Your badly mutated GULO (gulonolactone [L-] oxidase) gene has been robbing you of health all your life and limits your lifespan. It’s so badly mutated that the human variant is now called the GULOP pseudogene.Clarifying GLO, GULO and GULOP GLO is a protein enzyme called L-gulonolactone oxidase. L-gulonolactone oxidase catalyzes the ninth, critical step of ascorbic acid synthesis from glucose (blood sugar). The precursor L-gulono-1,4-lactone is a readily available product of glucose metabolism through the pentose phosphate cycle.

GULO is a gene that is called “L-gulonolactone oxidase gene.” A gene is NOT a protein. A gene is a sequence of DNA or RNA that codes for a molecule that has a function. In this case, GULO, is the gene that encodes for the enzyme GLO

GULOP is the human remnant of the gene that encodes L-gulonolactone oxidase in most other mammals. GULOP cannot generate a functional enzyme product and is therefore called a pseudogene.
Here’s what you can do about it to improve your health and increase your lifespan. Bill Sardi has been a guest of this column twice before, and has an overview of this subject scheduled for the October issue of the Journal of Orthomolecular Medicine. Specifically, we will chat with him about the latest research confirming the practical health and substantial longevity benefits of fully compensating for this defective pseudogene. The operative word here is “fully.” How much vitamin C is required to fully compensate for not having a working GULO gene? The paltry 60 milligrams that is the RDA or the several grams that animals make when they have a fully functioning GULO gene? What does the latest study suggest that the longevity increase can be?

Although humans have relatively low levels of vitamin C in their blood compared to other mammals, due to the lack of a functioning GULO gene, those having higher levels tend to live longer and have less heart disease and cancer, among other deadly diseases. As an example, a 16-year study reported in 2018 called the General Population Nutrition Intervention Trial, showed that the higher the blood levels of vitamin C were, the lower the incidence of cancer and heart disease. (1) The study was conducted by researchers from the USA National Cancer Institute and the Chinese National Cancer Institute. The 16-year study included 948 people aged 53 to 84 years at enrollment. Among participants whose blood vitamin C levels were among the top 25%, the risk of dying from any cause was 25% lower than the risk in participants whose vitamin C levels were among the lowest quarter.

Those whose blood vitamin C levels were among the highest 25% had a risk of dying from cancer or stroke that was 28% lower than participants whose vitamin C blood levels were in the lowest quarter. Likewise, the risk of dying from heart disease was 35% lower than subjects whose levels were lowest.

When subjects with low vitamin C levels (defined as 28 micromoles per liter or below) and normal levels (greater than 28 micromoles per liter) were compared, a normal level was associated with a 23% lower risk of premature mortality and a 38% lower risk of dying from heart disease, in comparison with low levels.

The researchers concluded, “In this long-term prospective cohort study, higher plasma vitamin C concentration was associated with lower total mortality, heart disease mortality and cancer mortality. Our results corroborate the importance of adequate vitamin C to human health. (1)

None of the participants had vitamin C blood levels comparable to what would be expected from persons having a fully functioning GULO gene. How much better would the difference be if the comparison was made to humans who had functioning GULO genes?

A practical technique of partially compensating for the inactive gene is available now, but an even more efficient technique of repairing the gene will be available in the just-around-the-corner future. Yes, the GULOP gene can be repaired and restored to a functioning GULO gene. With the development of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology the repair of many genes became possible.

Let’s review the problem that the GULOP causes before we chat with Bill Sardi about the solutions. Although I have mentioned the mutated GULOP and the findings of the late vitamin C researcher, Irwin Stone, many times over the 34 years of writing this column, I have never really discussed them in detail. That’s because until now, we didn’t know how to repair that mutated gene. Scientists have learned how to repair the gene in laboratory animals, and they are well along in elucidating how to repair it in humans.

Previously, I have mentioned that in chemist Stone’s more than 40 years of research on vitamin C, he had elucidated that mankind is one of the few critters who cannot manufacture ascorbic acid (vitamin C) in their bodies. Even the many thousands of animals that can synthesize vitamin C in their bodies, also eat many grams of food-grown vitamin C. Most plants also have this gene and can produce some vitamin C.

As many, if not most readers know, the intact GULO gene makes the active enzyme protein, L-gulonolactone oxidase (GLO) in most mammals and thousands of other animals. GLO is a compound required in the process that converts blood sugar (glucose) into ascorbic acid (vitamin C). In humans, the pseudogene GULOP is so damaged that it cannot make GLO and thus, mankind must get vitamin C solely from the diet. However, there is some evidence that this damaged gene can produce some vitamin C in the human fetus and in the neonate (newborn less than four weeks old). Genes become mutated when DNA “base pairs” (the four-nucleobase building-blocks of DNA) are altered or missing. Figure 1 graphically illustrates just how bad the gene is mutated in primates including man.

Figure 1. To illustrate the extent of damage to the human GULO pseudogene black boxes and white boxes marked with an “X” can be used. In this illustration, the black boxes represent the identical portions of the genes in both the rat gene and the human pseudogene. The white boxes marked with an “X” represent portions of the genes that are different due to mutations.

Comparing the human GULO pseudogene to its functional counterpart in the rat genome shows that some regions (called exons) are absent. This is represented schematically in Figure 1. This means that the human GULO pseudogene has only five exons out of the 12 found in the functional rat GULO gene. Other features of note associated with the human GULO pseudogene included one single nucleotide insertion, two single nucleotide deletions, and one triple nucleotide deletion. Researchers also identified additional “stop” codons.
Besides his elucidation of facts surrounding the missing vitamin C gene, we owe our thanks to Irwin Stone for getting Dr. Linus Pauling interested in vitamin C. Dr. Pauling introduced me to Stone while he was reviewing my manuscript for Supernutrition: Megavitamin Revolution. (2) Stone also reviewed my manuscript and on Sept. 13, 1971, he wrote to me, “the proper long-term megascorbic use of ascorbic acid will be the coming breakthrough in Geriatrics.” Well, that was almost 50 years ago. Scientists are now confirming the increased lifespan benefits. Bill Sardi will shortly review for us the recent evidence that is quite amazing and convincing.As Irwin Stone wrote in his 1972 book, human requirements for vitamin C should be based on comparison to the amount naturally produced by most animals as a liver metabolite. (3) Dr. Andrew Saul listed some of these in our January column. “Animals make a lot of vitamin C, he said, “in the neighborhood of 2,000 to 12,000 mg (2 – 12 grams) per day per human body-weight equivalent. Plus, they make considerably more vitamin C when they are becoming ill. A sick goat might make the human equivalent of 50,000 mg/day (50 grams per day).” (4)

In 1979, Irwin Stone published that, “To correct fully this human genetic defect and banish epidemic chronic subclinical scurvy requires daily intakes of ascorbate equivalent to, at least, the amounts synthesized by the other mammals. Humans kept on a long-term regime of full correction of this birth defect show great salutary benefits in health maintenance, disease therapy and slowing of the aging process.” (5)

Well, it’s 40 years later. That’s enough background and review. Now, let’s chat with Bill Sardi about the latest findings. We have discussed Hyaluronic Acid and Resveratrol with Bill in previous columns. (6,7)

Bill Sardi

Passwater: In your October Journal of Orthomolecular Medicine article, you describe several important advances in our knowledge of the human health and longevity benefits of vitamin C. (8) Please share some of these with our readers. What has been recently learned about how much vitamin C is required to fully compensate for the defective GULOP gene and what are the resulting health benefits?

Sardi: I must side-step your question momentarily to say I’m not sure readers will be able to fathom the gravity of this unprecedented moment in human history. What Irwin Stone predicted has now come into view. Full correction of this universal gene mutation that has plagued mankind has been within reach ever since vitamin C was synthesized and vitamin C pills were available. Only the ruling health authorities have kept this from becoming a reality, insisting 10 milligrams of vitamin C a day prevents overt symptoms of scurvy, but never addressing the incomplete repletion of vitamin C to blood levels achieved prior to a gene mutation that has plagued humanity for centuries. And, unexpectedly, beyond repetitious daily use of vitamin C it’s also now possible to edit the GULOP gene with the home use of a natural molecule. I hope what I just said gets readers’ attention.

Second, I’m not sure how to prepare readers to fully appreciate what we have learned, namely that humans via vitamin C restoration, can live far longer than imagined, even longer than calorie restricted diets that are widely hailed for their ability to double the lifespan and healthspan of laboratory animals.

Third, some preconceptions readers have may need to be cast aside. What we have learned via eloquent research conducted by Canadian investigators is that if what has been demonstrated in the animal laboratory can be extrapolated to humans, our lives are being cut short by two-thirds.

Passwater: How do we know this?

Sardi: For those who are not familiar with medical research, there is no way to conclusively prove this in humans, as that would take many decades and unbelievably large sums of money.

Passwater: The study will never be done. When I was the Research Director for the American Gerontological Research Laboratories in Rockville, MD, I addressed this at the 1970 Meeting of the Gerontological Society of America (which was held in Toronto). I had demonstrated 35% increases in median lifespans and 10% increases in maximum lifespans of several species of laboratory animals. (9) It had become apparent that no matter which specie of animal in which I demonstrated increased median and maxima lifespan, the criticisms were always, that 1) it still needed to be demonstrated in humans, and 2) that the increased longevity could be due to reductions in disease, not an effect on the basic aging process itself. Of course, there is still no agreement on what is the basic aging process. I proposed using biomarkers instead of human lifespan (10).

Seeing that this was hopeless, I decided to switch from gerontology to nutrition, where the health benefits could be taken advantage of in a practical manner in real time when it is needed.

Sardi: Because of this time factor, short-lived mammals like laboratory mice must be used. Here is a simplified explanation of the experiment conducted and published in the journal Aging and available for public review. (11) The lead scientists were from Centre de Recherche du CHU de Québec, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada, Centre for Education and Research on Aging and ANZAC Research Institute, University of Sydney and Concord Hospital, New South Wales, Australia, Quebec Heart and Lung Institute, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada and Centre de Recherche sur le Cancer de l’Université Laval, Hôpital Hôtel-Dieu de Québec, Quebec City, Quebec, Canada.

In their studies, researchers first supplemented vitamin C to rodents that naturally secrete vitamin C and thus naturally make the optimum amount that they need. They didn’t live any longer.

Passwater: How long did they live in their natural vitamin C-secreting state?

Sardi: About 23.8 months as a group and the longest living (maximum lifespan) was 30 months. So that is their designed-in lifespan. Their blood concentration of ascorbate (vitamin C) was ~58 micromole per blood sample.

Passwater: Then what?

Sardi: Then these researchers made the laboratory mice’s GULO gene dysfunctional – the precise predicament humans now find themselves in. These now genetically flawed mice were given just enough vitamin C so as not to develop scurvy. They lived ~8.5 months on average (Median lifespan). The maximum lifespan of this group was 16 months.

Now we have to stop right there and say these animals, when they have their naturally functioning GULO gene, live about 23.8 months.

Passwater: How does this fit with what we observe with humans since we have a dysfunctional gene like the modified mice?

Sardi: Irwin Stone noted that animals that naturally secrete vitamin C live 8-12 times beyond their age of physical maturity whereas animals like guinea pigs, primate monkeys and fruit bats that have the same GULOP gene mutation live only 2-3 times beyond their age of maturation. If vitamin C synthesis could be naturally restored, using these figures, humans would then be expected to live to 144-216 years.

Passwater: At least we would have a very significant lifespan increase. Other factors, such as walking in front of speeding trucks or other nutritional deficiencies, may become limiting factors. Limiting factors are like layers in an onion: peel one away and another is there. Even animals that produce their own vitamin C still die of other causes, but it’s important to do away with the biggest limiting factors to have a better chance.

In my opinion, the most important factor is to optimize vitamin C blood levels and the second most important factor is to optimize vitamin D blood levels. These two factors will account for substantial improvements in health and longevity, but the optimization of all nutrients will bring even further gains. This was my “Supernutrition Principle” that I introduced in 1975, but as it turns out, the levels required for optimization are higher than I projected then.

It has become clear that a vitamin C blood level above 60 µmol/L is necessary to optimize well-being and longevity; anything less than that is a deficiency that directly leads to shortened lifespan and increased disease.

Your Journal of Orthomolecular Medicine article then tells us something even more important. What did the researchers do next?

Sardi: The Canadian and Australian researchers took another group of mice and made their GULO gene dysfunctional like our GULOP gene. Then they supplemented their diet with vitamin C to achieve the same blood concentration as the rodents that naturally secrete vitamin C (60 micromole).

The result was these animals that had their vitamin C levels restored via supplementation lived on average 23.0 months and the longest living survived 32 months.

The vitamin C-supplemented mice with a dysfunctional GULO gene achieved a blood level (~60 micromole per blood sample) of vitamin C equal to that of mice that naturally produce vitamin C internally and lived 2.7 times longer than un-supplemented mice with a damaged GULO gene. (See Figure 2 below)

Figure 2. Courtesy of Bill Sardi

If this could be extrapolated to humans, individuals who achieve ~60.0+ micromole blood plasma concentrations of vitamin C would live 216.0 years compared to humans with low vitamin C blood concentrations who would likely live only 50-70 years. (Please see Figure 3.)
What this says, obviously, is if this discovery can be applied to humans, vitamin C supplementation to achieve a target blood concentration could plausibly result in humans living two-thirds longer (recall the animals’ lifespan jumped from 8.5 months to 23.0 months). We must abandon the practice of measuring intake levels and rely on blood concentration to guide us to achieve full correction of this gene mutation.

Passwater: I whole-heartedly agree. Blood levels and cell entry are what is important for nutrients. This has been my theme in several of my recent articles on vitamin C. As you said, “if” we can extrapolate to humans. That may be a big “if.” Other factors may then become limiting factors. Can we extrapolate from rodents to humans?

Sardi: Yes, some studies have been shown to extrapolate well. Others, less so.

Passwater: Even a modest extrapolation would have enormous benefits in health and longevity.

Sardi: Rodents do have about the same number of genes as humans (~25,000) and their genes are positioned similarly (homologous). The ascorbate blood levels of the animals whose GULOP gene was disengaged were ~11 micromole compared to the rodents that have an intact GULOP gene with a blood level ~58 micromoles.

Of interest, there are an estimated 15 million Americans with blood levels that low (11 micromoles). The average dietary intake of vitamin C is ~110 milligrams. We know some primate monkeys that don’t internally produce vitamin C consume 6000-8000 milligrams per day.

Most people living in developed countries have access to so-called vitamin C-rich foods (just 60 mg in an orange) and maintain blood levels in the 20-40 micromole range. A few people achieve higher blood levels, most all of them are supplement users. Yes, humans can now achieve 60+ micromole.

Steve Hickey, using National Institutes of Health data, estimates that a 500 mg oral dose of vitamin C will achieve a quasi-steady state ~130-170 micromole/liter, with variance from individual to individual. (12) The laboratory mice in the Canadian study had their blood levels rise 5-fold (11 to 58 micromole). Typical blood levels of humans range from 20-40 micromole and ~60 micromole among supplement users.

Figure 3. Extrapolating the experimental animal study to humans. Courtesy of Bill Sardi.

Passwater: We chatted with Dr. Hickey about this in the July issue. (14)

Sardi: Yes, according to Hickey, repeated consumption of 500 mg throughout the day (every 4-6 hours) would be anticipated to produce a 130-170 micromole level which would be a 3 to 8-fold increase in blood concentration (calculated for a 160-lb/70-kilogram adult). If consumers decide to take more than 500 milligrams at a time, absorption, the percentage of each corresponding increment, is diminished. For example, according to Hickey, a 1000 milligram dose is about 75% absorbed (which is a total of 750 milligrams absorbed) and only about 30% is absorbed when a 3000 mg dose is consumed (which is a total of 900 milligrams absorbed). Relatively low repeated doses achieve optimal absorption and optimal blood concentration.

This would likely require consumers purchase bottles of vitamin C and place them in the kitchen, in the car, in their desk at work and at their bedside, so they are conveniently within reach at different times of the day. Vitamin C pills can be inexpensively purchased. A 500 mg vitamin C tablet can cost under 5 to 8-cents X 4 = a day = or just $6.00-10.00 a month. The problem is compliance.

There is nothing scientifically or safety-wise keeping this knowledge from the public since the time Irwin Stone began advocating vitamin C be replaced to the same amount internally produced before the universal gene mutation affected mankind. Instead, public health authorities chose to steer the public to minimal doses that avert overt symptoms of scurvy, leaving the effects of the gene mutation never fully compensated for.

Stone estimated 1800-4000 milligrams of oral vitamin C per day would equal the amount unstressed humans would produce with a functional GULOP gene. (Perspectives In Biology & Medicine Vol. 10: 133, 1966) Given that vitamin C is rapidly excreted in urine flow in humans, the Dynamic Flow model of vitamin C supplementation as described by Drs. Steven Hickey, Hilary Roberts and Robert Cathcart is instructive. (14) Optimal (but not ultimate) vitamin C blood levels can be achieved by taking vitamin C throughout the day, 500 milligrams every 4-6 waking hours. That would amount to ~2000 milligrams a day which is right at the tolerable safe upper limit established by health authorities. Other researchers report a 1250 milligram dose taken every 3-4 hours would achieve peak blood plasma levels of ~134 micromole/liter. The ultimate maximum blood level that can be achieved via oral dosing is reported to be ~220 micromole. (14)

We must consider dynamic factors when we talk about vitamin C. The need or demand for vitamin C varies by the amount of physical or emotional stress. It needs to be said that severe physical or emotional stress, or disease, or diabetes, certain drugs (aspirin, steroids, acetaminophen, diuretics), tobacco use, all increase the demand for vitamin C. So dietary intake is not likely to make up for increased demand imposed by stress or other exogenous factors. So, the idea of correcting the gene mutation is of acute interest.

Passwater: What is typical for man?

Sardi: When under stress, humans release sugar and fat stores into the blood stream upon secretion of adrenal stress hormones. This facilitates the well-known adrenalin rush that humans need to flee danger. What I just said is that humans have high blood sugar (diabetes) and fat (cholesterol) levels in their blood when under stress. The animals that naturally secrete vitamin C enzymatically convert blood sugar into a sugar-like molecule we know as ascorbate (vitamin C). The more stress, the more sugar that is released. The more sugar that is released, the more vitamin C is made in vitamin C-secreting animals.

In animals, vitamin C is a stress hormone. Humans lost the ability to handle stress when the species incurred this universal gene mutation many generations ago. With tongue in cheek, I’ve often said if I take enough of these vitamin C pills I will die of nothing, but stress is going to kill me. Humans can take vitamin C pills throughout the day. But to fully make up for the gene mutation and handle stress, the gene would need to be re-activated.

Passwater: Can we raise our blood levels of vitamin C to that of the animals that produce their own, and when we do, what happens?

Sardi: Humans can take vitamin C throughout the day and achieve higher blood levels, but we simply don’t know how much we need to take when under duress — a lot more than 2000 mg/day. Switching the GULOP gene back on will restore man’s ability to deal with biological stress. Vitamin C will become a hormone once again.

Passwater: Did these studies show an increase in longevity as well?

Sardi: As previously mentioned, yes, the lab animals lived three times longer with repeated vitamin C supplementation throughout the day. There are a lot of corroborative studies showing vitamin C supplementation reduces mortality rates and even modest doses increase lifespan (300 mg achieved 6-year expansion in lifespan for males).

Passwater: In review of the study, these are the main points (Please see Figure 2) 1) Mice normally produce all the vitamin C that they need thanks to a healthy GULO gene. 2) Adding a small amount of oral vitamin C did not produce an observed benefit. 3) Inactivating their GULO gene that naturally produces vitamin C in their bodies, decreased their lifespans to near zero in the absence of additional dietary vitamin C. This is similar to the situation in humans. 4) Adding small amounts of vitamin C to the diets of the mice having the inactivated GULO genes that would otherwise produce vitamin C naturally in their bodies, is enough to prevent scurvy, but the mice still have a diminished lifespan and poor health. Their median lifespan was 8.5 months and their maximum lifespan was 16 months. This compares to their natural median lifespan of 23.8 months and their natural maximum lifespan of 30 months when they have their normal active GULO genes. This is similar to the situation in humans. This increased their lifespan some, but still far, far short of their natural lifespan. 5) Adding larger amounts of vitamin C to the diets of the mice having the inactive GULO genes in sufficient quantity to restore their blood vitamin C levels back to that normally produced when they have healthy GULO genes also restored their normal lifespans. A 2.7 times increase. This may be similar to the situation in humans. Absolute scientific proof will not be known for several generations.

In the meantime, people can choose to learn from the teachings of this study or go with the uninformed opinions of the anti-vitamin naysayers. It’s their lives. The risk is nil and the benefits may be enormous, even if not fully extrapolated to lifespan. There are many health benefits already known to come with optimization of blood levels of vitamin C.

In summary, the message, as Bill Sardi pointed out in the October JOM article, is “The striking discovery was that mice that were genetically altered to NOT produce vitamin C and then supplied with an ample amount of oral vitamin C to achieve a 61.0 micromole blood concentration, lived as long as mice that naturally produce their own vitamin C (23.0 months median lifespan/ 32.0 months maximum lifespan)!” (8)

Let’s take a break here and discuss the mechanisms involved next month in Part 2.
  1. Wang, S-M., Fan, J-H.,  Taylor, PR.,  et al., Association of plasma vitamin C concentration to total and cause-specific mortality: a 16-year prospective study in China. J Epidemiol Community Health. 2018 Aug 12. pii: jech-2018-210809. doi: 10.1136/jech-2018-210809.
  1. Passwater, R.A. Supernutrition: Megavitamin Revolution. Dial Press NY (1975).
(3) Stone, Irwin. The Healing Factor: Vitamin C Against Disease. Grosset & Dunlap. NY (1972)

(4) Passwater, R.A.” Oral High-Dose Vitamin C for Major Diseases

An Interview with Andrew W. Saul, Ph.D.”  Whole Foods Jan (2018).
  1. Stone, I. Homo sapiens ascorbicus, a biochemically corrected robust human mutant. Med Hypotheses. 1979 Jun;5(6):711-21.
  2. Passwater, R.A. Oral Hyaluronic Acid: Anti-aging, Skin, Joints and Healing: An Interview with Bill Sardi. Whole Foods (April 2003).
  1. Passwater, R.A. The RDA for Vitamin C Is Invalid: New Information. An Interview with Bill Sardi. Whole Foods (September 2005)
  1. Sardi, B. “Can Lifespan Be Dramatically Increased For Humans As Well As For Laboratory Animals?” In Press. Journal Orthomolecular Medicine. Scheduled for October 2018.
  2. Passwater, R.A. and Welker P. A. Human Aging Research, Part I. American Laboratory 3 (4) 36-40 (1971); International Laboratory 24-28 (May/June 1971).
  3. Passwater, R. A. Plans for a Large-Scale Study of Possible Retardation of the Human Aging Process. The Gerontologist 10 (3) 11, 28 (1970).
  4. Aumailley L, Warren A, Garand C, et al., Vitamin C modulates the metabolic and cytokine profiles, alleviates hepatic endoplasmic reticulum stress, and increases the life span of Gulo-/- mice. Aging 8(3) 458-83 (2016).
  5. Padayatty S.J., Sun H., Wang Y. et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Annals Internal Medicine 140: 533-37, 2004.
13: Passwater, R.A., The Science of Vitamin C Research on Optimizing Blood and Cellular Levels. An Interview with Steve Hickey, Ph.D. Whole Foods July 2018.
  1. Hickey, D.S., Roberts, H.J. and Cathcart, R.F. Dynamic flow: a new model for ascorbate, Journal Orthomolecular Medicine, Volume 20, No. 4, 2005.