COVID-19 - Revision history

Andrea: category change

2022-12-28T08:50:13Z

category change

← Older revision		Revision as of 08:50, 28 December 2022
Line 125:		Line 125:

	<references />		<references />
	~~[[Category:Pillar Articles]]~~
	[[Category:Main list]]		[[Category:Main list]]
	[[Category:Age-related diseases]]		[[Category:Age-related diseases]]
			[[Category:Fundamentals]]

Andrea: category change

2022-12-27T11:46:53Z

category change

← Older revision		Revision as of 11:46, 27 December 2022
Line 125:		Line 125:

	<references />		<references />
	~~[[Category:Longevity]]~~
	[[Category:Pillar Articles]]		[[Category:Pillar Articles]]
			[[Category:Main list]]
			[[Category:Age-related diseases]]

Dmitry Dzhagarov: /* COVID-19 may accelerate aging in humans */

2022-12-05T10:25:00Z

COVID-19 may accelerate aging in humans

← Older revision		Revision as of 10:25, 5 December 2022
Line 74:		Line 74:

	=== COVID-19 may accelerate aging in humans ===		=== COVID-19 may accelerate aging in humans ===
	Long COVID, also known as Post COVID, Long-Hauler's Syndrome or post-acute sequelae of COVID-19 (PASC), describes a non-specific cluster of long-term health consequences affecting multiple organ systems in those previously infected by COVID-19. This generally refers to chronic, residual consequences that range from neuropsychiatric ailments, to metabolic disease, and even frailty.		Long COVID, also known as Post COVID, Long-Hauler's Syndrome or post-acute sequelae of COVID-19 (PASC), describes a non-specific cluster of long-term health consequences affecting multiple organ systems in those previously infected by COVID-19. This generally refers to chronic, residual consequences that range from neuropsychiatric ailments, to metabolic disease, and even [[frailty]].

	One study of nursing home residents found an association between COVID-19 infection and exhibiting a state similar to accelerated aging.<ref name=":16">Greco, G. I., Noale, M., Trevisan, C., Zatti, G., Dalla Pozza, M., Lazzarin, M., ... & Sergi, G. (2021). Increase in Frailty in Nursing Home Survivors of Coronavirus Disease 2019: Comparison With Noninfected Residents. ''Journal of the American Medical Directors Association'', ''22''(5), 943-947.</ref> This included greater declines in walking speed and handgrip strength, with worsening of frailty as measured via a nursing-home specific frailty index.<ref name=":16" /> Due to preclinical data showing that SARS-CoV-2 can drive cellular senescence in human cells, an observational study is ongoing to determine whether senescence markers are increased in long COVID patients versus uninfected controls (Cellular Senescence and COVID-19 Long-Hauler Syndrome; [https://clinicaltrials.gov/ct2/show/NCT04903132 NCT04903132]).<ref name=":14" /> Clinical data is generally lacking to provide strong evidence of accelerated aging due to COVID-19.		One study of nursing home residents found an association between COVID-19 infection and exhibiting a state similar to accelerated aging.<ref name=":16">Greco, G. I., Noale, M., Trevisan, C., Zatti, G., Dalla Pozza, M., Lazzarin, M., ... & Sergi, G. (2021). Increase in Frailty in Nursing Home Survivors of Coronavirus Disease 2019: Comparison With Noninfected Residents. ''Journal of the American Medical Directors Association'', ''22''(5), 943-947.</ref> This included greater declines in walking speed and handgrip strength, with worsening of frailty as measured via a nursing-home specific frailty index.<ref name=":16" /> Due to preclinical data showing that SARS-CoV-2 can drive cellular senescence in human cells, an observational study is ongoing to determine whether senescence markers are increased in long COVID patients versus uninfected controls (Cellular Senescence and COVID-19 Long-Hauler Syndrome; [https://clinicaltrials.gov/ct2/show/NCT04903132 NCT04903132]).<ref name=":14" /> Clinical data is generally lacking to provide strong evidence of accelerated aging due to COVID-19.

	Currently there is a lack of research for Long COVID, but it is speculated that the biology of aging is closely related, in part due to multimorbidity from various affected organs.<ref name=":15" /> With the known ability of SARS-CoV-2 to induce cellular senescence in mice ''in vivo'' and human cells ''in vitro'', and the clinical characteristics of COVID-19, it has been hypothesized that the virus may accelerate aging in infected patients.<ref name=":14" /><ref name=":15">Gerdes, E. O. W., Vanichkachorn, G., Verdoorn, B. P., Hanson, G. J., Joshi, A. Y., Murad, M. H., Rizza, S. A., Tchkonia, T., & Kirkland, J. L. (2021). Role of senescence in the chronic health consequences of COVID-19. ''Translational Research''.</ref>		Currently there is a lack of research for Long COVID, but it is speculated that the biology of aging is closely related, in part due to multimorbidity from various affected organs.<ref name=":15" /> With the known ability of SARS-CoV-2 to induce cellular senescence in mice ''in vivo'' and human cells ''in vitro'', and the clinical characteristics of COVID-19, it has been hypothesized that the virus may accelerate aging in infected patients.<ref name=":14" /><ref name=":15">Gerdes, E. O. W., Vanichkachorn, G., Verdoorn, B. P., Hanson, G. J., Joshi, A. Y., Murad, M. H., Rizza, S. A., Tchkonia, T., & Kirkland, J. L. (2021). Role of senescence in the chronic health consequences of COVID-19. ''Translational Research''.</ref>

	=== Immune aging and vulnerability to infectious diseases ===		=== Immune aging and vulnerability to infectious diseases ===

Dmitry Dzhagarov: /* SARS-CoV-2 causes senescence in human cells */

2022-12-05T10:23:46Z

SARS-CoV-2 causes senescence in human cells

← Older revision		Revision as of 10:23, 5 December 2022
Line 62:		Line 62:
	</ref>		</ref>

	Cellular senescence is a major biological mechanism linked to aging which has been hypothesized to contribute to poor COVID-19 outcomes. It may help explain pathophysiological features such as macrophage dysfunction and the cytokine storm, as well as clinical manifestations such as the disproportionate mortality and reduced vaccine response of the biologically old.<ref name=":13" /> There is considerable overlap between ailments that are driven by senescence and that of COVID-19, such as lung dysfunction, frailty, cognitive decline, and heart damage.<ref name=":14" /> Inflammatory factors that make up the SASP, such as IL-6 and IL-8, have been associated with poor outcomes in COVID-19.<ref>Laing, A. G., Lorenc, A., Del Barrio, I. D. M., Das, A., Fish, M., Monin, L., ... & Hayday, A. C. (2020). A dynamic COVID-19 immune signature includes associations with poor prognosis. ''Nature medicine'', ''26''(10), 1623-1635.</ref>		Cellular senescence is a major biological mechanism linked to aging which has been hypothesized to contribute to poor COVID-19 outcomes. It may help explain pathophysiological features such as macrophage dysfunction and the cytokine storm, as well as clinical manifestations such as the disproportionate mortality and reduced vaccine response of the biologically old.<ref name=":13" /> There is considerable overlap between ailments that are driven by senescence and that of COVID-19, such as lung dysfunction, [[frailty]], cognitive decline, and heart damage.<ref name=":14" /> Inflammatory factors that make up the SASP, such as IL-6 and IL-8, have been associated with poor outcomes in COVID-19.<ref>Laing, A. G., Lorenc, A., Del Barrio, I. D. M., Das, A., Fish, M., Monin, L., ... & Hayday, A. C. (2020). A dynamic COVID-19 immune signature includes associations with poor prognosis. ''Nature medicine'', ''26''(10), 1623-1635.</ref>

	A recent study showed that in non-senescent cells SARS-CoV-2 is able to cause cellular senescence, while in senescent cells, increases the expression of the pro-inflammatory SASP that is associated with age-related diseases.<ref name=":14">Tripathi, U., Nchioua, R., Prata, L. G. L., Zhu, Y., Gerdes, E. O. W., Giorgadze, N., ... & Kirkland, J. L. (2021). SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. ''Aging (Albany NY)'', ''13''(18), 21838.</ref> The authors also found an increased expression of the senescent cell marker p16<sup>INK4a</sup> in lungs of patients who died to acute COVID-19, compared to dead controls who did not have diseases related to the lungs. Consistent with the ''in vitro'' data, this suggests that SARS-CoV-2 induces senescence.<ref name=":14" />		A recent study showed that in non-senescent cells SARS-CoV-2 is able to cause cellular senescence, while in senescent cells, increases the expression of the pro-inflammatory SASP that is associated with age-related diseases.<ref name=":14">Tripathi, U., Nchioua, R., Prata, L. G. L., Zhu, Y., Gerdes, E. O. W., Giorgadze, N., ... & Kirkland, J. L. (2021). SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. ''Aging (Albany NY)'', ''13''(18), 21838.</ref> The authors also found an increased expression of the senescent cell marker p16<sup>INK4a</sup> in lungs of patients who died to acute COVID-19, compared to dead controls who did not have diseases related to the lungs. Consistent with the ''in vitro'' data, this suggests that SARS-CoV-2 induces senescence.<ref name=":14" />

	In an ''in vitro'' model, senescent human kidney cells exposed to the SARS-CoV-2 spike protein-1 show an increase in senescence-associated inflammatory factors.<ref name=":12">Camell, C. D., Yousefzadeh, M. J., Zhu, Y., Prata, L. G. L., Huggins, M. A., Pierson, M., ... & Robbins, P. D. (2021). Senolytics reduce coronavirus-related mortality in old mice. ''Science''.</ref> Additionally, human lung epithelial cells exposed to various senescent cells show a significantly greater expression of ''ACE2'' and ''TMPRSS2'', which are COVID-19 viral entry genes.<ref name=":12" /> Similarly, another study of COVID-19 infected patients found evidence of cell senescence in airway mucosa, and higher expression of SASP inflammatory factors in blood.<ref name=":17">Lee, S., Yu, Y., Trimpert, J., Benthani, F., Mairhofer, M., Richter-Pechanska, P., ... & Schmitt, C. A. (2021). Virus-induced senescence is a driver and therapeutic target in COVID-19. ''Nature'', 1-7.</ref>		In an ''in vitro'' model, senescent human kidney cells exposed to the SARS-CoV-2 spike protein-1 show an increase in senescence-associated inflammatory factors.<ref name=":12">Camell, C. D., Yousefzadeh, M. J., Zhu, Y., Prata, L. G. L., Huggins, M. A., Pierson, M., ... & Robbins, P. D. (2021). Senolytics reduce coronavirus-related mortality in old mice. ''Science''.</ref> Additionally, human lung epithelial cells exposed to various senescent cells show a significantly greater expression of ''ACE2'' and ''TMPRSS2'', which are COVID-19 viral entry genes.<ref name=":12" /> Similarly, another study of COVID-19 infected patients found evidence of cell senescence in airway mucosa, and higher expression of SASP inflammatory factors in blood.<ref name=":17">Lee, S., Yu, Y., Trimpert, J., Benthani, F., Mairhofer, M., Richter-Pechanska, P., ... & Schmitt, C. A. (2021). Virus-induced senescence is a driver and therapeutic target in COVID-19. ''Nature'', 1-7.</ref>

	=== Senescent cell clearance reduces coronavirus mortality ===		=== Senescent cell clearance reduces coronavirus mortality ===

Geroscientist: /* COVID-19 */

2021-12-14T01:20:34Z

COVID-19

← Older revision		Revision as of 01:20, 14 December 2021
Line 83:		Line 83:
	Both immunosenescence and inflammaging are well-known biological mechanisms that underlie age-related susceptibility to various infectious diseases, such as the common cold, influenza, and pneumonia.		Both immunosenescence and inflammaging are well-known biological mechanisms that underlie age-related susceptibility to various infectious diseases, such as the common cold, influenza, and pneumonia.

	Immunosenescence is ~~characterised~~ by the age-related decline in the host's ability to mount an appropriate immune response to an infectious agent.<ref name=":6">Furman, D., Campisi, J., Verdin, E., Carrera-Bastos, P., Targ, S., Franceschi, C., ... & Slavich, G. M. (2019). Chronic inflammation in the etiology of disease across the life span. ''Nature medicine'', ''25''(12), 1822-1832.</ref> A major reason for this decline is related to atrophy of the thymus (thymic involution), an important organ that is important for generating naive T cells. It is therefore central to the adaptive immune system, which is integral to providing long-term protection against old and new infectious pathogens.		Immunosenescence is characterized by the age-related decline in the host's ability to mount an appropriate immune response to an infectious agent.<ref name=":6">Furman, D., Campisi, J., Verdin, E., Carrera-Bastos, P., Targ, S., Franceschi, C., ... & Slavich, G. M. (2019). Chronic inflammation in the etiology of disease across the life span. ''Nature medicine'', ''25''(12), 1822-1832.</ref> A major reason for this decline is related to atrophy of the thymus (thymic involution), an important organ that is important for generating naive T cells. It is therefore central to the adaptive immune system, which is integral to providing long-term protection against old and new infectious pathogens.

	Inflammaging describes the age-related systemic inflammation, which affects various systems across the body that leads to organ and tissue dysfunction.<ref name=":6" /> It is known that with aging, dysregulation of the innate immune system results in chronic hyperactivation, and becomes a key driver of multiple age-related diseases via chronic inflammation.<ref>Shaw, A. C., Goldstein, D. R., & Montgomery, R. R. (2013). Age-dependent dysregulation of innate immunity. ''Nature Reviews Immunology'', ''13''(12), 875-887.</ref>		Inflammaging describes the age-related systemic inflammation, which affects various systems across the body that leads to organ and tissue dysfunction.<ref name=":6" /> It is known that with aging, dysregulation of the innate immune system results in chronic hyperactivation, and becomes a key driver of multiple age-related diseases via chronic inflammation.<ref>Shaw, A. C., Goldstein, D. R., & Montgomery, R. R. (2013). Age-dependent dysregulation of innate immunity. ''Nature Reviews Immunology'', ''13''(12), 875-887.</ref>
Line 104:		Line 104:
	The primary rationale for why RTB101 has potential to show benefit for the 2019 strain of coronavirus stems from phase 2b and phase 3 clinical trial data of RTB101, showing fewer laboratory-confirmed (non-COVID-19) coronavirus cases, and reduced severity of coronavirus infection in elderly adults aged ≥ 65.<ref name=":18">Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell, K., Klickstein, L., ... & Shergill, S. (2021). Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. ''The Lancet Healthy Longevity'', ''2''(5), e250-e262.</ref> The phase 3 randomized, double-blind, placebo-controlled clinical trial for RTB101 was withdrawn in November 2019, following failure to meet its primary endpoint of reducing symptoms of respiratory tract infections (RTIs) in adults aged ≥ 65, with or without laboratory-confirmed viral illness.<ref name=":18" />		The primary rationale for why RTB101 has potential to show benefit for the 2019 strain of coronavirus stems from phase 2b and phase 3 clinical trial data of RTB101, showing fewer laboratory-confirmed (non-COVID-19) coronavirus cases, and reduced severity of coronavirus infection in elderly adults aged ≥ 65.<ref name=":18">Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell, K., Klickstein, L., ... & Shergill, S. (2021). Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. ''The Lancet Healthy Longevity'', ''2''(5), e250-e262.</ref> The phase 3 randomized, double-blind, placebo-controlled clinical trial for RTB101 was withdrawn in November 2019, following failure to meet its primary endpoint of reducing symptoms of respiratory tract infections (RTIs) in adults aged ≥ 65, with or without laboratory-confirmed viral illness.<ref name=":18" />

	Considering the positive clinical data from the phase 2 trials, which involved investigations of both everolimus (a ~~rapalogue~~) and RTB101, the failure of the later phase 3 trial has been attributed to the decision to move ahead with only RTB101.<ref name=":5">Kaeberlein, M. (2020). RTB101 and immune function in the elderly: Interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.		Considering the positive clinical data from the phase 2 trials, which involved investigations of both everolimus (a rapalog) and RTB101, the failure of the later phase 3 trial has been attributed to the decision to move ahead with only RTB101.<ref name=":5">Kaeberlein, M. (2020). RTB101 and immune function in the elderly: Interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.
	</ref> This is because only rapamycin, an allosteric inhibitor of mTOR, has demonstrated the extension of healthspan and lifespan in various animal models, with a rejuvenation of immune function; while RTB101, an ATP-competitive PI3K/mTOR dual kinase inhibitor of differing mechanism of action to rapamycin, has not yet demonstrated these effects in animal models.<ref name=":5" /> The decision to omit the use of everolimus and continue with RTB101 in the phase 3 trial is speculated to be related to the off-patent status; it would be prohibitive for a publicly-traded company with fiduciary responsibility to shareholders to advance a drug with no commercial potential into late-stage clinical trials.<ref name=":5" />		</ref> This is because only rapamycin, an allosteric inhibitor of mTOR, has demonstrated the extension of healthspan and lifespan in various animal models, with a rejuvenation of immune function; while RTB101, an ATP-competitive PI3K/mTOR dual kinase inhibitor of differing mechanism of action to rapamycin, has not yet demonstrated these effects in animal models.<ref name=":5" /> The decision to omit the use of everolimus and continue with RTB101 in the phase 3 trial is speculated to be related to the off-patent status; it would be prohibitive for a publicly-traded company with fiduciary responsibility to shareholders to advance a drug with no commercial potential into late-stage clinical trials.<ref name=":5" />

	Joan Mannick, the Chief Medical Officer of resTORbio, has since justified the trial's failure at several [https://www.youtube.com/watch?v=BVQci0V8uPk medical conferences] with the belief that it was related to a change in the primary endpoint~~, as~~ requested by the [[wikipedia:Food_and_Drug_Administration\|US FDA]], when the trial advanced from phase 2 to 3. In the prior successful phase 2 trial, the primary endpoint had been RTI symptoms ''with'' laboratory confirmation of a causative virus, but this endpoint was changed to RTI symptoms ''with or without'' laboratory-confirmed viral illness in the [https://clinicaltrials.gov/ct2/show/NCT04139915?cond=rtb101&draw=2&rank=1 failed phase 3 trial].<ref name=":18" /> This is a problem for interpreting the clinical trial because it was not the original endpoint for which the drug had showed ~~benefits, and is~~ also introduced as older adults inherently experience respiratory tract symptoms at greater rates, even ''without'' laboratory-confirmation of viral presence. </blockquote>		Joan Mannick, the Chief Medical Officer of resTORbio, has since justified the trial's failure at several [https://www.youtube.com/watch?v=BVQci0V8uPk medical conferences] with the belief that it was related to a change in the primary endpoint. This was requested by the [[wikipedia:Food_and_Drug_Administration\|US FDA]] when the trial advanced from phase 2 to 3. In the prior successful phase 2 trial, the primary endpoint had been RTI symptoms ''with'' laboratory confirmation of a causative virus, but this endpoint was changed to RTI symptoms ''with or without'' laboratory-confirmed viral illness in the [https://clinicaltrials.gov/ct2/show/NCT04139915?cond=rtb101&draw=2&rank=1 failed phase 3 trial].<ref name=":18" /> This is a problem for interpreting the clinical trial because it was not the original endpoint for which the drug had showed benefit in. Mannick has also argued that this introduced more noise to the trial, as older adults inherently experience respiratory tract symptoms at greater rates, even ''without'' laboratory-confirmation of viral presence. </blockquote>

	===== COVID-19 =====		===== COVID-19 =====

Geroscientist: /* COVID-19 as a disease of aging */

2021-12-06T05:34:26Z

COVID-19 as a disease of aging

← Older revision		Revision as of 05:34, 6 December 2021
Line 43:		Line 43:
	</ref> Furthermore, most pre-existing conditions that are risk factors for COVID-19 mortality are age-related diseases, which adds to the idea that biological aging is fundamental to the ability of SARS-CoV-2 (age-dependent mortality) to induce mortality the elderly.<ref name=":4" />		</ref> Furthermore, most pre-existing conditions that are risk factors for COVID-19 mortality are age-related diseases, which adds to the idea that biological aging is fundamental to the ability of SARS-CoV-2 (age-dependent mortality) to induce mortality the elderly.<ref name=":4" />

	=== Age and COVID-19 Infection Fatality ~~Rate~~ (IFR) ===		=== Age and COVID-19 Infection Fatality Ratio (IFR) ===
	In the research field of [[wikipedia:Epidemiology\|epidemiology]], the infection fatality ~~rate~~ (IFR) – the ratio of fatalities to total infections – is an important metric for determining the virulence of an infectious disease.<ref>Levin, A. T., Hanage, W. P., Owusu-Boaitey, N., Cochran, K. B., Walsh, S. P., & Meyerowitz-Katz, G. (2020). Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications. ''European journal of epidemiology'', 1-16.</ref> In the early stages of the pandemic, determining the IFR of COVID-19 was subject to significant uncertainty due to lack of data.		In the research field of [[wikipedia:Epidemiology\|epidemiology]], the infection fatality ratio (IFR) – the ratio of fatalities to total infections – is an important metric for determining the virulence of an infectious disease.<ref>Levin, A. T., Hanage, W. P., Owusu-Boaitey, N., Cochran, K. B., Walsh, S. P., & Meyerowitz-Katz, G. (2020). Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications. ''European journal of epidemiology'', 1-16.</ref> In the early stages of the pandemic, determining the IFR of COVID-19 was subject to significant uncertainty due to lack of data.

	One estimate found that the IFR of a given country's population was significantly dependent on the age structure, indicating that IFR is age-specific.<ref name=":7">O’Driscoll, M., Dos Santos, G. R., Wang, L., Cummings, D. A., Azman, A. S., Paireau, J., ... & Salje, H. (2021). Age-specific mortality and immunity patterns of SARS-CoV-2. ''Nature'', ''590''(7844), 140-145.</ref> For example, Japan had the highest estimated IFR of 1.09% (95% credible interval, 0.94–1.26%), whereas Kenya had the lowest estimated IFR of 0.09% (95% credible interval, 0.08–0.10%).<ref name=":7" /> This predominantly reflects demographic differences, partly related to a significantly larger proportion of elderly citizens in Japan .		One estimate found that the IFR of a given country's population was significantly dependent on the age structure, indicating that IFR is age-specific.<ref name=":7">O’Driscoll, M., Dos Santos, G. R., Wang, L., Cummings, D. A., Azman, A. S., Paireau, J., ... & Salje, H. (2021). Age-specific mortality and immunity patterns of SARS-CoV-2. ''Nature'', ''590''(7844), 140-145.</ref> For example, Japan had the highest estimated IFR of 1.09% (95% credible interval, 0.94–1.26%), whereas Kenya had the lowest estimated IFR of 0.09% (95% credible interval, 0.08–0.10%).<ref name=":7" /> This predominantly reflects demographic differences, partly related to a significantly larger proportion of elderly citizens in Japan .

Geroscientist: /* Fisetin */

2021-11-21T07:41:27Z

Fisetin

← Older revision		Revision as of 07:41, 21 November 2021
Line 112:		Line 112:
	<blockquote>		<blockquote>

	Unpublished data from the phase 2 trial of RTB101 for COVID-19 among nursing home patients treated within 3 days from testing positive saw promising results. None of those treated with RTB101 developed symptoms (n=18), while the placebo treated control group had 4 severe cases of disease and 2 deaths. While this was a statistically significant finding, larger trials are warranted for further evidence of potential benefit. </blockquote>		Unpublished data from the phase 2 trial of RTB101 for COVID-19 among nursing home patients treated within 3 days from testing positive saw promising results.<ref name=":19">Metabesity Conference, 2021, 'Targeting Metabesity 2021: Evidence 3 – Establishing Clear Pathways for Healthspan Products' https://www.youtube.com/watch?v=mg4jL_WdFd0</ref> None of those treated with RTB101 developed symptoms (n=18), while the placebo treated control group had 4 severe cases of disease and 2 deaths. While this was a statistically significant finding, larger trials are warranted for further evidence of potential benefit.<ref name=":19" /> </blockquote>

	=== Fisetin ===		=== Fisetin ===
	Fisetin is a [[Senolytics\|senolytic]] that is being investigated in two phase 2 clinical trials at the Mayo Clinic<ref>Kirkland, James L. ''COVID-FISETIN: A Phase 2 Placebo-Controlled Pilot Study in SARS-CoV-2 of Fisetin to Alleviate Dysfunction and Excessive Inflammatory Response in Hospitalized Adults''. Clinical trial registration, NCT04476953, clinicaltrials.gov, 16 Feb. 2021. ''clinicaltrials.gov'', <nowiki>https://clinicaltrials.gov/ct2/show/NCT04476953</nowiki>.</ref>, with the second trial being funded by the National Institute on Aging of the [[wikipedia:National_Institutes_of_Health\|US NIH]]<ref>PhD, James L. Kirkland, MD. ''COVID-FIS: A Phase 2 Placebo-Controlled Pilot Study in COVID-19 of Fisetin to Alleviate Dysfunction and Excessive Inflammatory Response in Older Adults in Nursing Homes''. Clinical trial registration, NCT04537299, clinicaltrials.gov, 1 June 2021. ''clinicaltrials.gov'', <nowiki>https://clinicaltrials.gov/ct2/show/NCT04537299</nowiki>.</ref>.		Fisetin is a [[Senolytics\|senolytic]] that is being investigated in two phase 2 clinical trials at the Mayo Clinic,<ref>Kirkland, James L. ''COVID-FISETIN: A Phase 2 Placebo-Controlled Pilot Study in SARS-CoV-2 of Fisetin to Alleviate Dysfunction and Excessive Inflammatory Response in Hospitalized Adults''. Clinical trial registration, NCT04476953, clinicaltrials.gov, 16 Feb. 2021. ''clinicaltrials.gov'', <nowiki>https://clinicaltrials.gov/ct2/show/NCT04476953</nowiki>.</ref> with the second trial being funded by the National Institute on Aging of the [[wikipedia:National_Institutes_of_Health\|US NIH.]]<ref>PhD, James L. Kirkland, MD. ''COVID-FIS: A Phase 2 Placebo-Controlled Pilot Study in COVID-19 of Fisetin to Alleviate Dysfunction and Excessive Inflammatory Response in Older Adults in Nursing Homes''. Clinical trial registration, NCT04537299, clinicaltrials.gov, 1 June 2021. ''clinicaltrials.gov'', <nowiki>https://clinicaltrials.gov/ct2/show/NCT04537299</nowiki>.</ref>

	For SARS-CoV-2, fibrosis of the lung tissue is a well-known serious complication following acute respiratory distress syndrome (ARDS). Senolytic drugs are capable of slowing and/or reversing age-related lung fibrosis in mice, as well as promoting health in multiple tissues/organs, and so may provide benefit for both acute and chronic manifestations of COVID-19.<ref name=":3" /> The pro-inflammatory secretions of senescent cells have been identified as key drivers of tissue and organ dysfunction with aging, which have been linked to the cytokine storm associated with COVID-19 ARDS.<ref name=":3" /> It is hypothesized that senolytics may alleviate the age-associated decline in lung function, in addition to improving immune function such as via the clearance of senescent T cells.<ref name=":3">Nehme, J., Borghesan, M., Mackedenski, S., Bird, T. G., & Demaria, M. (2020). Cellular senescence as a potential mediator of COVID‐19 severity in the elderly. ''Aging Cell'', ''19''(10), e13237</ref><ref>Akbar, A. N., & Gilroy, D. W. (2020). Aging immunity may exacerbate COVID-19. ''Science'', ''369''(6501), 256-257.</ref>		For SARS-CoV-2, fibrosis of the lung tissue is a well-known serious complication following acute respiratory distress syndrome (ARDS). Senolytic drugs are capable of slowing and/or reversing age-related lung fibrosis in mice, as well as promoting health in multiple tissues/organs, and so may provide benefit for both acute and chronic manifestations of COVID-19.<ref name=":3" /> The pro-inflammatory secretions of senescent cells have been identified as key drivers of tissue and organ dysfunction with aging, which have been linked to the cytokine storm associated with COVID-19 ARDS.<ref name=":3" /> It is hypothesized that senolytics may alleviate the age-associated decline in lung function, in addition to improving immune function such as via the clearance of senescent T cells.<ref name=":3">Nehme, J., Borghesan, M., Mackedenski, S., Bird, T. G., & Demaria, M. (2020). Cellular senescence as a potential mediator of COVID‐19 severity in the elderly. ''Aging Cell'', ''19''(10), e13237</ref><ref>Akbar, A. N., & Gilroy, D. W. (2020). Aging immunity may exacerbate COVID-19. ''Science'', ''369''(6501), 256-257.</ref>

Geroscientist: /* Aging, comorbidities, and COVID-19 */

2021-11-21T07:16:34Z

Aging, comorbidities, and COVID-19

← Older revision		Revision as of 07:16, 21 November 2021
Line 69:		Line 69:

	=== Senescent cell clearance reduces coronavirus mortality ===		=== Senescent cell clearance reduces coronavirus mortality ===
	Senolytic drugs selectively remove senescent cells from the body, which have been shown to delay and even partly reverse multiple age-related diseases, resulting in expanded healthy lifespan in mice.<ref>Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., ... & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18-28.</ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. ''Nature'', ''479''(7372), 232-236.</ref> In a preclinical study in old mice, the senolytic drug fisetin halved mortality due to coronavirus, with reduced expression of SASP inflammatory markers and improved immune function.<ref name=":12" /> This ~~preclinical~~ study also showed therapeutic benefit with dasatinib plus quercetin (D+Q), which is another class of senolytics used in combination.<ref name=":12" />		Senolytic drugs selectively remove senescent cells from the body, which have been shown to delay and even partly reverse multiple age-related diseases, resulting in expanded healthy lifespan in mice.<ref>Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., ... & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18-28.</ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. ''Nature'', ''479''(7372), 232-236.</ref> In a preclinical study in old mice, the senolytic drug fisetin halved mortality due to mouse hepatitis virus (MHV), a β-coronavirus in the same family as SARS-CoV-2, with reduced expression of SASP inflammatory markers and improved immune function.<ref name=":12" /> This mouse study also showed similar therapeutic benefit with dasatinib plus quercetin (D+Q), which is another class of senolytics used in combination.<ref name=":12" /> Consistent with COVID-19 epidemiology, young but not old mice were resistant to MHV infection; benefits of senolytics use were specific to the old mice.<ref name=":12" />

	Another study investigating senolysis in golden hamsters and mice infected with SARS-CoV-2 found significantly increased survival following treatment with senolytic drugs.<ref name=":17" /> In hamsters, the combination of dasatinib and quercetin led to a substantial reduction in histopathological features of lung disease with SASP factor expression more closely mirroring that of healthy control hamsters. In small groups of 5 mice, both D+Q and fisetin each had 5 of 5 mice survive at day 6, compared to 3 of 5 in the control group. The senolytic navitoclax did not exhibit as consistent an effect on several measures in either animal models.<ref name=":17" />		Another study investigating senolysis in golden hamsters and mice infected with SARS-CoV-2 found significantly increased survival following treatment with senolytic drugs.<ref name=":17" /> In hamsters, the combination of dasatinib and quercetin led to a substantial reduction in histopathological features of lung disease with SASP factor expression more closely mirroring that of healthy control hamsters. In small groups of 5 mice, both D+Q and fisetin each had 5 of 5 mice survive at day 6, compared to 3 of 5 in the control group. The senolytic navitoclax did not exhibit as consistent an effect on several measures in either animal models.<ref name=":17" />

Geroscientist: /* Aging, comorbidities, and COVID-19 */

2021-11-21T03:06:28Z

Aging, comorbidities, and COVID-19

← Older revision		Revision as of 03:06, 21 November 2021
Line 109:		Line 109:
	Joan Mannick, the Chief Medical Officer of resTORbio, has since justified the trial's failure at several [https://www.youtube.com/watch?v=BVQci0V8uPk medical conferences] with the belief that it was related to a change in the primary endpoint, as requested by the [[wikipedia:Food_and_Drug_Administration\|US FDA]], when the trial advanced from phase 2 to 3. In the prior successful phase 2 trial, the primary endpoint had been RTI symptoms ''with'' laboratory confirmation of a causative virus, but this endpoint was changed to RTI symptoms ''with or without'' laboratory-confirmed viral illness in the [https://clinicaltrials.gov/ct2/show/NCT04139915?cond=rtb101&draw=2&rank=1 failed phase 3 trial].<ref name=":18" /> This is a problem for interpreting the clinical trial because it was not the original endpoint for which the drug had showed benefits, and is also introduced as older adults inherently experience respiratory tract symptoms at greater rates, even ''without'' laboratory-confirmation of viral presence. </blockquote>		Joan Mannick, the Chief Medical Officer of resTORbio, has since justified the trial's failure at several [https://www.youtube.com/watch?v=BVQci0V8uPk medical conferences] with the belief that it was related to a change in the primary endpoint, as requested by the [[wikipedia:Food_and_Drug_Administration\|US FDA]], when the trial advanced from phase 2 to 3. In the prior successful phase 2 trial, the primary endpoint had been RTI symptoms ''with'' laboratory confirmation of a causative virus, but this endpoint was changed to RTI symptoms ''with or without'' laboratory-confirmed viral illness in the [https://clinicaltrials.gov/ct2/show/NCT04139915?cond=rtb101&draw=2&rank=1 failed phase 3 trial].<ref name=":18" /> This is a problem for interpreting the clinical trial because it was not the original endpoint for which the drug had showed benefits, and is also introduced as older adults inherently experience respiratory tract symptoms at greater rates, even ''without'' laboratory-confirmation of viral presence. </blockquote>

	====== COVID-19 ======		===== COVID-19 =====
	<blockquote>		<blockquote>

Geroscientist: /* Immune aging and vulnerability to infectious diseases */

2021-11-21T03:05:57Z

Immune aging and vulnerability to infectious diseases

← Older revision		Revision as of 03:05, 21 November 2021
Line 93:		Line 93:

	=== RTB101 ===		=== RTB101 ===
	<blockquote>RTB101 (dactolisib) is an FDA-approved drug used in oncology, with primary mechanism of action of ATP-competitive PI3K/mTOR dual kinase inhibition.		<blockquote>RTB101 (dactolisib) is an FDA-approved drug used in oncology, with primary mechanism of action of ATP-competitive PI3K/mTOR dual kinase inhibition. </blockquote>

	Inhibition of mTOR has been shown in human clinical studies to improve immune function in older adults.<ref>Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., ... & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. ''Science translational medicine'', ''6''(268), 268ra179-268ra179.</ref><ref>Mannick, J. B., Morris, M., Hockey, H. U. P., Roma, G., Beibel, M., Kulmatycki, K., ... & Klickstein, L. B. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. ''Science translational medicine'', ''10''(449).</ref> Phase 2 studies have shown that mTOR inhibitors can reduce viral infection severity and improve the effectiveness of vaccination, such as for influenza. This is in contrast to the known ability for rapamycin (and its analogues, e.g. everolimus) to induce immunosuppression, which is related to its primary indication as an FDA-approved liver and lung transplant drug.		===== Coronavirus (non COVID-19) =====
			<blockquote>Inhibition of mTOR has been shown in human clinical studies to improve immune function in older adults.<ref>Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., ... & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. ''Science translational medicine'', ''6''(268), 268ra179-268ra179.</ref><ref>Mannick, J. B., Morris, M., Hockey, H. U. P., Roma, G., Beibel, M., Kulmatycki, K., ... & Klickstein, L. B. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. ''Science translational medicine'', ''10''(449).</ref> Phase 2 studies have shown that mTOR inhibitors can reduce viral infection severity and improve the effectiveness of vaccination, such as for influenza. This is in contrast to the known ability for rapamycin (and its analogues, e.g. everolimus) to induce immunosuppression, which is related to its primary indication as an FDA-approved liver and lung transplant drug.

	Following the success of two [https://clinicaltrials.gov/ct2/show/NCT03373903?term=restorbio&draw=2&rank=4 phase 2 clinical trials] investigating mTOR inhibition for targeting the aging immune system, RTB101 (dactolisib) is currently being pursued for the treatment of COVID-19 in a phase 2a placebo-controlled trial, exploring the potential for preventing severe disease in asymptomatic elderly adults who have been exposed to COVID-19.<ref>Restorbio Inc. ''A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study of RTB101 as COVID-19 Post-Exposure Prophylaxis in Adults Age ≥65 Years''. Clinical trial registration, NCT04584710, clinicaltrials.gov, 5 Feb. 2021. ''clinicaltrials.gov'', https://clinicaltrials.gov/ct2/show/NCT04584710.</ref><ref>Restorbio Inc. ''Randomized Double Blind Placebo-Controlled Study to Determine If Prophylaxis With RTB101 Compared to Placebo Reduces Severity of Lab Confirmed COVID19 in Adults ≥65 Years in a Nursing Home in Which ≥1 Person(s) Have Lab Confirmed COVID19''. Clinical trial registration, NCT04409327, clinicaltrials.gov, 5 Feb. 2021. ''clinicaltrials.gov'', https://clinicaltrials.gov/ct2/show/NCT04409327.</ref>		Following the success of two [https://clinicaltrials.gov/ct2/show/NCT03373903?term=restorbio&draw=2&rank=4 phase 2 clinical trials] investigating mTOR inhibition for targeting the aging immune system, RTB101 (dactolisib) is currently being pursued for the treatment of COVID-19 in a phase 2a placebo-controlled trial, exploring the potential for preventing severe disease in asymptomatic elderly adults who have been exposed to COVID-19.<ref>Restorbio Inc. ''A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study of RTB101 as COVID-19 Post-Exposure Prophylaxis in Adults Age ≥65 Years''. Clinical trial registration, NCT04584710, clinicaltrials.gov, 5 Feb. 2021. ''clinicaltrials.gov'', https://clinicaltrials.gov/ct2/show/NCT04584710.</ref><ref>Restorbio Inc. ''Randomized Double Blind Placebo-Controlled Study to Determine If Prophylaxis With RTB101 Compared to Placebo Reduces Severity of Lab Confirmed COVID19 in Adults ≥65 Years in a Nursing Home in Which ≥1 Person(s) Have Lab Confirmed COVID19''. Clinical trial registration, NCT04409327, clinicaltrials.gov, 5 Feb. 2021. ''clinicaltrials.gov'', https://clinicaltrials.gov/ct2/show/NCT04409327.</ref>
Line 107:		Line 108:

	Joan Mannick, the Chief Medical Officer of resTORbio, has since justified the trial's failure at several [https://www.youtube.com/watch?v=BVQci0V8uPk medical conferences] with the belief that it was related to a change in the primary endpoint, as requested by the [[wikipedia:Food_and_Drug_Administration\|US FDA]], when the trial advanced from phase 2 to 3. In the prior successful phase 2 trial, the primary endpoint had been RTI symptoms ''with'' laboratory confirmation of a causative virus, but this endpoint was changed to RTI symptoms ''with or without'' laboratory-confirmed viral illness in the [https://clinicaltrials.gov/ct2/show/NCT04139915?cond=rtb101&draw=2&rank=1 failed phase 3 trial].<ref name=":18" /> This is a problem for interpreting the clinical trial because it was not the original endpoint for which the drug had showed benefits, and is also introduced as older adults inherently experience respiratory tract symptoms at greater rates, even ''without'' laboratory-confirmation of viral presence. </blockquote>		Joan Mannick, the Chief Medical Officer of resTORbio, has since justified the trial's failure at several [https://www.youtube.com/watch?v=BVQci0V8uPk medical conferences] with the belief that it was related to a change in the primary endpoint, as requested by the [[wikipedia:Food_and_Drug_Administration\|US FDA]], when the trial advanced from phase 2 to 3. In the prior successful phase 2 trial, the primary endpoint had been RTI symptoms ''with'' laboratory confirmation of a causative virus, but this endpoint was changed to RTI symptoms ''with or without'' laboratory-confirmed viral illness in the [https://clinicaltrials.gov/ct2/show/NCT04139915?cond=rtb101&draw=2&rank=1 failed phase 3 trial].<ref name=":18" /> This is a problem for interpreting the clinical trial because it was not the original endpoint for which the drug had showed benefits, and is also introduced as older adults inherently experience respiratory tract symptoms at greater rates, even ''without'' laboratory-confirmation of viral presence. </blockquote>

			====== COVID-19 ======
			<blockquote>

			Unpublished data from the phase 2 trial of RTB101 for COVID-19 among nursing home patients treated within 3 days from testing positive saw promising results. None of those treated with RTB101 developed symptoms (n=18), while the placebo treated control group had 4 severe cases of disease and 2 deaths. While this was a statistically significant finding, larger trials are warranted for further evidence of potential benefit. </blockquote>

	=== Fisetin ===		=== Fisetin ===