1028 replies to this topic

[RWhigham]

Cancer is my most likely cause of death

Short telomeres in old age cause mutations; mutations cause cancer.

I've been boosting telomerase with Gotu Kola to reduce my short telomeres to reduce cancer risk.

 

Cancer is rarely fatal at its original site. It's the metastases spreading everywhere that kills.

The discoverer of the "Hasini effect" found that tumor cells migrate when inflammatory cytokines reaches a critical concentration inside their tumor.

 

In old age, the main source of inflammatory cytokines is senescent cells. Unfortunately, most senolytics that kill these cells cause a lot of collateral damage. It seems to me that of the people that have taken them have increased their epigenetic age by doing so.

 

Two ways to reduce senescent cells without senolytics have been demonstrated. 1) thymus regeneration and 2) epigenetic-age reduction.

• Greg Fahy showed that regenerating the thymus gland greatly reduces senescent cells. If you live in California, you might be able to join his next thymus regeneration trial. (He uses about $15,000 of hgh per patient, provided free). His thymus regeneration also doubled LMR (leucocyte/monocyte rato) calculated from an inexpensive CBC (complete blood count). So you can test thymus regeneration with a CBC.

• Mice thymus glands were rejuvenated by large amounts of melatonin in their food. I'm hoping the large dose I take in the evening will work. Next year I'll get a CBC and find out.

• Harold Katcher showed that when he reduced the epigenetic age of rats their inflammatory cytokines fell to youthful levels. He and his partner Akshay Sanghvi are hoping to get FDA approval for a trial in humans .In a few years we may be able to get a series of injections from our doctors that rejuvenates nearly everything
• Turnbuckle's Stem Cell protocol (day 1) appears to lower epigenetic age, but only if telomerase stimulants are avoided. I plan to stop my telomerase simulation in the Fall and find out.
• Turnbuckle's day 2 senolytic protocol should be unnecessary since lowering epigenetic age should suffice to reduce senescent cells. 

I love Turnbuckles idea--stimulate mitochondrial fusion, then 3 hours later take a tsp of C60-in-EVOO and a bunch of amino acids to support stem cell division. Fusion can be stimulated by stearic acid (muffins are nicer than brownies) and PQQ, gynostemma pentaphyllum, leucine, creatine, glutathione, astaxanthin, CoQ10, and vit-C, and fission can be inhibited by disabling Drp1 with sulforaphane.

 

 

Edited by RWhigham, 25 May 2020 - 08:26 PM.

[Turnbuckle]

 

Cancer is my most likely cause of death

Short telomeres in old age cause mutations; mutations cause cancer.

 

 

 

Are you sure of that? Animals like rats with long telomeres typically have a lot of cancer and are short lived, while humans and other animals (esp. large ones) with relatively short telomeres are long lived. According to one paper --

 

On average, one in three persons in middle and high income countries is stricken with cancer during her/his life course. This high cancer incidence in contemporary humans is attributed to increased mutation burden brought about by rapid environmental changes caused by pollution, lifestyle and migration [22]. That said, from the evolutionary perspective, humans, who are middle-size but the longest-living terrestrial mammals, share comparatively short telomeres and repressed activity of telomerase in somatic tissues with African elephants, bowhead whales and other long-living large mammals [23,24]. Short telomeres and repressed telomerase would thus diminish the probability of attaining a critical number of replication-mediated mutations required for cancer development. That is because cells with short telomeres are prone to telomere-based senescence after fewer replications compared to cells with long telomeres. 

https://www.ncbi.nlm...les/PMC5903276/

 

 

See the figure below from this paper --

Attached Thumbnails

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[QuestforLife]

On the other hand, telomerase null mice have a HIGHER tumour incidence.

Basically there are TWO things going on. 1). Long telomeres reduce DNA mutation rate. BUT NOT TO ZERO. Therefore even with long telomeres some potentially cancer causing mutations will occur, proportional to the number of cells in the body.
2). Once a cell acquires relevant mutations and starts dividing out of control, the number of times it can divide is set by its original telomere length. Once it runs out of telomere (on its shortest chromosome) the growth will be arrested. This happens in our body all the time. The growth of cells then needs to turn the telomerase gene back on. It is reckoned this is unlikely, something like 1 in a million chance at most. So whether or not this will happen is down to how big the (so far benign) tumour got before it ran out of telomeres. If it divided into more than a million cells there is a good chance it will get the telomerase mutation it needs in atleast 1 cell in the lump and be able to become a malignant tumor. This is when it becomes clinical.

This model explains why large animals keep short telomeres compared to small animals (they have more cells so need to to minimise telomerase mutation chance more), why cancer cells activate telomerase but still like to keep their telomeres short (for increased mutation rates), and why children with long telomeres get cancer very rarely but when they do it's very serious.

I came up with this theory years ago whilst chatting to folks on Josh Mitteldorf's site. The scientists I shared it with said it was highly plausible. But it is still just a theory.

Edited by QuestforLife, 26 May 2020 - 07:11 AM.

[Andey]

So, it looks like we could agree that directly elongating telomeres via telomerase would go against protective mechanisms and higher average telomere length would be deceptive in this situation.

If we achieve the same elongation by removing cells with shorter telomers and adding cells with longer telomers this would also drive mean telomere length up but will produce a different(younger?) phenotype

[QuestforLife]

Like I said, I'm working on it. I believe reversing both telomere and methylation clocks is possible.

Comparisons in the absolute length of telomeres between species is not useful IMO. The ideal telomere length for humans is what we have in youth. That gives best health and minimum cancer rate (still not zero). As already discussed the evidence so far is we need to also make sure that telomere elongation isn't at the cost of increased methylation age.

[Turnbuckle]

 The ideal telomere length for humans is what we have in youth. That gives best health and minimum cancer rate (still not zero). As already discussed the evidence so far is we need to also make sure that telomere elongation isn't at the cost of increased methylation age.

 

 

Cells use telomere length as a clock to tell them when to commit suicide. Without cellular suicide, the body would become a nursing home very quickly. Thus the optimum length is not what we have in youth. In fact, that is only an average, as telomere length in many cell types grow short even in the young. They thus commit suicide and are replaced.

[QuestforLife]

Cells use telomere length as a clock to tell them when to commit suicide. Without cellular suicide, the body would become a nursing home very quickly. Thus the optimum length is not what we have in youth. In fact, that is only an average, as telomere length in many cell types grow short even in the young. They thus commit suicide and are replaced.

Let me be clear. Of course somatic cell lines should be replaced on schedule,as is done quickly in the young.

Telomere length, as measured in somatic tissues at any given moment in time, is an average and during life it declines. This does not mean that we want to prevent telomere shortening. But we do need cell replacements to keep pace with cell senescence.

An example of this is leukocytes. They lose ~70 base pairs of telomere per division. But over the course of a year they only lose ~70bps even though they must have divided a great number of times. Why is this? It reflects the fact that replacements (ultimately coming from bone marrow stem cells) almost perfectly keep up with leukocytes reaching cell senescence. But not quite.

It is this not quite perfect replacement that we are trying to solve.

[JamesPaul]

I'd like to understand this subject.  The abstract from the following paper 

“Anti-Aging Implications of Astragalus Membranaceus (Huangqi): A Well-Known Chinese Tonic,” Ping Liu et al., Aging Dis. 2017 Dec; 8(6): 868–886.

https://www.ncbi.nlm...les/PMC5758356/

 

says the following: “...Pharmacological research indicates that the extract component of Astragalus membranaceus can increase telomerase activity, and has ...anticancer...effects.”

 

This result appears to be inconsistent with the notion that lengthening telomeres increases cancer risk.  Is there an inconsistency?

[QuestforLife]

James Paul, I explained this above (6 posts up)

Edited by QuestforLife, 27 May 2020 - 06:25 AM.

[Turnbuckle]

It is this not quite perfect replacement that we are trying to solve.

 

 

Exactly. The gap between cellular senescence and replacement results in aging. But the average shortening of telomeres with chronological age is just a symptom of this failure, not the cause. 

[Turnbuckle]

I'd like to understand this subject.  The abstract from the following paper 

“Anti-Aging Implications of Astragalus Membranaceus (Huangqi): A Well-Known Chinese Tonic,” Ping Liu et al., Aging Dis. 2017 Dec; 8(6): 868–886.

https://www.ncbi.nlm...les/PMC5758356/

 

says the following: “...Pharmacological research indicates that the extract component of Astragalus membranaceus can increase telomerase activity, and has ...anticancer...effects.”

 

This result appears to be inconsistent with the notion that lengthening telomeres increases cancer risk.  Is there an inconsistency?

 

 

Astragalus is a complex mixture, and thus far it isn't known what component is responsible for the inhibition of some cancers. If you go to one of the references in the paper you cited, you'll find this --

 

 

The aqueous and organic extracts of AR were used in this study. But the organic extract had no effect on AGS growth (data not shown). So the effective anti-cancer components are in the aqueous extract. Polysaccharide[22], astragaloside[23], and flavonoids[24] have been found in AR. Some studies showed that the polysaccharides and flavonoids from other herbs had the anti-tumor efficiency in vitro and in vivo[25-29]. But up to now, there has no evidence showing that these compounds from AR have anti-cancer activity in vitro. Hence, further studies are required. Selenium toxicity has been confirmed in the livestock consuming plants of the genus Astragalus and selenium was reported to have the carcinostatic activity in the animals[30,31]. So selenium might play a critical role in AR inhibiting AGS growth.

https://www.ncbi.nlm...les/PMC4611425/

 

 

 

In another paper, several components of astragalus and from Centella asiatica were found to stimulate telomerase. One from Centella asiatica (08AGTLF) stimulated it 8.8 times, but several others were found to stimulate telomerase as well, though to a lesser degree--https://www.ncbi.nlm...les/PMC6755196/

 

And while the above compounds were found to depress apoptosis (as would be expected from a compound that lengthens telomeres), another paper found that a methanol extract of Centella asiatica induced apoptosis in several cancer cell lines -- https://www.ncbi.nlm...les/PMC2816528/

 

These results are not necessarily contradictory when you consider the complexity of herbal extracts, and it can't be assumed that lengthening telomeres per se will inhibit cancer. 

[JamesPaul]

QuestforLife and Turnbuckle, thank you for pointing me to your explanation and for the additional explanation.  I should have taken the time to read and understand prior posts before posting my question.

Your posts suggest that as members of each species live and reproduce, sooner or later, the germline will experience mutations that result in cancer in some individuals, and their defective genes will be passed on to the next generation if they reproduce before dying of cancer.  But those who don't get the cancer-causing genes will survive, as may others who don't develop cancer until late in life.

 

This paper 

“Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer,” Bruno Bernardes de Jesús et al., including María A. Blasco, EMBO Mol Med. 2012 Aug; 4(8): 691–704.

https://www.ncbi.nlm...les/PMC3494070/

suggests that the type of mouse studied had a shorter-than-optimal telomere length.  Because if the telomeres of old cells were extended, the likelihood of them or their "descendants" developing cancerous mutations would become larger. 

 

So if I have a shorter-than-optimal telomere length, then telomerase therapy may benefit me also. Conversely, if I have a longer-than-optimal telomere length, then telomerase therapy could increase my chance of cancer.

Edited by JamesPaul, 02 June 2020 - 10:26 PM.

[QuestforLife]

QuestforLife and Turnbuckle, thank you for pointing me to your explanation and for the additional explanation.  I should have taken the time to read and understand prior posts before posting my question.

Your posts suggest that as members of each species live and reproduce, sooner or later, the germline will experience mutations that result in cancer in some individuals, and their defective genes will be passed on to the next generation if they reproduce before dying of cancer.  But those who don't get the cancer-causing genes will survive, as may others who don't develop cancer until late in life.

 

This paper 

“Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer,” Bruno Bernardes de Jesús et al., including María A. Blasco, EMBO Mol Med. 2012 Aug; 4(8): 691–704.

https://www.ncbi.nlm...les/PMC3494070/

suggests that the type of mouse studied had a shorter-than-optimal telomere length.  Because if the telomeres of old cells were extended, the likelihood of them or their "descendants" developing cancerous mutations would become larger. 

 

So if I have a shorter-than-optimal telomere length, then telomerase therapy may benefit me also. Conversely, if I have a longer-than-optimal telomere length, then telomerase therapy could increase my chance of cancer.

 

One of the most important of Blasco's papers is  'Telomere shortening rate predicts species life span'  (www.pnas.org/cgi/doi/10.1073/pnas.1902452116). It shows that it is not telomere length that matters in lifespan, but RATE of SHORTENING. Hence short lived mice have longer telomeres than humans, but the rate of shortening is MUCH greater. 

 

Don't get caught up in worrying about the absolute telomere length too much as it varies between species and even between individuals, what we need is for the stem cell compartment to keep up with the attrition caused by living. Turnbuckle and I have had different approaches to doing this, but they both aim at the same thing; maintenance of tissues.

 

Mice have adopted the approach of active telomerase to maintain cellular replacement in the face of great oxidative stress and senescence, which works well in the wild, but once they live longer in the lab this leads almost invariably to cancer (as explained by my previous post - active telomerase is a free pass to any errant cell). Humans like many other larger animals have very low telomerase activity to combat this, which they need to do with so many more cells that can go bad(than a mouse); but humans can also afford to do this as cell loss is much reduced compared to a mouse because of less oxidative stress, etc. 

 

Active telomerase probably explains why mice age so quickly epigenetically as well, as their cells will quickly drift from the ideal 'blueprint' held in the stem cell compartment. The challenge for humans is to make sure we have enough cell replacements, without drifting from this blueprint. 

[RWhigham]

In a study of 65,000 people tracked for 7 yrs, average telomere length in PBMCs "robustly predicted longevity."  Peripheral Blood Leukocyte Telomere Length and Mortality Among 64 637 Individuals From the General Population

 

Correlation is not causation. In this study the shorter telomeres were associated with high blood pressure and LDL. This study may show that people who age the fastest because of life style choices like diet also shorten their telomeres fastest.

 

I find this study's scatter plot of 65,000 telomere measurements informative. It looks like the average length is near constant up to age 50, then declines linearly above age 50 at about 20.6 bp (base pairs) per year. For the 1st 50 years. it appears the average length is abut 5.1 kbp.

 

The authors have drawn a single straight line on their scatter plot, which would start at 5.581 kbp at birth, declining at 17.4 bp per year thereafter. However, a piece-wise linear line fits the average length at each age better).

 

Blasco indicated that across species and phyla, the rate-of-shortening can predicts lifespan, typically with a 25% decline during an average lifespan and 50% decline during a maximum lifespan. For constant rate of shortening, this makes Max lifespan double Avg lifespan. But Blasco only measured differential lengths over a portion of various lifespans. The scatter plot measurements below cover a comprehensive range of human ages.

 

Edited by RWhigham, 03 June 2020 - 07:00 PM.

[Gediminas Jesinas]

Centella asiatica is interesting and more potent telomerase activator than astragalus root although it's discovery is very recent and little is known about how to use gotu kola. Does anybody know pentacyclic triterpenoids chemical properties such as solubility? In papper it was mentioned that gotu kola extracts were prepared using ethanol. Astragalus CA and astragaloside iv need also to be prepared as ethanol tincture because it's only food grade solvent for these compounds.

 

For telomerase activation concentrated extracts are required of gotu kola? Why not to take just gotu kola as it is in higher doses, there are also great nutrients in them? Centella asiatica in right conditions can grow aggressively so that could eliminate need to buy it.

[Turnbuckle]

 

In a study of 65,000 people tracked for 7 yrs, average telomere length in PBMCs robustly predicted longevity. Peripheral Blood Leukocyte Telomere Length and Mortality Among 64 637 Individuals From the General Population

 

 

 

I don't see where they say it's robust. They say--

 

The multivariable-adjusted hazard ratio of all-cause mortality was 1.40 (95% confidence interval [CI] = 1.25 to 1.57) for individuals in the shortest vs the longest decile. 

 

 

A hazard ratio of 1.4 is smaller than other things, like smoking status. And the third reference from that paper indicates the difficulty of using telomere length to predict the outcomes for specific diseases--

 

Evidence from recent large studies has supported rejection of the hypothesis, with considerable statistical power, that reduced telomere length in leucocytes predicts the risk of cancer or pulmonary disease independently of age. However, in the general population and in patients with cancer, short leucocyte telomere length is associated with increased risk of early death, even after adjustment for age, gender, smoking and other risk factors.

https://onlinelibrar...1111/joim.12083

 

[RWhigham]

The normal shortening of telomeres has a period of high rate-of-shortening followed by a low rate-of- shortening for 3 or 4 years before cancer diagnosis. The authors believe that this pattern would provide an accurate early predictor of cancer if telomere length were monitored. Blood Telomere Length Attrition and Cancer Development in the Normative Aging Study Cohort  "Age-related BTL [blood telomere length] attrition was faster in cancer cases pre-diagnosis than in cancer free participants, followed by decelerated attrition in cancer cases resulting in longer BTL three or four years pre-diagnosis." 

 

Re: "Robustly predicted". My mistake. This was from Josh Mitteldorf's critique Large New Study Tracks Telomere Length and Mortality instead of from the article itself.

 

Edited by RWhigham, 03 June 2020 - 07:59 PM.

[Andey]

Interesting article from Dmitry Dzhagarov

He argues that we should add ROCK and 5-LOX inhibitors in addition to a senolitic treatment to proper displace senescent cells 

https://www.academia.edu/s/2fc0cf2608

I created a pdf from it, as academia.edu wants us to jump through hoops to access it https://drive.google...iew?usp=sharing

 

[QuestforLife]

Interesting article from Dmitry Dzhagarov
He argues that we should add ROCK and 5-LOX inhibitors in addition to a senolitic treatment to proper displace senescent cells
https://www.academia.edu/s/2fc0cf2608
I created a pdf from it, as academia.edu wants us to jump through hoops to access it https://drive.google...iew?usp=sharing

Dimitry knows his stuff.

5-LOX inhibition is related to TGF-B inhibition, and is believed to boost telomerase as well as stop fibrosis and inflammation.

Zileuton, the asthma drug, is the obvious drug choice for 5-LOX inhibition, though I don't know how easy it is to source.

From a supplement point of view I used the Life Extension apreflex (Alpha keto botswellic acid) previously (see my past report), with good results.

[Keizo]

Interesting!

 

now what i noticed is that you had the greatest effect following 20 g fish oil followed by liposomal resveratrol

 

Resv.'s problem has always been bioavailability. So what I am wondering is if you found a way to create maximum resv bioavailability using mega dosing of fish oil + lipid soluble resv. 

 

 

Just from a physics perspective if you got powder of resveratrol it would make sense to mix it with pure fat, before ingesting. 5x bioavailability according to Sinclair if you take it with some fat. That's how I make my "liposomal" "nano-particle-surrounded" resveratrol, take 500-1000mg cheapest trans-resveratrol powder (from bulkpowders, 99,x%) put it in my mouth and take a chug of olive oil, rinse it then swallow.

Going to try and take it with my krill oil capsules in the future (right now) as well.

 

I'm pretty sure resveratrol is unlikely to cause a rush of energy, at least on its own. I have no idea how that could possibly happen. Isn't the mechanism more of a long run thing? and resv might even make your energy levels worse short term? I have on occasion experienced a slight tension after resv. intake. If you get enough of it in your system you will more likely experience nausea (as in you take many grams). If anything resveratrol has a slight negative effect on my mood, and it's not a feel good supplement for me, at least not in the short run. Various fish oils and so forth I can see having an obvious effect on mood.

[QuestforLife]

Absolutely, resveratrol is fat soluble, although I've noted effects after prolonged dosing even just taking capsules on their own. Resveratrol makes me very alert mentally, but you are right it doesn't tend to boost energy generally . I never managed to replicate the super energy boost I had that one time from resveratrol and fish oil. I had a similar thing with NMN+antioxidants, a massive boost in energy that wasn't repeatable.

Having said that taking resveratrol, NMN, nicotinamide or excessive antioxidants in the evening makes me buzzy and wake up very early, so that might be related. There's probably a link between circadian rhythm and the oxidised/reduced state of cells.

I have recently started taking fish oil again after a long pause (years) and the first time I took it I did notice a spike in energy, nothing like as profound as the time with resveratrol but noticeable. I suspect it is related to mitochondrial fusion and sirt3+4 - I did some research on this a while back (it's in the thread somewhere) and mitochondrial fusion is related to the storage of triglycerides. But exactly how this is related to resveratrol (other than resveratrol being fat soluble), which tends to increase fission, is unknown at this point.

Regarding your comment on resveratrol and mood, I've noticed it decreases sex drive after prolonged dosing and a testosterone blood test seemed to confirm this. I know resveratrol is supposed to be an aromatase inhibitor so increase testosterone and decrease estrogen, but that has not been my experience. I am.assuming here you're a man, I don't know what the effect on a woman would be.

Edited by QuestforLife, 11 June 2020 - 02:47 PM.

[JamesPaul]

Thanks to the recent posters for your insights, including the rate of telomere shortening being key to long lifespan. 

A supplement advertised to inhibit 5-LOX ("Reduloxin") contains celery seed.  The component said to inhibit 5-LOX is n-butyl-phthalide.

Another supplement from the same company (Advanced Bionutritionals) contains 5-LOXIN, a trademarked product standardized to contain 85% AKBA (3-O-acetyl-11-keto-beta-boswellic acid), also advertised to inhibit 5-LOX, hence the name.

 

(I don't own stock in any supplement company.)

[QuestforLife]

Thanks to the recent posters for your insights, including the rate of telomere shortening being key to long lifespan.
A supplement advertised to inhibit 5-LOX ("Reduloxin") contains celery seed. The component said to inhibit 5-LOX is n-butyl-phthalide.
Another supplement from the same company (Advanced Bionutritionals) contains 5-LOXIN, a trademarked product standardized to contain 85% AKBA (3-O-acetyl-11-keto-beta-boswellic acid), also advertised to inhibit 5-LOX, hence the name.

(I don't own stock in any supplement company.)

Thanks, I haven't heard of Reduloxin.

I got the name wrong but AKBA is the active ingredient of apresflex, which is what is used in the Life Extension supplement I used. I believe the concentration is 20% but it's more bioavailable than earlier versions of the same supplement that were at 30% and hence was more effective for arthritis in a head to head comparison.

https://www.ncbi.nlm...les/PMC2974165/

Aflapin® is a novel synergistic composition derived from Boswellia serrata gum resin (Indian Patent Application No. 2229/CHE/2008). Aflapin is significantly better as an anti-inflammatory agent compared to the Boswellia extracts presently available in the market. A 90-day, double-blind, randomized, placebo-controlled study was conducted to evaluate the comparative efficacy and tolerability of 5-Loxin® and Aflapin® in the treatment of osteoarthritis (OA) of the knee (Clinical trial registration number: ISRCTN80793440). Sixty OA subjects were included in the study. The subjects received either 100 mg (n=20) of 5-Loxin® or 100 mg (n=20) of Aflapin® or a placebo (n=20) daily for 90 days. Each patient was evaluated for pain and physical functions by using the standard tools (visual analog scale, Lequesne's Functional Index, and Western Ontario and McMaster Universities Osteoarthritis Index) at the baseline (day 0), and at days 7, 30, 60 and 90. A battery of biochemical parameters in serum, urine and hematological parameters in citrated whole blood were performed to assess the safety of 5-Loxin® and Aflapin® in OA subjects. Fifty seven subjects completed the study. At the end of the study, both 5-Loxin® and Aflapin conferred clinically and statistically significant improvements in pain scores and physical function scores in OA subjects. Interestingly, significant improvements in pain score and functional ability were recorded as early as 7 days after initiation of the study in the treatment group supplemented with 100 mg Aflapin. Corroborating the improvements in pain scores in treatment groups, our in vitro studies provide evidences that Aflapin® is capable of inhibiting cartilage degrading enzyme MMP-3 and has the potential to regulate the inflammatory response by inhibiting ICAM-1. Aflapin® and 5-Loxin® reduce pain and improve physical functions significantly in OA subjects. Aflapin exhibited better efficacy compared to 5-Loxin®. In comparison with placebo, the safety parameters were almost unchanged in the treatment groups. Hence both 5-Loxin® and Aflapin® are safe for human consumption.

Edited by QuestforLife, 11 June 2020 - 03:08 PM.

[Keizo]

Absolutely, resveratrol is fat soluble, although I've noted effects after prolonged dosing even just taking capsules on their own. Resveratrol makes me very alert mentally, but you are right it doesn't tend to boost energy generally . I never managed to replicate the super energy boost I had that one time from resveratrol and fish oil. I had a similar thing with NMN+antioxidants, a massive boost in energy that wasn't repeatable.

Having said that taking resveratrol, NMN, nicotinamide or excessive antioxidants in the evening makes me buzzy and wake up very early, so that might be related. There's probably a link between circadian rhythm and the oxidised/reduced state of cells.

I have recently started taking fish oil again after a long pause (years) and the first time I took it I did notice a spike in energy, nothing like as profound as the time with resveratrol but noticeable. I suspect it is related to mitochondrial fusion and sirt3+4 - I did some research on this a while back (it's in the thread somewhere) and mitochondrial fusion is related to the storage of triglycerides. But exactly how this is related to resveratrol (other than resveratrol being fat soluble), which tends to increase fission, is unknown at this point.

Regarding your comment on resveratrol and mood, I've noticed it decreases sex drive after prolonged dosing and a testosterone blood test seemed to confirm this. I know resveratrol is supposed to be an aromatase inhibitor so increase testosterone and decrease estrogen, but that has not been my experience. I am.assuming here you're a man, I don't know what the effect on a woman would be.

Yeah years ago I just took the pure resv. powder with water (like 250-500mg resv for some months), that did seem to produce some immediate effect too ....mostly negative, barely nausea (which I assume is from one of the PDE inhibitions,) and slight tension. I guess I could call it an energizing or mental alertness effect (I think at one point I wrote on the forum saying I got some physical endurance for a few weeks from it, but it was vague), but I don't think of it so much in positive terms, like I feel kind of "Meh" after I take it. I think the most noticeable effect I get from it is these very mild aches in tendons or whatnot people have been mentioning since forever, but I don't get it as much now as I used to.

 

I honestly think it might have significant effect as a SERM or aromatase inhibitor for some people even in these "low" doses people take e.g. 500mg up to a few grams - I did a few calculations way back based on animal studies and I think my lowest est for significant AI/SERM effect was something like 1.5 grams in human or not much more than that, --- it's really weird that I coincidentally doubled my testicular size during this resv regimen years ago, at age 23-24 --- either the resv. and/or increased nutrition incl vitamin d3. Either way I have been taking it now recently for a few weeks, and I can't say it has enhanced my libido (but I don't think it did back then either, and I dont think equating how one feel with hormone levels is too exact, but I did end up feeling better eventually coinciding with the testicular increase), so maybe it was the diet/d3 that did the change before (I had borderline low BMI) or that I'm now at the point where my hormone levels (presumably, judging by physical/mental parameters) are so much more solid that some slight SERM/AI effect won't nudge the balance or be noticeable. 

 

I did take 750mg resv with the olive oil and some omega3 capsules and krill oil capsules today. Now 2 hours later it's either me getting into some sort of flow by writing posts here and sitting still too much and thus getting sorta foggy, or what I took. So I do get an agitation type effect with slight foggy sort of feeling, sort of what I get from maybe racetams. Actually it mostly reminds me of how I react to piracetam, but more subtle, which is why I think it mostly is the krill+fish oil, I think I'm quite sensitive to cholinergic stuff. I will probably take this before going to bed instead in the future, if I can make that work. 

Edited by Keizo, 11 June 2020 - 03:26 PM.

[QuestforLife]

I should have added, although I don't feel energised by resveratrol generally, and always end up stopping it because of the drop in sex drive, protracted use does give me INSANE endurance during exercise - running, judo, kickboxing etc. I had the same endurance effect from pterostilbene. I assumed it was to do with mitophagy.

[QuestforLife]

Yes to both. The epitalon definitely increases telomere length as per my LifeLength results in November, but it seems this might have been at the cost of additional aging as measured via methylation.

I will probably use alpha ketoglutarate (helps demethylases) for a while, maybe a statin-sartan cycle and recheck methylation in a few months.

A quick update

After my last testing, which showed an increase in biological age as measured by methylation, I decided to pause the telomerase activation (a have a good idea for how to lengthen telomeres in stem cells only that I'll post on later) and use a protocol to decrease epigenetic age. I alluded to this previously; I'm using alpha ketoglutarate (a salt form from Kirkman labs). In the first 3 months I focussed on AKG. In the second 3 months I'm doing AKG with some additional supplements for AMPK activation and other things to help with beta oxidation, which I think will be synergistic. Once I have the results from both phases I'll see how to reintroduce a telomere lengthening protocol.

I'm currently in the second 3 month phase. I'm awaiting the results of the AKG only phase. I'm using Trume, which is finally available to ship to the UK. It's not as accurate as Zymo but less than half the price, so I can do much more regular testing.

References:
AKG and progenitor cells, doi:10.3390/ijms19040943
AKG and epigenetic influence via TET
https://doi.org/10.1111/acel.13059
AKG and AMPK
doi:10.1016/j.cmet.2016.08.010.

Edited by QuestforLife, 08 July 2020 - 07:25 AM.

[Andey]

I don't know what to make of it but I did Trume test and it came up +7.5 years to my actual age.

It could be true but TBH I dont trust it much because I generally get compliments about how young I look, not otherwise, and I trust this `metric` more.

If its an adequate measurement it could be because I have a very long abx treatment a few years ago and was in a very rough state. It could also be that taking Everolimus (esp sublingually as its a saliva sample) messes up methylation(IDK what cell types are present in a saliva sample).

For me its too many unknown with methylation clocks and what they mean, but sure I want this number as low as possible)

[QuestforLife]

Hi Andey

We've discussed this to death both here with Turnbuckle and elsewhere with Josh Mitteldorf. It seems that telomerase (not long telomeres necessarily) increases epigenetic age as measured by methylation. It may be possible to increase telomeres in stem cells only, and this would be done via TERC (the telomere RNA template) not TERT (the protein that does the replication). This is because stem cells already have TERT, and upregulating TERC will only affect them, not the bulk of somatic cells that don't have TERT. This will probably be done within a few years based on using drugs intended for hepatitis B (https://doi.org/10.1...tem.2020.03.016).

It seems we already have powerful enough TERT activators in all cells, as my LifeLength results have shown. A 1000bp elongation in the shortest telomeres is fairly simple to achieve.

If you have long telomeres, as I do (now), I think it's safe to let them shorten for a while, and concentrate on methylation age. I agree it's just a metric, but the link to TET enzymes and how they're required for reprogramming (see Sinclair's work, https://doi.org/10.1101/710210)is a game changer for me. Alternatively you could switch to a weaker telomerase activator like gotu kola, whilst also trying to reverse aging as measured by methylation.

Edited by QuestforLife, 08 July 2020 - 08:05 AM.

[QuestforLife]

Some more information on AKG I posted on Turnbuckle's thread.

Alpha ketoglutarate is an important intermediate in the Krebs cycle. It is linked to calorie restriction because AMPK increases the enzyme step before AKG (isocitrate dehydrogenase), hence increasing its concentration. AKG has epigenetic effects because it is a cofactor in the TET enzymes, which can remove methylation. This is most likely the mechanism behind its purported effects, but there are many interlinked pathways in energy metabolism and epigenetic control so it's hard to say for sure. It also leads to a reduction in triglycerides and cholesterol because increasing the rate of the Krebs cycle increases the requirement on acetyl coA, which starts drawing on beta oxidation. Therefore there is probably also a link between the effects of AKG and eating stearic acid, which increases beta oxidation. I can dig out a tonme of references if anyone wants them.

Incidentally AKG has been used in salt form (with calcium or magnesium or a mix) for years, I can't see how Rejuvant have a patent. So there is no need to buy their expensive supplement.

[Andey]

Hi,

Thank you, interesting information indeed.

 

I think, even with small setbacks, we are going in the right direction, at least subjectively I feel myself at my best.