Telomeres - Revision history

Dmitry Dzhagarov: /* GV1001 */

2024-09-14T08:18:53Z

GV1001

← Older revision		Revision as of 08:18, 14 September 2024
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	GV1001 was used for the treatment of Alzheimer's disease patients with moderate to severe dementia and confirmed that, compared to those in the placebo, GV1001 significantly improved the Alzheimer's disease patient’s cognitive function.<ref>Koh, S. H., Kwon, H. S., Choi, S. H., Jeong, J. H., Na, H. R., Lee, C. N., ... & Lee, K. Y. (2021). Efficacy and safety of GV1001 in patients with moderate-to-severe Alzheimer’s disease already receiving donepezil: A phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. Alzheimer's research & therapy, 13, 1-11. PMID: 33771205 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995588/ PMC7995588] DOI: 10.1186/s13195-021-00803-w</ref>		GV1001 was used for the treatment of Alzheimer's disease patients with moderate to severe dementia and confirmed that, compared to those in the placebo, GV1001 significantly improved the Alzheimer's disease patient’s cognitive function.<ref>Koh, S. H., Kwon, H. S., Choi, S. H., Jeong, J. H., Na, H. R., Lee, C. N., ... & Lee, K. Y. (2021). Efficacy and safety of GV1001 in patients with moderate-to-severe Alzheimer’s disease already receiving donepezil: A phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. Alzheimer's research & therapy, 13, 1-11. PMID: 33771205 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995588/ PMC7995588] DOI: 10.1186/s13195-021-00803-w</ref>
	According to the hypothesis (Park H. et al., 2024) GV1001 binds to GnRHRs and activates downstream signaling pathways, increasing cAMP levels. This pathway might affect the degradation of Aβ peptides, reduction of p-tau, modulation of neuroinflammation (i.e., reducing pro-inflammatory and increasing anti-inflammatory microglia and astrocytes), and suppression of neuronal loss.<ref>Park, H., Kwon, H. S., Lee, K. Y., Kim, Y. E., Son, J. W., Choi, N. Y., ... & Koh, S. H. (2024). GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer’s disease mouse model. Brain, Behavior, and Immunity, 115, 295-307. PMID: 37884161 [https://doi.org/10.1016/j.bbi.2023.10.021 DOI: 10.1016/j.bbi.2023.10.021]</ref>		According to the hypothesis (Park H. et al., 2024) GV1001 binds to GnRHRs and activates downstream signaling pathways, increasing cAMP levels. This pathway might affect the degradation of Aβ peptides, reduction of p-tau, modulation of neuroinflammation (i.e., reducing pro-inflammatory and increasing anti-inflammatory microglia and astrocytes), and suppression of neuronal loss.<ref>Park, H., Kwon, H. S., Lee, K. Y., Kim, Y. E., Son, J. W., Choi, N. Y., ... & Koh, S. H. (2024). GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer’s disease mouse model. Brain, Behavior, and Immunity, 115, 295-307. PMID: 37884161 [https://doi.org/10.1016/j.bbi.2023.10.021 DOI: 10.1016/j.bbi.2023.10.021]</ref>

			==== [[TERT activator compound (TAC)]] ====

	== Telomeres in aging and age-related diseases ==		== Telomeres in aging and age-related diseases ==

Dmitry Dzhagarov: /* Telomeres in aging and age-related diseases */

2024-09-14T08:12:02Z

Telomeres in aging and age-related diseases

← Older revision		Revision as of 08:12, 14 September 2024
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	== Telomeres in aging and age-related diseases ==		== Telomeres in aging and age-related diseases ==
	Telomere dysfunction has been described as one of the 9 [[Hallmarks of Aging]], as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues.<ref>Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., ... & Pierce, B. L. (2020). Determinants of telomere length across human tissues. ''Science'', ''369''(6509), eaaz6876.</ref><ref name=":1">Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>		Telomere dysfunction has been described as one of the 9 [[Hallmarks of Aging]], as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues.<ref>Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., ... & Pierce, B. L. (2020). Determinants of telomere length across human tissues. ''Science'', ''369''(6509), eaaz6876.</ref><ref name=":1">Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref> Telomere maintenance is a crucial aspect of cellular biology, influencing aging and cancer development. Three major factors are collectively involved in this context: '''the shelterin complex''',<ref>Wolf, S. E., & Shalev, I. (2023). The shelterin protein expansion of telomere dynamics: Linking early life adversity, life history, and the hallmarks of aging. Neuroscience & Biobehavioral Reviews, 152, 105261. PMID: 37268182 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10527177/ PMC10527177] DOI: 10.1016/j.neubiorev.2023.105261</ref> the '''CTC1-STN1-TEN1 (CST) complex''',<ref>Cai, S. W., & de Lange, T. (2023). CST–Polα/Primase: the second telomere maintenance machine. Genes & Development, 37(13-14), 555-569. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10499019/ PMC10499019] DOI: 10.1101/gad.350479.123</ref> and '''telomerase'''.<ref>Boccardi, V., & Marano, L. (2024). Aging, Cancer, and Inflammation: The Telomerase Connection. International Journal of Molecular Sciences, 25(15), 8542. PMID: 39126110 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11313618/ PMC11313618] DOI: 10.3390/ijms25158542</ref>

	The rate of telomere attrition changes throughout the lifetime, and is much faster in the first two years of life than during later life.<ref>Frenck Jr, R. W., Blackburn, E. H., & Shannon, K. M. (1998). The rate of telomere sequence loss in human leukocytes varies with age. ''Proceedings of the National Academy of Sciences'', ''95''(10), 5607-5610.</ref> On average, telomere length in human leukocytes was found to shorten by 30-35 base pairs per year, reaching about 6 thousand base pairs in people over 60 years old.<ref>Calado, R. T., & Dumitriu, B. (2013, April). Telomere dynamics in mice and humans. In ''Seminars in hematology'' (Vol. 50, No. 2, pp. 165-174). WB Saunders.</ref> Telomeric length of 5 thousand base pairs has been suggested to be a "telomeric brink" denoting a high risk of imminent death.<ref name=":2">Steenstrup, T., Kark, J. D., Verhulst, S., Thinggaard, M., Hjelmborg, J. V., Dalgård, C., ... & Aviv, A. (2017). Telomeres and the natural lifespan limit in humans. ''Aging (Albany NY)'', ''9''(4), 1130.</ref> Although most people do not reach the telomeric brink in their lifetime, further extension of human longevity might be increasingly constrained by telomere length.		The rate of telomere attrition changes throughout the lifetime, and is much faster in the first two years of life than during later life.<ref>Frenck Jr, R. W., Blackburn, E. H., & Shannon, K. M. (1998). The rate of telomere sequence loss in human leukocytes varies with age. ''Proceedings of the National Academy of Sciences'', ''95''(10), 5607-5610.</ref> On average, telomere length in human leukocytes was found to shorten by 30-35 base pairs per year, reaching about 6 thousand base pairs in people over 60 years old.<ref>Calado, R. T., & Dumitriu, B. (2013, April). Telomere dynamics in mice and humans. In ''Seminars in hematology'' (Vol. 50, No. 2, pp. 165-174). WB Saunders.</ref> Telomeric length of 5 thousand base pairs has been suggested to be a "telomeric brink" denoting a high risk of imminent death.<ref name=":2">Steenstrup, T., Kark, J. D., Verhulst, S., Thinggaard, M., Hjelmborg, J. V., Dalgård, C., ... & Aviv, A. (2017). Telomeres and the natural lifespan limit in humans. ''Aging (Albany NY)'', ''9''(4), 1130.</ref> Although most people do not reach the telomeric brink in their lifetime, further extension of human longevity might be increasingly constrained by telomere length.

	Accelerated telomere shortening and dysfunction has been linked to several age-related diseases, such as chronic obstructive pulmonary disease, metabolic syndrome, liver cirrhosis, atherosclerosis, osteoporosis, chronic kidney disease.<ref>Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022). Telomere dysfunction in ageing and age-related diseases. ''Nature cell biology'', ''24''(2), 135-147.</ref> However, associations between telomere length and age-dependent conditions are often inconsistent and the molecular understanding of these associations is still lacking.<ref name=":1" /> There is currently insufficient clinical evidence to use telomere length or shortening rate as biomarkers for human aging, but research in this area is ongoing.<ref>Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>		Accelerated telomere shortening and dysfunction has been linked to several age-related diseases, such as chronic obstructive pulmonary disease, metabolic syndrome, liver cirrhosis, atherosclerosis, osteoporosis, chronic kidney disease.<ref>Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022). Telomere dysfunction in ageing and age-related diseases. ''Nature cell biology'', ''24''(2), 135-147.</ref> However, associations between telomere length and age-dependent conditions are often inconsistent and the molecular understanding of these associations is still lacking.<ref name=":1" /> There is currently insufficient clinical evidence to use telomere length or shortening rate as biomarkers for human aging, but research in this area is ongoing.<ref>Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>

	== Telomeres and telomerase in cancer and other diseases ==		== Telomeres and telomerase in cancer and other diseases ==

Dmitry Dzhagarov: /* Telomerase */

2024-02-16T18:51:00Z

Telomerase

← Older revision		Revision as of 18:51, 16 February 2024
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	== Telomerase ==		== Telomerase ==
	Telomerase is an enzyme that elongates telomeres. It consists of an RNA subunit (TERC) and a protein subunit, telomerase reverse transcriptase (TERT). TERT is able to bind the end part of the chromosome’s telomeric sequence and synthesise new telomeric repeats using TERC as a template. Telomerase is abundantly present in germ cells, stem cells and most cancer cells. Differentiated (non-dividing) cells show modest or undetectable expression levels of telomerase. <ref>Cong, Yu-Sheng, m.fl. ”Human Telomerase and Its Regulation”. ''Microbiology and Molecular Biology Reviews'', vol. 66, nr 3, september 2002, s. 407–25. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1128/MMBR.66.3.407-425.2002</nowiki>.</ref>		Telomerase is an enzyme that elongates telomeres. It consists of an RNA subunit (TERC) and a protein subunit, telomerase reverse transcriptase (TERT). TERT is able to bind the end part of the chromosome’s telomeric sequence and synthesise new telomeric repeats using TERC as a template. Telomerase is abundantly present in germ cells, stem cells and most cancer cells. Differentiated (non-dividing) cells show modest or undetectable expression levels of telomerase. <ref>Cong, Yu-Sheng, m.fl. ”Human Telomerase and Its Regulation”. ''Microbiology and Molecular Biology Reviews'', vol. 66, nr 3, september 2002, s. 407–25. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1128/MMBR.66.3.407-425.2002</nowiki>.</ref>

			==== GV1001 ====
			'''GV1001''' is a small peptide containing 16 amino acids that mimics a fragment of the active catalytic site of human telomerase reverse transcriptase (hTERT).<ref>Park, H. H., Lee, K. Y., Kim, S., Lee, J. W., Choi, N. Y., Lee, E. H., ... & Koh, S. H. (2014). The novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. Neurobiology of aging, 35(6), 1255-1274. PMID: 24439482 DOI: 10.1016/j.neurobiolaging.2013.12.015</ref> GV1001 peptide can be recognized by the immune system that reacts by killing the telomerase-active cells.<ref>Tian, X., Chen, B., & Liu, X. (2010). Telomere and telomerase as targets for cancer therapy. Applied biochemistry and biotechnology, 160(5), 1460-1472. PMID: 19412578 DOI: 10.1007/s12010-009-8633-9</ref><ref>Inderberg-Suso, E. M., Trachsel, S., Lislerud, K., Rasmussen, A. M., & Gaudernack, G. (2012). Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001. Oncoimmunology, 1(5), 670-686. PMID: 22934259 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429571/ PMC3429571] DOI: 10.4161/onci.20426</ref> GV1001 has antioxidant and neuroprotective effects in neural stem cells, which appear to be mediated by scavenging free radicals, increasing survival signals and decreasing death signals.<ref>Park, H. H., Yu, H. J., Kim, S., Kim, G., Choi, N. Y., Lee, E. H., ... & Koh, S. H. (2016). Neural stem cells injured by oxidative stress can be rejuvenated by GV1001, a novel peptide, through scavenging free radicals and enhancing survival signals. Neurotoxicology, 55, 131-141. PMID: 27265016 DOI: 10.1016/j.neuro.2016.05.022</ref>

			GV1001 was used for the treatment of Alzheimer's disease patients with moderate to severe dementia and confirmed that, compared to those in the placebo, GV1001 significantly improved the Alzheimer's disease patient’s cognitive function.<ref>Koh, S. H., Kwon, H. S., Choi, S. H., Jeong, J. H., Na, H. R., Lee, C. N., ... & Lee, K. Y. (2021). Efficacy and safety of GV1001 in patients with moderate-to-severe Alzheimer’s disease already receiving donepezil: A phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. Alzheimer's research & therapy, 13, 1-11. PMID: 33771205 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995588/ PMC7995588] DOI: 10.1186/s13195-021-00803-w</ref>
			According to the hypothesis (Park H. et al., 2024) GV1001 binds to GnRHRs and activates downstream signaling pathways, increasing cAMP levels. This pathway might affect the degradation of Aβ peptides, reduction of p-tau, modulation of neuroinflammation (i.e., reducing pro-inflammatory and increasing anti-inflammatory microglia and astrocytes), and suppression of neuronal loss.<ref>Park, H., Kwon, H. S., Lee, K. Y., Kim, Y. E., Son, J. W., Choi, N. Y., ... & Koh, S. H. (2024). GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer’s disease mouse model. Brain, Behavior, and Immunity, 115, 295-307. PMID: 37884161 [https://doi.org/10.1016/j.bbi.2023.10.021 DOI: 10.1016/j.bbi.2023.10.021]</ref>

	== Telomeres in aging and age-related diseases ==		== Telomeres in aging and age-related diseases ==

Dmitry Dzhagarov: /* Telomeres and telomerase in anti-aging therapies */

2023-09-13T19:37:56Z

Telomeres and telomerase in anti-aging therapies

← Older revision		Revision as of 19:37, 13 September 2023
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	== Telomeres and telomerase in anti-aging therapies ==		== Telomeres and telomerase in anti-aging therapies ==
			=== Age-reversing telomerase mRNA therapeutics ===
			A dogma arose in the 1990s that telomerase causes cancer. This is wrong and set back the field by decades. The reality is that permanent telomerase supports cancer, whereas healthy stem cells frequently turn on telomerase transiently throughout our lives to stave off the devastating effects of short telomeres.<ref>[https://longevity.technology/news/telomere-boosting-mrna-therapeutic-turns-back-the-aging-clock/ Rejuvenation Technologies is targeting longevity and age-related disease with telomerase-based mRNA therapies]</ref> A single dose of '''telomerase mRNA delivered in vivo using lipid nanoparticles''' reverses years of telomere shortening in hours.<ref>[https://longevity.technology/news/rejuvenation-technologies-exits-stealth-with-10-6m-for-age-reversing-mrna-therapeutics/ Rejuvenation Technologies exits stealth with $10.6m for age-reversing mRNA therapeutics]</ref>

	==== Mice ====		==== Mice ====
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	Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.<ref>Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. ''EMBO molecular medicine'', ''4''(8), 691-704.</ref> Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.		Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.<ref>Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. ''EMBO molecular medicine'', ''4''(8), 691-704.</ref> Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.

	In a 2022 study by Jaijyan and colleagues, monthly treatment of mice with a cytomegalovirus vector expressing mouse TERT extended median lifespan by 41.4%.<ref name=":4">Jaijyan, D. K., Selariu, A., Cruz-Cosme, R., Tong, M., Yang, S., Stefa, A., ... & Zhu, H. (2022). New intranasal and injectable gene therapy for healthy life extension. ''Proceedings of the National Academy of Sciences'', ''119''(20), e2121499119.</ref><ref>https://www.chemistryworld.com/news/gene-therapy-showcases-technique-to-extend-life-in-mice/4015718.article?utm_campaign=cw_shared&utm_medium=post&utm_source=navigator accessed 05 Aug 2022</ref> Both intranasal and injectable preparations of the vector were tested, and performed equally well in delivering gene therapy to multiple organs, without increasing cancer or unwanted side effects. The sample size was small, with a total of 16 mice across the 2 delivery groups. However, the extent of lifespan extension was striking and requires further testing, such as in different mice strains and with larger sample sizes. The observed extension of lifespan also suggests that telomerase may actually decrease cancer risk, consistent with a younger phenotype by influencing aging.<ref name=":3" /><ref name=":4" />		In a 2022 study by Jaijyan and colleagues, monthly treatment of mice with a cytomegalovirus vector expressing mouse TERT extended median lifespan by 41.4%.<ref name=":4">Jaijyan, D. K., Selariu, A., Cruz-Cosme, R., Tong, M., Yang, S., Stefa, A., ... & Zhu, H. (2022). New intranasal and injectable gene therapy for healthy life extension. ''Proceedings of the National Academy of Sciences'', ''119''(20), e2121499119.</ref><ref>https://www.chemistryworld.com/news/gene-therapy-showcases-technique-to-extend-life-in-mice/4015718.article?utm_campaign=cw_shared&utm_medium=post&utm_source=navigator accessed 05 Aug 2022</ref> Both intranasal and injectable preparations of the vector were tested, and performed equally well in delivering gene therapy to multiple organs, without increasing cancer or unwanted side effects. The sample size was small, with a total of 16 mice across the 2 delivery groups. However, the extent of lifespan extension was striking and requires further testing, such as in different mice strains and with larger sample sizes. The observed extension of lifespan also suggests that telomerase may actually decrease cancer risk, consistent with a younger phenotype by influencing aging.<ref name=":3" /><ref name=":4" />

	== References ==		== References ==

Andrea: category change

2022-12-27T21:52:37Z

category change

← Older revision		Revision as of 21:52, 27 December 2022
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	~~'''Telomere''' -~~ a region of repetitive nucleotide sequences at the end of linear DNA chromosomes. Together with associated proteins, telomeres protect the terminal regions of chromosomal DNA from degradation and ensure the integrity of chromosomes. Telomere dysfunction has been described as one of the molecular [[Hallmarks of Aging\|hallmarks of ageing]].		A telomere is a region of repetitive nucleotide sequences at the end of linear DNA chromosomes. Together with associated proteins, telomeres protect the terminal regions of chromosomal DNA from degradation and ensure the integrity of chromosomes. Telomere dysfunction has been described as one of the molecular [[Hallmarks of Aging\|hallmarks of ageing]].

	== History ==		== History ==
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	Telomerase is an enzyme that elongates telomeres. It consists of an RNA subunit (TERC) and a protein subunit, telomerase reverse transcriptase (TERT). TERT is able to bind the end part of the chromosome’s telomeric sequence and synthesise new telomeric repeats using TERC as a template. Telomerase is abundantly present in germ cells, stem cells and most cancer cells. Differentiated (non-dividing) cells show modest or undetectable expression levels of telomerase. <ref>Cong, Yu-Sheng, m.fl. ”Human Telomerase and Its Regulation”. ''Microbiology and Molecular Biology Reviews'', vol. 66, nr 3, september 2002, s. 407–25. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1128/MMBR.66.3.407-425.2002</nowiki>.</ref>		Telomerase is an enzyme that elongates telomeres. It consists of an RNA subunit (TERC) and a protein subunit, telomerase reverse transcriptase (TERT). TERT is able to bind the end part of the chromosome’s telomeric sequence and synthesise new telomeric repeats using TERC as a template. Telomerase is abundantly present in germ cells, stem cells and most cancer cells. Differentiated (non-dividing) cells show modest or undetectable expression levels of telomerase. <ref>Cong, Yu-Sheng, m.fl. ”Human Telomerase and Its Regulation”. ''Microbiology and Molecular Biology Reviews'', vol. 66, nr 3, september 2002, s. 407–25. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1128/MMBR.66.3.407-425.2002</nowiki>.</ref>

	== Telomeres in ~~ageing~~ and age-related diseases ==		== Telomeres in aging and age-related diseases ==
	Telomere dysfunction has been described as one of the 9 [[Hallmarks of Aging]], as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues.<ref>Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., ... & Pierce, B. L. (2020). Determinants of telomere length across human tissues. ''Science'', ''369''(6509), eaaz6876.</ref><ref name=":1">Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>		Telomere dysfunction has been described as one of the 9 [[Hallmarks of Aging]], as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues.<ref>Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., ... & Pierce, B. L. (2020). Determinants of telomere length across human tissues. ''Science'', ''369''(6509), eaaz6876.</ref><ref name=":1">Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>

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	== References ==		== References ==
	[[Category:~~Longevity~~]]		<references />
	[[Category:~~Drafts~~]]		[[Category:Main list]]
			[[Category:Aging pathways and hallmarks]]

Andrea: removed draft banner

2022-09-15T13:09:28Z

removed draft banner

← Older revision		Revision as of 13:09, 15 September 2022
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	~~{{Draft-article}}~~

	'''Telomere''' - a region of repetitive nucleotide sequences at the end of linear DNA chromosomes. Together with associated proteins, telomeres protect the terminal regions of chromosomal DNA from degradation and ensure the integrity of chromosomes. Telomere dysfunction has been described as one of the molecular [[Hallmarks of Aging\|hallmarks of ageing]].		'''Telomere''' - a region of repetitive nucleotide sequences at the end of linear DNA chromosomes. Together with associated proteins, telomeres protect the terminal regions of chromosomal DNA from degradation and ensure the integrity of chromosomes. Telomere dysfunction has been described as one of the molecular [[Hallmarks of Aging\|hallmarks of ageing]].

Geroscientist: /* Telomeres and telomerase in anti-aging therapies */

2022-08-09T12:15:08Z

Telomeres and telomerase in anti-aging therapies

← Older revision		Revision as of 12:15, 9 August 2022
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	Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.<ref>Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. ''EMBO molecular medicine'', ''4''(8), 691-704.</ref> Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.		Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.<ref>Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. ''EMBO molecular medicine'', ''4''(8), 691-704.</ref> Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.

	In a 2022 study by Jaijyan and colleagues, monthly treatment of mice with a cytomegalovirus vector expressing mouse TERT extended median lifespan by 41.4%.<ref>Jaijyan, D. K., Selariu, A., Cruz-Cosme, R., Tong, M., Yang, S., Stefa, A., ... & Zhu, H. (2022). New intranasal and injectable gene therapy for healthy life extension. ''Proceedings of the National Academy of Sciences'', ''119''(20), e2121499119.</ref><ref>https://www.chemistryworld.com/news/gene-therapy-showcases-technique-to-extend-life-in-mice/4015718.article?utm_campaign=cw_shared&utm_medium=post&utm_source=navigator accessed 05 Aug 2022</ref> Both intranasal and injectable preparations of the vector were tested, and performed equally well in delivering gene therapy to multiple organs, without increasing cancer or unwanted side effects. The sample size was small, with a total of 16 mice across the 2 delivery groups. However, the extent of lifespan extension was striking and requires further testing, such as in different mice strains and with larger sample sizes.		In a 2022 study by Jaijyan and colleagues, monthly treatment of mice with a cytomegalovirus vector expressing mouse TERT extended median lifespan by 41.4%.<ref name=":4">Jaijyan, D. K., Selariu, A., Cruz-Cosme, R., Tong, M., Yang, S., Stefa, A., ... & Zhu, H. (2022). New intranasal and injectable gene therapy for healthy life extension. ''Proceedings of the National Academy of Sciences'', ''119''(20), e2121499119.</ref><ref>https://www.chemistryworld.com/news/gene-therapy-showcases-technique-to-extend-life-in-mice/4015718.article?utm_campaign=cw_shared&utm_medium=post&utm_source=navigator accessed 05 Aug 2022</ref> Both intranasal and injectable preparations of the vector were tested, and performed equally well in delivering gene therapy to multiple organs, without increasing cancer or unwanted side effects. The sample size was small, with a total of 16 mice across the 2 delivery groups. However, the extent of lifespan extension was striking and requires further testing, such as in different mice strains and with larger sample sizes. The observed extension of lifespan also suggests that telomerase may actually decrease cancer risk, consistent with a younger phenotype by influencing aging.<ref name=":3" /><ref name=":4" />

	== References ==		== References ==
	[[Category:Longevity]]		[[Category:Longevity]]
	[[Category:Drafts]]		[[Category:Drafts]]

Geroscientist: /* Telomeres in ageing and age-related diseases */

2022-08-09T12:11:29Z

Telomeres in ageing and age-related diseases

← Older revision		Revision as of 12:11, 9 August 2022
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	Telomere dysfunction has been described as one of the 9 [[Hallmarks of Aging]], as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues.<ref>Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., ... & Pierce, B. L. (2020). Determinants of telomere length across human tissues. ''Science'', ''369''(6509), eaaz6876.</ref><ref name=":1">Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>		Telomere dysfunction has been described as one of the 9 [[Hallmarks of Aging]], as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues.<ref>Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., ... & Pierce, B. L. (2020). Determinants of telomere length across human tissues. ''Science'', ''369''(6509), eaaz6876.</ref><ref name=":1">Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>

	The rate of telomere attrition changes throughout the lifetime, and is much faster in the first two years of life than during later life. <ref>Frenck Jr, R. W., Blackburn, E. H., & Shannon, K. M. (1998). The rate of telomere sequence loss in human leukocytes varies with age. ''Proceedings of the National Academy of Sciences'', ''95''(10), 5607-5610.</ref> On average, telomere length in human leukocytes was found to shorten by 30-35 base pairs per year, reaching about 6 thousand base pairs in people over 60 years old. <ref>Calado, R. T., & Dumitriu, B. (2013, April). Telomere dynamics in mice and humans. In ''Seminars in hematology'' (Vol. 50, No. 2, pp. 165-174). WB Saunders.</ref> Telomeric length of 5 thousand base pairs has been suggested to be a "telomeric brink" denoting a high risk of imminent death. <ref name=":2">Steenstrup, T., Kark, J. D., Verhulst, S., Thinggaard, M., Hjelmborg, J. V., Dalgård, C., ... & Aviv, A. (2017). Telomeres and the natural lifespan limit in humans. ''Aging (Albany NY)'', ''9''(4), 1130.</ref> Although most people do not reach the telomeric brink in their lifetime, further extension of human longevity might be increasingly constrained by telomere length.		The rate of telomere attrition changes throughout the lifetime, and is much faster in the first two years of life than during later life.<ref>Frenck Jr, R. W., Blackburn, E. H., & Shannon, K. M. (1998). The rate of telomere sequence loss in human leukocytes varies with age. ''Proceedings of the National Academy of Sciences'', ''95''(10), 5607-5610.</ref> On average, telomere length in human leukocytes was found to shorten by 30-35 base pairs per year, reaching about 6 thousand base pairs in people over 60 years old.<ref>Calado, R. T., & Dumitriu, B. (2013, April). Telomere dynamics in mice and humans. In ''Seminars in hematology'' (Vol. 50, No. 2, pp. 165-174). WB Saunders.</ref> Telomeric length of 5 thousand base pairs has been suggested to be a "telomeric brink" denoting a high risk of imminent death.<ref name=":2">Steenstrup, T., Kark, J. D., Verhulst, S., Thinggaard, M., Hjelmborg, J. V., Dalgård, C., ... & Aviv, A. (2017). Telomeres and the natural lifespan limit in humans. ''Aging (Albany NY)'', ''9''(4), 1130.</ref> Although most people do not reach the telomeric brink in their lifetime, further extension of human longevity might be increasingly constrained by telomere length.

	Accelerated telomere shortening and dysfunction has been linked to several age-related diseases, such as chronic obstructive pulmonary disease, metabolic syndrome, liver cirrhosis, atherosclerosis, osteoporosis, chronic kidney disease. <ref>Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022). Telomere dysfunction in ageing and age-related diseases. ''Nature cell biology'', ''24''(2), 135-147.</ref> However, associations between telomere length and age-dependent conditions are often inconsistent and the molecular understanding of these associations is still lacking.<ref name=":1" /> There is currently insufficient clinical evidence to use telomere length or shortening rate as biomarkers for human aging, but research in this area is ongoing.<ref>Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>		Accelerated telomere shortening and dysfunction has been linked to several age-related diseases, such as chronic obstructive pulmonary disease, metabolic syndrome, liver cirrhosis, atherosclerosis, osteoporosis, chronic kidney disease.<ref>Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022). Telomere dysfunction in ageing and age-related diseases. ''Nature cell biology'', ''24''(2), 135-147.</ref> However, associations between telomere length and age-dependent conditions are often inconsistent and the molecular understanding of these associations is still lacking.<ref name=":1" /> There is currently insufficient clinical evidence to use telomere length or shortening rate as biomarkers for human aging, but research in this area is ongoing.<ref>Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>

	== Telomeres and telomerase in cancer and other diseases ==		== Telomeres and telomerase in cancer and other diseases ==
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	==== Mice ====		==== Mice ====
	Mice engineered with much longer telomeres than those of the natural species showed improved mitochondrial function, improved metabolic parameters, decreased cancer, and increased longevity (12.75% increase in median longevity). <ref>Muñoz-Lorente, M. A., Cano-Martin, A. C., & Blasco, M. A. (2019). Mice with hyper-long telomeres show less metabolic aging and longer lifespans. ''Nature communications'', ''10''(1), 1-14.</ref><ref>CNIO researchers obtain the first mice born with hyper-long telomeres and show that it is possible to extend life without any genetic modification - CNIO, accessed 05 Aug 2022</ref>		Mice engineered with much longer telomeres than those of the natural species showed improved mitochondrial function, improved metabolic parameters, decreased cancer, and increased longevity (12.75% increase in median longevity). <ref name=":3">Muñoz-Lorente, M. A., Cano-Martin, A. C., & Blasco, M. A. (2019). Mice with hyper-long telomeres show less metabolic aging and longer lifespans. ''Nature communications'', ''10''(1), 1-14.</ref><ref>CNIO researchers obtain the first mice born with hyper-long telomeres and show that it is possible to extend life without any genetic modification - CNIO, accessed 05 Aug 2022</ref> Due to concerns related to the association between telomerase expression and cancer, this was an important finding that suggests that telomere length per se does not increase cancer risk in mice.<ref name=":3" />

	Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.<ref>Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. ''EMBO molecular medicine'', ''4''(8), 691-704.</ref> Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.		Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.<ref>Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. ''EMBO molecular medicine'', ''4''(8), 691-704.</ref> Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.

Geroscientist: /* Telomeres and telomerase in cancer and other diseases */

2022-08-09T12:00:03Z

Telomeres and telomerase in cancer and other diseases

← Older revision		Revision as of 12:00, 9 August 2022
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	== Telomeres in ageing and age-related diseases ==		== Telomeres in ageing and age-related diseases ==
	Telomere dysfunction has been described as one of the 9 [[Hallmarks of Aging]], as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues. <ref>Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., ... & Pierce, B. L. (2020). Determinants of telomere length across human tissues. ''Science'', ''369''(6509), eaaz6876.</ref> <ref name=":1">Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>		Telomere dysfunction has been described as one of the 9 [[Hallmarks of Aging]], as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues.<ref>Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., ... & Pierce, B. L. (2020). Determinants of telomere length across human tissues. ''Science'', ''369''(6509), eaaz6876.</ref><ref name=":1">Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>

	The rate of telomere attrition changes throughout the lifetime, and is much faster in the first two years of life than during later life. <ref>Frenck Jr, R. W., Blackburn, E. H., & Shannon, K. M. (1998). The rate of telomere sequence loss in human leukocytes varies with age. ''Proceedings of the National Academy of Sciences'', ''95''(10), 5607-5610.</ref> On average, telomere ~~lenght~~ in human leukocytes was found to shorten ~~with~~ 30-35 base pairs per year, reaching about 6 thousand base pairs in people over 60 years old. <ref>Calado, R. T., & Dumitriu, B. (2013, April). Telomere dynamics in mice and humans. In ''Seminars in hematology'' (Vol. 50, No. 2, pp. 165-174). WB Saunders.</ref> Telomeric length of 5 thousand base pairs has been suggested to be a "telomeric brink" denoting a high risk of imminent death. <ref name=":2">Steenstrup, T., Kark, J. D., Verhulst, S., Thinggaard, M., Hjelmborg, J. V., Dalgård, C., ... & Aviv, A. (2017). Telomeres and the natural lifespan limit in humans. ''Aging (Albany NY)'', ''9''(4), 1130.</ref> Although most people do not reach the telomeric brink in their lifetime, further extension of human longevity might be increasingly constrained by telomere ~~lenght~~.		The rate of telomere attrition changes throughout the lifetime, and is much faster in the first two years of life than during later life. <ref>Frenck Jr, R. W., Blackburn, E. H., & Shannon, K. M. (1998). The rate of telomere sequence loss in human leukocytes varies with age. ''Proceedings of the National Academy of Sciences'', ''95''(10), 5607-5610.</ref> On average, telomere length in human leukocytes was found to shorten by 30-35 base pairs per year, reaching about 6 thousand base pairs in people over 60 years old. <ref>Calado, R. T., & Dumitriu, B. (2013, April). Telomere dynamics in mice and humans. In ''Seminars in hematology'' (Vol. 50, No. 2, pp. 165-174). WB Saunders.</ref> Telomeric length of 5 thousand base pairs has been suggested to be a "telomeric brink" denoting a high risk of imminent death. <ref name=":2">Steenstrup, T., Kark, J. D., Verhulst, S., Thinggaard, M., Hjelmborg, J. V., Dalgård, C., ... & Aviv, A. (2017). Telomeres and the natural lifespan limit in humans. ''Aging (Albany NY)'', ''9''(4), 1130.</ref> Although most people do not reach the telomeric brink in their lifetime, further extension of human longevity might be increasingly constrained by telomere length.

	Accelerated telomere shortening and dysfunction has been linked to several age-related diseases, such as chronic obstructive pulmonary disease, metabolic syndrome, liver cirrhosis, atherosclerosis, osteoporosis, chronic kidney disease. <ref>Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022). Telomere dysfunction in ageing and age-related diseases. ''Nature cell biology'', ''24''(2), 135-147.</ref> However, associations between telomere length and age-dependent conditions are often inconsistent and molecular understanding of these associations is still lacking. <ref name=":1" />		Accelerated telomere shortening and dysfunction has been linked to several age-related diseases, such as chronic obstructive pulmonary disease, metabolic syndrome, liver cirrhosis, atherosclerosis, osteoporosis, chronic kidney disease. <ref>Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022). Telomere dysfunction in ageing and age-related diseases. ''Nature cell biology'', ''24''(2), 135-147.</ref> However, associations between telomere length and age-dependent conditions are often inconsistent and the molecular understanding of these associations is still lacking.<ref name=":1" /> There is currently insufficient clinical evidence to use telomere length or shortening rate as biomarkers for human aging, but research in this area is ongoing.<ref>Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>

	== Telomeres and telomerase in cancer and other diseases ==		== Telomeres and telomerase in cancer and other diseases ==
	Increased levels of telomerase have been found in the vast majority of human cancers, whereas mutations decreasing telomerase function cause a range of genetic disorders, such as dyskeratosis congenita, idiopathic pulmonary fibrosis and bone marrow failure. <ref>Roake, C. M., & Artandi, S. E. (2020). Regulation of human telomerase in homeostasis and disease. ''Nature reviews Molecular cell biology'', ''21''(7), 384-397.</ref> Longer telomere lenghts have been associated with higher risk of melanoma, lung cancer, prostate cancer, and chronic lymphocytic leukemia. <ref name=":2" />		Increased levels of telomerase have been found in the vast majority of human cancers, whereas mutations decreasing telomerase function cause a range of genetic disorders, such as dyskeratosis congenita, idiopathic pulmonary fibrosis and bone marrow failure.<ref>Roake, C. M., & Artandi, S. E. (2020). Regulation of human telomerase in homeostasis and disease. ''Nature reviews Molecular cell biology'', ''21''(7), 384-397.</ref> Longer telomere lenghts have been associated with higher risk of melanoma, lung cancer, prostate cancer, and chronic lymphocytic leukemia. <ref name=":2" />

	== Telomeres and telomerase in anti-aging therapies ==		== Telomeres and telomerase in anti-aging therapies ==

Geroscientist: /* Telomeres and telomerase in anti-aging therapies */

2022-08-09T11:56:00Z

Telomeres and telomerase in anti-aging therapies

← Older revision		Revision as of 11:56, 9 August 2022
Line 31:		Line 31:
	Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.<ref>Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. ''EMBO molecular medicine'', ''4''(8), 691-704.</ref> Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.		Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.<ref>Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. ''EMBO molecular medicine'', ''4''(8), 691-704.</ref> Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.

	In a 2022 study by Jaijyan and colleagues, monthly treatment of mice with a cytomegalovirus vector expressing mouse TERT extended median lifespan by 41.4%.<ref>Jaijyan, D. K., Selariu, A., Cruz-Cosme, R., Tong, M., Yang, S., Stefa, A., ... & Zhu, H. (2022). New intranasal and injectable gene therapy for healthy life extension. ''Proceedings of the National Academy of Sciences'', ''119''(20), e2121499119.</ref><ref>https://www.chemistryworld.com/news/gene-therapy-showcases-technique-to-extend-life-in-mice/4015718.article?utm_campaign=cw_shared&utm_medium=post&utm_source=navigator accessed 05 Aug 2022</ref> Both intranasal and injectable preparations of the vector were tested, and performed equally well in delivering gene therapy to multiple organs, without increasing cancer or unwanted side effects. The sample size was small, with a total of 16 mice across the 2 delivery groups, ~~but~~ the extent of lifespan extension was striking and requires further testing, such as in different mice strains and with larger sample sizes.		In a 2022 study by Jaijyan and colleagues, monthly treatment of mice with a cytomegalovirus vector expressing mouse TERT extended median lifespan by 41.4%.<ref>Jaijyan, D. K., Selariu, A., Cruz-Cosme, R., Tong, M., Yang, S., Stefa, A., ... & Zhu, H. (2022). New intranasal and injectable gene therapy for healthy life extension. ''Proceedings of the National Academy of Sciences'', ''119''(20), e2121499119.</ref><ref>https://www.chemistryworld.com/news/gene-therapy-showcases-technique-to-extend-life-in-mice/4015718.article?utm_campaign=cw_shared&utm_medium=post&utm_source=navigator accessed 05 Aug 2022</ref> Both intranasal and injectable preparations of the vector were tested, and performed equally well in delivering gene therapy to multiple organs, without increasing cancer or unwanted side effects. The sample size was small, with a total of 16 mice across the 2 delivery groups. However, the extent of lifespan extension was striking and requires further testing, such as in different mice strains and with larger sample sizes.

	== References ==		== References ==
	[[Category:Longevity]]		[[Category:Longevity]]
	[[Category:Drafts]]		[[Category:Drafts]]