276 replies to this topic

[Rocket]

Most people can tell if a person is in their late 30's or early 40's, the question is, why? Things begin to decline around this time, why? Grey hair, wrinkles, athletes even retire around this age. If there aren't enough senescent cells at this point to matter, then a buildup of senescent cells or SASP is not really as big of an aging factor as we thought, at least not at this point. It may still be more related to Advanced Glycation Endproducts, glucosepane mostly but also pentosidine and fructosamine.

Its the extracellular matrix that gives away age in 30s and 40s. Wrinkles like crows feet are NOT senescent cells.

Athletes retire around 35 because connective tissue fails.... Shoulders and knees and spinal discs. That's not senescent cells! That is wear and tear on tissues that don't repair like themselves like a skin bruise.

Also the loss of hgh takes its toll on not repairing the body like when younger. That is NOT senescent cells Nate.

Senescent cells contribute VERY VERY VERY little to 35 and 40 year old people.


Senescent cells have been hyped up to be the bogey man on this site. True in old age they accumulate enough to be a large part of aging, but hardly the major 70% factor of aging that people want them to be.

30 year olds should not be taking FOXO4. 40 sure. 50 definitely.

Senescent cells are not the difference between 25 and 35!!!!!

Loss of hgh, connective tissue degradation, extracellular matrix damage, mitochondrial changes, gene expression... Loss of muscle, thinning skin. Things like v02 max and cardiovascular health are secondary aging that can be controlled through exercise and diet.

People are going to be let down by FOXO4 if they think they are going to look younger or become younger.... Your shoulders and discs and tendons won't rejuvenate. Your vascular system won't decalcify. Your brain won't turn 22 again. If you're old enough some biomarkers may improve like egfr, which is important but.......

Edited by Rocket, 21 March 2018 - 01:14 AM.

[Nate-2004]

I agree, and I'm guessing by and large that's glucosepane? As someone in his 40's I'm more interested in rejuvenation therapies that involve repairing the ECM.

[Rocket]

I agree, and I'm guessing by and large that's glucosepane? As someone in his 40's I'm more interested in rejuvenation therapies that involve repairing the ECM.

Its not even ages at 35 and 40 making you look older. Thinning skin. Loss of fat. Sun damage. Stress. Wear and tear from youth and partying and abusing your body. And yes, mitochodrial loss of function and gene expression.

If you want to improve your external ECM the you should try dermarolling.

At this time there is nothing you can do for the internal ECM and restoring strength to connective tissue. Anabolics like nandrolne are known to increase collages production in connective tissue... So you can try that. I know its definitely helped me with a shoulder injury to continue weight training with heavy weights. But its illegal and you need to take a host of supportive chemicals to maintain health since it affects lipids and the liver and can lead to gyno ... But it works,

Edited by Rocket, 21 March 2018 - 01:48 AM.

[Nate-2004]

I've stayed out of the sun most of my life, though I did go through a short phase of trying to tan in my 20's but it was a 6 month thing, for the most part I've avoided sun for this reason, still, not enough to slow that damage. Why do we lose subcutaneous fat? Why do we lose skin elasticity? Why does it thin? What are the root causes here? I'm specifically talking about ages 25 to 45. Aside from photodamage, which for me is rare, what else is there?

 

We know how to target mitochondrial dysfunction issues but I'm guessing it's all mostly advanced glycation end products, otherwise what else is there?

 

I can tell you, there is nothing out there yet that can break the crosslinks that cause this yet.

Edited by Nate-2004, 21 March 2018 - 02:04 AM.

[QuestforLife]

Skin turns over every month (roughly). As telomeres shorten they turnover less often. So you have a given cell for longer.  In older cells' metabolism and autophagy is reduced so proteins hang around for longer and are more likely to be damaged by ROS or bonded to glucose. That is probably all there is to it in middle age.

 

But there are lots of complicated downstream consequences. The stratum corneum starts to let moisture though so your skin gets drier. I'm not sure why subcutaneous fat is lost so early in life - but I have been working on replacing mine with glitazone treatment (stimulates adipocyte differentiation). It seems to be working.

 

Dermarolling also works because it forces the skin cells to replace more regularly. From this we can gather that the body is very conservative and always holds back considerable replenishment capacity. 

 

I wouldn't stress yourself over glucosepane - I've never seen any evidence that this is a big deal at age 40. It builds up slowly and forms a minority of the sugary crosslinks you have at any given time (even if it is the most persistent component). We'll get a glucosepane breaker by the time we really need it (yes I donate to SENS).

Edited by QuestforLife, 21 March 2018 - 10:51 AM.

[Nate-2004]

Skin turns over every month (roughly). As telomeres shorten they turnover less often. So you have a given cell for longer.  In older cells' metabolism and autophagy is reduced so proteins hang around for longer and are more likely to be damaged by ROS or bonded to glucose. That is probably all there is to it in middle age.

 

But there are lots of complicated downstream consequences. The stratum corneum starts to let moisture though so your skin gets drier. I'm not sure why subcutaneous fat is lost so early in life - but I have been working on replacing mine with glitazone treatment (stimulates adipocyte differentiation). It seems to be working.

 

Dermarolling also works because it forces the skin cells to replace more regularly. From this we can gather that the body is very conservative and always holds back considerable replenishment capacity. 

 

I wouldn't stress yourself over glucosepane - I've never seen any evidence that this is a big deal at age 40. It builds up slowly and forms a minority of the sugary crosslinks you have at any given time (even if it is the most persistent component). We'll get a glucosepane breaker by the time we really need it (yes I donate to SENS).

 

I've never seen any convincing before / after photos of dermarolling. 

 

Interesting take though. So we're back to telomeres and ROS on this. I haven't heard of glitazone, I tried voluplus but it did literally nothing.

 

I looked up glitazones and apparently it adds new fat and reduces insulin resistance. Is it topical or oral or injected? Where are you getting this?

Edited by Nate-2004, 21 March 2018 - 12:06 PM.

[Rocket]

Skin turns over every month (roughly). As telomeres shorten they turnover less often. So you have a given cell for longer. In older cells' metabolism and autophagy is reduced so proteins hang around for longer and are more likely to be damaged by ROS or bonded to glucose. That is probably all there is to it in middle age.

But there are lots of complicated downstream consequences. The stratum corneum starts to let moisture though so your skin gets drier. I'm not sure why subcutaneous fat is lost so early in life - but I have been working on replacing mine with glitazone treatment (stimulates adipocyte differentiation). It seems to be working.

Dermarolling also works because it forces the skin cells to replace more regularly. From this we can gather that the body is very conservative and always holds back considerable replenishment capacity.

I wouldn't stress yourself over glucosepane - I've never seen any evidence that this is a big deal at age 40. It builds up slowly and forms a minority of the sugary crosslinks you have at any given time (even if it is the most persistent component). We'll get a glucosepane breaker by the time we really need it (yes I donate to SENS).

Totally agree with you over AGES and 40.

Also you're right about the body holding back on tremendous replenishment capacity. I broke my second metatarsal on January 9. 6weeks later I was back in the gym doing squats. I even quit wearing the plastic boot over 2 weeks early and did everything I wasn't supposed to do like walk barefoot at home. I am approaching mid 40s and thought i was in for months of pain and limping. Nope. Healed up like a youngster and totally pain free, knock on wood. Even the doctor warned me I was in for months of pain ahead of me. Nope.

I do take 15g of vitamin c for cardiovascular so maybe it helped bone heal through the same pathway it prevents damage to arteries... Idk.

But back to senescent cells, sort of like AGES I doubt there is very much affect on the body until mid 40s. I just don't understand why the young guys in their 30s are bothering to damage their body to eliminate NO harmful senescent cells that their immune system was going to eliminate anyway. Every medicine contains poison afterall.

And back to Nate, dermarolling is sworn to by many people. So is that blood plasma platelet therapy that Kim Kardashian uses. The science behind it seems valid.

Edited by Rocket, 22 March 2018 - 01:33 AM.

[QuestforLife]

Nate - I bought pioglitazone from Aipctshop in tablet form. For more info please read 2010 paper 'Pioglitazone Increases the Proportion of Small Cells in Human Abdominal Subcutaneous Adipose Tissue.' I did it for 6 rather than the full 12 weeks of the study. I wouldn't recommend anyone else trying this however, without being very well informed and read up on the small but real increase in the chance of bladder cancer.

 

Rocket - ditto, I tore a ligament in my finger and was told 8 weeks in a splint, then 3-4 months of physio with no weights or Judo in that time. I was out of the splint in 4 weeks and back to Judo at 6 weeks. What to Doctors know, eh?

[Nate-2004]

Thanks for the info guys. I'll look into this. I think this is highly relevant because the message by and large lately is that senescent cells are a major root cause of aging, yet if people who are showing the early signs of age in their 30's and 40's, the signs you described above, do not have a number of senescent cells that would have much of an effect in terms of SASP, then we're looking at another phase of aging that doesn't include the main targets. I'm still not so sure the root cause of this decline in subcutaneous fat, collagen, hyaluronic acid, elastin, bone density, increased stiffness in joints and muscles, a drop in growth hormone and other biomarkers doesn't have a root cause. I'm not so sure what, if not AGEs, are at the root of this decline. What specifically is signaling cells to turn over less and become more conservative?

 

It appears I've been wasting time somewhat on trying to eliminate or as far as this thread that I started, revive senescent cells.

 

BTW any recommendations on a dermaroller? How many mm? 1mm? Maybe I'll take these questions to another thread.

 

Who is marking all my posts as dangerous and irresponsible lately? I hate these features, they just give trolls something to annoy people with.

[pamojja]

 

Who is marking all my posts as dangerous and irresponsible lately? I hate these features, they just give trolls something to annoy people with.

 

It more and more reminds me of the Orwellian Chinese Social Credit System. I mean I understand that misjudgments can be made, by assuming such would encourage more quality contributions. But de facto and for a couple of years has scared away most quality contributors, and made a feast of mobbing trolls out of this forum.

[QuestforLife]

Hi Nate

 

This is my opinion, albeit one based on reading hundreds of papers over the years (if not thousands), but the early phases of aging are likely caused by the slowing down phase of (mitotic) cells rather than their senescence. Going back to the paper that started this thread - I still think this intervention is valid (if it can be made to work in vivo), because there are many cells that are approaching senescence all the time (before arrest, apoptosis or immune clearance and replacement), and if we could rejuvenate these that would effectively be a genuine reversal of aging, because you would not be relying (as so many interventions do) on faster replacement from what is a finite stem cell pool, but would be getting a free lunch (younger cells) for nothing.

 

Incidentally I originally criticized the paper in question for not proving that the cells they had rejuvenated in vitro were genuinely senescent, but this is irrelevant for our purposes as near senescent or senescent rejuvenation is still useful in vivo. This is not senescent cell clearance, it is putting such cells back to work.

 

Regarding my plan to use pterostilbene instead of resveratrol, I've had incredible difficulty getting pterostilbene powder in the UK and several cancelled orders later and I've finally got a bag of tablets that I'm emptying out myself. I took 1g (of actual pterostilbene, total weight is more like 6g) last night and another 1 g this morning in a fruit juice. Have had no stomach upsets so far. I intend to continue this for another 1 day (48 hours total) and will report back any results.

 

I don't know who is marking down your posts Nate, I've up-rated a few of them to balance things out!

 

 

[Nate-2004]

I wonder how we can reverse the slowing down. If by that you mean cell turnover, then early aging is something that's not as prioritized or looked at in terms of rejuvenation research. It would be great to see more followup on this resveratrol study though because maybe that's the key, but maybe not. What would happen if we sped these things back up? Would that be a short term gain with long term negative consequences if other things aren't dealt with?

 

Yeah without knowing if pterostilbene is the same you're shooting in the dark. Apigenin is something you'll want to take with resveratrol, since resveratrol improves the bioavailability (cmax) of apigenin I assume that apigenin might also improve the bioavailability of resveratrol, since it's a competition thing. I noticed that while apigenin helps me sleep better, if I take it with resv, it keeps me awake. All speculation based on a study I linked in the Manipulating Mitochondrial Dynamics thread and elsewhere.

 

Thanks for the vote ups, but just so you know, the green ones are the only one that counts, the middle ones are neutral. It's a weird system.

Edited by Nate-2004, 22 March 2018 - 06:26 PM.

[QuestforLife]

Well that's a good question Nate and what people have been debating about telomerase treatment since the late 90s; undoubtedly it rejuvenates (speeds up) cells, but does it encourage cancers? Based on my understanding, the answer is no, but others disagree. A similar thing could be said for this resveratrol treatment; is it a good idea to put old cells back to work? Again, my reading is the situation is that extending telomeres is sufficient to make an old cell good again, others may disagree. But I take some heart that resveratrol is known to be strongly anti cancer and I think very short telomeres are a cause of cancer.

I've completed my pterostilbene dosing. I took 6grams over 72 hours in the end. Based on the paper I think it's the backbone common to all the resveratrol analogues, resveratrol itself, and indeed pterostilbene that is the magic ingredient that permits telomere elongation in old cells. But I have doubts someone of my age (39) has sufficient old cells to benefit from this treatment. Still, I see this as a sensible preventative treatment.

[QuestforLife]

Just an quick update - I haven't given up on this treatment, I've just been spending alot of time trying to obtain some pure pterostilbene powder. Last time I emptied out 50mg pterostilbene pills in order to get a 1g dose AM and PM, but this meant ingesting lots of filler. Despite this I seemed to get some encouraging effects. Nothing huge, but I noticed a definite athletic uptick a day or two after dosing. I've experienced improved endurance with resveratrol and pterostilbene in much lower doses before, so I can't attribute this to rejuvenation of cells necessarily. But I also seemed to get strength improvements this time. To reiterate, this is just a cautious, anecdotal report at this stage.

 

This time I took 1g pure pterostilbene powder morning and evening. I discovered pterostilbene is VERY hydrophobic and just floats around on top of water in little balls, making it rather difficult to ingest. You can pop it straight into your mouth (after measuring out the correct amount on accurate scales), but there is the danger of inhaling and coughing it out again, plus I found my teeth were quite sensitive to the stuff.  So I settled on mixing it into a small quantity of olive oil. It tasted bitter, but palatable. I haven't yet settled on a final way of doing this and will continue to experiment. I did three days in a row AM and PM. This should have given various tissues in my body a sufficient dose of pterostilbene to rejuvenate old cells. To do the calculations on amounts I used human data for resveratrol adjusted for pterostilbene based on a comparison of resveratrol and pterostilbene in rats.

 

Papers;

1.Phase I Dose Escalation Pharmacokinetic Study in Healthy Volunteers of Resveratrol, a Potential Cancer Chemopreventive Agent

2. Pharmacokineticandsafetyprofileoftransresveratrolinarisingmultiple-dosestudyinhealthy volunteers

3. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats

 

This is the best I have to go on for now, but I'm reasonably confident I'm getting more than a sufficient dose at 1g, twice a day..

 

There are many unknowns here that are not covered by the original in vitro paper - how short do the telomeres of an old cell need to be to be affected by this treatment; what tissues are taking up pterostilbene; what is the rate at which telomeres are being shortened in various proliferative tissues (i.e. how often do I need to repeat this experiment)?

 

I expect that as a person ages if we could take a snapshot of all his or her telomeres, you'd see a bell curve gradually distorted and compressed toward the bottom end. Assuming this treatment is successful, I'd hope to be cutting off the bottom tail of the bell curve and moving those cells to somewhere near the peak of the bell curve. My guess is that this treatment should be quite successful in the peripheral blood and vessel walls, and it should be noticeable in a telomere test that looks at more than just mean lengths. So to this end I'm looking into getting a Life Length test.

 

I will report back when I get these results. I will probably continue to do 3 days of AM and PM doses every week or two.

[recon]

Just an quick update - I haven't given up on this treatment, I've just been spending alot of time trying to obtain some pure pterostilbene powder. Last time I emptied out 50mg pterostilbene pills in order to get a 1g dose AM and PM, but this meant ingesting lots of filler. Despite this I seemed to get some encouraging effects. Nothing huge, but I noticed a definite athletic uptick a day or two after dosing. I've experienced improved endurance with resveratrol and pterostilbene in much lower doses before, so I can't attribute this to rejuvenation of cells necessarily. But I also seemed to get strength improvements this time. To reiterate, this is just a cautious, anecdotal report at this stage.

This time I took 1g pure pterostilbene powder morning and evening. I discovered pterostilbene is VERY hydrophobic and just floats around on top of water in little balls, making it rather difficult to ingest. You can pop it straight into your mouth (after measuring out the correct amount on accurate scales), but there is the danger of inhaling and coughing it out again, plus I found my teeth were quite sensitive to the stuff. So I settled on mixing it into a small quantity of olive oil. It tasted bitter, but palatable. I haven't yet settled on a final way of doing this and will continue to experiment. I did three days in a row AM and PM. This should have given various tissues in my body a sufficient dose of pterostilbene to rejuvenate old cells. To do the calculations on amounts I used human data for resveratrol adjusted for pterostilbene based on a comparison of resveratrol and pterostilbene in rats.

Papers;
1.Phase I Dose Escalation Pharmacokinetic Study in Healthy Volunteers of Resveratrol, a Potential Cancer Chemopreventive Agent
2. Pharmacokineticandsafetyprofileoftransresveratrolinarisingmultiple-dosestudyinhealthy volunteers
3. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats

This is the best I have to go on for now, but I'm reasonably confident I'm getting more than a sufficient dose at 1g, twice a day..

There are many unknowns here that are not covered by the original in vitro paper - how short do the telomeres of an old cell need to be to be affected by this treatment; what tissues are taking up pterostilbene; what is the rate at which telomeres are being shortened in various proliferative tissues (i.e. how often do I need to repeat this experiment)?

I expect that as a person ages if we could take a snapshot of all his or her telomeres, you'd see a bell curve gradually distorted and compressed toward the bottom end. Assuming this treatment is successful, I'd hope to be cutting off the bottom tail of the bell curve and moving those cells to somewhere near the peak of the bell curve. My guess is that this treatment should be quite successful in the peripheral blood and vessel walls, and it should be noticeable in a telomere test that looks at more than just mean lengths. So to this end I'm looking into getting a Life Length test.

I will report back when I get these results. I will probably continue to do 3 days of AM and PM doses every week or two.

We cannot be sure that pterostilbene has the same effect as resveratrol. Plus, we’re not even sure if resveratrol has as good in-vivo effects.

Then again, I’m taking pterostilbene at 250 mg daily.
You can try megaresveratrol.net. Not sure about the quality but they sell bulk and cheap 250 mg packs of resveratrol and pterostilbene.

Additionally, I think you should probably take resveratrol along with pterostilbene. They have synergistic effect on absorption.

[QuestforLife]

Thanks for the tip on megaresveratrol.net

 

As for using pterostilbene, I've explained my reasons for believing it will have the desired effect up thread. I know what amount of resveratrol one needs to typically ingest in order to get the serum values used in the paper, and I know (roughly, based on a comparison between resveratrol and pterostilbene in rats), what this means for ingesting pterostilbene instead. No synergistic effects of ingesting both are required.

 

But yes, I agree there are lots of unknowns. Hence I want to get a telomere profile from life length. I may need to get several.

 

 

[QuestforLife]

I'm still trialing large doses of pterostilbene - typically I do a couple of days a week, with 1g in the AM and PM. I don't have a lot to report so far. I am considering switching to a liposomal variety to get better tissue distribution and higher serum values. I am still looking into getting a Life Length test, but this requires a venous draw, and there are no participating clinics nearby.

 

Anyway, I will be looking for a certain distribution of telomere lengths with very few shorts, as a metric for the success of this procedure.

 

Anyone else have anything to report?

[Nate-2004]

I got nothing though I've been fasting quite a bit lately, 24 hrs each day (one meal a day) this week and I've been taking resveratrol with my coffee along with 100% cocoa. While fasting may be a good way to add to the effects of resveratrol it's questionable whether its bioavailability is any good, considering no fatty acids are involved during fasting, but I still wanted to experiment with whether fasting enhanced its effects at all. I ran out of the liposomal stuff. Also taking 500mg NR on these days, split between morning and before bed.

 

I did notice one negative thing and that's joint pain in my right thumb, but could be a nocebo effect or completely unrelated.

Edited by Nate-2004, 31 May 2018 - 03:16 PM.

[Castiel]

I've stayed out of the sun most of my life, though I did go through a short phase of trying to tan in my 20's but it was a 6 month thing, for the most part I've avoided sun for this reason, still, not enough to slow that damage. Why do we lose subcutaneous fat? Why do we lose skin elasticity? Why does it thin? What are the root causes here? I'm specifically talking about ages 25 to 45. Aside from photodamage, which for me is rare, what else is there?

 

We know how to target mitochondrial dysfunction issues but I'm guessing it's all mostly advanced glycation end products, otherwise what else is there?

 

I can tell you, there is nothing out there yet that can break the crosslinks that cause this yet.

 

Not sure, but I've heard infrared has benefits for skin.   While UV has negative downsides it may be that the infrared from the sun has benefits, assuming that is true, haven't looked to deeply into it.   If it turns out true, UV free infrared or maybe even just red light therapy might show benefits.

[Castiel]

I got nothing though I've been fasting quite a bit lately, 24 hrs each day (one meal a day) this week and I've been taking resveratrol with my coffee along with 100% cocoa. While fasting may be a good way to add to the effects of resveratrol it's questionable whether its bioavailability is any good, considering no fatty acids are involved during fasting, but I still wanted to experiment with whether fasting enhanced its effects at all. I ran out of the liposomal stuff. Also taking 500mg NR on these days, split between morning and before bed.

 

I did notice one negative thing and that's joint pain in my right thumb, but could be a nocebo effect or completely unrelated.

 

 

What resveratrol dose?   I think one would have to look at how NAD+ levels change throughout fast duration for optimal time.

 

Bioavailabilty? Fatty acids?  Could you clarify?

[Castiel]

Will add that googling found a reddit question without source saying that I think Valter longo had recommended against resveratrol + fasting.  But googling couldn't find any such source.  

[Nate-2004]

Will add that googling found a reddit question without source saying that I think Valter longo had recommended against resveratrol + fasting.  But googling couldn't find any such source.  

 

I doubt that's even true that he said that. I can't find any source for that either.

[Castiel]

I doubt that's even true that he said that. I can't find any source for that either.

 

 

I find it doubtful that he said that too.  If fasting increases NAD+, it should be synergistic with resveratrol and may even help bypass the issue of NAD+ drops with age.

[triguy]

I think I'm going to focus on Metformin. I can get that, and my sister who is a medical researcher, just came back from a conference, and reported that the docs there were saying that soon everyone might be on it - proven antiaging effect.

 

Anyone following the rapamycin thread?

 

 

fyi

 

metformin decreases igf-1

 

 

https://www.hindawi....i/2017/9058307/

I'm still trialing large doses of pterostilbene - typically I do a couple of days a week, with 1g in the AM and PM. I don't have a lot to report so far. I am considering switching to a liposomal variety to get better tissue distribution and higher serum values. I am still looking into getting a Life Length test, but this requires a venous draw, and there are no participating clinics nearby.

 

Anyway, I will be looking for a certain distribution of telomere lengths with very few shorts, as a metric for the success of this procedure.

 

Anyone else have anything to report?

 

"liposomal variety"

 

Brand?  company??

[QuestforLife]

I've tried Actinovo Pterostilbene before.

But I still have lots of the powder left, so I may try and make it myself. The prices for liposomal supplements is too high IMO, although of the lot, Actinovo are the most reasonable.

I'm waiting for a life length telomere result - it may tell me something about the effectiveness of pterostilbene.at rescuing cells with short telomeres.

[Rocket]

https://www.longecit...lism-and-aging/

[ta5]

Grapefruit is just one of many CYP1A2 inhibitors. Curcumin and Cimetidine also do this. See wikipedia. Note: I have experienced sudden caffeine intolerance via massive curcumin and alcohol for 2-3 weeks. Recovered my ability to drink coffee after 2 weeks dry and no supplements. CYP1A2 is responsible for 87% of liver metabolism of caffeine. So when you get caffeine intolerance, I suspect, you have probably fried your CYP1A2.

 

Here are a few more. Below are from my notes on CYP1A2. The numbers are PMIDs. My comments might be wrong, so double-check the references.

 

Coffee increases CYP1A2: 18157525

Resveratrol also inhibits CYP1A2: 15369802 11294598 12818727 (but something else in red wine is a stronger inhibitor)

Resveratrol CYP1A2 induction at high does: 25473508

Red wine solids inhibit CYP1A2: 11701226 12818727

Curcumin inhibits CYP1A2

Green tea/EGCG has no or minimal effect on CYP1A2: 17164372

Green tea inhibits CYP1A2, and Grape seed inhibits CYP1A2: 27298605

Fo-ti inhibits CYP1A2: 25975098 25350237

Fish oil increases CYP1A2: 24771368

I3C may increase CYP1A2: 21113494 23330137 10798223

Valerian and Ginkgo biloba increased the activity CYP1A2: 17214607

Horse chestnut, Echinacea purpurea and common sage inhibited CYP1A2: 17214607

Rosmarinic acid has neglegable effect on CYP1A2: 25442272

Bacopa and Gotu Kola "contribute negligible interaction potential with CYP isozymes" CYP1A2: 27030208

Bacopa is a potent inhibitor of CYP1A2 : 24566323

Ashwagandha had no effect; gotu kola inhbited CYP1A2; quercetin potent inhibition of CYP1A2: 25938222

Profound multi-vitamin deficiency is associated with a decrease in the expression of CYP1A2: 24220160

"This study confirms an enhancing effect of acetaminophen and coffee on CYP1A2 activity and suggests an inhibitory effect of estrogens, alcohol and food sources of lutein and alpha-tocopherol on [CYP1A2]": 9110357

[Castiel]

Regards senescent cells and regards the extracellular matrix and aging.

 

I've heard that as telomeres shorten detrimental epigenetic changes occur even long prior to senescence being reached.  Second even a very small number of senescent cells can detrimentally affect a tissue.

 

 

The extracellular space is not a quiet place and certainly not a place where protein molecules can quietly “retire” for a few decades. To the contrary, the molecules come and go, subject to continual degradation and replacement. Aging doesn’t occur simply because molecules “sit around and fall apart”. Aging occurs because molecules aren’t turned over as quickly as we age....

 

Whether you are six or sixty, your collagen and elastin molecules are steadily breaking down and failing. The difference is not the rate of damage, but the rate of turnover. This is the rate at which molecules – such as collagen and elastin — are recycled and replaced. In young skin, collagen turnover can be as high as 10% per day, but the rate of turnover falls steadily with chronological age, or more specifically, with cell aging. As cells are lost and replaced by cell division, the telomeres shorten, gene expression changes, and molecular turnover slows down. The older your cells, the slower the rate at which they replace damaged extracellular proteins, whether collagen, elastin, or any other protein (such as beta amyloid in the elderly patient with Alzheimer’s disease). No wonder our skin becomes fragile, loses elasticity, and develops wrinkles....

 

The key to extracellular aging isn’t the damage, but the rate of turnover. The practical implication is that whether we are talking about collagen, elastin, beta amyloid, or dozens of other types of extracellular protein, we can effectively intervene by resetting gene expression. Whether we are looking at skin, joints, bone, or brains, the potential is an innovative and effective intervention for age-related problems.-Dr. Michael Fossel http://www.michaelfossel.com/blog/

 

Restoring telomeres reverses practically all changes and restores youthful gene expression, rejuvenating a cell, iirc.   Cells taken from old humans create frail old skin in labs, while young cells create thick young skin.   Reset the telomeres, and the old cells create thick young tissue just like the young cells. (research at geron, as commented on the book by Dr. Michael Fossel The telomerase revolution).

 

Note that in this thread resveratrol is shown to appear to lengthen telomeres and rejuvenate even senescent cells.   It affects hundreds of genes and multiple sirtuins.

 

Edited by Castiel, 12 August 2018 - 05:54 AM.

[Castiel]

Comment from John on joshmitteldorf's blog 

 

I have looked into the recent ‘splicing factor’ study. If you examine the study, you can see that one of the ‘resveralogues’ that they looked at was resveratrol itself. In fact, resveratrol itself led to the greatest increase in telomere length of any of the tested compounds. This was obtained by innoculating the cells in 5 micromolar resveratrol for 24 hours and it resulted in dramatic reversal of cellular senescence and doubling of telomere length. This is a concentration that is easily obtained in human plasma after oral resveratrol.-John

 

I would hypothesize, that unless the study dismissed it, it may be that it also lengthens telomeres in other non senescent cells also rejuvenating them.

 

Also not sure how they ensure no sirtuins were activated and affected the splicing factors.  They seem to mention only testing against sirt1 but resveratrol also activates other sirtuins, and analogues might as well.

 

Another thing skimmed over the article, not sure how they arrived at 5micromole for 24 hours.   Would be interesting to research various doses, unless they did so and I missed it, might be the dose or time could be reduced.

 

Also Sardi seemed to suggest doses near 3000mg may be harmful, but supposedly longevinex appears to have no issue.

http://www.resveratr...sveratrol/1635/

That article links to the following study

 

A group of rats were force-fed three different doses of resveratrol or Longevinex (2.5 mg/kg, 25 mg/kg and 100 mg/kg) for up to 30 days, while the control group was only given placebo. The results showed hormesis for pure resveratrol, which was cardioprotective at lower doses and detrimental for higher doses, but surprisingly Longevinex did not display any hormetic action. In the concentration range studied, Longevinex remained cardioprotective even at 100 mg/100 g body weight - a dose that killed 100% of the hearts when tested with pure resveratrol. https://www.ncbi.nlm...ardioprotection

 

That seems surprising, would need to check whether there's conflict of interest on authors, but assuming there aren't that is interesting.

 

The grant for the research is from a resveratrol related corp.  Which seems conflicting, but does not  necessarily invalidate research.   Need to see other studies confirming or refuting.

Edited by Castiel, 12 August 2018 - 07:27 AM.

[Castiel]

Did some more research on the dosing that's been tested in humans, think it was the study Questforlife mentioned.

 

Megadose study.  Single dose of up to 5g trans resveratrol.

 

 

Volunteers received uncoated immediate-release caplets containing 500 mg resveratrol. Caplets were manufactured by Royalmount Pharma using material synthesized under good manufacturing practice. Resveratrol in these caplets was stable under normal conditions (60% relative humidity, 25°C) for the period of time covering the duration of the trial and under conditions of accelerated decomposition (75% relative humidity, 40°C) for at least 180 days.

Peak plasma levels of resveratrol at the highest dose were 539 ± 384 ng/mL (2.4 μmol/L, mean ± SD; n = 10)

The plasma half lives of the three resveratrol conjugates, 3.2 to 11.5 h for the sulfate and 2.9 to 10.6 h for the glucuronides, were similar to those of parent resveratrol (2.9-8.9 h). http://cebp.aacrjour...ntent/16/6/1246

 

5g didn't look much better than 2.5g dose, looking at the graph almost the same.

 

In any case it appeared 2.4micromole/L was easily achieved without any enzyme blocker companion.   Also maybe I'm reading wrong but it said half life of unmetabolized could be up to around 8.9hr quite good.
What seemed worrisome was that it said metabolites were 20 fold more common, so if metabolite formation was severely inhibited it could go up to 20x the concentration of unmetabolized resveratrol.
5 micromole/L doesn't seem that hard to accomplish and sustain for several hrs, actually if I read that right seems quite easy to overdose if you block metabolite creation too much.   But a protocol should be developed to see what the optimal dose and duration of exposure is, as well as the doses of any enzyme blocker companions.

 

This was also interesting

 

 We have shown in one of our recent studies that resveratrol induced the activation of SirT1, SirT3, and SirT4, and the phosphorylation of FoxO1 and fprk-head box protein O3a (FoxO3a) as well as PBEF proteins  https://www.ncbi.nlm...les/PMC2990065/

 

 

Will note that if any of the sirtuins that use NAD+ are involved in affecting the splicing factors, boosting NAD+ may also lower the required dose of resveratrol to accomplish said feat.    

Edited by Castiel, 12 August 2018 - 10:22 AM.