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Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination

fluvastatin valsartan sirt1 prkaa klotho

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#1 smithx

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Posted 01 May 2019 - 09:55 AM


Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat “Aging-Related Disorders”

 

https://www.mdpi.com...7/20/8/1844/htm

 

 

Abstract: The incidence of aging-related disorders may be decreased through strategies influencing the expression of longevity genes. Although numerous approaches have been suggested, no effective, safe, and easily applicable approach is yet available. Efficacy of low-dose fluvastatin and valsartan, separately or in combination, on the expression of the longevity genes in middle-aged males, was assessed. Stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin-valsartan combination (10 and 20 mg, respectively), and placebo (control) were analyzed. They were taken before and after 30 days of treatment and, additionally, five months after treatment discontinuation. The expression of the following longevity genes was assessed: SIRT1, PRKAA, KLOTHO, NFE2L2, mTOR, and NF-κB. Treatment with fluvastatin and valsartan in combination significantly increased the expression of SIRT1 (1.8-fold; p < 0.0001), PRKAA (1.5-fold; p = 0.262) and KLOTHO (1.7-fold; p < 0.0001), but not NFE2L2, mTOR and NF-κB. Both fluvastatin and valsartan alone significantly, but to a lesser extent, increased the expression of SIRT1, and did not influence the expression of other genes. Five months after treatment discontinuation, genes expression decreased to the basal levels. In addition, analysis with previously obtained results revealed significant correlation between SIRT1 and both increased telomerase activity and improved arterial wall characteristics. We showed that low-dose fluvastatin and valsartan, separately and in combination, substantially increase expression of SIRT1, PRKAA, and KLOTHO genes, which may be attributed to their so far unreported pleiotropic beneficial effects. This approach could be used for prevention of ageing (and longevity genes)–related disorders.

 


 

Discussion:

 

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The results of the present study indicate that our innovative approach using short-term low-dose fluvastatin and valsartan has a potential in inducing the expression of certain longevity genes. These effects could be anti-aging or rejuvenating as well as act as a potential specific prevention/treatment for “aging-related” disorders. It can be speculated that using cycling, intermittent treatment with low-dose combination (every 6–12 years) starting at middle-age could postpone the occurrence of aging-related disorders. On the other hand, this approach could be used in the same population and with the same aim as metformin in the MILES trial. One of the major advantages of this approach is its cyclic, intermittent character, which, as previously described, could potentially activate the beneficial longevity genes for a time short enough not activate their contra regulatory mechanisms as well. With intermittently repeating cycles, this could lead to repetitive beneficial activations of the protective longevity genes. Thus, it could be speculated that the cumulative effect of these repeating cycles of treatment might eventually lead to successful specific prevention/treatment of “aging-related” disorders, most likely cardiovascular “aging-related” disorders.

 

 


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#2 QuestforLife

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Posted 01 May 2019 - 07:18 PM

For considerably more on the intermittent statin-sartan angle, see here:

https://www.longecit...es/#entry862269

What's new in this study is that they've linked their previous studies to new data on longevity genes: SIRT1, KLOTHO, etc.

But if they'd done a proper literature search, the authors would have found that statins are ROCK inhibitors, which affect the cytoskeleton allowing cells to be 'conditionally reprogrammed back into progenitor cells.

I believe the consequences are earth shattering for the longevity field.

Edited by QuestforLife, 01 May 2019 - 07:35 PM.


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#3 smithx

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Posted 01 May 2019 - 08:18 PM

My cardiologist just agreed to prescribe the fluvastatin-valsartan combination (10 and 20 mg, respectively) after initially saying that the study was "fascinating but not clinically actionable", because I pointed out that it's similar to what he was recommending for me anyway.

 

I have been taking 5mg of rapamycin every 8-9 days lately and also about 400-500mg of NMN (among other things). QuestforLife, have you found any reason to not take these all at the same time?

 

I'm planning to take the fluvastatin-valsartan combination for 30 days, then off for at least 3-5 months, then do it again (assuming I tolerate the statin, which is by no means assured). Any other comments on this?

 

 

 


Edited by smithx, 01 May 2019 - 08:19 PM.


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#4 QuestforLife

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Posted 01 May 2019 - 08:59 PM

That's great you got your doctor to prescribe this!

I've played around with different dosages and lengths of treatment and I'd say they've got it pretty much spot on. Shouldn't get any side effects at that dose and for only a month. If concerned you could take Q10 over the month as well.

Yes 2-3 times a year is optimum, and another study by the same lead author showed the benefits could be recaptured on repetition of the protocol.

I'm optimistic this means CVD can be postponed almost inevitably.

Personally I wouldn't take Rapamycin during the month of treatment. On one hand Rapamycin might have beneficial effects on progenitor cells, but it also discourages proliferation - and we want all the new endothelial cells to replicate during the month as much as possible.
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#5 smithx

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Posted 01 May 2019 - 09:06 PM

Thanks for the suggestion.

 

One reason I'm concerned is that my 1st cousin had horrible rhabdomyolysis side effects on statins and I might have a similar reaction.

 

 



#6 QuestforLife

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Posted 02 May 2019 - 05:59 AM

Thanks for the suggestion.

One reason I'm concerned is that my 1st cousin had horrible rhabdomyolysis side effects on statins and I might have a similar reaction.


Reactions can also depend on polymorphism s. I stay away from fluvastatin for that reason, but had no problems with atorvastatin.
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#7 cassioBJJ

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Posted 02 May 2019 - 05:20 PM

Do you think rosuvastatin+losartan would have this positive effect as well?



#8 smithx

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Posted 02 May 2019 - 06:33 PM

Could you say more about this? Not sure I understand.

 

Reactions can also depend on polymorphism s. I stay away from fluvastatin for that reason, but had no problems with atorvastatin.

 



#9 QuestforLife

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Posted 02 May 2019 - 08:35 PM

Could you say more about this? Not sure I understand.

I'm heterogeneous for a polymorphism on SLCO1B1, which makes me more likely to develop myopathy with some Statins.

Actually looking it up fluvastatin is NOT on the list but atorvastatin IS. I've never experienced myopathy from atorvastatin though, but I've never taken it for longer than a month.

Come to think of it statin toxicity of some kind is probably why dosing Statins for longer produces a worse result than for a shorter time (see my thread for details of other studies where Janic et al. showed the optimum period with rats was six weeks).

Edited by QuestforLife, 02 May 2019 - 08:37 PM.


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#10 ironfistx

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Posted 03 May 2019 - 05:48 AM

Aren't statins supposed to be horrible?

Edited by ironfistx, 03 May 2019 - 05:48 AM.

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#11 QuestforLife

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Posted 03 May 2019 - 06:51 AM

Aren't statins supposed to be horrible?

I personally would never take Statins permanently, though they are associated with lower mortality from all causes, even with side effects.

From my research into Statins, their Rho Kinase (ROCK) inhibition effect on the cytoskeleton, which is a side effect of its inhibition on the melvonate pathway (chloresterol synthesis), encourages conditional reprogramming of somatic cells back into progenitor cells. But only for the duration of the treatment. Once Statins are removed, cells re-differentiate.

But inhibiting the melvonate pathway has lots of other effects, some harmful, so you don't want to do it too long.

Additionally, I believe Statins inhibit autophagy (don't have the reference to hand but will find it later), so you definitely want to take breaks from it.

So all in all Statins are a powerful medicine with good and bad effects, but which we can nevertheless use in the battle against aging.

One other note - David Sinclair has been on high dose Statins his whole adult life (familial high chloresterol), but hasn't had problems as far as I know. Could the resveratrol and more recently NMN been protective? Or maybe having high chloresterol is protective of the chloresterol lowering effects of Statins. Just speculating.

Edited by QuestforLife, 03 May 2019 - 06:52 AM.

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#12 Andey

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Posted 03 May 2019 - 07:52 AM

I'm heterogeneous for a polymorphism on SLCO1B1, which makes me more likely to develop myopathy with some Statins.

Actually looking it up fluvastatin is NOT on the list but atorvastatin IS. I've never experienced myopathy from atorvastatin though, but I've never taken it for longer than a month.

Come to think of it statin toxicity of some kind is probably why dosing Statins for longer produces a worse result than for a shorter time (see my thread for details of other studies where Janic et al. showed the optimum period with rats was six weeks).

 

Is it https://www.snpedia.....php/Rs4149056?

People with this polymorphism probably would be better off with water soluble statins that dont penetrate much cross brain blood barrier.

Though fat soluble ones are arguably more prevalent on the market as they have much longer half life and have better compliance.

I ve thought about getting pravastatin as the  most basic, short lived water soluble statin but could not find it locally, ended up with atorvastatin as usual







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