechanisms of action. Oncotarget. 2017;8(27):45008-45019. doi:10.18632/oncotarget.16726
- Serena Galiè, Silvia Canudas, Jananee Muralidharan, Jesús García-Gavilán, Mònica Bulló, Jordi Salas-Salvadó, Impact of Nutrition on Telomere Health: Systematic Review of Observational Cohort Studies and Randomized Clinical Trials, Advances in Nutrition, Volume 11, Issue 3, May 2020, Pages 576–601,
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Dr. Ana Baroni MD. Ph.D.
Scientific & Medical Advisor
Quality Garant
Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.
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