Former Visiting Professor Patrick Holford is Head of Science and Education at Biocare who display the indulgence of peculiarly fond family members in declaring him to be an innovative thinker and expert despite the many faux pas and errors that have been highlighted in his work. Biocare must be delighted to have their most high profile media nutritionist’s work featured in News of the World (NotW): Look 10 Years Younger with the H-Factor.
Now, we regularly review Holford’s overblown rhetoric about homocysteine (Hcy) as a “crystal ball for…future health”. Holford has a strong financial interest in the topic as it allows him to recommend a package of tests, consultations with nutritonistas and supplements that total £380-720 person, per year, not including the basic Holford package of recommended supplements.[a]
We’re accustomed to Holford’s usual health claims for Hcy that lack robust clinical support so we were a little surprised to see that he has now aggrandised its significance to include rejuvenation and the deceleration of ageing.
Homocysteine…if you care about your looks (and who doesn’t?), commit it to memory. With the right diet, homocysteine – or H-factor – can rejuvenate cells, leaving you with youthful-looking skin. Although too much can cause premature ageing.
“The discovery of this simple protein has revolutionised the way we look at ageing,” says Patrick [Holford]. “H-factor is a toxic protein that the body makes from food. If you’ve got the right nutrients in your diet, H-factor turns into a substance called SAM which plays a crucial part in the rejuvenation of all cells. But if you’re not getting those critical vitamins and minerals, or they’re being depleted through stress, H-factor builds up in the blood and becomes a toxin, causing the reverse – accelerated ageing.”
So that’s the science bit.
As ever, it’s difficult to know where to start but let’s state that “that’s the science bit” according to Holford and it doesn’t follow that it is either accurate or verifiable. It is always tricky to tell what is attributable to Holford in these matters and what is the responsibility of ‘helpful’ newspaper sub-editors although some of the errors in this piece are recurrent in Holford’s work despite the number of times he has been corrected.
We would agree that the “right diet” is a good concept although we doubt there is substantial evidence that it can ‘rejuvenate’ cells or transform the appearance of skin.[b]
One point on which we have corrected Holford many times, but he seems not to grasp, is that Hcy is more correctly classed as an amino acid than a protein. We would also raise an objection to the notion that Hcy is intrinsically toxic to people in good general health and without other contraindications.
Holford does mention some of the other factors relating to Hcy levels but he makes it implicit rather than explicit in the rather unhelpful H-Factor Test at the foot of the article: we should remind readers that the test has not been validated as an adequate proxy for estimating Hcy levels.
Hcy levels are intimately related to demographics such as age and gender plus lifestyle choices such as smoking, alcohol consumption, restrictive diets or drug interventions such as methotrexate or corticosteroids. As a handwave summary: the dose makes the poison when it comes to judgments of toxicity (in the absence of extreme hypersensitivity, allergy or pre-disposing conditions which may be genetic or acquired); baldly suggesting that Hcy is toxic without placing that in any form of context is unhelpful and promotes a dubious educational message.
We would probably not agree on Hcy ‘revolutionising the way we look at ageing’ but that is nugatory in the overall scheme.
Referring to H-Factor rather than Hcy for the next section about SAM continues Holford’s non-educational theme. When Holford writes, “H-factor turns into a substance called SAM”, we think you’ll find that:
- Holford is wrong
- it’s a bit more complicated than that.
Crudely, the sequence is (omitting the pathways, enzymes etc.):
(Dietary) methionine -> SAM -> SAH -> Hcy.
Methionine is an essential amino acid – we consume it as part of our diet, we don’t synthesise it. We use methionine and its products in various biochemical processes in the body.
As per the diagram, methionine is converted to the methyl-donor S-adenosylmethionine (SAM) by methionine adenosyltransferase and is demethylated to S-adenosylhomocysteine (SAH) and adenosylhomocysteinase converts SAH to homocysteine. (SAM is remarkably useful as a methyl donor via various important methyl transferase reactions that influence DNA, RNA etc. and may be crudely characterised as associated with appropriate gene expression and cell function)
Referring to the diagram, Hcy is processed and becomes other molecules through two different pathways: trans-sulfuration and re-methylation.
The process of trans-sulfuration yields cystathionine and then cysteine which is used in various interesting and useful pathways.
The process of re-methylation of Hcy through the folate cycle is notable because:
- it reduces total homocysteine levels
- re-methylation can produce methionine.
And then the whole merry dance may begin again.
So, it should be clear that Holford is wrong when he says that “H-factor turns into a substance called SAM”. Methionine is converted to SAM and that yields SAH and Hcy.
Holford’s explanation is wrong. Nonetheless, he ploughs on to give some (largely) unexceptional dietary advice along with a recommendation that you should “Pop a pill” and
Find a multivitamin with at least 20mg of B6, 200mcg of folic acid, 10mcg of B12 and 10mg of zinc.
However, it is equally irritating that Holford omitted to explain that supplementation is not advisable for everyone and there is a complicated picture that suggests that supplements of some of the vitamins that he recommends seem to be associated with greater risk of some cancers and there may be an important distinction to be made between the benefits of dietary folate and folic acid supplements. See, e.g., the discussion in: Folic Acid for the Prevention of Colorectal Adenomas,[c] Folate and Cancer—Timing Is Everything, and Folic Acid and Risk of Prostate Cancer: Results From a Randomized Clinical Trial[d] There are even tentative suggestions that there are some demographic groups for which folic acid supplementation may accelerate the transformation of pre-malignant tumours into a clinically significant cancer.
Given that Holford is effectively advocating a lifelong commitment to managing Hcy levels through supplementation, it is a little irresponsible that the NotW item did not mention that it may be inappropriate to take his recommended amounts of supplements:
- if pregnant, planning a pregnancy or breastfeeding
- if under medical supervision because these supplements may be contraindicated or actually create medication conflicts
- because long term daily intake of amounts greater than 100mg of Vitamin B6 may lead to mild tingling and numbness – Holford, of course, does not state an advisory upper-limit recommending daily supplementation of “at least 20mg of B6” and, in combination with other sources, this may be particularly unwise in the light of recent concerns about B6 and rectal cancer in women.[e]
We must emphasise that folic acid supplements have clear benefits for some demographics such as women who may conceive or are in the first trimester of pregnancy. Nonetheless, we have alluded to the complex and unclear findings relating to supplementation and cancer. Dr Steve Murphy advocates personalised medicine but as a Gene Sherpa argues that lowering homocysteine hasn’t had the expected clinical effects and that there are some groups for whom the recommended vitamin supplementation is contra-indicated.
In the absence of clear evidence that points to a clinical benefit, it seems unwise to take even a small risk with supplementation in default of appropriate advice from an appropriately-qualified medical adviser. The odour of sanctity enriches the air as we piously observe that (in default of contraindications) supplementation is no substitute for a good, varied diet.
However, if readers are not interested in supplementation but wondering about the value of measuring Hcy levels just to ‘know the number’ in the same way as (say) cholesterol, then consider this fine advice from Vasan.
Regardless of the purpose for its use, a new biomarker will be of clinical value only if it is accurate, it is reproducibly obtained in a standardized fashion, it is acceptable to the patient, it is easy to interpret by clinicians, it has high sensitivity and high specificity for the outcome it is expected to identify, it explains a reasonable proportion of the outcome independent of established predictors consistently in multiple studies, and there are data to suggest that knowledge of biomarker levels changes management.
Hcy does not seem to meet Vasan’s criteria for a practical and useful biomarker. Overall, it does not seem as if Hcy testing and therapeutic intervention by supplementation is ready to go mainstream for the general population. The hype seems to run ahead of the evidence for the clinical benefits of reducing Hcy levels and we can find no indication that it would ‘transform the skin’ or ‘reverse ageing’.
The next time that Holford updates his modestly-named Bible of Optimum Nutrition, his account of the significance of homocysteine and his recommendations should be firmly relegated to the status of apocrypha.
[a] Holford recommends that readers should check their Hcy levels with a blood test, 2-3 times a year: the test costs £75 per time. His recommended product is his formula Connect. Connect costs from £24.42 for 90 days to £24.42 for 30 days, depending on the recommended dose. There is no information about the bioavailability of the contents, so it is unclear if it is appropriate to expect your GP or Practice Nurse to advise you on your Connect dosage; you might need to pay to consult a nutritionist or similar. A nutritionist might base his/her recommendations on an inappropriate interpretation of research and some unsupported beliefs. The worst case costing per person is that the tests cost £225 per year, the Connect supplement around £293, and the consultations for tweaking the supplement levels around £200 for a total of £718: the best case costing is £383.
It should be noted that Holford typically recommends that all targeted supplements like this are taken alongside his usual basic recommendations that work out at around £5.68 per person, per day for an adult. To be fair, Holford does have a daily Optimum Nutrition product that is £48.89, per person, for a 28 day supply which approximates to £1.75 per day or approx. £638.75 per person, per year.
[b] Standard skin care advice usually acknowledges that genetics has a reasonable contribution to the state of the skin; plus appropriate use of sun screen and safe observance of sun exposure advice.
[c] Folic Acid for the Prevention of Colorectal Adenomas.
We found no clear evidence that folic acid supplementation provided any health benefits. Although a significant excess of prostate cancers was observed in the folate group, this might be spurious given the number of adverse events evaluated. A recent randomized trial of folic acid in combination with B vitamins for vascular disease also suggested that treatment with these agents may increase the risk of colon cancer (RR, 1.36; 95% CI, 0.89-2.08; P = .16) and prostate cancer (RR, 1.21; 95% CI, 0.86-1.72; P = .28), although these results were not statistically significant.46 Observational studies regarding prostate cancer have been mixed. Some studies reported an increased risk of prostate cancer in association with high folate intake or blood levels, but these results were not statistically significant or were limited to early-stage cancers.47-49 A case-control study reported a statistically significant, favorable role of dietary folate on prostate cancer risk.50
Data regarding the association between folate status and risk of prostate cancer are sparse and conflicting. We studied prostate cancer occurrence in the Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas conducted between July 6, 1994, and December 31, 2006…Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7%…in the folic acid group and 3.3%…in the placebo group…. In contrast, baseline dietary folate intake and plasma folate in nonmultivitamin users were inversely associated with risk of prostate cancer, although these associations did not attain statistical significance in adjusted analyses. These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid–containing supplements vs natural sources of folate. [Emphasis added.]
there was a strong positive association between vitamin B-6 and rectal cancer among women (RR = 3.57; P-trend = 0.01). Our findings suggest that relatively high methionine intake may protect against proximal colon cancer in men and rectal cancer in women but that folate may not have a protective effect. This is the 2nd prospective cohort study in which vitamin B-6 intake was associated with increased risk of rectal tumors in women, which might suggest that this vitamin enhances rectal cancer in women.
 Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, Snover DC, Church TR, Allen JI, Robertson DJ, Beck GJ, Bond JH, Byers T, Mandel JS, Mott LA, Pearson LH, Barry EL, Rees JR, Marcon N, Saibil F, Ueland PM, Greenberg ER; Polyp Prevention Study Group. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007 June; vol 297(21): pp. 2351-9.
 Ulrich, C.M. and Potter, J.D. Folate and Cancer—Timing Is Everything. JAMA. 2007 June; vol 297: pp 2408-2409.
 Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, Burke CA, McKeown-Eyssen GE, Baron JA. Folic Acid and Risk of Prostate Cancer: Results From a Randomized Clinical Trial. J Natl Cancer Inst. 2009 Mar 10. [Epub ahead of print] PMID: 19276452.
 de Vogel S, Dindore V, van Engeland M, Goldbohm RA, van den Brandt PA, Weijenberg MP. Dietary Folate, Methionine, Riboflavin, and Vitamin B-6 and Risk of Sporadic Colorectal Cancer. J Nutr. 2008 Dec;138(12):2372-8. PMID: 19022960
 Vasan RS. (2006) Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 113: 2335-2362.
Never Mind the Research Quality, Feel the Fear: Justifying Homocysteine Tests
Homocysteine: Helpful or Hoax Asks Patrick Holford
How Relevant Are Holford’s Claims About Homocysteine Levels? Part 1
How Relevant Are Holford’s Claims About Homocysteine Levels? Part 2
Patrick Holford, Alzheimer’s Disease, Homocysteine Tests and Supplements
Polypills or Vitamins for Homocysteine and Cardiovascular Risks: the Hype is Ahead of the Evidence
Gene Sherpa on homocysteine