Rapamycin - Revision history

Dmitry Dzhagarov: /* Manipulating metabolic pathways - differences to calorie restriction */

2024-06-19T16:21:31Z

Manipulating metabolic pathways - differences to calorie restriction

← Older revision		Revision as of 16:21, 19 June 2024
Line 62:		Line 62:

	=== Manipulating metabolic pathways - differences to calorie restriction ===		=== Manipulating metabolic pathways - differences to calorie restriction ===
	Rapamycin has often been described as a 'calorie restriction (CR) mimetic'.<ref name=":15">Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":4" /> This is in part because CR also inhibits the nutrient-sensing mammalian target of rapamycin (mTOR) pathway.<ref name=":3">Cornu, M., Albert, V., & Hall, M. N. (2013). mTOR in aging, metabolism, and cancer. ''Current opinion in genetics & development'', ''23''(1), 53-62.</ref> mTOR plays key roles in cellular growth in response to amino acids, including effects that inhibit cancer and aging mechanisms.<ref name=":3" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> However, later studies have disentangled the effects of rapamycin from that of caloric restriction, showing that they differ significantly.<ref name=":15" /><ref name=":4">Unnikrishnan, A., Kurup, K., Salmon, A. B., & Richardson, A. (2020). Is rapamycin a dietary restriction mimetic?. ''The Journals of Gerontology: Series A'', ''75''(1), 4-13.</ref> For example, unlike 5 months of CR, rapamycin does not decrease leptin, insulin, IGF-1, or FGF-21 in genetically diverse UM-HET3 mice.<ref name=":15" /> This has important implications for understanding biological aging, including the possibility of using CR and rapalogs in combination therapy to slow aging.<ref name=":4" />		Rapamycin has often been described as a 'calorie restriction (CR) mimetic'.<ref name=":15">Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":4" /> This is in part because CR also inhibits the nutrient-sensing mammalian target of rapamycin (mTOR) pathway.<ref name=":3">Cornu, M., Albert, V., & Hall, M. N. (2013). mTOR in aging, metabolism, and cancer. ''Current opinion in genetics & development'', ''23''(1), 53-62.</ref> '''[[mTOR]]''' plays key roles in cellular growth in response to amino acids, including effects that inhibit cancer and aging mechanisms.<ref name=":3" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> However, later studies have disentangled the effects of rapamycin from that of caloric restriction, showing that they differ significantly.<ref name=":15" /><ref name=":4">Unnikrishnan, A., Kurup, K., Salmon, A. B., & Richardson, A. (2020). Is rapamycin a dietary restriction mimetic?. ''The Journals of Gerontology: Series A'', ''75''(1), 4-13.</ref> For example, unlike 5 months of CR, rapamycin does not decrease leptin, insulin, IGF-1, or FGF-21 in genetically diverse UM-HET3 mice.<ref name=":15" /> This has important implications for understanding biological aging, including the possibility of using CR and rapalogs in combination therapy to slow aging.<ref name=":4" />

	Though distinct from CR, fasting inhibits muscle-specific mTOR signaling with reduced effect in old vs young mice, indicating a poorer autophagy and proteosomal degradation response with age.<ref>White, Z., White, R. B., McMahon, C., Grounds, M. D., & Shavlakadze, T. (2016). High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state. ''The international journal of biochemistry & cell biology'', ''78'', 10-21.</ref><ref>[https://www.ncbi.nlm.nih.gov/pubmed/21179166/ Sengupta, S., Peterson, T. R., Laplante, M., Oh, S., & Sabatini, D. M. (2010). mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. ''Nature'', ''468''(7327), 1100-1104.]</ref> However, the ability for rapamycin to inhibit mTOR appears to remain robust throughout life, and significant extension of median and maximal lifespan can be achieved even when treatment is initiated in mid-to-late life.<ref name=":5" /><ref>Blagosklonny, M. V. (2019). Rapamycin for longevity: opinion article. ''Aging (Albany NY)'', ''11''(19), 8048.		Though distinct from CR, fasting inhibits muscle-specific mTOR signaling with reduced effect in old vs young mice, indicating a poorer autophagy and proteosomal degradation response with age.<ref>White, Z., White, R. B., McMahon, C., Grounds, M. D., & Shavlakadze, T. (2016). High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state. ''The international journal of biochemistry & cell biology'', ''78'', 10-21.</ref><ref>[https://www.ncbi.nlm.nih.gov/pubmed/21179166/ Sengupta, S., Peterson, T. R., Laplante, M., Oh, S., & Sabatini, D. M. (2010). mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. ''Nature'', ''468''(7327), 1100-1104.]</ref> However, the ability for rapamycin to inhibit mTOR appears to remain robust throughout life, and significant extension of median and maximal lifespan can be achieved even when treatment is initiated in mid-to-late life.<ref name=":5" /><ref>Blagosklonny, M. V. (2019). Rapamycin for longevity: opinion article. ''Aging (Albany NY)'', ''11''(19), 8048.
	</ref> Rapamycin contrasts significantly with CR and fasting, in that the latter could be detrimental when used in late life.<ref>Kemnitz, J. W. (2011). Calorie restriction and aging in nonhuman primates. ''Ilar Journal'', ''52''(1), 66-77.</ref><ref>Goto, S., Takahashi, R., Radak, Z., & Sharma, R. (2007). Beneficial biochemical outcomes of late‐onset dietary restriction in rodents. ''Annals of the New York Academy of Sciences'', ''1100''(1), 431-441.</ref><ref>Kristan, D. M. (2008). Calorie restriction and susceptibility to intact pathogens. ''Age'', ''30''(2), 147-156.</ref> Rapamycin also targets multiple diseases of aging, but seemingly in a segmented, tissue-specific manner.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref>		</ref> Rapamycin contrasts significantly with CR and fasting, in that the latter could be detrimental when used in late life.<ref>Kemnitz, J. W. (2011). Calorie restriction and aging in nonhuman primates. ''Ilar Journal'', ''52''(1), 66-77.</ref><ref>Goto, S., Takahashi, R., Radak, Z., & Sharma, R. (2007). Beneficial biochemical outcomes of late‐onset dietary restriction in rodents. ''Annals of the New York Academy of Sciences'', ''1100''(1), 431-441.</ref><ref>Kristan, D. M. (2008). Calorie restriction and susceptibility to intact pathogens. ''Age'', ''30''(2), 147-156.</ref> Rapamycin also targets multiple diseases of aging, but seemingly in a segmented, tissue-specific manner.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref>

	=== mTORC1 and mTORC2 ===		=== mTORC1 and mTORC2 ===

Geroscientist: /* Yeast */

2024-06-19T07:26:52Z

Yeast

← Older revision		Revision as of 07:26, 19 June 2024
Line 27:		Line 27:
	==== Middle-aged mice ====		==== Middle-aged mice ====
	Several recent studies have shown that rapamycin can extend the lifespan of middle-aged or aged mice. One study showed that treating 20-month-old mice (the equivalent of 56–69 years in humans) with rapamycin for only 3 months resulted in a dramatic increase in median lifespan of up to 60%.<ref>Bitto, A., Ito, T.K., Pineda, V.V., LeTexier, N.J., Huang, H.Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K. and Meza, D., 2016. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. ''elife'', ''5'', p.e16351.</ref> A study from 2020 showed that administering rapamycin in late life enhanced the lifespan of male but not female mice, providing evidence for sex differences in rapamycin response.<ref>[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13269 Strong, R., Miller, R. A., Bogue, M., Fernandez, E., Javors, M. A., Libert, S., ... & Harrison, D. E. (2020). Rapamycin‐mediated mouse lifespan extension: Late‐life dosage regimes with sex‐specific effects. ''Aging cell'', ''19''(11), e13269.]</ref> Aged female mice administered rapamycin once every 5 days starting at 20 months of age also extended lifespan.<ref>Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent administration of rapamycin extends the lifespan of female C57BL/6J mice. ''J Gerontol A Biol Sci Med Sci''. 2016 Jul; 71(7):876-81. doi: [https://academic.oup.com/biomedgerontology/article/71/7/876/2605199 10.1093/gerona/glw064]. Epub 2016 Apr 18. PMID: 27091134; PMCID: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906329/ PMC4906329]</ref> These studies were important as they suggest that much of the health and longevity benefits of rapamycin could be achieved even when dosed in late life or intermittently, as opposed to only being effective with continual dosing in early life.		Several recent studies have shown that rapamycin can extend the lifespan of middle-aged or aged mice. One study showed that treating 20-month-old mice (the equivalent of 56–69 years in humans) with rapamycin for only 3 months resulted in a dramatic increase in median lifespan of up to 60%.<ref>Bitto, A., Ito, T.K., Pineda, V.V., LeTexier, N.J., Huang, H.Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K. and Meza, D., 2016. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. ''elife'', ''5'', p.e16351.</ref> A study from 2020 showed that administering rapamycin in late life enhanced the lifespan of male but not female mice, providing evidence for sex differences in rapamycin response.<ref>[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13269 Strong, R., Miller, R. A., Bogue, M., Fernandez, E., Javors, M. A., Libert, S., ... & Harrison, D. E. (2020). Rapamycin‐mediated mouse lifespan extension: Late‐life dosage regimes with sex‐specific effects. ''Aging cell'', ''19''(11), e13269.]</ref> Aged female mice administered rapamycin once every 5 days starting at 20 months of age also extended lifespan.<ref>Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent administration of rapamycin extends the lifespan of female C57BL/6J mice. ''J Gerontol A Biol Sci Med Sci''. 2016 Jul; 71(7):876-81. doi: [https://academic.oup.com/biomedgerontology/article/71/7/876/2605199 10.1093/gerona/glw064]. Epub 2016 Apr 18. PMID: 27091134; PMCID: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906329/ PMC4906329]</ref> These studies were important as they suggest that much of the health and longevity benefits of rapamycin could be achieved even when dosed in late life or intermittently, as opposed to only being effective with continual dosing in early life.

	~~=== Yeast ===~~
	Inhibition of TOR signalling by rapamycin significantly increases the lifespan of yeast known as ''Saccharomyces cerevisiae.''<ref>Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K., & Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. ''Genes & development'', ''20''(2), 174-184.</ref>

	=== Flies ===		=== Flies ===
Line 37:		Line 34:
	TOR inhibition by rapamycin extends lifespan in ''Caenorhabditis elegans,'' a roundworm nematode widely used in research areas of the biology of aging. The beneficial effects of rapamycin in ''C. elegans'' seem to be mediated via the SKN-1/Nrf and DAF-16/FoxO pathways.<ref>Robida-Stubbs, S., Glover-Cutter, K., Lamming, D. W., Mizunuma, M., Narasimhan, S. D., Neumann-Haefelin, E., ... & Blackwell, T. K. (2012). TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. ''Cell metabolism'', ''15''(5), 713-724.</ref>		TOR inhibition by rapamycin extends lifespan in ''Caenorhabditis elegans,'' a roundworm nematode widely used in research areas of the biology of aging. The beneficial effects of rapamycin in ''C. elegans'' seem to be mediated via the SKN-1/Nrf and DAF-16/FoxO pathways.<ref>Robida-Stubbs, S., Glover-Cutter, K., Lamming, D. W., Mizunuma, M., Narasimhan, S. D., Neumann-Haefelin, E., ... & Blackwell, T. K. (2012). TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. ''Cell metabolism'', ''15''(5), 713-724.</ref>

	=== ~~Age~~-related diseases ===		=== Yeast ===
			Inhibition of TOR signalling by rapamycin significantly increases the lifespan of brewer's yeast, ''Saccharomyces cerevisiae.''<ref>Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K., & Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. ''Genes & development'', ''20''(2), 174-184.</ref>

			== Effects on age-related diseases ==
	Rapamycin has been investigated in specific diseases, showing major impacts on reducing mouse cancer risk, cardiac diseases, neurodegenerative-like processes, and many other pathologies.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.		Rapamycin has been investigated in specific diseases, showing major impacts on reducing mouse cancer risk, cardiac diseases, neurodegenerative-like processes, and many other pathologies.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.
	</ref>		</ref>

Geroscientist: /* Non-human primates */

2024-06-19T06:28:06Z

Non-human primates

← Older revision		Revision as of 06:28, 19 June 2024
Line 11:		Line 11:

	=== Non-human primates ===		=== Non-human primates ===
	Unpublished and preliminary data presented by Dr Adam Salmon at the American Aging Association annual meeting (June, 2024) showed that rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' The extension of lifespan was associated with improved healthspan, with preserved cognitive health, and reduced burden of age-related disease in treated marmosets. Rapamycin was delivered orally at 1 mg/kg/day.		Unpublished and preliminary data presented by Dr Adam Salmon at the American Aging Association annual meeting (June, 2024) showed that rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' The extension of lifespan was associated with improved healthspan, with preserved cognitive health and a reduced burden of age-related disease in treated marmosets versus placebo. Rapamycin was delivered orally at 1 mg/kg/day.

	=== Dogs ===		=== Dogs ===

Geroscientist: /* Non-human primates */

2024-06-19T06:27:12Z

Non-human primates

← Older revision		Revision as of 06:27, 19 June 2024
Line 11:		Line 11:

	=== Non-human primates ===		=== Non-human primates ===
	Unpublished and preliminary data presented by Dr Adam Salmon at the American Aging Association annual meeting (June, 2024) showed ~~the~~ rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' Rapamycin was delivered orally at 1 mg/kg/day.		Unpublished and preliminary data presented by Dr Adam Salmon at the American Aging Association annual meeting (June, 2024) showed that rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' The extension of lifespan was associated with improved healthspan, with preserved cognitive health, and reduced burden of age-related disease in treated marmosets. Rapamycin was delivered orally at 1 mg/kg/day.

	=== Dogs ===		=== Dogs ===

Geroscientist: /* Non-human primates */

2024-06-19T06:25:18Z

Non-human primates

← Older revision		Revision as of 06:25, 19 June 2024
Line 11:		Line 11:

	=== Non-human primates ===		=== Non-human primates ===
	Unpublished data presented by Dr Adam Salmon at the American Aging Association annual meeting (2024) showed the rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' Rapamycin was delivered orally at 1 mg/kg/day.		Unpublished and preliminary data presented by Dr Adam Salmon at the American Aging Association annual meeting (June, 2024) showed the rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' Rapamycin was delivered orally at 1 mg/kg/day.

	=== Dogs ===		=== Dogs ===

Geroscientist: /* Dogs */

2024-06-19T06:24:51Z

Dogs

← Older revision		Revision as of 06:24, 19 June 2024
Line 9:		Line 9:

	== Evidence of increased healthspan or lifespan ==		== Evidence of increased healthspan or lifespan ==

			=== Non-human primates ===
			Unpublished data presented by Dr Adam Salmon at the American Aging Association annual meeting (2024) showed the rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' Rapamycin was delivered orally at 1 mg/kg/day.

	=== Dogs ===		=== Dogs ===

Dmitry Dzhagarov: /* Rapalogs */

2023-12-07T18:05:13Z

Rapalogs

← Older revision		Revision as of 18:05, 7 December 2023
Line 116:		Line 116:
	Despite mTOR being the prime target against many age-related and chronic pathologies, relatively few mTOR inhibitors have been developed to slow the aging process.<ref>Mao, B., Zhang, Q., Ma, L., Zhao, D. S., Zhao, P., & Yan, P. (2022). Overview of research into mTOR inhibitors. Molecules, 27(16), 5295. PMID: 36014530 PMC9413691 https://doi.org/10.3390/molecules27165295</ref> Rapalogs are molecules with similar mechanism to rapamycin, primarily via mTORC1 inhibition. These drugs are generally predicted to function similarly to rapamycin in enhancing lifespan and reducing age-related decline in physiological function. For example, small molecule, '''TKA001''', selected based on in silico predictions, extends the lifespan of ''Caenorhabditis elegans'', suggesting that TKA001 is able to slow aging in vivo.<ref>Vidovic, T., Dakhovnik, A., Hrabovskyi, O., MacArthur, M. R., & Ewald, C. Y. (2023). AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans. International journal of molecular sciences, 24(9), 7850. PMID: 37175557 PMC10177929 https://doi.org/10.3390/ijms24097850</ref>		Despite mTOR being the prime target against many age-related and chronic pathologies, relatively few mTOR inhibitors have been developed to slow the aging process.<ref>Mao, B., Zhang, Q., Ma, L., Zhao, D. S., Zhao, P., & Yan, P. (2022). Overview of research into mTOR inhibitors. Molecules, 27(16), 5295. PMID: 36014530 PMC9413691 https://doi.org/10.3390/molecules27165295</ref> Rapalogs are molecules with similar mechanism to rapamycin, primarily via mTORC1 inhibition. These drugs are generally predicted to function similarly to rapamycin in enhancing lifespan and reducing age-related decline in physiological function. For example, small molecule, '''TKA001''', selected based on in silico predictions, extends the lifespan of ''Caenorhabditis elegans'', suggesting that TKA001 is able to slow aging in vivo.<ref>Vidovic, T., Dakhovnik, A., Hrabovskyi, O., MacArthur, M. R., & Ewald, C. Y. (2023). AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans. International journal of molecular sciences, 24(9), 7850. PMID: 37175557 PMC10177929 https://doi.org/10.3390/ijms24097850</ref>
	However, only one rapalog, everolimus, has published clinical data in this context.<ref>[https://www.thelancet.com/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=8&doi=10.1016/S2666-7568(20)30068-4&key=24379984&cf= Kaeberlein, M. (2013). mTOR inhibition: from aging to autism and beyond. ''Scientifica'', ''2013''.]</ref> RTB101 has also been described as a selective mTOR inhibitor, but some controversy exists.<ref>Kaeberlein, M. (2020). RTB101 and immune function in the elderly: interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.</ref><ref>Bischof, E., Siow, R. C., Zhavoronkov, A., & Kaeberlein, M. (2021). The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), e105-e111.</ref>		However, only one rapalog, everolimus, has published clinical data in this context.<ref>[https://www.thelancet.com/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=8&doi=10.1016/S2666-7568(20)30068-4&key=24379984&cf= Kaeberlein, M. (2013). mTOR inhibition: from aging to autism and beyond. ''Scientifica'', ''2013''.]</ref> RTB101 has also been described as a selective mTOR inhibitor, but some controversy exists.<ref>Kaeberlein, M. (2020). RTB101 and immune function in the elderly: interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.</ref><ref>Bischof, E., Siow, R. C., Zhavoronkov, A., & Kaeberlein, M. (2021). The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), e105-e111.</ref>
	Newer rapalogs have been discovered that are more selective for mTORC1 than rapamycin. One company that screened a library of modified rapalogs identified a compound, '''DL001''', with significantly greater (40 times more selective than rapamycin) selectivity for mTORC1 than rapamycin.<ref>Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., ... & Lamming, D. W. (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature communications, 10(1), 3194. PMID: 31324799 PMC: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642166/ 6642166] DOI: 10.1038/s41467-019-11174-0</ref> Mice treated with DL001 had reduced glucose intolerance, dyslipidemia and immune disruption as compared to mice treated in parallel with rapamycin. The ''in silico'' molecular docking analysis revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. These molecules can serve as macrocyclic scaffolds for developing new rapalog compounds targeting the mTOR.<ref>Parate, S., Kumar, V., Hong, J. C., & Lee, K. W. (2023). Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches. Computational Biology and Chemistry, 107875.		Newer rapalogs have been discovered that are more selective for mTORC1 than rapamycin. One company that screened a library of modified rapalogs identified a compound, '''DL001''', with significantly greater (40 times more selective than rapamycin) selectivity for mTORC1 than rapamycin.<ref>Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., ... & Lamming, D. W. (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature communications, 10(1), 3194. PMID: 31324799 PMC: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642166/ 6642166] DOI: 10.1038/s41467-019-11174-0</ref> Mice treated with DL001 had reduced glucose intolerance, dyslipidemia and immune disruption as compared to mice treated in parallel with rapamycin. The ''in silico'' molecular docking analysis revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. These molecules can serve as macrocyclic scaffolds for developing new rapalog compounds targeting the mTOR.<ref>Parate, S., Kumar, V., Hong, J. C., & Lee, K. W. (2023). Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches. Computational Biology and Chemistry, 107875. https://doi.org/10.1016/j.compbiolchem.2023.107875</ref>
	https://doi.org/10.1016/j.compbiolchem.2023.107875</ref>
			Antiemetic; piperazine-derivative antihistamine '''meclizine''', which is often available over the counter, is also found to be an mTOR inhibitor that male-specificly extends median lifespan in male mice by '''8%'''.<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Rosenthal, N., Korstanje, R., Fernandez, E., ... & Miller, R. A. (2023). Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. GeroScience, 1-22. PMID: 38041783 [https://doi.org/10.1007/s11357-023-01011-0 DOI: 10.1007/s11357-023-01011-0]</ref> Meclizine also is Toll-like receptor 4 (TLR4) inhibitor. Toll like receptors role is to detect pathogen molecules and initiate an immunologic response to them especially through production of pro-inflammatory cytokines and increased levels of type I interferon production.<ref>Zali, H., Golchin, A., Farahani, M., Yazdani, M., Ranjbar, M. M., & Dabbagh, A. (2019). FDA approved drugs repurposing of Toll-like receptor4 (TLR4) candidate for neuropathy. Iranian Journal of Pharmaceutical Research: IJPR, 18(3), 1639. PMID: 32641971 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934974/ PMC6934974] DOI: 10.22037/ijpr.2019.2394</ref>

	=== mTOR inhibition improves immune function in the elderly ===		=== mTOR inhibition improves immune function in the elderly ===

Dmitry Dzhagarov at 11:15, 18 November 2023

2023-11-18T11:15:56Z

← Older revision		Revision as of 11:15, 18 November 2023
Line 4:		Line 4:
	Rapamycin was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune® by Pfizer.<ref>Accessdata.fda.gov. 2021. ''Drug Approval Package: Rapamune (Sirolimus) NDA# 021083''. [online] Available at: <<nowiki>https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm</nowiki>> [Accessed 27 May 2021].</ref> At a high dose, rapamycin has an immunosuppressant function that is used in preventing rejection of kidney transplants by the immune system. It is also used to coat coronary stents, and to treat rare lung diseases.<ref>Doggrell, S. (2006). Sirolimus- or paclitaxel-eluting stents for coronary artery revascularisation. ''Expert Opinion On Pharmacotherapy'', ''7''(2), 225-228. <nowiki>https://doi.org/10.1517/14656566.7.2.225</nowiki></ref> The patent on rapamycin has expired, and pharmacological companies have developed similar drugs such as everolimus.<ref>Cancer, C. (2021). ''Everolimus - Drug Information - Chemocare''. Chemocare.com. Retrieved 27 May 2021, from <nowiki>http://chemocare.com/chemotherapy/drug-info/everolimus.aspx</nowiki>.</ref>		Rapamycin was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune® by Pfizer.<ref>Accessdata.fda.gov. 2021. ''Drug Approval Package: Rapamune (Sirolimus) NDA# 021083''. [online] Available at: <<nowiki>https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm</nowiki>> [Accessed 27 May 2021].</ref> At a high dose, rapamycin has an immunosuppressant function that is used in preventing rejection of kidney transplants by the immune system. It is also used to coat coronary stents, and to treat rare lung diseases.<ref>Doggrell, S. (2006). Sirolimus- or paclitaxel-eluting stents for coronary artery revascularisation. ''Expert Opinion On Pharmacotherapy'', ''7''(2), 225-228. <nowiki>https://doi.org/10.1517/14656566.7.2.225</nowiki></ref> The patent on rapamycin has expired, and pharmacological companies have developed similar drugs such as everolimus.<ref>Cancer, C. (2021). ''Everolimus - Drug Information - Chemocare''. Chemocare.com. Retrieved 27 May 2021, from <nowiki>http://chemocare.com/chemotherapy/drug-info/everolimus.aspx</nowiki>.</ref>

	Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":2" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref>		Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":2" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref><ref>Mannick, J. B., & Lamming, D. W. (2023). Targeting the biology of aging with mTOR inhibitors. Nature Aging, 1-19. PMID: 37142830 PMC10330278 [https://www.nature.com/articles/s43587-023-00416-y DOI: 10.1038/s43587-023-00416-y]</ref>

	Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":2">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref> It is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>		Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":2">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref> It is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

Dmitry Dzhagarov: /* Rapalogs */

2023-09-09T19:21:40Z

Rapalogs

← Older revision		Revision as of 19:21, 9 September 2023
Line 114:		Line 114:

	== Rapalogs ==		== Rapalogs ==
	Rapalogs are molecules with similar mechanism to rapamycin, primarily via mTORC1 inhibition. These drugs are generally predicted to function similarly to rapamycin in enhancing lifespan and reducing age-related decline in physiological function. However, only one rapalog, everolimus, has published clinical data in this context.<ref>[https://www.thelancet.com/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=8&doi=10.1016/S2666-7568(20)30068-4&key=24379984&cf= Kaeberlein, M. (2013). mTOR inhibition: from aging to autism and beyond. ''Scientifica'', ''2013''.]</ref> RTB101 has also been described as a selective mTOR inhibitor, but some controversy exists.<ref>Kaeberlein, M. (2020). RTB101 and immune function in the elderly: interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.</ref><ref>Bischof, E., Siow, R. C., Zhavoronkov, A., & Kaeberlein, M. (2021). The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), e105-e111.</ref>		Despite mTOR being the prime target against many age-related and chronic pathologies, relatively few mTOR inhibitors have been developed to slow the aging process.<ref>Mao, B., Zhang, Q., Ma, L., Zhao, D. S., Zhao, P., & Yan, P. (2022). Overview of research into mTOR inhibitors. Molecules, 27(16), 5295. PMID: 36014530 PMC9413691 https://doi.org/10.3390/molecules27165295</ref> Rapalogs are molecules with similar mechanism to rapamycin, primarily via mTORC1 inhibition. These drugs are generally predicted to function similarly to rapamycin in enhancing lifespan and reducing age-related decline in physiological function. For example, small molecule, '''TKA001''', selected based on in silico predictions, extends the lifespan of ''Caenorhabditis elegans'', suggesting that TKA001 is able to slow aging in vivo.<ref>Vidovic, T., Dakhovnik, A., Hrabovskyi, O., MacArthur, M. R., & Ewald, C. Y. (2023). AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans. International journal of molecular sciences, 24(9), 7850. PMID: 37175557 PMC10177929 https://doi.org/10.3390/ijms24097850</ref>
			However, only one rapalog, everolimus, has published clinical data in this context.<ref>[https://www.thelancet.com/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=8&doi=10.1016/S2666-7568(20)30068-4&key=24379984&cf= Kaeberlein, M. (2013). mTOR inhibition: from aging to autism and beyond. ''Scientifica'', ''2013''.]</ref> RTB101 has also been described as a selective mTOR inhibitor, but some controversy exists.<ref>Kaeberlein, M. (2020). RTB101 and immune function in the elderly: interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.</ref><ref>Bischof, E., Siow, R. C., Zhavoronkov, A., & Kaeberlein, M. (2021). The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), e105-e111.</ref>
	Newer rapalogs have been discovered that are more selective for mTORC1 than rapamycin. One company that screened a library of modified rapalogs identified a compound, '''DL001''', with significantly greater (40 times more selective than rapamycin) selectivity for mTORC1 than rapamycin.<ref>Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., ... & Lamming, D. W. (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature communications, 10(1), 3194. PMID: 31324799 PMC: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642166/ 6642166] DOI: 10.1038/s41467-019-11174-0</ref> Mice treated with DL001 had reduced glucose intolerance, dyslipidemia and immune disruption as compared to mice treated in parallel with rapamycin. The ''in silico'' molecular docking analysis revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. These molecules can serve as macrocyclic scaffolds for developing new rapalog compounds targeting the mTOR.<ref>Parate, S., Kumar, V., Hong, J. C., & Lee, K. W. (2023). Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches. Computational Biology and Chemistry, 107875.		Newer rapalogs have been discovered that are more selective for mTORC1 than rapamycin. One company that screened a library of modified rapalogs identified a compound, '''DL001''', with significantly greater (40 times more selective than rapamycin) selectivity for mTORC1 than rapamycin.<ref>Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., ... & Lamming, D. W. (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature communications, 10(1), 3194. PMID: 31324799 PMC: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642166/ 6642166] DOI: 10.1038/s41467-019-11174-0</ref> Mice treated with DL001 had reduced glucose intolerance, dyslipidemia and immune disruption as compared to mice treated in parallel with rapamycin. The ''in silico'' molecular docking analysis revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. These molecules can serve as macrocyclic scaffolds for developing new rapalog compounds targeting the mTOR.<ref>Parate, S., Kumar, V., Hong, J. C., & Lee, K. W. (2023). Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches. Computational Biology and Chemistry, 107875.
	https://doi.org/10.1016/j.compbiolchem.2023.107875</ref>		https://doi.org/10.1016/j.compbiolchem.2023.107875</ref>

Dmitry Dzhagarov: /* Improving immune function in older adults for respiratory tract infections, including coronaviruses */

2023-05-10T15:31:34Z

Improving immune function in older adults for respiratory tract infections, including coronaviruses

← Older revision		Revision as of 15:31, 10 May 2023
Line 137:		Line 137:

	This trial is being run by the biopharmaceutical company resTORbio and has obtained funding from the National Institute on Aging (NIA/NIH). The studies with dactolisib for COVID-19 is one of several clinical trials in the aging biology field aiming to target aging to improve the aging immune system.<ref name=":12" />		This trial is being run by the biopharmaceutical company resTORbio and has obtained funding from the National Institute on Aging (NIA/NIH). The studies with dactolisib for COVID-19 is one of several clinical trials in the aging biology field aiming to target aging to improve the aging immune system.<ref name=":12" />

			== See also ==
			* [https://en.longevitywiki.org/wiki/Isomyosamine Isomyosamine] ('''MYMD-1®''') <ref>Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. 78(2), 227-235 PMID 35914953 doi:10.1093/gerona/glac142</ref>

	== References ==		== References ==