Over the past 10 years, there has been enormous attention given to serum vitamin D level and its association with human health. Fish oil supplementation has also received quite a bit of attention. We therefore found it remarkable that a new study from Manson et al.¹ published in the New England Journal of Medicine showed no reduction in cancer or cardiovascular mortality with a median of 5 years of supplementation with 2,000 IU of vitamin D and 1 g of fish oil in nearly 17,000 men and women over age 50.

From a scientific perspective, it is important to make some distinctions here. Some studies have indeed shown an association between the amount of vitamin D in the blood and the risk for disease or early death. For example, in a meta-analysis of prospective studies, Tomson et al.² reported a linear, inverse association between plasma vitamin D and risk of vascular- and non-vascular mortality, such that those in the top quarter of vitamin D levels had 21% lower vascular mortality and 28% lower all-cause mortality in the following 13 years. That sounds good! But then why don’t we see a benefit with supplementation?

When comparing these two studies, we find two important differences. They are:

The length of follow-up, and
How plasma vitamin D becomes elevated.

In the supplementation study, the researchers only followed the study participants for 5 years (so far), while the participants in the prospective study were followed for 13 years. So, vitamin D and fish oil supplementation may eventually yield a reduction in mortality—it may be that one needs to take them longer than 5 years. We hope to see the results of a longer follow-up period.

However, we are particularly intrigued by the second question: how does plasma vitamin D become elevated? In the prospective study by Tomson et al., the researchers simply took blood tests, recorded the vitamin D levels of the study participants, and tabulated who died, and their cause of death, over the next 13 years. There was no intervention to control serum vitamin D. But we know that the most influential factor for vitamin D level is sunlight (especially UV-B) exposure on the skin. And this is the important confounding factor for the supplementation study.

We have recently explored the many physiological effects of sunlight exposure, including enhancement of cortisol level, reduction in fatigue, treatment of depression, reduction of LDL-cholesterol, enhancement of nocturnal melatonin secretion, and more recently, activation of hair stem cells and hair regeneration in mice.³

Given the many physiological effects of sunlight exposure, we suspect the study of supplemental vitamin D and fish oil failed to find a mortality benefit, even though high vitamin D levels are associated with lower mortality, because it is not vitamin D that reduces mortality—it is sunlight exposure which reduces mortality—and it also happens to increase serum vitamin D.

There have been reports of sunlight exposure being associated with lower risks of cancer, and even lower risk of all-cause mortality. For example, Vuong et al.⁴ reported a 35-45% lower risk of melanoma with high occupational sun exposure. This suggests that regular sun exposure reduces the risk of fatal skin cancer, contradicting many guidelines urging avoidance of sun exposure. And in a study of nearly 30,000 Swedish women, Lindqvist et al.⁵ reported that avoidance of sun exposure “is a risk factor for death of a similar magnitude as smoking.” Yikes.

If sunlight exposure is so bad for human health, we shouldn’t see this large of a positive effect from sun exposure in multiple human studies. And yet the higher sunlight exposure in these studies is highly likely to be associated with higher vitamin D levels, which in-turn is associated with lower disease risk. So why didn’t vitamin D supplementation result in lower mortality? What’s going on here?

This brings us to the dog metaphor in the title of this article,

It is said that when a dog is wagging its tail, it is happy. However, that does not mean that if you wag the dog’s tail, your doing so will make it happy. The happiness is the cause of the tail-wagging, not the other way around. We suspect a similar relationship between sunlight exposure, vitamin D, and reduced mortality.

It appears that sunlight exposure is the cause of both reduced mortality and higher vitamin D levels. If sunlight exposure is indeed the cause of reduced mortality, then a study raising vitamin D levels without the additional sun exposure should result in no reduction in mortality. We see just this result in the recent report from Manson et al. The elevated vitamin D level is simply a covariate with sunlight exposure. In other words, wagging the dog’s tail (vitamin D supplementation) does not make the dog happy (does not reduce mortality, independent of sunlight exposure).

In essence, Manson et al.’s study of vitamin D and fish oil supplementation may serve as a negative control for testing the effect of sunlight exposure on mortality, illustrating that there is no mortality benefit without the additional sunlight exposure, even if you raise vitamin D level.

As for the study by Manson et al., we hope that team is continuing to follow-up with their cohort. We think it prudent to wait for the results from a longer supplementation period before concluding that vitamin D supplementation does not reduce human mortality. Until then, we are working a bit more sunlight exposure (without sunburn) into our lifestyles.

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Sources:

¹Manson JE et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019 Jan 3;380(1):33-44. doi: 10.1056/NEJMoa1809944. PMID 30415629.

²Tomson J, Emberson J, Hill M, Gordon A, Armitage J, Shipley M, Collins R, Clarke R. Vitamin D and risk of death from vascular and non-vascular causes in the Whitehall study and meta-analyses of 12,000 deaths. Eur Heart J. 2013 May;34(18):1365-74. doi: 10.1093/eurheartj/ehs426. PMID 23257953.

³Fan SM et al. External light activates hair follicle stem cells through eyes via an ipRGC-SCN-sympathetic neural pathway. Proc Natl Acad Sci U S A. 2018 Jul 17;115(29):E6880-E6889. doi: 10.1073/pnas.1719548115. PMID 29959210.

⁴Vuong K, McGeechan K, Armstrong BK; AMFS Investigators; GEM Investigators, Cust AE. Occupational sun exposure and risk of melanoma according to anatomical site. Int J Cancer. 2014 Jun 1;134(11):2735-41. doi: 10.1002/ijc.28603. PMID 24288300.

⁵Lindqvist PG, Epstein E, Nielsen K, Landin-Olsson M, Ingvar C, Olsson H. Avoidance of sun exposure as a risk factor for major causes of death: a competing risk analysis of the Melanoma in Southern Sweden cohort. J Intern Med. 2016 Oct;280(4):375-87. doi: 10.1111/joim.

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Wagging the Dog's Tail Doesn't Make it Happy