Vitamin C Reduces Human Mortality

Source: https://www.lifeexte...uman-Mortality/

I am in. Is there a consensus in which kind is best to supplement?

Long term users who have benefited for many years, especially from intractable chronic disease, have no doubt. However, all others still can't agree. One such discussion: https://www.longecit...ystemic-health/
 

While Im a fan of vitamin c (despite me not taking it atm due to acidity) I do would have to say I have a strong dislike for lifeextension website blog posts... theres simply too much of an overhyped marketing factor in it.

So for everyone like me who dont want to dig through the bogus bullshit over at the LE website heres the link to the actual study: 

Association of plasma vitamin C concentration to total and cause-specific mortality: a 16-year prospective study in China. (not sponsored by any vitamin c supplement seller it seems)

https://www.ncbi.nlm...pubmed/30100578

Something I would like to add (not sure how relevant it is but it could be): both resveratrol (and other antidiabetic compounds) aswell as vitamin c seem to upregulate PON1. This powerfully controls lipid peroxidation among many other things that are important. In fact PON1 plays a crucial role in detoxicfication of homocysteine junk called homocysteine thiolactone:

https://en.wikipedia.org/wiki/PON1

Serum paraoxonase/arylesterase 1 (PON1) also known as A esterase , homocysteine thiolactonase or serum aryldialkylphosphatase 1 is an enzyme that in humans is encoded by the PON1 gene.

"PON1 is responsible for hydrolysing organophosphate pesticides and nerve gasses. Polymorphisms in the PON1 gene significantly affect the catalytic ability of the enzyme.^[10]

PON1 (paraoxonase 1) is also a major anti-atherosclerotic component of high-density lipoprotein (HDL).^[11][12] The PON1 gene is activated by PPAR-γ, which increases synthesis and release of paraoxonase 1 enzyme from the liver, reducing atherosclerosis.^[13]

The "natural" substrates for PON1 appear to be lactones.^[14] However, PON1 has evolved to be a highly promiscuous enzyme capable of hydrolysing a wide variety of substrates such as lactones (including a number of important pharmaceutical agents such as statins), glucuronide drugs, thiolactones, arylesters, cyclic carbonates, organophosphorus pesticides and nerve gases such as sarin, soman and VX, oestrogen esters and lipid peroxides(oxidised lipids)."

"PON1 was first discovered through its ability to hydrolyse and therefore detoxify organophosphorus compounds which are widely used as pesticides and nerve gases. Despite decades of research it is only now becoming clear that PON1 protects humans from the acute and chronic harmful effects of these compounds^[20][21] Low PON1 activity found in children may increase their susceptibility to organophosphates.

Oxidised-lipids are the major cause of inflammation and are responsible for the initiation and/or propagation of several inflammatory diseases including atherosclerosis (heart disease and stroke), diabetes, liver and kidney diseases, rheumatic diseases, eye diseases (macular degeneration), cancer and HIV infection^{[citation needed]}. Because of its ability to destroy oxidised-lipids PON1 appears to play some role in all these diseases. However, the greatest research interest has been the role of PON1 in atherosclerosis, where, because of its ability to remove harmful oxidised-lipids, PON1 protects against the development of atherosclerosis^[22] Oxidized polyunsaturated fatty acids (notably in oxidized low-density lipoprotein) form lactone-like structures that are PON substrates.^[23]

PON1 also protects against bacterial infection by destroying the bacterial signalling molecules that cause gram negative bacteria to invade human tissue and form colonies, thus PON1 contributes to the bodies innate immunity^[24]"

https://en.wikipedia...ki/Homocysteine

Homocysteine can cyclize to give homocysteine thiolactone, a five-membered heterocycle. Because of this "self-looping" reaction, homocysteine-containing peptides tend to cleave themselves by reactions generating oxidative stress.^[9]

Homocysteine also acts as an allosteric antagonist at Dopamine D₂ receptors.^[10] It has been proposed that both homocysteine and its thiolactone may have played a significant role in the appearance of life on the early Earth.^[11]

Now obviously resveratrol alone isnt unique in inducing PON1 (vitamin c, quercetin and low alcohol intake also do so), but the MOA by which it does seems rather unique from what I understand.

Induction of the Paraoxonase-1 Gene Expression by Resveratrol

https://www.ahajourn...146530.24736.ce

"Methods and Results— PON-1 activity assays, Northern blot, and transfection experiments showed that resveratrol increased the PON-1 gene expression in human hepatocyte primary cultures and in the HuH7 hepatoma cell line involving a transcriptional mechanism. The resveratrol effect was not ERα-dependent and was surprisingly mediated by the aryl hydrocarbon receptor (AhR) and an unconventional AhR responsive element in the PON-1 gene promoter. This agonist effect of resveratrol was specific for this DNA motif and was not observed on classical AhR responsive elements.

The human paraoxonase-1 (PON-1) is a high-density lipoprotein-associated enzyme displaying protective properties toward cardiovascular disease. We show that resveratrol, a wine component, increases the PON-1 gene expression in human hepatocytes and in the HuH7 hepatoma cell line by an unusual AhR-mediated transcriptional mechanism."

Whats kind of unique about it is that resveratrol seems to also be an AHr antagonist (selective one) and thus blocking blocking the formation of carcinogens such as those in car exhaust and cigarette smoke AND at the same time increase the defense against toxins and endogenous created junk by inducing PON1.

Edited by MankindRising, 16 March 2019 - 11:20 PM.

I am in. Is there a consensus in which kind is best to supplement?

Try the time-release Vitamin C   --  that will ensure you constantly have a healthy supply of it

Try the time-release Vitamin C -- that will ensure you constantly have a healthy supply of it

Won't this supplement hinder my response to exercise?

Depends, in studies it seem to do to some extent.

In real life and my case of a 60% walking-disability due to PAD (considered a progressive and non-reversible chronic disease) and a 80% stenosis at my abdominal aorta, which initially allowed me to walk 300-400 meters only at a time (10 years ago), improved very fast to at least being able to walk 1 hour at a time, after reaching a higher therapeutic dose of at least 6 g/d after one year (together with lysine, as part of Linus Pauling's recommendations). So with a chronic disease, where walking has become the only kind of exercise tolerated, at least in my case it improved.

2012 had a setback to only 1/2 hr walking distance due to a chronic bronchitis that whole year. Finally that cured with a lot of sunshine and sea-breeze at a South-Indian beach for 4 months. Which for its beneficial effects I repeated from then on, by staying each winter for 6 weeks on vacation there. Which additionally allowed to exercise in swimming, and much further than at home in Europe. Where I only get to 20 minutes at a time due to shivering, while relaxed swimming in the tepid Ocean there allowed up to 40 minutes at a time.

However, only after 6 years of high dose vitamin C (in average at about 23 g/d for that time period) the 60% walking-disability was officially revoked, and given a remaining general 50% disability for remaining general symptoms similar to CFS instead.

Finally this year winter swimming in the Arabic sea each day up to 40 minutes again, after some weeks I thought I will probably never be able any longer at a time. But then it gave way and even been able to swim 70 minutes at a time the last 2 weeks.

That's of course only one anecdotal experience, additional with a very nasty usually non-reversible chronic disease. However, since exercise capacity is really not difficult to ascertain, it is easy enough to find out by how any intake is affecting oneself, and therefore really no need for believing in studies.

 

Try the time-release Vitamin C -- that will ensure you constantly have a healthy supply of it

If one goes the for me effective route of taking teaspoon fulls of pure ascorbic acid 3-4 times a day in a glass of water - than I would highly disadvise to use any capsule or tablet products, but only pure powder mixed in water. For avoiding all the binder, filler and additives. Which other than ascorbic acid can't be healthy in the many grams range for many years.

Though only my anecdotal experience, I have taken various amounts of Vit C throughout my life, from young adulthood, and continuing as of today, so at least 40+ yrs. Never less than 500 mg/day normally, typically 1g/day, but when ill (colds/flu/etc) sometimes as much as 1g/hr while awake. I'm not any great athlete, but have gotten more fit in later life by some measures, and have been generally healthy throughout. 

Back in the day, I was a great fan of Linus Pauling, who was a promoter of Vitamin C for many ills. I took that to heart and I can't say I've ever regretted it. In fact, I highly recommend using Vitamin C to anyone.

I'm not stating this as a fact, but my interpretation of those studies showing that antioxidants can reduce the response to exercise is that they are looking at artificial high-intensity short-term exercise. The kind that "shocks" muscle cells into growing or firing more forcefully.

In this situation the intensity is managed so as to not damage the cells. For example, nobody starts an exercise program by running 10 miles at maximum speed, but in an uncontrolled situation this might be suddenly necessary in an emergency or when fleeing danger or whatever. In the latter situation, you might well say that antioxidants are highly beneficial by reducing oxidative stress and improving the recovery time.

In other words, the effect may be real, but in everyday experience it could be either desirable or undesirable depending on the context. And if you exercise regularly, even if you take supplements of course you'll still see a longterm health & fitness benefit. I don't see how anyone could doubt that.

Edited by joelcairo, 20 March 2019 - 08:52 PM.

I'm not stating this as a fact, but my interpretation of those studies showing that antioxidants can reduce the response to exercise is that they are looking at artificial high-intensity short-term exercise. The kind that "shocks" muscle cells into growing or firing more forcefully.

 

In this situation the intensity is managed so as to not damage the cells. For example, nobody starts an exercise program by running 10 miles at maximum speed, but in an uncontrolled situation this might be suddenly necessary in an emergency or when fleeing danger or whatever. In the latter situation, you might well say that antioxidants are highly beneficial by reducing oxidative stress and improving the recovery time.

 

In other words, the effect may be real, but in everyday experience it could be either desirable or undesirable depending on the context. And if you exercise regularly, even if you take supplements of course you'll still see a longterm health & fitness benefit. I don't see how anyone could doubt that.

My take, as a lifelong lifter and biologist, is that reducing oxidative damage during training will reduce the body's response to said exercise over the short term, ie during the recovery period. In lifting you are quite literally damaging muscle cells in order to spur a repair response by the body in the hopes of adapting to the new stressor. Inflammation is a key part of this process so adding endogenous anti inflammatories or antioxidants will dull the signaling cascade that triggers the adaptation.

If one is training for a specific goal such as preparation for a contest, then I would say to not take high levels of vitamin C or NSAIDS as that can potentially blunt gains. For the rest of us non-competitors, I think it's fine as reducing exercise induced cellular damage is likely beneficial over the long term/lifetime.

Is it because oxidative stress can activate SIRT genes? So, if one was taking SIRT activators like NMN, Pterostilbene, and Resveratrol? I've heard of SIRT activators like NMN turn on many (all?) of the same genes that exercise does.

I've supplemented C all my life, but along the way, I've learned a couple of tips to optimize effectiveness.  

Everyone thinks of Vitamin-C as an antioxidant, but it can also have pro-oxidant properties in the presence of unbound transition metals, specifically iron.  

Look Here: http://flipper.diff....p/pathways/6861

"Iron and ascorbic acid form a potentially toxic cocktail. The chemical mechanisms given above have been established demonstrating the potential for these compounds to interact and oxidatively damage surrounding tissues."

If you wish to optimize Vitamin-C's benefit, make sure your iron homeostasis is also optimized.  Ferritin should be in the lower third (less than 100) and iron saturation (TSAT) in the middle third of normal range if you want to avoid Fenton / Haber-Weiss redox cycling and hydroxyl radical generation.  

Iron chelators like Curcumin, Quercetin & IP6 (inositol hexaphospahte) can also help optimize the antioxidant potential of Vitamin-C.  

Vitamin-C also GREATLY increases absorption of non-heme dietary iron, & thus I consider it an "empty stomach" supplement.  Taking Vitamin-C with iron fortified foods is a recipe for inflammation of the gut and body.  

A low iron environment will supercharge the effectiveness of Vitamin-C.  Lower doses will be more effective, and you'll avoid potential for redox cycling and aggravation of "Ferrotoxic Disease"

https://www.longecit...isease-omnibus/

  Stay Healthy My Friends!  

Edited by Dorian Grey, 27 March 2019 - 06:54 AM.

I think we need to see "antioxidants" in two categories: radical scavengers like Vit C, E, A and Longevity and metabolic pathways modulators with or without antioxidant properties.
Last category include the typical ones: Quercetin, Curcumin, Resveratrol, Ginseng, Fisetin, Andrographis Paniculata*, Sulforaphane*, Berberine, Rhodiola, Gingko, Centella Asiatica, Grape Seed Extract, Emblica Officinalis, Jiaogulan, Boswellia Serrata, Astragalus.... and so on #zizek

** Are two examples of the strange and contradictory effects of natural extracts in the body, both are potent Nrf2 activators, these supplement could protect healthy cells but selectively damage unhealthy ones. Some of thes activates AMPK but at the same time  could enhance regenerative and some anabolic pathways like neurogenesis. The more I learn about natural plant extracts the less I understand about how these things works. Some of these compounds have direct antioxidant properties like Emblica Officinalis other has less antioxidant properties like resveratrol but works indirectly like one by activating Sirt1 and reducing inflammation by mimicking a CRON diet.

What happens if you take Resveratrol+Jiaogulan (Sirt1+AMPK activator) before weight lifting training followed by a protein shake? enhanced muscle growth, reduced muscle growth, it prevents mTOR? I don't know.

Apparently is best to take antioxidants in the recovery period. Recently I started to experiment with Na-R-ALA and I love it, I'm just loosing body fat by taking it.

It apparently enhances my Insulin sensivity, thats why I started using before exercise in a fasted state. At least I can see that it does not prevent muscle growth if followed by protein consumption. ALA is another special case, it has antioxidant properties, activates Nrf2 also and some studies show AMPK and Sirt1 activation properties. 

I will start to see how Na-R-ALA works after the exercise and just before the protein consumption. 

I will include Vitamin C in my daily regimen. For years we have had good supplements/drugs around us for preventing disease and slowing aging but nobody believe it could work, other though that aging and disease was a inevitable thing of luck, a propertie of being alive. Others have tended to believe that to prevent aging we need expensive drugs and very advanced technology.

Apparently supplements or drugs that are reliable and effective have been in circulation for quite some time and at low cost:
-Niacin
-Vitamin C
-Glucosamine

The cheap oldies.

add a good diet, exercise, fasting and you could have some success . Now we have things like NAD+ boosters, Sirt1 activators, Mitochondrial antioxidants, enhanced drugs like liposomal Curcumin, Na-R-ALA, an easy access to machines like ICES, PEMF. 

Maybe I'm being very optimistic today?.... well at least if someone has not enough money to spend in "high end drugs" there are some things that can be done with the cheap oldies

Edited by BieraK, 24 June 2019 - 09:33 AM.

Vitamin C inhibits glycation and the formation of AGE’s. Especially when taken with meals.
..
https://www.ncbi.nlm...pubmed/14962639

That second study I copied in the following thread, when it still was openly available: http://www.longecity...156#entry797721

And is not only remarkable in that the antiglycation-effect doesn't has anything to do with or without meals, but purely the amount of ascorbic acid taken throughout the day:

The patients had been encouraged as part of their treatment to supplement AA. Self-reported daily intake varied from 0 to 20 g/day. The plasma AA levels ranged from 11.4 to 517 µmol/L and correlated well with the reported intake. Regression analysis of their GHb and plasma AA values showed a statistically significant inverse association (eg, each 30 µmol/L increase in plasma AA concentration resulted in a decrease of 0.1 in GHb).

The usual reference range for plasma ascorbic acid is 0.4-2.0 mg/dl, which is about 22.7-113.6 µmol/L. While the majority of the population is even below 1 mg/dl, 20g-per-day-dosers in this New-Zealand study had up to 9.1 mg/dl. Which compared to non-supplementers would mean a decrease in HbA1c of 1.5%!

Edited by pamojja, 24 June 2019 - 08:56 PM.

Fruit and vegetable intake would increase plasma vitamin C, and hence in non-supplement users plama C is a marker of F&V intake.This could easily account for the results from the engadin's citation.

There have been numerous randomized controlled trials on vitamin C supplementation with all-cause mortality as an endpoint.The Cochrane metaanalysis from 2012 looked at 29 such trials involving vitamin C, and found no effect (RR 1.02, 95% CI 0.98 to 1.07)

Bjelakovic et al, 2012. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane database system rev, (3).

The body rapidly excretes vitamin C when concentrations exceed about 80 μM, so we must inquire why restricting concentrations beyond this level is adaptive. One reason may be the activity of ascorbate in reducing Fe³⁺ to more reactive Fe²⁺, and Cu²⁺ to more reactive Cu¹⁺, through the Fenton reaction, causing proxidant effects in some tissues, notably lens crystallins leading to cataract. There are other health issues with supplement level vitamin C, for example as its metabolized to oxalate before excretion, supplemental vitamin C is associated wih kidney stones. 

Buettnez and Jurkiewicz, 1996. Catalytic metals, ascorbate and free radicals: combinations to avoid. Radiation res, 145(5), pp.532-541.

Fan et al, 2006. Vitamin C mediates chemical aging of lens crystallins by the Maillard reaction in a humanized mouse model. Proc Nati Ac Sci, 103(45), pp.16912-16917.

Rautiainen et al, 2009. Vitamin C supplements and the risk of age-related cataract: a population-based prospective cohort study in women. Am J clin nut, 91(2), pp.487-493.

Thomas et al, 2013. Ascorbic acid supplements and kidney stone incidence among men: a prospective study. JAMA int medi, 173(5), pp.386-388.

There's one useful clinical application of vitamin C in those not suffering from scurvy: intravenous injections of high dose vitamin C to potentiate the pro-oxidative effects of some forms of cancer chemotherapy. Otherwise, I can't imagine why anyone who has surveyed the literature, and eats a diet rich in fruits and vegetables, would care a whit about it.

Edited by Darryl, 24 June 2019 - 10:31 PM.

The body rapidly excretes vitamin C when concentrations exceed about 80 μM, so we must inquire why restricting concentrations beyond this level is adaptive. ..

 

Otherwise, I can't imagine why anyone who has surveyed the literature, and eats a diet rich in fruits and vegetables, would care a whit about it.

Above study just posted above yours shows the myth about vitamin C being excreted above certain levels also reached by diet, just not true. Though true that those 20g-per-day-dosers reached only about 6-7 times higher 517 µmol/L by 200 times higher ascorbic acid intake. Plasma levels nevertheless still were 6-7 times higher at all the times!

One reason one would care a lot about it are chronic diseases, where one often has nothing more to loose than just to try it, and experience the amazing benefits oneself. And a plasma vitamin C test is easy to get oneself, to prove that the whole literature only testing the minutia of low dose vitamin C not appropriate for catching the efficacy of oral high dose vitamin C.

Just came across an experience of Irvine Stone, in which the blood concentration of an individual with cancer taking 150 g/d of ascorbic acid orally was measured:

http://orthomolecular.org/library/jom/2005/pdf/2005-v20n04-p230.pdf

 

Another was Albert Szent-Gyorgyi. In a 1982 letter,14 Stone tells Szent-Gyorgyi of a friend of his who, was diagnosed with prostate cancer at age 44 and then treated with surgery and radiation. A few years later, the cancer had metastasized to the pelvic bone and the patient was declared terminal and given about a year to live. However, Stone writes:

“Since he began taking 80 grams a day in 1979, his well-being has been excellent. He says he feels great most of the time, has also been able to continue working every day and lives a fairly normal life of the years since November 1978 when orthodox medicine said he would be dead. Visually he looks more like an athlete than a terminal cancer patient...

In the last few weeks he has been able to improve his well-being by increasing his ascorbate intake to 130 to 150 grams per day! He has been taking oral doses every hour of 5 to 10 grams of a mixture of nine parts sodium ascorbate plus one part ascorbic acid dissolved in water. These doses are well tolerated and within “bowel tolerance” and he has had no trouble from diarrhea except just lately when he had to reduce the 150 grams a day to 130 grams.

I believe his case is a classic and a good demonstration that if sufficient ascorbate is given to fully counteract all the incident stresses, then the cancer can be controlled. If given early enough in this disease, then cancer may no longer be a problem. Up to now we just haven’t realized how big these daily controlling doses have to be.”

Stone adds that the man’s doctor “ran some ascorbate determinations on Joe’s blood and came up with the highest blood levels I ever saw. At one point it was 35 mg%! Our so-called “normal” but scorbutic population averages 1 mg% or less, our kidney threshold is 1.4 mg%...

I would like to see a crash ascorbate program started on terminal cancer patients using doses in the ranges found to keep his cancer under control. Since these “terminals” have been abandoned by orthodox medicine, they have nothing to lose but their ill health.”

The usual reference range for plasma ascorbic acid is 0.4-2.0 mg/dL, which is about 22.7-113.6 µmol/L. While the majority of the population is even below 1 mg/dl, 20g-per-day-dosers in the New-Zealand study had up to 9.1 mg/dl. Though I'm not sure mg% correlates to mg/dl, by the statement that 1 mg% would be normal it does seem so. Therefore serum levels of even up to 35 mg/dl or 15380 µmol/L are possible orally, in individuals with such high bowel tolerance due to severe conditions.

But sadly in my experience, no actual measurements of oral high dose vitamin C plasma serum levels will ever convince the believer of the NIH myth. As Darryl just exemplified.

Edited by pamojja, 25 June 2019 - 09:17 AM.