Abstract & Commentary
Long-term Multivitamin Use in Older Men: Are There Benefits for the Brain?
By Luke Fortney, MD
Meriter Medical Group, Madison, WI
Dr. Fortney reports no financial relationships relevant to this field of study.
Synopsis: Over a period of 12 years, daily intake of a multivitamin among nearly 6000 healthy elderly male physicians did not provide any cognitive benefits or protection compared to placebo.
Source:Grodstein F, et al. Long-term multivitamin supplementation and cognitive function in men. Ann Intern Med 2013;159:806-814.
The question of whether or not to take a daily multivitamin (MVI) has long been debated. But just as "healthy" can be defined in various ways, so too is this question. What, if any, for whom, and for what conditions does taking what vitamins and at what time potentially have any benefit or risk? Researchers from the Physician's Health Study II (PHS) evaluated this broad and elusive question in several ways, including change in cognitive decline. Many vitamins and nutritional cofactors are intrinsically involved in the cellular and physiologic function of the brain, and there are several indirect strands of evidence that point to a possible link between increased vitamin levels and improved brain function.1
From 1997 to 2011, researchers from the PHS II conducted a randomized, double-blind, placebo-controlled substudy that evaluated the effect of taking a general daily multivitamin (Centrum Silver) on cognitive function in male physicians aged ≥ 65 years. In total, nearly 6000 participants were evaluated using a total of five validated tests that assess cognitive function, which was a prespecified outcome measure. The primary outcome was a composite average score of global cognition, conducted by annual telephone interviews. Among these, verbal memory was identified specifically due to the fact that it is strongly associated with risk of Alzheimer's dementia.
In the end, this well-designed and conducted study found no cognitive change in any of the tests over time between the multivitamin and placebo groups. In fact, the changes they saw over time on these scores were smaller than the decline expected for every 1 year of aging. Researchers concluded that in male physicians aged ≥ 65 years, long-term use of a daily MVI did not provide any cognitive benefits.
The researchers of this PHS II substudy are forthcoming in identifying possible limitations, although there are few. First, results from other randomized, controlled trials of MVIs and cognition have not found any clear benefits among well-nourished and otherwise healthy adults.2 In this study, it is very likely that the participants, who were older male physicians, were already too well nourished to observe any benefits. Further, this study population was highly educated, and outcomes may not be the same for people with less education or those who may be at risk for inadequate dietary intake of essential vitamins and minerals.
But the no effects outcome of this study also may be due to use of a low-quality product. A Consumerlab.com review of 75 different multivitamin brands found defects in nearly 40% of all products examined.3 The Multivitamin Guide blog tested more than 100 brands for composition, bioavailability, synergistic effect, and potency. Out of a possible 10 points for overall quality, the product used in this study was given a score of 4.6 and ranked #54 overall.4
Yet another limitation may be that at
≥ 65 years of age, supplementation with a daily MVI may be too late to notice any meaningful benefit on cognitive decline. For example, it is known that the progressive deficits associated with dementia are part of a process that begins years before symptoms are detected. Interestingly, in another, but separate, substudy of the PHS II, younger participants who were randomly assigned to receive beta-carotene had better performance on overall global cognitive and verbal memory after an average of 18 years of supplementation, suggesting at least that very long-term supplementation at younger ages may be required to notice any meaningful benefit.
The strengths of this study are numerous. It boasts a large sample size — that was more than sufficiently powered — and had a long duration of randomized, placebo-controlled treatment. The use of multiple validated cognitive assessments over many years with few dropouts adds further strength to the validity of the results. What's more, the study benefited from high levels of MVI and placebo treatment adherence. Further, participant characterizations at the time of initial randomization are nearly identical between both the intervention and placebo groups as well. The researchers go on to suggest, very appropriately, that even though this study does not show any benefit in cognitive health by supplementing with a daily MVI among older male adults, there may still be other unknown health effects from regular MVI use in other groups of people.
In terms of general vitamin use overall, research is showing that at least some benefits for various conditions among different groups of people are very likely. For example, among people at risk for inadequate dietary intake of important relevant vitamins (e.g., folate, vitamin B12, iron, vitamin C, thiamine, etc.), there are clear and well-understood health benefits.5 For cognitive health, research suggests that there may be some benefits for use of vitamin E in women with low levels6 and for B-vitamins among women at high risk for cardiovascular disease (CVD).7 However, the Nurses' Health Study found no association between intake of antioxidants from foods and vitamins and rate of cognitive decline over 4 years among more than 16,000 women.8 Additionally, a recent 6-month, single-blind, randomized, controlled study among 56 non-obese adults found that, in addition to taking a daily MVI, the addition of 10 popular cardiovascular antioxidant supplements — resveratrol, green tea extract, pomegranate extract, quercetin, acetyl-l-carnitine, lipoic acid, curcumin, sesamin, cinnamon extract, and fish oil — did not demonstrate any change in arterial stiffness, endothelial function, body fat, blood pressure, lipids, glucose, insulin, IGF-1, or other markers of inflammation and oxidative stress.9 This suggests that, at least in the short term among healthy non-obese adults, antioxidant supplementation beyond what's available from the diet may not have any effect on cognition or CVD one way or the other.
Evidence supporting the general use of MVIs for health benefits is mixed. In 2013, the United States Preventive Services Task Force (USPSTF) reported that only limited evidence supports any benefit from taking a daily MVI for the prevention of cancer or CVD.10 However, the VITAL cohort study (VITamins And Lifestyle) found an inverse relationship between incidence of hematologic malignancies and high use of garlic and grape seed supplements over several years among 66,227 men and women aged 50-76 years in Washington state.11 One limited study found that among 138 healthy adults, daily use of a MVI containing high levels of B vitamins was associated with improvements in measures of stress, physical fatigue, and anxiety compared to placebo over 16 weeks.12 Another small, double-blind, placebo-controlled, crossover, randomized trial found that even use of a daily MVI for a short period of time may help facilitate psychological and physical recovery and ability during high-intensity military training.13
In another arm of the PHS II, daily MVI use was associated with a reduction in total cancers among 1312 men with a history of cancer. However, that reduction in cancer incidence did not differ significantly when compared to more than 13,000 men who did not previously have any history of cancer.14 Adding to the uncertainty, the Iowa Women's Health Study found that some commonly used dietary vitamin and mineral supplements (such as iron) may be associated with increased total mortality risk.15 At the very least, however, it appears that the daily use of MVIs does not increase all-cause mortality from CVD and cancer, and may even provide a modest protective benefit overall.16
A separate substudy of the PHS II examined the relationship between MVIs and various lifestyle, clinical, and dietary factors among 18,040 middle-aged men. Overall, the study found that 36% of participants reported current MVI use, which was in turn associated with an increased tendency to consume more fruit and vegetables, whole grains, tea, and nuts, and to be more physically active.17 One obvious takeaway conclusion from this substudy is that healthier people appear to be more likely to take a daily MVI compared to unhealthy people.
Recent studies have shown, again, the significant benefits that a healthy lifestyle can have. Even the simplest things can have a big impact. For example, eating handful of mixed nuts every day has been shown to significantly reduce all-cause mortality by about 20%.18 Furthermore, eating a Mediterranean-style diet over many years is associated with increased cognitive function19 and healthier aging with a decreased risk of dementia among women.20 Similarly, independent of metabolic health status, analyses show that obese individuals have an increased risk for death and CVD over the long-term.21 Another study, which monitored the health habits of 2235 men over a 35-year period, found that exercise significantly reduces the risk of dementia.22
In deciding whether to use a daily MVI, it appears that ultimately there is very low risk with low cost, and it may have modest health benefits overall. However, it is clear that nothing trumps a healthy lifestyle, which continues to be the most important way to decrease the risk of CVD, cognitive decline, cancer, and risk of early death.23-25 In his book In Defense of Food, Michael Pollan offers a solution that may, after all is said and done, be the most reasonable: "Be as vitamin-conscious as the person who takes supplements, but don't actually take them."
- Kennedy DO, Haskell CF. Vitamins and cognition: What is the evidence? Drugs 2011;71:1957-1971.
- Grima NA, et al. The effects of multivitamins on cognitive performance: A systematic review and meta-analysis. J Alzheimers Dis 2012;29:561-569.
- Product Review: Multivitamin and Multimineral Supplement Review. Available at: www.consumerlab.com/reviews/multivitamin_review_comparisons/multivitamins/. Accessed Feb. 11, 2014.
- Looking for a Good Multivitamin? Compare over 100 Vitamin Brands. Available at: www.multivitaminguide.org Accessed Feb. 11, 2014.
- Comerford KB. Recent developments in multivitamin/mineral research. Adv Nutr 2013;4:644-656.
- Kang JH, et al. A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med 2006;166:2462-2468.
- Kang JH, et al. A trial of B vitamins and cognitive function among women at high risk of cardiovascular disease. Am J Clin Nutr 2008;88:1602-1610.
- Devore EE, et al. Total antioxidant capacity of diet in relation to cognitive function and decline. Am J Clin Nutr 2010;92:1157-1164.
- Soare A, et al. Multiple dietary supplements do not affect metabolic and cardiovascular health. Aging (Albany NY) 2013 Sep 4; [Epub ahead of print].
- Fortnmann SP, et al. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: An updated systematic evidence review for the US Preventive Services Task Force. Ann Intern Med 2013;159:824-834.
- Walter RB, et al. Vitamin, mineral, and specialty supplements and risk of hematologic malignancies in the prospective VITamins And Lifestyle (VITAL) study. Cancer Epidemiol Biomarkers Prev 2011;20:2298-2308.
- Pipingas A, et al. The effects of multivitamin supplementation on mood and general well-being in healthy young adults. A laboratory and at-home phone assessment. Appetite 2013;69:123-136.
- Li X, et al. Effects of a multivitamin/multimineral supplement on young males with physical overtraining: A placebo-controlled, randomized, double-blinded cross-over trial. Biomed Environ Sci 2013;26:599-604.
- Gaziano JM, et al. Multivitamins in the prevention of cancer in men: The Physicians' Health Study II randomized controlled trial. JAMA 2012;308:1871-1880.
- Mursu J, et al. Dietary supplements and mortality rate in older women: The Iowa Women's Health Study. Arch Intern Med 2011;171:1625-1633.
- Alexander DD, Weed DL, Chang ET et al. A systematic review of multivitamin-mineral use and cardiovascular disease and cancer incidence and total mortality. J Am Coll Nutr 2013;32:339-354.
- Rautiainen S, et al. Who uses multivitamins? A cross-sectional study in the Physicians' Health Study. Eur J Nutr 2013 Oct 30; [Epub ahead of print].
- Bao Y, et al. Association of nut consumption with total and cause-specific mortality. N Engl J Med 2013;369:2001-2011.
- Wengreen H, et al. Prospective study of Dietary Approaches to Stop Hypertension- and Mediterranean-style dietary patterns and age-related cognitive change: The Cache County Study on Memory, Health, and Aging. Am J Clin Nutr 2013;98:1263-1271.
- Samieri C, et al. The association between dietary patterns a midlife and health in aging: An observational study. Ann Intern Med 2013;159:584-591.
- Kramer CK, et al. Are metabolically healthy overweight and obesity benign conditions? A systematic review and meta-analysis. Ann Intern Med 2013;159:758-769.
- Elwood P, et al. Healthy lifestyles reduce the incidence of chronic diseases and dementia: Evidence from the Caerphilly cohort study. PLoS One 2013;8:e81877.
- Mokdad AH, et al. Actual causes of death in the United States, 2000. JAMA 2004;291:1238-1245.
- Ford ES, et al. Healthy living is the best revenge: Findings from the European Prospective Investigation Into Cancer and Nutrition-Potsdam study. Arch Intern Med 2009;169:1355-1362.
- Kopes-Kerr C. Preventive Health: Time for Change. Am Fam Physician 2010;82:610-614.