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The Dark Side of Antioxidants
Not all vitamins are good for all people, all the time. In fact, some can kill you. And guess what? We know where the bodies are buried.
The story of the dark side of antioxidant research isn't well known outside of medical circles. It's an unseemly story, profoundly unsettling; a story that refuses to be made pretty or happy or uplifting no matter how hard you try to duct-tape a silver lining around it. It doesn't fit the "antioxidants are good for you" mantra that sells billions of dollars per year of blueberry- and pomegranate-fortified granola bars and tocopherol-enrichened cereals, acai-berry Jell-O mixes, juices and yogurts with added vitamins, organic baby foods, and so forth, not to mention the billions of dollars of nutritional supplements sold each year (to say nothing of the sub-industry of books and magazines devoted to nutrition).
Still, it's a story that needs to be told. And some of us know where the bodies are buried.
For decades, mainstream medicine pooh-poohed the possibility that vitamins or supplements could "move the needle" on major diseases. Two-time Nobel laureate Linus Pauling was harshly criticized in the 1970s and 80s for suggesting a role for Vitamin C in prevention and treatment of cancer. Even so, laboratory workers had known for years that changes to diet could influence the rate of tumor appearance in lab animals. By the early 1980s, case-control studies and epidemiological evidence from a variety of sources had begun to accumulate, showing that persons who routinely ate large quantities of fresh fruits and vegetables consistently did better with regard to cardiovascular disease (and other diseases) than most people.
In 1981, Sir Richard Peto and colleagues published a paper in Nature that dared asked the simple question: "Can dietary beta-carotene materially reduce human cancer rates?" (Nature, 290:201-208) Shortly thereafter, the National Cancer Institute (whose Chemoprevention branch was headed by Dr. Michael B. Sporn, one of the coauthors of the Nature article) decided to green-light two large intervention-based studies of the cancer-preventing effects of nutritional supplements: a study in Finland involving beta-carotene and alpha-tocopherol (Vitamin E), and a U.S.-based study involving retinol (a form of Vitamin A) and beta-carotene.
The Finland study (conducted by Finland's National Institute for Health and Welfare) was initially designed to encompass 18,000 male smokers between the ages of 50 and 69. Why just smokers? And why male, and 50+ years old? Lung cancer is ten times more likely to affect smokers; hence a cancer study limited to smokers would need only a tenth as many participants as a study involving the general population. Based on what was known about the age-specific rates of lung cancer among Finnish men, study designers calculated that the desired effect size (a hoped-for 25% decrease in cancer incidence over a period of 6 years) would be measurable with the required level of statistical relevance if 18,000 older male smokers made up the study group. As it turned out, the age distribution of actual volunteers didn't match the demographics of the eligibility group (volunteers tended to be toward the young end of the eligibility range), and as a result the study's enrollment target had to be reset to 27,000 in order to get good statistical relevance.
Full-scale recruitment of subjects into the ATBC (Alpha-Tocopherol Beta-Carotene) Lung Cancer Prevention Study began in April 1985 and continued until a final enrollment of 29,246 men occurred in June 1988. Enrollees were randomized into one of four equal-sized groups, receiving either 50 mg/day (about 6 times the RDA) of alpha-tocopherol, or 20 mg/day of beta-carotene (equivalent to around 3 times the RDA of Vitamin A), or AT and BC together, or placebo only.
At the same time, which is to say starting in 1985 (after some very small, very brief pilot studies to validate recruitment mechanics), the Carotene and Retinol Efficacy Trial (CARET) started enrolling volunteers in the U.S. Unlike Finland's ATBC study, volunteers for CARET were both male and female and were heavy smokers or came from asbestos-exposed workplace environments. They ranged in age from 45 to 69 and were divided initially into four groups (30 mg/day beta carotene only, 25,000 IU retinol-only, carotene plus retinol, or placebo), but in 1988 the treatment groups were consolidated into one group taking both beta-carotene and retinol. The study design called for continuing the vitamin regimen through 1997, with reporting of results to occur in 1998.
Alas, things went horribly awry, and CARET never got that far.
When the Finns reported results from the ATBC study in April 1994, it sent shock waves through the medical world. Not only had alpha-tocopherol and beta-carotene not provided the expected protective effect against lung cancer; the supplement-treated groups actually experienced more cancer than the placebo group—18% more, in fact.
This was an astonishing result, utterly bewildering, as it contradicted numerous prior animal studies that had shown Vitamin E and beta-carotene to be promising cancer preventatives. Surely an error had occurred. Something had to have gone wrong. One thing it couldn't be was chance variation: with almost 30,000 participants (three quarters of them in treatment groups), this was not a small study. The results couldn't be a statistical fluke.
As it turns out, the Finnish investigators had actually done a meticulous job from start to finish. In analyzing their data, they had looked for possible confounding factors. The only thing they found of interest was that heavy drinkers in the treatment group got cancer more often than light drinkers.
Two weeks before the Finnish study hit, the National Cancer Institute was awash in conference calls. Accounts vary as to who knew what, when, but CARET's lead investigator, who had seen the Finnish group's data prior to publication, knew that NCI now had a serious problem on its hands. CARET was doing essentially the same experiment the Finns had done, except it was giving even bigger doses of supplements to its U.S. participants, and the study was due to run for another three and a half years. What if CARET's treatment group was also experiencing elevated cancer rates? Participants might be dying needlessly.
When statisticians presented interim results to CARET's Safety Endpoint Monitoring Committee in August 1994, four months after the Finnish study appeared in print, it became clear that CARET participants were, if anything, faring worse than the patients in the ATBC study. Even so, the safety committee found itself deadlocked on whether to call a premature halt to CARET. The study's formal stopping criteria (as given by something called the O’Brien–Fleming early-stopping boundary) had not been met. Ultimately a decision was made to continue to accumulate more data.
A second interim statistical analysis was presented to CARET's safety committee in September 1995, one year after the first analysis. According to the committee:
At that time it was clear that the excess of lung cancer had continued to accumulate in the intervention regimen at about the same rate during the time since the first interim analysis. Further, the cardiovascular disease excess persisted. The conditional power calculations showed that it was extremely unlikely that the trial could show a beneficial effect of the intervention, even if the adverse effect ceased to occur and a delayed protective effect began to appear.Therefore the SEMC voted unanimously to recommend to NCI that the trial regimen should be stopped but the follow-up should continue.
The study was halted—but not until January 1996, nearly two years after final publication of the Finnish results. (Even then, CARET participants were contacted by snail mail to let them know of the study's early termination and the reasons for it. See this writeup for details.)
CARET's results were published in The New England Journal of Medicine in May 1996. Once again, shock waves reverberated throughout the medical world. Participants who took beta-carotene and Vitamin A supplements had shown a 28% higher rate of lung cancer. They also fared 26% worse for cardiovascular-related mortality, and 17% worse for all-cause mortality.
There was great reluctance in the medical community to believe the results. Perhaps the even-worse results of the CARET study (relative to the Finnish experiment) had to do with the decision to include 2,044 asbestos-exposed individuals in the treatment group of 9,241 persons? Not so, it turns out. Segment analysis of the asbestos group's data relative to the heavy-smoker group showed that "There was no statistical evidence of heterogeneity of the relative risk among these subgroups."
What the CARET study had, in fact, done was not just replicate the ATBC results but provide the beginnings of a dose-response curve. The Finns had used 20 mg/day of beta-carotene; CARET employed a 50% higher dose. The result had been 50% more cancer.
It was hard to understand the results of the ATBC and CARET studies in light of the fact that another large trial involving beta-carotene, the Physicians' Health Study, had reported neither harm nor benefit from 50 mg of beta carotene taken every other day for 12 years. However, the Physicians' Health Study population was younger and healthier than ATBC or CARET study groups and was predominantly (89%) made up of non-smokers. This turned out to be quite important. (Read on.)
It's been almost 20 years since the ATBC and CARET results were reported. What have we learned in that time?
In 2007, Bjelakovic et al. undertook a systematic review of existing literature on antioxidant studies covering the time frame 1977 to 2006. The systematic review procedure was conducted using the well-regarded methodology of the Cochrane Collaboration, a group that specializes in (and is known for) high-quality meta-analyses. In analyzing the 47 most rigorously designed studies of supplement effectiveness, Bjelakovic et al. found that 15,366 study subjects (out of a total treatment population of 99,095 persons) died while taking antioxidants, whereas 9,131 placebo-takers, in control groups totalling 81,843 persons, died in those same studies. (This is not including ATBC or CARET results.) The studies in question used beta-carotene, Vitamin E, Vitamin A, Vitamin C, and/or selenium.
In a separate meta-analysis, Miller et al. found a dose-dependent relationship of Vitamin E with all-cause mortality for 135,967 participants in 19 clinical trials. At daily doses below about 150 International Units, Vitamin E appears to be helpful; above that, harmful. Miller et al. concluded:
In view of the increased mortality associated with high dosages of beta-carotene and now vitamin E, use of any high-dosage vitamin supplements should be discouraged until evidence of efﬁcacy is documented from appropriately designed clinical trials.
How are we to make sense of these results? Why have so many studies shown a harmful effect for antioxidants when so many other studies (particularly those carried out in animals, but also those carried out in predominantly healthy human populations) have shown a clear benefit?
The answer may have to do with something called apoptosis, otherwise known as programmed cell death. The body has ways of determining when cells have become dysfunctional to the point of needing to be told to shut down. Most cancer therapies exert their effect by inducing apoptosis, and it's fairly well accepted that in normal, healthy individuals, precancerous cells are constantly being formed, then destroyed through apoptosis. Antioxidants are known to interfere with apoptosis. In essence, they promote the survival of normal cells as well as cells that shouldn't be allowed to live.
If you're a young non-smoker in good health, the level of cell turnover (from apoptosis) in your body is nowhere near as high as the level of turnover in an older person, or someone at high risk of cancer. Therefore, antioxidants are apt to do more good than harm in a young, healthy person. But if your body is harboring cancer cells, you don't want antioxidants to encourage their growth by interfering with their apoptosis. That's the real lesson of antioxidant research.
The food industry and the people who make nutritional supplements have no interest in telling you any of the things you've read here. But now that you know the story of the dark side of antioxidants (a story made possible by thousands of ordinary people who died in the name of science), you owe it to yourself to take the story to heart. If you're a smoker or at high risk for heart disease or cancer, consider scaling back your use of antioxidant supplements (Vitamins A and E in particular); it could save your life. And please, if you found any of this information helpful, share it with family, friends, Facebook and Twitter followers, and others. The story needs to get out.
The COVID-19 pandemic is making health disparities in the United States crystal clear. It is a clarion call for health care systems to double their efforts in vulnerable communities.
- The COVID-19 pandemic has exacerbated America's health disparities, widening the divide between the haves and have nots.
- Studies show disparities in wealth, race, and online access have disproportionately harmed underserved U.S. communities during the pandemic.
- To begin curing this social aliment, health systems like Northwell Health are establishing relationships of trust in these communities so that the post-COVID world looks different than the pre-COVID one.
COVID-19 deepens U.S. health disparities<p>Communities on the pernicious side of America's health disparities have their unique histories, environments, and social structures. They are spread across the United States, but they all have one thing in common.</p><p>"There is one common divide in American communities, and that is poverty," said <a href="https://www.northwell.edu/about/leadership/debbie-salas-lopez" target="_blank">Debbie Salas-Lopez, MD, MPH</a>, senior vice president of community and population health at Northwell Health. "That is the undercurrent that manifests poor health, poor health outcomes, or poor health prognoses for future wellbeing."</p><p>Social determinants have far-reaching effects on health, and poor communities have unfavorable social determinants. To pick one of many examples, <a href="https://www.npr.org/2020/09/27/913612554/a-crisis-within-a-crisis-food-insecurity-and-covid-19" target="_blank" rel="noopener noreferrer">food insecurity</a> reduces access to quality food, leading to poor health and communal endemics of chronic medical conditions. The U.S. Centers for Disease Control and Prevention has identified some of these conditions, such as obesity and Type 2 diabetes, as increasing the risk of developing a severe case of coronavirus.</p><p>The pandemic didn't create poverty or food insecurity, but it exacerbated both, and the results have been catastrophic. A study published this summer in the <em><a href="https://link.springer.com/article/10.1007/s11606-020-05971-3" target="_blank">Journal of General Internal Medicine</a></em> suggested that "social factors such as income inequality may explain why some parts of the USA are hit harder by the COVID-19 pandemic than others."</p><p>That's not to say better-off families in the U.S. weren't harmed. A <a href="https://voxeu.org/article/poverty-inequality-and-covid-19-us" target="_blank" rel="noopener noreferrer">paper from the Centre for Economic Policy Research</a> noted that families in counties with a higher median income experienced adjustment costs associated with the pandemic—for example, lowering income-earning interactions to align with social distancing policies. However, the paper found that the costs of social distancing were much greater for poorer families, who cannot easily alter their living circumstances, which often include more individuals living in one home and a reliance on mass transit to reach work and grocery stores. They are also disproportionately represented in essential jobs, such as retail, transportation, and health care, where maintaining physical distance can be all but impossible.</p><p>The paper also cited a positive correlation between higher income inequality and higher rates of coronavirus infection. "Our interpretation is that poorer people are less able to protect themselves, which leads them to different choices—they face a steeper trade-off between their health and their economic welfare in the context of the threats posed by COVID-19," the authors wrote.</p><p>"There are so many pandemics that this pandemic has exacerbated," Dr. Salas-Lopez noted.</p><p>One example is the health-wealth gap. The mental stressors of maintaining a low socioeconomic status, especially in the face of extreme affluence, can have a physically degrading impact on health. <a href="https://www.scientificamerican.com/index.cfm/_api/render/file/?method=inline&fileID=123ECD96-EF81-46F6-983D2AE9A45FA354" target="_blank" rel="noopener noreferrer">Writing on this gap</a>, Robert Sapolsky, professor of biology and neurology at Stanford University, notes that socioeconomic stressors can increase blood pressure, reduce insulin response, increase chronic inflammation, and impair the prefrontal cortex and other brain functions through anxiety, depression, and cognitive load. </p><p>"Thus, from the macro level of entire body systems to the micro level of individual chromosomes, poverty finds a way to produce wear and tear," Sapolsky writes. "It is outrageous that if children are born into the wrong family, they will be predisposed toward poor health by the time they start to learn the alphabet."</p>Research on the economic and mental health fallout of COVID-19 is showing two things: That unemployment is hitting <a href="https://www.pewsocialtrends.org/2020/09/24/economic-fallout-from-covid-19-continues-to-hit-lower-income-americans-the-hardest/" target="_blank" rel="noopener noreferrer">low-income and young Americans</a> most during the pandemic, potentially widening the health-wealth gap further; and that the pandemic not only exacerbates mental health stressors, but is doing so at clinically relevant levels. As <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413844/" target="_blank" rel="noopener noreferrer">the authors of one review</a> wrote, the pandemic's effects on mental health is itself an international public health priority.
Working to close the health gap<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yNDc5MDk1MS9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYxNTYyMzQzMn0.KSFpXH7yHYrfVPtfgcxZqAHHYzCnC2bFxwSrJqBbH4I/img.jpg?width=980" id="b40e2" class="rm-shortcode" data-rm-shortcode-id="1b9035370ab7b02a0dc00758e494412b" data-rm-shortcode-name="rebelmouse-image" />
Northwell Health coronavirus testing center at Greater Springfield Community Church.
Credit: Northwell Health<p>Novel coronavirus may spread and infect indiscriminately, but pre-existing conditions, environmental stressors, and a lack of access to care and resources increase the risk of infection. These social determinants make the pandemic more dangerous, and erode communities' and families' abilities to heal from health crises that pre-date the pandemic.</p><p>How do we eliminate these divides? Dr. Salas-Lopez says the first step is recognition. "We have to open our eyes to see the suffering around us," she said. "Northwell has not shied away from that."</p><p>"We are steadfast in improving health outcomes for our vulnerable and underrepresented communities that have suffered because of the prevalence of chronic disease, a problem that led to the disproportionately higher death rate among African-Americans and Latinos during the COVID-19 pandemic," said Michael Dowling, Northwell's president and CEO. "We are committed to using every tool at our disposal—as a provider of health care, employer, purchaser and investor—to combat disparities and ensure the <a href="https://www.northwell.edu/education-and-resources/community-engagement/center-for-equity-of-care" target="_blank" rel="noopener noreferrer">equity of care</a> that everyone deserves." </p><p>With the need recognized, Dr. Salas-Lopez calls for health care systems to travel upstream and be proactive in those hard-hit communities. This requires health care systems to play a strong role, but not a unilateral one. They must build <a href="https://www.northwell.edu/news/insights/faith-based-leaders-are-the-key-to-improving-community-health" target="_blank" rel="noopener noreferrer">partnerships with leaders in those communities</a> and utilize those to ensure relationships last beyond the current crisis. </p><p>"We must meet with community leaders and talk to them to get their perspective on what they believe the community needs are and should be for the future. Together, we can co-create a plan to measurably improve [community] health and also to be ready for whatever comes next," she said.</p><p>Northwell has built relationships with local faith-based and community organizations in underserved communities of color. Those partnerships enabled Northwell to test more than 65,000 people across the metro New York region. The health system also offered education on coronavirus and precautions to curb its spread.</p><p>These initiatives began the process of building trust—trust that Northwell has counted on to return to these communities to administer flu vaccines to prepare for what experts fear may be a difficult flu season.</p><p>While Northwell has begun building bridges across the divides of the New York area, much will still need to be done to cure U.S. health care overall. There is hope that the COVID pandemic will awaken us to the deep disparities in the US.</p><p>"COVID has changed our world. We have to seize this opportunity, this pandemic, this crisis to do better," Dr. Salas-Lopez said. "Provide better care. Provide better health. Be better partners. Be better community citizens. And treat each other with respect and dignity.</p><p>"We need to find ways to unify this country because we're all human beings. We're all created equal, and we believe that health is one of those important rights."</p>
Philosopher Nick Bostrom's "singleton hypothesis" predicts the future of human societies.
- Nick Bostrom's "singleton hypothesis" says that intelligent life on Earth will eventually form a "singleton".
- The "singleton" could be a single government or an artificial intelligence that runs everything.
- Whether the singleton will be positive or negative depends on numerous factors and is not certain.
Want to Retain American Jobs? Stop Blaming Globalization<div class="rm-shortcode" data-media_id="oxK8j1xN" data-player_id="FvQKszTI" data-rm-shortcode-id="2cf425d7b91ed2a6fc4fe19d065f3408"> <div id="botr_oxK8j1xN_FvQKszTI_div" class="jwplayer-media" data-jwplayer-video-src="https://content.jwplatform.com/players/oxK8j1xN-FvQKszTI.js"> <img src="https://cdn.jwplayer.com/thumbs/oxK8j1xN-1920.jpg" class="jwplayer-media-preview" /> </div> <script src="https://content.jwplatform.com/players/oxK8j1xN-FvQKszTI.js"></script> </div>
Shannon Lee shares lessons from her father in her new book, "Be Water, My Friend: The Teachings of Bruce Lee."
- Bruce Lee would have turned 80 years old on November 27, 2020. The legendary actor and martial artist's daughter, Shannon Lee, shares some of his wisdom and his philosophy on self help in a new book titled "Be Water, My Friend: The Teachings of Bruce Lee."
- In this video, Shannon shares a story of the fight that led to her father beginning a deeper philosophical journey, and how that informed his unique expression of martial arts called Jeet Kune Do.
- One lesson passed down from Bruce Lee was his use and placement of physical symbols as a way to help "cement for yourself this new way of being, or this new lesson you've learned." By working on ourselves (with the right tools), we can develop the skills necessary to rise and conquer new challenges.
How to deal with "epistemic exhaustion."