Analysis reveals which nutrients can make a difference at higher doses 01/09/2020
Many people are understandably skeptical about dietary supplements.
That’s largely because studies probing their value have produced conflicting conclusions.
For example, while some evidence reviews have questioned the value of daily multivitamins, others have detected definite benefits.
We covered some of the contrasting evidence in Are Multivitamins Worse than Worthless? and Vitamin Studies Paint a More Positive Prevention Picture.
And research continues to find benefits from specific supplemental nutrients — as well as widespread nutrient deficiencies along Americans.
Why can’t researchers always come to clear conclusions? We see five explanations:
- Epidemiological studies, which provide much of the evidence, can’t prove a cause-effect relationship between higher or lower intakes of a nutrient and health outcomes — they can only reveal statistical associations between nutrient intakes and health outcomes.
- Few of the clinical trials conducted to test the effects of dietary supplements last long enough to reveal possible long-term benefits.
- Most clinical studies are designed to detect the effects of supplemental nutrients on the risk for a specific disease(s), rather than to detect any general “anti-aging” effects.
- Most clinical studies test the effects of a single supplemental nutrient, rather than the effects of multiple nutrients. Conversely, clinical studies that test the effects of multiple nutrients make it impossible to identify the effects of any one of those nutrients.
- Clinical trials of sufficient size and length to prove the effect of a drug or nutrient on a health condition cost about one quarter billion dollars. Government has never provided that level of funding, and private companies have little incentive to spend huge sums to test the effects of nutrients, which are not easy to patent and thereby profit from.
These barriers to certainty explain why professor Bruce Ames, PhD — one of the world’s most published and honored biochemists — thinks we need to view the value of micronutrients in a very different way. (To learn more about him, see “Who is Bruce Ames?” at the end of this article.)
Dr. Ames’ work has been focused on lengthening people’s “health spans”. Your lifespan is how many years you live, while your health span is how long you live in good health — which should matter as much or more than lifespan.
Let’s delve into his theory about the long-term effects of micronutrients —the vitamins and minerals officially deemed essential, plus other, more obscure compounds — and list the ones he identifies.
Health span and the triage theory of micronutrients
The research led by Dr. Ames highlights the often-overlooked fact that most vitamins and minerals — and certain supposedly “non-essential” nutrients — affect and/or are needed to build key enzymes.
Accordingly, the same nutrients we need to survive and maintain basic bodily functions — such as vitamin D, omega-3 fatty acids, selenium, and magnesium — are also critical components of or influences on enzymes required for long-term health.
Those long-term maintenance tasks include addressing the DNA damage and inflammation caused by an excess of the unstable oxygen molecules known as free radicals, which are proven to promote chronic health conditions such as cardiovascular disease, dementia, autoimmune disorders, and cancer.
The body is usually able to control the free radicals produced as a natural, even necessary, byproduct of digestion and metabolism. But it's less able to handle an extreme overload of free radicals, which is typically caused by poor diets, pollution, alcohol/drug abuse, and sedentary lifestyles.
When the body is faced with shortages of key nutrients, it must “ration” them, enabling enzymes critical to our immediate survival and reproductive capacity to keep functioning at the expense of longer-term physiological needs.
Dr. Ames’ team has published substantial evidence that such trade-offs can be seen in people with chronic, low-level deficiencies in vitamin K and selenium, which are key components of 16 and 25 different enzymes, respectively.
For example, studies from Dr. Ames' lab suggest that, when forced to ration scarce vitamin K for its critical role in blood clotting, the body produces fewer enzymes required for keeping arteries clear — an effect that's been linked to higher risk of death from cardiovascular disease.
Ames calls this theoretical framework “triage theory,” echoing a method used by health professionals to prioritize patients for treatment based on the seriousness of their illness or injury.
As Ames wrote, “The prevention of the degenerative diseases of aging is a different science than curing disease: it will involve expertise in metabolism, nutrition, biochemistry and genetic regulatory elements and polymorphisms.”
(We’ve covered development of triage theory since Dr. Ames first proposed it: see Selenium Seen as Key Anti-Aging Ally, Magnesium Shortage Speeds Aging of America, and Seafood Mineral May Deter Diabetes.
Dr. Ames also makes an important socio-economic point: “This approach is critical for lowering medical costs. It has been estimated that the E.U. would save about $4 billion from osteoporosis alone by using vitamin D and calcium supplementation.”
Similarly, Harvard University researchers have estimated that the well-documented lack of omega-3 fatty acids in the average American’s diet causes many premature death: see Omega-3 Deficiency May Cause 90,000-Plus Deaths Annually.
The 40+ nutrients critical to long-term health maintenance
Dr. Ames argues that most American diets are deficient in micronutrients that promote longevity and curb the risk of chronic conditions such as heart disease, cancer, and neurodegeneration (e.g., dementia).
However, the research cited in Dr. Ames’ new review shows that almost three out of four (70%) Americans are deficient in one or more key nutrients.
Most are not so deficient as to put their immediate health at risk from diseases such as rickets or scurvy, but Ames notes that even minor vitamin deficiencies could impact long-term health.
Dr. Ames brought the implications of his findings back to basics: “Diet is very important for our long-term health and this theoretical framework just reinforces that you should try to do what your mother told you: eat your veggies, eat your fruit, give up sugary soft drinks and [nutritionally] empty carbohydrates.”
His evidence review summarizes more than a decade of research in his laboratory at Children’s Hospital Oakland Research Institute (CHORI), which is affiliated with the University of California, San Francisco (UCSF).
Dr. Ames’ new paper encompasses a detailed survey of evidence published by other scientists and does not depend on his own research.
In brief, Dr. Ames concludes that healthy aging can be extended by consuming optimal levels of 30 essential vitamins and essential minerals, and that these nutrients — along with 11 others not currently considered essential — constitute a class of “longevity vitamins” that can extend a person’s “health span”.
In addition to the nine essential amino acids, these include:
- Vitamins — vitamin A, B vitamins*, vitamin C, choline, vitamin D, vitamin E**, and vitamin K
- Omega-3 fatty acids — DHA and EPA, which are found only in seafood and supplements.
- Minerals/elements — calcium, chloride, chromium, cobalt, copper, iodine, iron, manganese, magnesium, molybdenum, phosphorus, potassium, selenium, sodium, sulfur, and zinc.
*B1 (thiamin), B2 (riboflavin), B3 (niacin), B5 (pantothenate), B6 (e.g., pyridoxine), B12 (cobalamins), biotin, and folate (folic acid is the synthetic form in supplements and fortified foods).
**Vitamin E is a complex of tocopheryl and tocotrienol compounds. Although tocopherols are more commonly used in supplements, tocotrienols are highly valuable but often overlooked.
Importantly, Dr. Ames calls for classifying the amino acid taurine as a conditional vitamin, and for classifying it and 10 other compounds as “longevity vitamins”:
- Ergothioneine — An antioxidant found in mushrooms.
- PQQ — A metabolite produced by bacteria in the human gut.
- Queuine — A metabolite produced by bacteria in the human gut.
- Carotenoids: Lutein, zeaxanthin, lycopene, alpha and beta-carotene, beta-cryptoxanthin, and the marine carotenoid called astaxanthin.
To learn more about ergothioneine — and other valuable nutrients in fungi — see Newly Discovered Magic in Mushrooms.
Like CoQ10, PQQ is a co-enzyme whose antioxidant capacity helps defend against mitochondrial decay and dysfunction.
Queuine is the most obscure micronutrient in Dr. Ames' list, and as a French-American team wrote, “[Queuine is] an important but under-recognized micronutrient for plants, animals, and fungi … [making it] a micronutrient or even a vitamin.” (Zallot R et al. 2014)
Likewise, as Irish researchers said, “Micronutrients from the diet and gut microbiota are essential to human health and wellbeing. Arguably, among the most intriguing and enigmatic of these micronutrients is queuine …”. (Fergus C et al. 2015)
The Irish team noted that yogurt and milk contain “appreciable amounts of queuine and are likely to be sufficient to meet physiological requirements”.
Food remains the best source of most of the nutrients in Dr. Ames list, but you can’t easily obtain enough of all the micronutrients in it unless your diet includes foods across the spectrum, from meats and fish to fruits, vegetables, dairy, and mushrooms.
Supplements appear to be the only good sources of PQQ and astaxanthin. Although astaxanthin occurs in the flesh of wild salmon — and accounts for its red/orange color — the amounts (measured in micrograms) are probably too small to make much difference.
Importance of diet to optimal health
Dr. Ames suspects many more longevity vitamins may remain to be discovered.
That’s because — unlike so-called “essential” micronutrients such as vitamin C, that were originally identified because we quickly become sick without them — the damage caused by shortages of these micronutrients is, by nature, an insidious and slow process into old age.
In other words, the identification of “longevity vitamins” requires very long-term observation, which is difficult and costly.
Ames, who has published more than 500 scientific papers in a career spanning nearly seven decades, ranks his triage theory among his most important work. “This may be a theoretical paper, but I hope it can add a few years to everyone’s lives.”
Who is Bruce Ames?
Bruce Ames is probably best known for devising the “Ames test” during the 1970s — a laboratory method still used today that is designed to rapidly predict a chemical’s potential to cause cancer.
He’s currently a Senior Scientist at Children's Hospital Oakland Research Institute (CHORI), director of its Nutrition & Metabolism Center, and a University of California, Berkeley Professor Emeritus of Biochemistry and Molecular Biology.
Dr. Ames is also a member of the National Academy of Sciences, a past board member of the National Cancer Institute, and has been awarded — among many other honors — the U.S. National Medal of Science, the American Society for Microbiology Lifetime Achievement Award, and the Gold Medal Award of the American Institute of Chemists.
Awards and prestigious posts don’t guarantee a scientist’s infallibility — for example, Nobel Prize winning chemist Linus Pauling made unsupported claims for vitamin C — but they indicate the degree to which his or her colleagues respect their work and judgment.
- Ames BN. Optimal micronutrients delay mitochondrial decay and age-associated diseases. Mech Ageing Dev. 2010 Jul-Aug;131(7-8):473-9. doi: 10.1016/j.mad.2010.04.005. Epub 2010 Apr 24. Review.
- Ames BN. Prevention of mutation, cancer, and other age-associated diseases by optimizing micronutrient intake. J Nucleic Acids. 2010 Sep 22;2010. pii: 725071. doi: 10.4061/2010/725071.
- Ames BN. Prolonging healthy aging: Longevity vitamins and proteins. Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):10836-10844. doi: 10.1073/pnas.1809045115. Epub 2018 Oct 15.
- Blumberg JB, Frei BB, Fulgoni VL, Weaver CM, Zeisel SH. Impact of Frequency of Multi-Vitamin/Multi-Mineral Supplement Intake on Nutritional Adequacy and Nutrient Deficiencies in U.S. Adults. Nutrients. 2017 Aug 9;9(8). pii: E849. doi: 10.3390/nu9080849.
- Fergus C et al. The Queuine Micronutrient: Charting a Course from Microbe to Man. Nutrients 2015, 7(4), 2897-2929; https://doi.org/10.3390/nu7042897
- Lal A, Ames BN. Association of chromosome damage detected as micronuclei with hematological diseases and micronutrient status. Mutagenesis. 2011 Jan;26(1):57-62. doi: 10.1093/mutage/geq081. Review.
- McCann JC, Ames BN. Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging. FASEB J. 2011 Jun;25(6):1793-814. doi: 10.1096/fj.11-180885. Epub 2011 Mar 14. Review.
- McCann JC, Ames BN. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr. 2009 Oct;90(4):889-907. doi: 10.3945/ajcn.2009.27930. Epub 2009 Aug 19. Review.
- Mietus-Snyder ML et al. A nutrient-dense, high-fiber, fruit-based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-wk trial. FASEB J. 2012 Aug;26(8):3515-27. doi: 10.1096/fj.11-201558. Epub 2012 May 1
- Müller M et al. Dynamic modulation of Dnmt2-dependent tRNA methylation by the micronutrient queuine. Nucleic Acids Res. 2015 Dec 15;43(22):10952-62. doi: 10.1093/nar/gkv980. Epub 2015 Sep 30.
- Wang X, Matuszek Z, Huang Y, Parisien M, Dai Q, Clark W, Schwartz MH, Pan T. Queuosine modification protects cognate tRNAs against ribonuclease cleavage. RNA. 2018 Oct;24(10):1305-1313. doi: 10.1261/rna.067033.118. Epub 2018 Jul 3.
- Zallot R, Brochier-Armanet C, Gaston KW, Forouhar F, Limbach PA, Hunt JF, de Crécy-Lagard V. Plant, animal, and fungal micronutrient queuosine is salvaged by members of the DUF2419 protein family. ACS Chem Biol. 2014 Aug 15;9(8):1812-25. doi: 10.1021/cb500278k. Epub 2014 Jun 17.