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A New Understanding of Telomere Attrition

The DNA damage response and cellular senescence are strongly linked.


In Nature Cell Biology, a team of researchers has presented a current review of telomeres and how they relate to aging, reflecting modern research into a decades-old topic.

Telomeres and cellular senescence

This paper touches upon senescent cells and the senescence-associated secretory phenotype (SASP) that they excrete. As this paper explains, cellular senescence is initiated by a constant DNA damage response (DDR): DNA repair mechanisms, which are capable of fixing DNA damage caused by other methods, are ineffective against DNA damage caused by shortened telomeres [1]. Additionally, the SASP itself drives DDR against telomere-associated DNA foci [2].

The researchers also report that telomere DNA is uniquely sensitive to oxidative damage. This process, called TelOxidation [3], harms the activity of the telomere-lengthening enzyme telomerase [4] and telomere-binding proteins, thus leading to further telomere damage [5].

Multiple other hallmarks of aging are mentioned as being affected by telomere attrition, leading the researchers to suggest that this hallmark is more prominent in aging than otherwise thought [6].

Diseases related to telomere dysfunction

This review includes a lengthy list of age-related diseases that research has shown are relevant to telomeres. This includes lung diseases such as idiopathic pulmonary fibrosis [7] and chronic obstrucive pulmonary disorder (COPD) [8], both of which are also strongly related to cellular senescence. There is also evidence suggesting a causal relationship between aplastic anemia and telomere attrition in people [9], and short telomeres may be a cause of kidney fibrosis [10].

The researchers also point to evidence of telomere attrition being involved in many other disorders, including a syndrome related to stem cell exhaustion, cardiovascular diseases, diabetes and other metabolic issues, arthritis, atherosclerosis, and brain disorders such as Alzheimer’s and Parkinson’s.


To cap off this review, the researchers discuss the possibility of telomere lengthening as a therapy. They name the telomere lengthening molecule TERT, suggesting that cells can be encouraged to increase its production and that it can be delivered, itself, as a drug. Of course, this approach might have side effects [11], so the clinical trial process is necessary to ensure safety.

The importance of telomere attrition is a somewhat divisive topic in the longevity community, with some schools of thought holding it to be much more important than others. As the hallmarks of aging build upon and strongly interact with one another, it is very unlikely that telomerase reactivation would be completely ineffective, and it is equally unlikely that it would be a complete cure for telomere-related diseases. To deal with these intertwined hallmarks, a combination approach that simultaneously deals with telomerase and cellular senescence, along withย other aspects of aging, is much more likely to be effective; the more completely and thoroughly we can directly and safely target the hallmarks of aging, the better.

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[1] Hewitt, G., Jurk, D., Marques, F. D. M., Correia-Melo, C., Hardy, T., Gackowska, A., & Anderson, R. 818 Taschuk, M., Mann, J., and Passos, JF (2012) Telomeres are favoured targets of a persistent DNA 819 damage response in ageing and stress-induced senescence. Nature communications, 3, 708-820.

[2] Victorelli, S., Lagnado, A., Halim, J., Moore, W., Talbot, D., Barrett, K., … & Passos, J. F. (2019). Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. The EMBO journal, 38(23), e101982.

[3] Jacome Burbano, M. S., Cherfils-Vicini, J., & Gilson, E. (2021). Neutrophils: mediating TelOxidation and senescence. The EMBO Journal, 40(9), e108164.

]4] Fouquerel, E., Lormand, J., Bose, A., Lee, H. T., Kim, G. S., Li, J., … & Opresko, P. L. (2016). Oxidative guanine base damage regulates human telomerase activity. Nature structural & molecular biology, 23(12), 1092-1100.

[5] Opresko, P. L., Fan, J., Danzy, S., Wilson III, D. M., & Bohr, V. A. (2005). Oxidative damage in telomeric DNA disrupts recognition by TRF1 and TRF2. Nucleic acids research, 33(4), 1230-1239.

[6] Chakravarti, D., LaBella, K. A., & DePinho, R. A. (2021). Telomeres: history, health, and hallmarks of aging. Cell, 184(2), 306-322.

[7] Lee, S., Islam, M. N., Boostanpour, K., Aran, D., Jin, G., Christenson, S., … & Bhattacharya, M. (2021). Molecular programs of fibrotic change in aging human lung. Nature communications, 12(1), 1-10.

[8] Ahmad, T., Sundar, I. K., Tormos, A. M., Lerner, C. A., Gerloff, J., Yao, H., & Rahman, I. (2017). Shelterin telomere protection protein 1 reduction causes telomere attrition and cellular senescence via sirtuin 1 deacetylase in chronic obstructive pulmonary disease. American journal of respiratory cell and molecular biology, 56(1), 38-49.

[9] Townsley, D. M., Dumitriu, B., Liu, D., Biancotto, A., Weinstein, B., Chen, C., … & Young, N. S. (2016). Danazol treatment for telomere diseases. New England Journal of Medicine, 374(20), 1922-1931.

[10] Saraswati, S., Martรญnez, P., Graรฑa-Castro, O., & Blasco, M. A. (2021). Short and dysfunctional telomeres sensitize the kidneys to develop fibrosis. Nature Aging, 1(3), 269-283.

[11] Martรญnez, P., & Blasco, M. A. (2011). Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nature Reviews Cancer, 11(3), 161-176.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called โ€œreal life.โ€ Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
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