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Abrogation of Age-Induced MicroRNA-195 Rejuvenates the Senescent Mesenchymal Stem Cells by Reactivating Telomerase

telomerase mir-195

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#1 alc

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Posted 28 December 2015 - 01:38 AM


From the study:

"In this study, we investigated the role of miRNAs involved in stem cell aging and their impact on cardiac
repair. Here we report our novel findings that regenerative ability of aged stem cells is deteriorated by
increased expression of miR-195 which targets telomerase reverse transcriptase (Tert) gene, and abrogation
of miR-195 in aged stem cells markedly induces Tert reactivation, resulting in significant telomere
re-lengthening. Additionally, we show that transplantation of aged stem cells lacking miR-195 significantly
reduced infarction size and concomitant improvement of cardiac function. These findings demonstrate
that silencing miR-195 reverses the senescence clock in aged stem cells by telomerase
reactivation. The strategy of modification of miRs in stem cells holds great promise for stem cell based
repair of aging myocardium."

 

 

"Here we present the first evidence that miR-195 overexpressed in
old MSCs (OMSCs) induces stem cell senescence deteriorating their regenerative ability by directly
deactivating telomerase reverse transcriptase (Tert), and abrogation of miR-195 can reverse stem
cell aging."


here is the study:

http://onlinelibrary.../stem.2211/epdf


... "Abrogation of miR-195 Rejuvenates OMSCs through Telomere Relengthening and Antiaging Markers
Reactivation" ...

 


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#2 HighDesertWizard

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Posted 28 December 2015 - 02:36 AM

 


#3 alc

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Posted 28 December 2015 - 12:20 PM

@ HighDesertWizard - thanks for the link. I'll look at and read it.



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#4 Rocket

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Posted 29 December 2015 - 03:29 AM

For those who aren't cell biologists, is epitalon and cycloastragenol going to help? Or what about Bioviva and it's Telomerase activation via gene therapy? It seems we already know quite well how to activate Telomerase, there is study after study showing how beneficial it is to health, and yet I hear of nothing being investigated in humans, except for self experimenters here with what is commercially available.

Edited by Rocket, 29 December 2015 - 03:32 AM.

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#5 elfanjo

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Posted 05 January 2016 - 01:36 PM

@Rocket Keep in mind that telomerase activation is seen in many cancers. Human trials will not happen until we understand more about the risks of these therapies

#6 Logic

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Posted 07 January 2016 - 09:39 AM

Anti-angiogenic miR-195 levels were significantly enhanced by exercise training in the middle-aged group only. These results indicated that the exercise-induced adaptation of muscle capillarity was attenuated in middle-aged rats, possibly by the lower induction of VEGF and up-regulation of anti-angiogenic miRNA expression.

http://www.wageninge....3920/CEP150007



#7 Rocket

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Posted 28 January 2016 - 03:10 PM

@Rocket Keep in mind that telomerase activation is seen in many cancers. Human trials will not happen until we understand more about the risks of these therapies

 

I understand that, but old age is also seen in many cancers.  I don't buy into the argument that cancers express telomerase and therefore telomerase causes cancer.  If I thought that I wouldn't experiment with HGH promoters given that cancer has it's hands on everything that is implicated in growth.


Edited by Rocket, 28 January 2016 - 03:11 PM.


#8 niner

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Posted 29 January 2016 - 03:13 AM

Hepatology. 2013 Aug;58(2):654-66. doi: 10.1002/hep.26378. Epub 2013 Jun 26.
Genome-wide screening reveals that miR-195 targets the TNF-α/NF-κB pathway by down-regulating IκB kinase alpha and TAB3 in hepatocellular carcinoma.
Ding J, Huang S, Wang Y, Tian Q, Zha R, Shi H, Wang Q, Ge C, Chen T, Zhao Y, Liang L, Li J, He X.

Nuclear factor kappa B (NF-κB) is an important factor linking inflammation and tumorigenesis. In this study we experimentally demonstrated through a high-throughput luciferase reporter screen that NF-κB signaling can be directly targeted by nearly 29 microRNAs (miRNAs). Many of these miRNAs can directly target NF-κB signaling nodes by binding to their 3' untranslated region (UTR). miR-195, a member of the miR-15 family, is frequently down-regulated in gastrointestinal cancers, especially in hepatocellular carcinoma (HCC). The expression level of miR-195 is inversely correlated with HCC tumor size. We further show that miR-195 suppresses cancer cell proliferation and migration in vitro and reduces tumorigenicity and metastasis in vivo. Additionally, miR-195 may exert its tumor suppressive function by decreasing the expression of multiple NF-κB downstream effectors by way of the direct targeting of IKKα and TAB3.
CONCLUSION:

Multiple miRNAs are involved in the NF-κB signaling pathway and miR-195 plays important inhibitory roles in cancer progression and may be a potential therapeutic target.

PMID: 23487264

 

This is the link that HDW posted.  It looks like miR-195 has an anti-cancer function.  This might make it dangerous to attempt to turn it off.  If I understand this correctly, the tumor suppression is brought about by an increase in NF-kB.  This is done by downregulating IKKa, an inhibitor activator of NFkB.  [Nevermind.  I'm not sure what they mean in last sentence of the abstract, and don't have full text.]

 

Many aspects of the biochemistry of aging are probably anti-cancer strategies.


Edited by niner, 30 January 2016 - 03:15 AM.


#9 Logic

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Posted 29 January 2016 - 01:14 PM

This is the link that HDW posted.  It looks like miR-195 has an anti-cancer function.  This might make it dangerous to attempt to turn it off.  If I understand this correctly, the tumor suppression is brought about by an increase in NF-kB.  This is done by downregulating IKKa, an inhibitor of NFkB.  Many aspects of the biochemistry of aging are probably anti-cancer strategies.


Yep; I'm leaning that way too:
It looks as though cells 'compromise' epigenetically with less efficient function as a means of not becoming cancerous and killing us immediately.
It sees this compromise is necessitated by:

  • The buildup of AGEs, lipofuscin etc.
  • Low level chronic infections.
  • Ever increasing gut  permeability with age. (high cell turnover = short telomerase...)

These are what trigger TNF-alpha, NF-kB etc. ie: inflammation, leading to less telomerase  and thus a 'older/compromised' phenotype and stem cell  inaction.

ie: aging.

 

The outlier is DNA breaks, but their repair is also compromised by the above.

 

Ie:  Fix the above and optimal/young cell function is no longer likely to cause cancer, causing cells to revert to their er... old/young selves, as seen in parabiosis experiments.

 

IMHO!?

:)



#10 Avatar of Horus

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Posted 29 January 2016 - 05:06 PM

Just a correction:

the IKKa is a NFkB activator: it (in the IKK complex, which also includes IKKb and IKKg/NEMO) phosphorylates and induces degradation of the NFkB inhibitor IkB protein complex, and also in the cell nucleus it mediates the phosphorylation of specific histone 3 residues at NFkB-responsive gene promoters.


Edited by Avatar of Horus, 29 January 2016 - 05:07 PM.


#11 niner

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Posted 30 January 2016 - 03:19 AM

Just a correction:

the IKKa is a NFkB activator: it (in the IKK complex, which also includes IKKb and IKKg/NEMO) phosphorylates and induces degradation of the NFkB inhibitor IkB protein complex, and also in the cell nucleus it mediates the phosphorylation of specific histone 3 residues at NFkB-responsive gene promoters.

 

Thanks Avatar.  I edited my post to reflect this.  On reflection, I'm not really sure what they were trying to say in the last sentence of the abstract.



#12 Tom Andre F. (ex shinobi)

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Posted 18 March 2016 - 01:00 AM

 

Hepatology. 2013 Aug;58(2):654-66. doi: 10.1002/hep.26378. Epub 2013 Jun 26.
Genome-wide screening reveals that miR-195 targets the TNF-α/NF-κB pathway by down-regulating IκB kinase alpha and TAB3 in hepatocellular carcinoma.
Ding J, Huang S, Wang Y, Tian Q, Zha R, Shi H, Wang Q, Ge C, Chen T, Zhao Y, Liang L, Li J, He X.

Nuclear factor kappa B (NF-κB) is an important factor linking inflammation and tumorigenesis. In this study we experimentally demonstrated through a high-throughput luciferase reporter screen that NF-κB signaling can be directly targeted by nearly 29 microRNAs (miRNAs). Many of these miRNAs can directly target NF-κB signaling nodes by binding to their 3' untranslated region (UTR). miR-195, a member of the miR-15 family, is frequently down-regulated in gastrointestinal cancers, especially in hepatocellular carcinoma (HCC). The expression level of miR-195 is inversely correlated with HCC tumor size. We further show that miR-195 suppresses cancer cell proliferation and migration in vitro and reduces tumorigenicity and metastasis in vivo. Additionally, miR-195 may exert its tumor suppressive function by decreasing the expression of multiple NF-κB downstream effectors by way of the direct targeting of IKKα and TAB3.
CONCLUSION:

Multiple miRNAs are involved in the NF-κB signaling pathway and miR-195 plays important inhibitory roles in cancer progression and may be a potential therapeutic target.

PMID: 23487264

 

This is the link that HDW posted.  It looks like miR-195 has an anti-cancer function.  This might make it dangerous to attempt to turn it off.  If I understand this correctly, the tumor suppression is brought about by an increase in NF-kB.  This is done by downregulating IKKa, an inhibitor activator of NFkB.  [Nevermind.  I'm not sure what they mean in last sentence of the abstract, and don't have full text.]

 

Many aspects of the biochemistry of aging are probably anti-cancer strategies.

 

 

Im not an expert like you niner but this is same story for sirt1. Actually we have to look for stuff that are tumor selective. The only root I can found is the NAD+ / NADH ratio

 







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