62 replies to this topic

[Andey]

Another bit of information is that SIRT6 extends lifespan in male mice only. Is it a coincidence with Entolimod study?

https://www.nature.c...ature10815#ref4

Authors of the study links it to the decreased IGF signaling, as only male mice have IGF decreased with SIRT6(to the levels of females). 

In control mice maximum lifespan was 1000 days for males, 1200 for females, with SIRT6 overexpression made those equal 1200 for both males and females.

This study doesnt left much space for retrotranposons action on lifespan.

Edited by Andey, 03 September 2019 - 07:59 AM.

[QuestforLife]

I would speculate Andey that it is suppression of growth that leads to the extension of male lifespan only. This links in with what we know about cellular division forcing previously damaged cells into senescence. This is also probably why males benefit more from a higher rapamycin dose than females.

 

I would say a better approach is senolytics - as it clears the cells that cause frailty and contribute to exhaustion of the immune system. 

 

Nice though that our understanding of LINE-1 is tying in nicely with other theories of aging.

[Andey]

 

Nice though that our understanding of LINE-1 is tying in nicely with other theories of aging.

 

  Gudkov, though, have a point with the "hard stop" on mortality, I believe we still dont sure what it is.

We have outliers as centenarians and IGF associated mutations are concentrated in those more than in general public but it could still be that we are missing one ot two critical factors that could change the mortality curve to a less steep one. 

Edited by Andey, 03 September 2019 - 09:19 AM.

[Ovidus]

From this study https://www.hindawi....l/2019/2818415/ in Fig 3 looks like various retrotranposons expressed differently in different tissues at different time, expression of some fall during aging. One could argue that some of them could have some function and suppressing all of them would lead to some lost.

https://www.hindawi....9/2818415/fig3/

That said looking at this graph LINEs are going only up with age.

 

In this context activating SIRT6, only to suppress what is supposed in the cell program to suppress, looks like a more prudent approach.

 

I would hate to have this all end up in "Oh OK, we should all be eating more berries" 
Can we really hope to upregulate SIRT6 to levels that are needed to sufficiently suppress LINE1? Very doubtful. Also, in general suppressing something is easier.

 

Again, at the risk of repeating what I already stated: 
Any strtaegy that we can come up with, such as upregulating SIRT6 to deal with the problem will be much more unproven than using Lamivudine, which has been shown to -at least to some extent- accomplish the goal we are after. 

 

Basically it comes to this: At the doses we likely need, what are the long term issues / risks associated with Lamivudine?

[QuestforLife]

  Gudkov, though, have a point with the "hard stop" on mortality, I believe we still dont sure what it is.

We have outliers as centenarians and IGF associated mutations are concentrated in those more than in general public but it could still be that we are missing one ot two critical factors that could change the mortality curve to a less steep one. 

 

That's hardly a mystery in my opinion - human cells have their regenerative ability radically scaled back after embryonic stage, therefore our cells have limited plasticity to respond to injury (stemness) , limited number of divisions (telomeres) and the combined effect of this is our tissues are unmaintainable in the long run.

 

Mike West is of the opinion this is a pleiotrophic adaptation to keep us cancer-free during childbearing years, even though this then causes cancer rates (along with all other age-related diseases) to rise post reproduction. 

 

https://www.ncbi.nlm...otype of cancer.

 

Abstract

Growing evidence supports the antagonistic pleiotropy theory of mammalian aging. Accordingly, changes in gene expression following the pluripotency transition, and subsequent transitions such as the embryonic-fetal transition, while providing tumor suppressive and antiviral survival benefits also result in a loss of regenerative potential leading to age-related fibrosis and degenerative diseases. However, reprogramming somatic cells to pluripotency demonstrates the possibility of restoring telomerase and embryonic regeneration pathways and thus reversing the age-related decline in regenerative capacity. A unified model of aging and loss of regenerative potential is emerging that may ultimately be translated into new therapeutic approaches for establishing induced tissue regeneration and modulation of the embryo-onco phenotype of cancer.

 

He's certainly right about the consequences, whether or not you agree with the pleiotropy argument.

  

 I would hate to have this all end up in "Oh OK, we should all be eating more berries"

 

This made me laugh and I agree. I can do without more poorly bioavailable flavanoids in my system.

[Andey]

That's hardly a mystery in my opinion - human cells have their regenerative ability radically scaled back after embryonic stage, therefore our cells have limited plasticity to respond to injury (stemness) , limited number of divisions (telomeres) and the combined effect of this is our tissues are unmaintainable in the long run.

 

 

   I found it quite strange that a lot of various interventions only "square" the mortality curve. Looks like there is some unaddressed problem that stops the music no matter what and without it we would just get more and more people to the edge but nobody could cross it. Its in line with what Gudkov said, if it caused by damage accumulation than mortality curve should just shift further in time with each independent intervention, but its not the case.

[Andey]

 

Basically it comes to this: At the doses we likely need, what are the long term issues / risks associated with Lamivudine?

 

  Its definitely not all flowers, and to use it we probably need hard science not just an interesting hypothesis

https://journals.plo...pone.0085637#s3

[smithx]

Any strtaegy that we can come up with, such as upregulating SIRT6 to deal with the problem will be much more unproven than using Lamivudine, which has been shown to -at least to some extent- accomplish the goal we are after. 

 

Basically it comes to this: At the doses we likely need, what are the long term issues / risks associated with Lamivudine?

 

 

Upregulating SIRT6 seems like a very important part of any strategy because SIRT6 seems to be one of the main ways that LINE1 is inhibited. Another mechanism seems to be endogenous antisense promoter and RNA interference (see https://www.ncbi.nlm...les/PMC2875337/ for example).

 

Lamivudine is an analog of cytidine and therefore has the potential to cause major unintended problems if it is incorporated into DNA. It has been implicated in, itself, causing DNA damage (although primarily in vitro). There are numerous side effects, and it is unclear how much or if the suppression of the LINE1 reverse transcriptase outweighs these side effects long term.

 

In a search of the literature I was not so far able to find any discussion of dose-dependency of Lamivudine side effects. So even though the required dose for our purposes may be 50% or less than the standard dose of 150mg 2xd it's unclear how much better that would be.

 

This abstract is tantalizing, but I haven't been able to find any more details on it so far so I've asked the author if she can share some more information:

 

Characterizing small molecule inhibitors of the LINE1 endonuclease

https://www.fasebj.o...upplement.lb107

 

What we need is a small molecule which has a high selectivity and specificity to the LINE1 reverse transcriptase, and which therefore won't cause other problems. Lamivudine has neither of those, unfortunately.

Edited by smithx, 03 September 2019 - 06:54 PM.

[smithx]

This paper does confirm that pioglitazone upregulates SIRT6:

 

Reciprocal role of SIRT6 and Hexokinase 2 in the regulation of autophagy driven monocyte differentiation.

https://www.ncbi.nlm...pubmed/28935467

 

 

  Ive digged a bit and 50 studies later...

Looks like SIRT6 is responsible with repression of retrotransposons in general and LINE1 in particular https://www.nature.c...cles/ncomms6011

 

It also looks like we could use pioglitazone to increase both SIRT1 and SIRT6 https://journals.plo...al.pone.0105456 (not the pioglitazone but same class of drugs)

SIRT6 as all SIRTs is dependant on NAD+, so precursors should give some advantage here and some synergy with PGZ

 

P.S. I was surprised to see that PGZ leaded to better all cause mortality compared to metformin https://www.bmj.com/...c12246264307aa1

 

[Ovidus]

Upregulating SIRT6 seems like a very important part of any strategy because SIRT6 seems to be one of the main ways that LINE1 is inhibited. Another mechanism seems to be endogenous antisense promoter and RNA interference (see https://www.ncbi.nlm...les/PMC2875337/ for example).

 

Lamivudine is an analog of cytidine and therefore has the potential to cause major unintended problems if it is incorporated into DNA. It has been implicated in, itself, causing DNA damage (although primarily in vitro). There are numerous side effects, and it is unclear how much or if the suppression of the LINE1 reverse transcriptase outweighs these side effects long term.

 

In a search of the literature I was not so far able to find any discussion of dose-dependency of Lamivudine side effects. So even though the required dose for our purposes may be 50% or less than the standard dose of 150mg 2xd it's unclear how much better that would be.

 

This abstract is tantalizing, but I haven't been able to find any more details on it so far so I've asked the author if she can share some more information:

 

Characterizing small molecule inhibitors of the LINE1 endonuclease

https://www.fasebj.o...upplement.lb107

 

What we need is a small molecule which has a high selectivity and specificity to the LINE1 reverse transcriptase, and which therefore won't cause other problems. Lamivudine has neither of those, unfortunately.

Spot on

The two videos I posted on the other thread say essentially the same thing and claim that we need something that more specifically targets LINE1.

 

 

 

This paper does confirm that pioglitazone upregulates SIRT6:

 

Reciprocal role of SIRT6 and Hexokinase 2 in the regulation of autophagy driven monocyte differentiation.

https://www.ncbi.nlm...pubmed/28935467

How about long term use of pioglitazone ?
I am not seeing much in the way of serious side effects but will look further

What do people think of that?

[Andey]

 

How about long term use of pioglitazone ?
I am not seeing much in the way of serious side effects but will look further

What do people think of that?

 

  The more I study about it the more interesting it seems.

  Main risk is that It increases bladder cancer risk (1.9x), but in the same time decreases overall cancer risk because of its inhibition of more frequent cancers like liver or colon cancers.

  People talk a lot about metformin and that it decreases all cause mortality of T2D patients to the level below healthy controls. Pioglitazone leads to even better all cause mortality compared to metformin, and that despite the fact that pioglitazone is a second line antidiabetic drug and get prescribed to a sicker patient population.

  Its too good to be true, so I am probably missing something)

 

  I have already  taken it for some period for a different reason at minimal dosage with no side effects, only thing I ve noticed is that my ALT dropped from 22 to 14 while taking it.

[Ovidus]

  The more I study about it the more interesting it seems.

  Main risk is that It increases bladder cancer risk (1.9x), but in the same time decreases overall cancer risk because of its inhibition of more frequent cancers like liver or colon cancers.

  People talk a lot about metformin and that it decreases all cause mortality of T2D patients to the level below healthy controls. Pioglitazone leads to even better all cause mortality compared to metformin, and that despite the fact that pioglitazone is a second line antidiabetic drug and get prescribed to a sicker patient population.

  Its too good to be true, so I am probably missing something)

 

  I have already  taken it for some period for a different reason at minimal dosage with no side effects, only thing I ve noticed is that my ALT dropped from 22 to 14 while taking it.

 

All morning long I have been thinking why Pioglitazone sounds so familiar. Now I recall

 

 

We had discussed this here on this site as a means to look younger, because it will shift fat from visceral to subcutaneous

https://journals.plo...al.pone.0109134

 

Some had speculated that this will help you regain the "plump and full" look on the face, though that is more speculation than proven fact. Very interesing, no? The above study is just one example... many other papers make the same observation.

 

Regarding bladder cancer risk; what is the absolute risk? 1.9 times a low base risk may not be too much and bladder cancer is not very common. It is entirely possible that the result may not be replicable.  

[Andey]

 

Regarding bladder cancer risk; what is the absolute risk? 1.9 times a low base risk may not be too much and bladder cancer is not very common. It is entirely possible that the result may not be replicable.  

 

 

  Its complicated and depends on gender and ethnicity 

https://www.ncbi.nlm...es/PMC5773684/ 

Than it makes sense to stratify further by smoking, obesity, age and other risk factors

[sub7]

 

 

This abstract is tantalizing, but I haven't been able to find any more details on it so far so I've asked the author if she can share some more information:

 

Characterizing small molecule inhibitors of the LINE1 endonuclease

https://www.fasebj.o...upplement.lb107

 

 

Absolutely very intriguing

I looked at sci-hub and cannot find this paper.

any other way to see the full text?

[smithx]

Absolutely very intriguing

I looked at sci-hub and cannot find this paper.

any other way to see the full text?

 

It may have been a conference talk and otherwise unpublished. So far no response from the author.
 

[Ovidus]

OK, so I have been reading on Pioglitazone and it seems doable really.

Bladder cancer risk very likely is a statistical mishap 

On the other fronts, it appears to decrease overall mortality risk, reduces insulin needed to shuttle nutrients into cells, which is a huge positive and doesn't seem to have many side effects.

 

With the added benefit of SIRT activation, this thing is feasible IMO.

 

What do people think? IS anyone seriously considering taking Pioglitazone?

[QuestforLife]

OK, so I have been reading on Pioglitazone and it seems doable really.

Bladder cancer risk very likely is a statistical mishap 

On the other fronts, it appears to decrease overall mortality risk, reduces insulin needed to shuttle nutrients into cells, which is a huge positive and doesn't seem to have many side effects.

 

With the added benefit of SIRT activation, this thing is feasible IMO.

 

What do people think? IS anyone seriously considering taking Pioglitazone?

 

I took it for a couple of months for the aforementioned small fat cell increase affect. I didn't experience any obvious side effects. Didn't note much increase in subQ fat either. As the cells are small this doesn't mean too much however, especially as I was starting very lean.

 

The question is, if you were taking this, what would be the changes you were looking for and how would you measure them? It don't think taking PGZ permanently because of a theorised benefit on suppressing TEs is justified. Not unless you can actually measure the benefit.

[Ovidus]

I took it for a couple of months for the aforementioned small fat cell increase affect. I didn't experience any obvious side effects. Didn't note much increase in subQ fat either. As the cells are small this doesn't mean too much however, especially as I was starting very lean.

 

The question is, if you were taking this, what would be the changes you were looking for and how would you measure them? It don't think taking PGZ permanently because of a theorised benefit on suppressing TEs is justified. Not unless you can actually measure the benefit.

 

No we way we lay people on this forum can reliably measure either Line1 replication or SIRT activation -and I cannot think of anything else we can use even as a reasonable proxy which would be measurable really.

As far as whether there is enough evidence to warrant taking it.... Maybe

It does have proven benefits as I stated before in this thread

If it also activates SIRT -even if such Sirtuin activation cannot silence Line1 replication- to me that makes it worth taking. Sirtuins are a plus, a major plus, in my book.

 

It is a personal decision, but when there are people taking Metformin without having diabetes (purely for longevity purposes), is Pioglitazone really a worse candidate?

[orion22]

where can you buy Pioglitazone without prescription and i googled a little and i see its hard to find because not many people are using it 

[smithx]

Not an endorsement of the concept, and I certainly advise consulting a doctor and not just buying drugs online. But alldaychemist has it by Cipa, which is considered to be a fairly reliable Indian pharma company.

 

One question though is: by how much does Pioglitazone increase SIRT6. The paper cited shows that it was increased somewhat in vitro in monocytes but I haven't so far found a reference quantifying the increase or in vivo (live animals).

 

If the increase is nominal, it may not be worth the risk, and would not be the solution to suppressing LINE1 ORF2 that we're looking for.

Edited by smithx, 15 September 2019 - 08:48 PM.

[trying2survive]

hi, Capsaicin suppresses ORF2 L1 https://www.ncbi.nlm...les/PMC6214084/

and apparently Icariin from horny goat weed has some small effect.

Reading about lamivudine/stavudine -apparently can cause mtDNA depletion.

[William Sterog]

Is not consumption of capsaicin containing foods associated with neurodegeneration in epidemiological studies and have also been found that capsaicin itself is neurotoxic?

https://www.ncbi.nlm...pubmed/31137805

https://www.ncbi.nlm...pubmed/2358547/

https://www.ncbi.nlm...pubmed/3310520/

https://www.ncbi.nlm...pubmed/6153557/

[smithx]

Bumping this because I think it's one of the most important threads on this forum and is not being given the attention it deserves. The reason is probably the title: This is actually a discussion about "Endogenous retroviruses as a primary cause of aging". Can any mod rename this thread? It needs more exposure!

 

I am now up to 12 blackcurrant capsules per day (6 capsules 2x per day) in an effort to get enough cyanidin to make a difference in SIRT6 activity. I also supplement with sublingual NMN for the same purpose.

 

I have not seen anything new about LINE1 reverse transcriptase inhibitors, nor does anyone seem to be talking much about endogenous retroviruses as possibly one of the primary causes of aging. But I still think they will pretty soon.

 

Has anyone found any new information that would be helpful?

Edited by smithx, 10 October 2020 - 04:55 AM.

[aribadabar]

Bumping this because I think it's one of the most important threads on this forum and is not being given the attention it deserves. The reason is probably the title: This is actually a discussion about "Endogenous retroviruses as a primary cause of aging". Can any mod rename this thread? It needs more exposure!

 

I am now up to 12 blackcurrant capsules per day (6 capsules 2x per day) in an effort to get enough cyanidin to make a difference in SIRT6 activity. I also supplement with sublingual NMN for the same purpose.

 

I have not seen anything new about LINE1 reverse transcriptase inhibitors, nor does anyone seem to be talking much about endogenous retroviruses as possibly one of the primary causes of aging. But I still think they will pretty soon.

 

Has anyone found any new information that would be helpful?

 

I have nothing material to add but I suggest you switch 3x4 or even 4x3 Blackcurrant caps instead of 2x6 caps as anthocyanins are rapidly excreted and if you would like to maintain steady-state concentrations more frequent dosing is preferable.
 

[sub7]

 

So even though the required dose for our purposes may be 50% or less than the standard dose of 150mg 2xd it's unclear how much better that would be.

 

Sorry if I missed your explanation of this, but why 50%. Why not just 10% or 20% ?

 

Any evidence that 50% is a good starting point?

[smithx]

We're talking about Lamivudine, and since is an analog of cytidine which is an RNA base pair, it would be probably something like chronically taking remdesivir, which would not be likely to be a good idea: if the cost of inhibiting endogenous retrotranscriptases is disrupting all of your RNA synthesis, the benefit would probably not be there.

 

About the dosing, it was speculation, but my point was that this drug is probably not what we want.

 

What we need is something that has a high binding affinity to the retrotranscriptase and inhibits it without affecting anything else.

 

 

Sorry if I missed your explanation of this, but why 50%. Why not just 10% or 20% ?

 

Any evidence that 50% is a good starting point?

 

 

[sub7]

We're talking about Lamivudine, and since is an analog of cytidine which is an RNA base pair, it would be probably something like chronically taking remdesivir, which would not be likely to be a good idea: if the cost of inhibiting endogenous retrotranscriptases is disrupting all of your RNA synthesis, the benefit would probably not be there.

 

About the dosing, it was speculation, but my point was that this drug is probably not what we want.

 

What we need is something that has a high binding affinity to the retrotranscriptase and inhibits it without affecting anything else.

It should not be something we would need to speculate about. This drug has been taken for extended periods of time by patients, no?

I have searched around and not found any scary side effects from long term use really

 

Instead

 

Long-term lamivudine therapy reduces the risk of long-term complications of chronic hepatitis B infection even in patients without advanced disease

:text=Conclusions%3A%20Long-term%20lamivudine%20treatment,still%20better%20than%20untreated%20patients' class='bbc_url' title='External link' rel='nofollow external'>https://pubmed.ncbi....reated patients.

 

 

This study was carried on for at least 5 years and drug was dosed daily

https://link.springe...2325-008-0038-6

 

What kinds of effects have you heard of ?

[smithx]

My concern is that if nucleoside analogs can get incorporated into normal DNA/RNA they interfere with the cell's metabolism in a potentially destructive and very counter-productive way.

 

On doing some more searching it appears that lamivudine may not have this problem (although it does still have serious potential side effects that need to be monitored particularly with regard to the liver).

 

In this article:

Critical Review
Twenty-Five Years of Lamivudine: Current and Future Use for the Treatment of HIV-1 Infection

https://journals.lww...rent_and.1.aspx

 

They say:

 

Lamivudine is a nucleoside analog of 2′-deoxycytosine9 that exerts its antiviral effects by acting as a DNA chain terminator (Fig. 1). The active anabolite of 3TC, lamivudine 5′-triphosphate, is formed from phosphorylation by intracellular kinases and competes with naturally occurring cytidine triphosphate for incorporation into DNA.14,15 Lamivudine is a potent inhibitor of the reverse transcriptase (RT) enzymes of HIV-1, with in vitro IC50 in different cell lines with different HIV-1 strains ranging from 0.002 to 1.14 μM9,11–13 and IC50 against HBV of 0.1 μM10 with limited cell toxicity at concentrations >1000-fold than those effective against HIV. The unnatural nucleoside structure of 3TC, an L-(−)-enantiomer, is not recognized as a substrate by human polymerases (all natural nucleosides have a D configuration) at biologically relevant concentrations. The unique chemical structure of 3TC, which is characterized by excellent antiviral activity with little toxicity, strongly contributes to its clinical success.

 

So it may in fact be worth exploring further.

 

 

 

[sub7]

Excellent news

Now, how can we begin to guess what dosage would be required to suppress LINE1?

Gudkov did not release what types of doses he used on the dogs, did he?

 

Also

"The unique chemical structure of 3TC, which is characterized by excellent antiviral activity with little toxicity, strongly contributes to its clinical success."

 

I was under the impression that it would work on retroviruses only. Would the above imply that it has general anti-viral activity?

[smithx]

I don't think that "anti-viral" implies it would work against any viruses except retroviruses.