130 replies to this topic

[albedo]

Results of TRIIM trial by Dr Greg Fahy are out and are encouraging !!

https://www.nature.c...586-019-02638-w

Cannot open https://doi.org/10.1111/acel.13028 though ...

 

Here it is:

https://drive.google...gzSXJKVzg4/view

 

[Nate-2004]

The last trial on the second cohort ended in 2017, wow, we're only just now seeing the results published? This stuff is way too slow.

[Engadin]

Can anyone provide any clue about why the study's results have taken so long to reach public diffusion?. I find myself unable to find any reasonable one.

Edited by Engadin, 07 September 2019 - 08:04 PM.

[albedo]

More insight in Josh's excellent blog:

https://joshmitteldo...-else/#comments

[Rocket]

Can anyone provide any clue about why the study's results have taken so long to reach public diffusion?. I find myself unable to find any reasonable one.

Been public for a long time.

[Engadin]

Can anyone provide any clue about why the study's results have taken so long to reach public diffusion?. I find myself unable to find any reasonable one.

 

 

Well, it looks like researchers were aiming to another target (regenerating the thymus gland) and that taking the epigenetic clock 2,5 years back in time is an unexpected collateral result of their tests, FOXNews dixit. That makes a bit more sense.

[Kentavr]

Melatonin rejuvenates degenerated thymus and redresses peripheral immune functions in aged mice

https://www.ncbi.nlm...ubmed/12880677/

And if you add melatonin?

Edited by Kentavr, 08 September 2019 - 12:27 PM.

[Engadin]

Well, it looks like researchers were aiming to another target (regenerating the thymus gland) and that taking the epigenetic clock 2,5 years back in time is an unexpected collateral result of their tests, FOXNews dixit. That makes a bit more sense.

 

 

A confirmation from the Josh Mitteldorf blog referred to the delay in publishing the unexpected epigenetic clock reversion:

 

 

 

This level of success might have led to a modestly encouraging publication, but fortuitously, Fahy made contact with Horvath toward the end of the study, and Horvath volunteered to analyze changes in the subjects’ methylation. (TRIIM had preserved some blood samples from each of the patients at each time point, so this could be done retrospectively.) The result demonstrated a decrease in methylation age, consistent enough to be visible in a sample of only 9 subjects. This was the first time that a treatment in humans led to a setback of the epigenetic clock.

[YOLF]

Melatonin rejuvenates degenerated thymus and redresses peripheral immune functions in aged mice

https://www.ncbi.nlm...ubmed/12880677/

And if you add melatonin?

 

Melatonin raises night time growth hormone levels and has some p53 action. I would expect that it would be an improvement.

 

John D250, a body builder who posts here was saying that additional IGF1-LR3 (an active domain of growth hormone) when taken with growth hormone reduces or eliminates the diabetes risk.

[OP2040]

It's hard to say what caused the reversal since there were at least 4  simultaneous interventions.  For all we know, it could even be the Zinc.  The most intriguing result would be if if it was the metformin that caused it.  There is the TAME trial, which is great because it is explicitly looking at aging.  That is progress, but as usual we won't see results until the year 2100 long after we are all dead.  I'm all fired up this morning because I was just reading some article criticizing Japan for speeding up it's trial process and providing spinal cord patients with stem cell treatments.  It's funny how those articles never fail to mention the various scammers and petty profiteers that have an interest in such speediness.  And they always fail to mention the billion dollar drug winners that have a huge vested interest in making  the system move as slow as possible.

 

Anyway, back to the topic.  Out of all the interventions used, I think it makes the most sense that it was the metformin providing the anti-aging result.  We already know that metformin has this result n animals.  Whereas none of the other interventions show any such  thing.  In fact, growth hormone increases the IGF pathway and therefore it's extremely unlikely to be the cause.

 

The thymic regrowth aspect is interesting and exciting.  But if it can be deduced that the metformin caused the aging clock to go backwards, that is much more of a bombshell IMO.  And much more useful in the near term.  

[QuestforLife]

It's hard to say what caused the reversal since there were at least 4  simultaneous interventions.  For all we know, it could even be the Zinc.  The most intriguing result would be if if it was the metformin that caused it.  There is the TAME trial, which is great because it is explicitly looking at aging.  That is progress, but as usual we won't see results until the year 2100 long after we are all dead.  I'm all fired up this morning because I was just reading some article criticizing Japan for speeding up it's trial process and providing spinal cord patients with stem cell treatments.  It's funny how those articles never fail to mention the various scammers and petty profiteers that have an interest in such speediness.  And they always fail to mention the billion dollar drug winners that have a huge vested interest in making  the system move as slow as possible.

 

Anyway, back to the topic.  Out of all the interventions used, I think it makes the most sense that it was the metformin providing the anti-aging result.  We already know that metformin has this result n animals.  Whereas none of the other interventions show any such  thing.  In fact, growth hormone increases the IGF pathway and therefore it's extremely unlikely to be the cause.

 

The thymic regrowth aspect is interesting and exciting.  But if it can be deduced that the metformin caused the aging clock to go backwards, that is much more of a bombshell IMO.  And much more useful in the near term.  

 

I have the opposite opinion.

 

It is most likely that the growth hormone (and maybe DHEA) has caused the REVERSION in methylation age. This can be explained by it stimulating quiescent stem cells to replace blood cells more quickly (so it appears that the population has got younger). This is unlikely to extend life in my opinion; it is more likely to shorten it, although from a certain point of view, it is making you younger. 

 

At best metformin might SLOW the clock, not reverse it. But it could extend life.

[Kentavr]

I have the opposite opinion.

It is most likely that the growth hormone (and maybe DHEA) has caused the REVERSION in methylation age. This can be explained by it stimulating quiescent stem cells to replace blood cells more quickly (so it appears that the population has got younger). This is unlikely to extend life in my opinion; it is more likely to shorten it, although from a certain point of view, it is making you younger.

At best metformin might SLOW the clock, not reverse it. But it could extend life.

I agree with you.

However, there is one circumstance: the GrimAge methylation clock is currently the most accurate clock that can predict the date of your DEATH (please pay attention to this).

And the fact that they were reversed by 2.5 years means that the date of death is postponed by 2.5 years.

Edited by Kentavr, 09 September 2019 - 03:43 PM.

[YOLF]

Well, something else might still get them, so it hasn't necessarily added 2.5 years, just made them 2.5 years younger.

 

All in all, I'd say it's all doing the trick. How much can metformin do by itself? Well, there's the French paradox. France is where metformin got it's start, so some of it is from oak tannins, some is from wine resveratrol, and some from metformin? 

 

I wonder at what point 2.5 years was achieved? Can we expect additional results from taking these things longer? If not, then it's more of a maintenance therapy as opposed to anything permanent. People taking metformin don't continue to get younger when they take it for a long period of time and the benefits disappear a few days after they stop taking it. Growth hormone on the other hand could potentially achieve more lasting results. If it were my study, I'd dump another dozen or so things into it.

[Kentavr]

I wonder at what point 2.5 years was achieved? Can we expect additional results from taking these things longer? If not, then it's more of a maintenance therapy as opposed to anything permanent...

In the first 9 months of the experiment, aging rolled back slowly, at a rate of about 0.72 years per year, and by the end of the experiment - much faster: from 9 to 12 months, the subjects were younger at a rate of 6.5 years per year (!)

So, there was an accumulation effect, and then there was a breakthrough!

The reason for this acceleration is still unclear, however, the participants retained a new biological age six months after the termination of the experiment.

Edited by Kentavr, 09 September 2019 - 07:04 PM.

[Kentavr]

In fact, 9 months was preparing the body for change.

Then in 3 months there was a qualitative leap. This cannot be a coincidence.

Something happened.

I assume that the thymus has begun, which began cleansing the body of debris. As a result, epigenetic age has decreased.

[Nate-2004]

I still think thymic regrowth may be at the root of it all, but I'm more curious about the HGH dosage involved here. It was 0.015mg/kg which for me is 1.5mg, was that daily?

 

A regrown thymus would take care of a lot of problems, not just immune related health but senescent cell related aging. I imagine there were a lot of secondary features involved here. While certainly IGF1 is associated with shorter lifespan maybe it doesn't have to be long term therapy with HGH to get the thymus back to a 10 year old size. How quickly and how often would it revert to its previously atrophied state?

Edited by Nate-2004, 09 September 2019 - 07:28 PM.

[Kentavr]

I still think thymic regrowth may be at the root of it all, but I'm more curious about the HGH dosage involved here. It was 0.015mg/kg which for me is 1.5mg, was that daily?

A regrown thymus would take care of a lot of problems, not just immune related health but senescent cell related aging. I imagine there were a lot of secondary features involved here. While certainly IGF1 is associated with shorter lifespan maybe it doesn't have to be long term therapy with HGH to get the thymus back to a 10 year old size. How quickly and how often would it revert to its previously atrophied state?

I also think it could be a combination of metformin and growth hormone:

1. Metformin mimics the feeling of hunger, which increases FOXO1, which provides for the division of stem cells.

2. Growth hormone stimulates cell division.

3. Since FOXO1 is activated, stem cells divide symmetrically.

The result is a decrease in epigenetic age.

[QuestforLife]

I also think it could be a combination of metformin and growth hormone:


3. Since FOXO1 is activated, stem cells divide symmetrically.

Do you have any references for FOXO1 influencing stem cell division?

[OP2040]

Whatever the root cause, I hope they continue to follow these people for some time and gather more data.  The logical thing to do would be to take a huge battery of tests, and try to establish age-related correlations with other parameters.  Two years of real age reversal is probably not enough time to easily note phenotypic changes.  But gather a bunch of data and do statistical analysis and you will have a treasure trove of clues.  True, you will not officially be able to say anything scientifically authoritative about said correlations, especially without the "before" baseline.   But they could lead to many other hypotheses and discoveries. 

 

 

[QuestforLife]

Do you have any references for FOXO1 influencing stem cell division?

 

It would be interesting to see if you could keep oxidative stress extremely low whilst using growth hormone and thereby give stem cells no choice but to replicate symmetrically.  A bodybuilder told me that above a certain dose of astaxanthin, muscle growth is completely abolished. 

Edited by QuestforLife, 10 September 2019 - 02:31 PM.

[Kentavr]

It would be interesting to see if you could keep oxidative stress extremely low whilst using growth hormone and thereby give stem cells no choice but to replicate symmetrically. A bodybuilder told me that above a certain dose of astaxanthin, muscle growth is completely abolished.

There is nothing surprising.

Exercise is microtrauma of the muscles. To heal microtraumas, cells use signaling molecules that are radicals.

Astaxanthin traps radicals. No radicals - no muscle growth.

Now information on oxidative stress: growth hormone does not cause it. So I don’t see the relationship here.

[Kentavr]

Do you have any references for FOXO1 influencing stem cell division?

Read here with the help of Google translator, everything is written in detail here:

https://nestarenie.ru/fmd.html

Look at the picture in the middle of the text of this large article (where it says: FOXO1).

Also there are links to the studies themselves.

Edited by Kentavr, 10 September 2019 - 04:32 PM.

[QuestforLife]

There is nothing surprising.

Exercise is microtrauma of the muscles. To heal microtraumas, cells use signaling molecules that are radicals.

Astaxanthin traps radicals. No radicals - no muscle growth.

Now information on oxidative stress: growth hormone does not cause it. So I don’t see the relationship here.

I know that about microtrauma and radicals, that is why I posted it.

The relation with GH is that it will wake up quiescent stem cells. If oxidative stress is kept low maybe they will increase their number rather than differentiate.

[Kentavr]

I suppose that in the TRIIM study of Dr. Greg Faha, patients were "rocked like a boat":

1. On the one hand - imitation of hunger (decrease in IGF-1) when taking metformin.

2. On the other hand - the urge to cell division due to the intake of HGH.

Explanation:

Typically, when fasting, the body decreases IGF-1 and increases FOXO1.

Upon termination of starvation, IGF-1 rises, but at the same time, FOXO1 rapidly falls.

If you follow the FMD diet more than 4-6 times, an interesting situation occurs: after the termination of the diet, IGF-1 grows, but FOXO1 does fall only after some time (!). On the 8th cycle of the FMD diet, this delay can be up to 1 week!

The following situation occurs: the body begins to "grow" with increased FOXO1, and it stimulates the symmetrical division of stem cells.

As a result, the number of stem cells increases, and the epigenetic age decreases.

I think this happened in the TRIIM study: IGF-1 (reason: HGH) was increased in the body while simulating fasting (reason: metformin).

For 9 months, the “boat rocked”, and the epigenetic age went down.

As in the case of the FMD diet, a significant effect occurred after some time (in this case, from 9 to 12 months).

Edited by Kentavr, 10 September 2019 - 05:09 PM.

[Kentavr]

The number of CD38s has also decreased in the patient’s body, namely, CD38 breaks down NMN!

Read the study carefully:

"Second, the great majority of monocytes are CD38‐positive. CD38 is an NADase ectoenzyme and a degrader of the NAD+ precursor, nicotinamide mononucleotide, and increased CD38 expression with age appears to be the primary cause of age‐related tissue NAD+ depletion in mice and most likely in man as well (Camacho‐Pereira et al., 2016). Induction of CD38 with aging has been proposed to be driven by age‐related inflammation, and to originate in inflammatory cells residing in tissues (Camacho‐Pereira et al., 2016), which in principle might include monocytes. Although many other immune cells express CD38, we did not detect any other CD38+ immune cell population that declined in response to thymus regeneration treatment, suggesting that monocytes may be of particular significance. Our observation of a decline in CRP in combination with reduced monocyte levels therefore suggests the possibility of an increase in tissue NAD+ levels"

https://onlinelibrar...1111/acel.13028

This means that researchers have found one way to naturally restore the NMN content in the body!

[ta5]

Astaxanthin traps radicals. No radicals - no muscle growth.

 

Building strength, endurance, and mobility using an astaxanthin formulation with functional training in elderly

(Sorry, I know it's fairly off topic.)

[QuestforLife]

Building strength, endurance, and mobility using an astaxanthin formulation with functional training in elderly
(Sorry, I know it's fairly off topic.)

Some inflammatory cytokines found in the elderly break down muscle, and in this case antioxidants such as NAC (and now astaxanthin) have been found to be helpful and assist in muscle growth. Whether or not it would be a good idea to combine them with weight lifting I doubt, probably best to kept them away from the beneficial inflammation that occurs during repair.

[Kentavr]

Interestingly, in the TRIIM study, low-cost drugs triggered the reverse of the biological clock.

It is very pleasing!

[Nate-2004]

Interestingly, in the TRIIM study, low-cost drugs triggered the reverse of the biological clock.

It is very pleasing!

 

Not necessarily, could still have been the growth hormone in combination. It could be that the thymus growth helped indirectly somehow. Nobody knows.

Edited by Nate-2004, 14 September 2019 - 02:42 PM.

[Kentavr]

Not necessarily, could still have been the growth hormone in combination. It could be that the thymus growth helped indirectly somehow. Nobody knows.

It also bothers me that all study participants were active in the field of life extension, and their age was already pushed back at the beginning of the study.

However, it is unlikely that all 9 people took the same drugs, except for those that they needed for the study.

The likelihood that an unknown combination of drugs has affected is minimal.