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He came down hard on nutrition in a pull-no-punches 2013 British Medical Journal editorial titled, “Implausible results in human nutrition research,” in which he noted, “Almost every single nutrient imaginable has peer reviewed publications associating it with almost any outcome.”

Ioannidis told me that sussing out the connection between diet and health — nutritional epidemiology — is enormously challenging, and “the tools that we’re throwing at the problem are not commensurate with the complexity and difficulty of the problem.” The biggest of those tools is observational research, in which we collect data on what people eat, and track what happens to them.

He lists plant-based foods — fruit, veg, whole grains, legumes — but acknowledges that we don’t understand enough to prescribe specific combinations or numbers of servings.

funding bias isn’t the only kind. “Fanatical opinions abound in nutrition,” Ioannidis wrote in 2013, and those have bias power too.

“Definitive solutions won’t come from another million observational papers or small randomized trials,” reads the subtitle of Ioannidis’s paper. His is a burn-down-the-house ethos.

When it comes to actual dietary recommendations, the disagreement is stark. “Ioannidis and others say we have no clue, the science is so bad that we don’t know anything,” Hu told me. “I think that’s completely bogus. We know a lot about the basic elements of a healthy diet.”

Give tens of thousands of people that FFQ, and you end up with a ginormous repository of possible correlations. You can zero in on a vitamin, macronutrient or food, and go to town. But not only are you starting with flawed data, you’ve got a zillion possible confounding variables — dietary, demographic, socioeconomic. I’ve heard statisticians call it “noise mining,” and Ioannidis is equally skeptical. “With this type of data, you can get any result you want,” he said. “You can align it to your beliefs.”

Big differences in what people eat track with other differences. Heavy plant-eaters are different from, say, heavy meat-eaters in all kinds of ways (income, education, physical activity, BMI). Red meat consumption correlates with increased risk of dying in an accident as much as dying from heart disease. The amount of faith we put in observational studies is a judgment call.

I find myself in Ioannidis’s camp. What have we learned, unequivocally enough to build a consensus in the nutrition community, about how diet affects health? Well, trans-fats are bad.

Over and over, large population studies get sliced and diced, and it’s all but impossible to figure out what’s signal and what’s noise. Researchers try to do that with controlled trials to test the connections, but those have issues too. They’re expensive, so they’re usually small and short-term. People have trouble sticking to the diet being studied. And scientists are generally looking for what they call “surrogate endpoints,” like increased cholesterol rather than death from heart disease, since it’s impractical to keep a trial going until people die.

, what do we do? Hu and Ioannidis actually have similar suggestions. For starters, they both think we should be looking at dietary patterns rather than single foods or nutrients. They also both want to look across the data sets. Ioannidis emphasizes transparency. He wants to open data to the world and analyze all the data sets in the same way to see if “any signals survive.” Hu is more cautious (partly to safeguard confidentiality

I have a suggestion. Let’s give up on evidence-based eating. It’s given us nothing but trouble and strife. Our tools can’t find any but the most obvious links between food and health, and we’ve found those already.

Instead, let’s acknowledge the uncertainty and eat to hedge against what we don’t know

We’ve got two excellent hedges: variety and foods with nutrients intact (which describes such diets as the Mediterranean, touted by researchers). If you severely limit your foods (vegan, keto), you might miss out on something. Ditto if you eat foods with little nutritional value (sugar, refined grains). Oh, and pay attention to the two things we can say with certainty: Keep your weight down, and exercise.

I used to say I could tell you everything important about diet in 60 seconds. Over the years, my spiel got shorter and shorter as truisms fell by the wayside, and my confidence waned in a field where we know less, rather than more, over time. I’m down to five seconds now: Eat a wide variety of foods with their nutrients intact, keep your weight down and get some exercise.

In contrast to a previous study6, they observed a robust lifespan extension in male mice fed a BCAA-restricted diet throughout life, equal to the benefits of dietary protein restriction.

Interestingly, female mice showed no lifespan extension from BCAA or dietary protein restriction, and if BCAA restriction was started during middle age, the benefits on males were greatly reduced. Thus, both studies collectively point to mTOR as a primary mediator of the benefits associated with BCAA restriction (Fig. 1).

A clear picture is emerging of how specific amino acids are sensed by sestrin to regulate mTOR signalling and autophagy and so preserve the function of intestinal stem cells during ageing.

Genetic background is crucial in the response to dietary restriction, with an identical low-calorie regimen increasing lifespan in some mouse strains but shortening it in others

There is also evidence that dietary restriction initiated later in life might have reduced benefits in rodents and, in some cases, result in premature death

Taken together, these observations suggest that although protein- and BCAA-restricted diets are a powerful research tool for exploring the fundamental mechanisms of ageing, it is premature to recommend adoption by the general population.

These are the Frankenstein remedies — botanicals, herbs, minerals, enzymes, amino acids, dried stuff. They’re “natural.” They’re not cheap. And Americans pop them like Skittles, despite recent studies showing that nearly a third of all herbal supplements on the market may be outright frauds.

To understand how we got here, you have to go back to 1994, when Senator Orrin G. Hatch of Utah midwifed through Congress a new industry protected from all but minimal regulation. It is also an industry that would make many of his closest associates and family members rich. In turn, they’ve rewarded him with sizable campaign contributions.

Even though serious illnesses, and some deaths are on the rise from misuse of these supplements, Hatch is determined to keep regulators at bay. “I am committed to protect this industry and the integrity of its products,” he told a gathering of potency pill-pushers and the like in Utah last fall.

what about the medical implications? These pills and powders can’t, by law, make specific claims to cure anything. So they claim to make you healthier. The consumer is left playing doctor, reading questionable assertions that course through the unfiltered garbage of the Internet.

there was this finding reported in the authoritative Annals of Internal Medicine: “Enough is enough: Stop wasting money on vitamin and mineral supplements.”

So, the industry keeps growing, with 65,000 dietary supplements now on the market, consumed by nearly half of all Americans. The larger issue is mistrust of authority, a willful ignorance that knows no political side. Thus, right-wing libertarians promote a freewheeling market of quack products, while left-wing conspiracy theorists disdain modern medicine in favor of anything sold as “natural” or vaguely countercultural. These are some of the same people who will not vaccinate their children.

Often, preliminary studies fuel irrational exuberance about a promising dietary supplement, leading millions of people to buy in to the trend. Many never stop. They continue even though more rigorous studies — which can take many years to complete — almost never find that vitamins prevent disease, and in some cases cause harm

There’s no conclusive evidence that dietary supplements prevent chronic disease in the average American, Dr. Manson said. And while a handful of vitamin and mineral studies have had positive results, those findings haven’t been strong enough to recommend supplements to the general American public, she said.

The National Institutes of Health has spent more than $2.4 billion since 1999 studying vitamins and minerals. Yet for “all the research we’ve done, we don’t have much to show for it,” said Dr. Barnett Kramer, director of cancer prevention at the National Cancer Institute.

A big part of the problem, Dr. Kramer said, could be that much nutrition research has been based on faulty assumptions, including the notion that people need more vitamins and minerals than a typical diet provides; that megadoses are always safe; and that scientists can boil down the benefits of vegetables like broccoli into a daily pill.

when researchers tried to deliver the key ingredients of a healthy diet in a capsule, Dr. Kramer said, those efforts nearly always failed.

It’s possible that the chemicals in the fruits and vegetables on your plate work together in ways that scientists don’t fully understand — and which can’t be replicated in a table

The body naturally regulates the levels of many nutrients, such as vitamin C and many B vitamins, Dr. Kramer said, by excreting what it doesn’t need in urine. He added: “It’s hard to avoid getting the full range of vitamins.”

Without even realizing it, someone who eats a typical lunch or breakfast “is essentially eating a multivitamin,”

More important, perhaps, is that most Americans get plenty of the essentials, anyway. Although the Western diet has a lot of problems — too much sodium, sugar, saturated fat and calories, in general — it’s not short on vitamins

Not all experts agree. Dr. Walter Willett, a professor at the Harvard T.H. Chan School of Public Health, says it’s reasonable to take a daily multivitamin “for insurance.” Dr. Willett said that clinical trials underestimate supplements’ true benefits because they aren’t long enough, often lasting five to 10 years. It could take decades to notice a lower rate of cancer or heart disease in vitamin taker

For Charlsa Bentley, 67, keeping up with the latest nutrition research can be frustrating. She stopped taking calcium, for example, after studies found it doesn’t protect against bone fractures. Additional studies suggest that calcium supplements increase the risk of kidney stones and heart disease.

People who take vitamins tend to be healthier, wealthier and better educated than those who don’t, Dr. Kramer said. They are probably less likely to succumb to heart disease or cancer, whether they take supplements or not. That can skew research results, making vitamin pills seem more effective than they really are

Because folic acid can lower homocysteine levels, researchers once hoped that folic acid supplements would prevent heart attacks and strokes.In a series of clinical trials, folic acid pills lowered homocysteine levels but had no overall benefit for heart disease, Dr. Lichtenstein said

When studies of large populations showed that people who eat lots of seafood had fewer heart attacks, many assumed that the benefits came from the omega-3 fatty acids in fish oil, Dr. Lichtenstein said.Rigorous studies have failed to show that fish oil supplements prevent heart attacks

But it’s possible the benefits of sardines and salmon have nothing to do with fish oil, Dr. Lichtenstein said. People who have fish for dinner may be healthier as a result of what they don’t eat, such as meatloaf and cheeseburgers.

“Eating fish is probably a good thing, but we haven’t been able to show that taking fish oil [supplements] does anything for you,

In the tiny amounts provided by fruits and vegetables, beta carotene and similar substances appear to protect the body from a process called oxidation, which damages healthy cells, said Dr. Edgar Miller, a professor of medicine at Johns Hopkins School of Medicine.Experts were shocked when two large, well-designed studies in the 1990s found that beta carotene pills actually increased lung cancer rates.

Likewise, a clinical trial published in 2011 found that vitamin E, also an antioxidant, increased the risk of prostate cancer in men by 17 percent

“Vitamins are not inert,” said Dr. Eric Klein, a prostate cancer expert at the Cleveland Clinic who led the vitamin E study. “They are biologically active agents. We have to think of them in the same way as drugs. If you take too high a dose of them, they cause side effects.”

“We should be responsible physicians,” she said, “and wait for the data.”

“Is there a weight of evidence that says we can totally ignore both dietary cholesterol and LDL? Absolutely not,” he said. “You can legitimately say we’re starting to rethink some things, but ignoring LDL could absolutely result in heart attacks and strokes.

The medical community’s understanding of the danger of cholesterol is changing. Many cardiologists are starting to think that independent of other considerations, the level of LDL in our blood may not be as important as it previously seemed.

In November, the American Heart Association and the American College of Cardiology released new guidelines that redefined the use of statins. While they continue to recommend that people at high risk for heart disease and people with LDL levels above 189 take a statin, the long-standing goal of lowering one’s LDL level to 70 is no longer deemed worthwhile to monitor.

Katz acknowledges that dietary cholesterol may be an innocuous part of an overall healthy diet. “The problem is that people are going to get their dietary cholesterol from things other than fish and eggs; they’re going to get it from meats and dairies. The problem with diets like that is if you eat more of A, you’re probably going to eat less of B. So people who are eating more meat and dairy and high-fat, high-cholesterol foods are eating fewer plants—they’re not eating beans; they’re not eating lentils. So yes, I think it’s entirely confabulated and contrived, and potentially dangerous on the level of lethal.”

Having talked to all of these people and read their work, here is how I walk away from this. Oxidative stress will increasingly be the target of medical treatments and preventive diets. We’ll hear more about the role of blood sugar in Alzheimer’s and continue to focus on moderating intake of refined carbohydrates. The consensus remains that too much LDL is bad for you. We do not have reason to believe that gluten is bad for most people. It does cause reactive symptoms in some people. Peanuts can kill some people, but that does not mean they are bad for everyone

I agree with Katz that the diets consistently shown to have good long-term health outcomes—both mental and physical—include whole grains and fruits, and are not nearly as high in fat as what Perlmutter proposes.

In clearing our plates of meat, eggs and cheese (fat and protein), we ate more grains, pasta and starchy vegetables (carbohydrates). Over the past 50 years, we cut fat intake by 25 percent and increased carbohydrates by more than 30 percent, according to a new analysis of government data. Yet recent science has increasingly shown that a high-carb diet rich in sugar and refined grains increases the risk of obesity, diabetes and heart disease — much more so than a diet high in fat and cholesterol.

In 2013, government advice to reduce salt intake (which remains in the current report) was contradicted by an authoritative Institute of Medicine study. And several recent meta-analyses have cast serious doubt on whether saturated fats are linked to heart disease, as the dietary guidelines continue to assert.

Much of the epidemiological data underpinning the government’s dietary advice comes from studies run by Harvard’s school of public health. In 2011, directors of the National Institute of Statistical Sciences analyzed many of Harvard’s most important findings and found that they could not be reproduced in clinical trials.

Today, we are poised to make the same mistakes. The committee’s new report also advised eliminating “lean meat” from the list of recommended healthy foods, as well as cutting back on red and processed meats. Fewer protein choices will likely encourage Americans to eat even more carbs. It will also have policy implications: Meat could be limited in school lunches and other federal food programs.

It’s possible that a mostly meatless diet could be healthy for all Americans — but then again, it might not be. We simply do not know. There are no rigorous clinical trials on such a diet, and although epidemiological data exists for adult vegetarians, there is none for children.

We have to start looking more skeptically at epidemiological studies and rethinking nutrition policy from the ground up.

Until then, we would be wise to return to what worked better for previous generations: a diet that included fewer grains, less sugar and more animal foods like meat, full-fat dairy and eggs

. In 2009, the researchers reported in the Journal of the American Medical Association that taking high doses of vitamin B12 along with folic acid (technically vitamin B9) was associated with greater risk of cancer and all-cause mortality.

There are legitimate and important uses for B-vitamin supplements, but the emerging evidence suggests we’re best to treat them more like pharmaceuticals than like panaceas to be shoveled into us in pursuit of energy, metabolic fortitude, “cardioprotection,” “bone wellness,” or whatever way in which we’d like to be better.

The research team is quick to note that the doses of B vitamins in question are enormous. The U.S. Recommended Dietary Allowance for B6 is 1.7 milligrams per day, and for B12 it’s 2.4 micrograms. The high-risk group in the study was taking around 20 times these amounts.That could seem nonsensical, except that these are the doses for sale at healthy-seeming places like Whole Foods and GNC. Many sellers offer daily 100-milligram B6 pills. B12 is available in doses of 5,000 micrograms.

Lung-cancer risk among men who took 20 milligrams of B6 daily for years was twice that of men who didn’t. Among people who smoke, the effect appeared to be synergistic, with B6 usage increasing risk threefold. The risk was even worse among smokers taking B12. Using more than 55 micrograms daily appeared to almost quadruple lung-cancer risk.

The current law gives consumers no reason to expect that risks will be listed on the labels of these products, or that health claims are accurate. A product like a high-dose B6 and B12 supplement hits shelves, and only decades later do researchers begin to understand the long-term health effects, who might benefit from taking it, and who might be harmed.  

“Diets are an extreme case of accepting evidence we want to believe,”

That includes doctors, he added, who overlook that the evidence for the low-fat diets they often recommend is the sort “we would never accept in the practice of medicine.”

Doctors are in a bind, said Dr. Daniel J. Rader, a heart disease specialist at the University of Pennsylvania. When patients ask what to eat, he said, “you have to give them something.”

the best they have are studies that look at intermediate markers of risk, like cholesterol levels. In the end, he said, “most doctors just give dietary platitudes.”

In support of that idea, half a dozen Nobel laureates and other prominent scientists are working with two small companies offering NR supplements.

This time his lab made headlines by reporting that the mitochondria in muscles of elderly mice were restored to a youthful state after just a week of injections with NMN (nicotinamide mononucleotide), a molecule that naturally occurs in cells and, like NR, boosts levels of NAD.

It should be noted, however, that muscle strength was not improved in the NMN-treated mice

a single dose of NR resulted in statistically significant increases” in NAD in humans—the first evidence that supplements could really boost NAD levels in people.

When NAD levels drop, as they do with aging, SIRT1 activity falls off, which in turn makes the crucial signals fade, leading to mitochondrial dysfunction and all the ill effects that go with it.

NAD boosters might work synergistically with supplements like resveratrol to help reinvigorate mitochondria and ward off diseases of aging

Test-tube and rodent studies also suggest that pterostilbene is more potent than resveratrol when it comes to improving brain function, warding off various kinds of cancer and preventing heart disease.

Even before Sinclair's paper, researchers had shown in 2012 that when given doses of NR, mice on high-fat diets gained 60 percent less weight than they did on the same diets without NR. Further, none of the mice on NR showed signs of diabetes, and their energy levels improved. The scientists reportedly characterized NR's effects on metabolism as "nothing short of astonishing."

The Sinclair group's NAD paper drew attention partly because it showed a novel way that NAD and sirtuins work together. The researchers discovered that cells' nuclei send signals to mitochondria that are needed to maintain their normal operation. SIRT1 helps insure the signals get through. When NAD levels drop, as they do with aging, SIRT1 activity falls off, which in turn makes the crucial signals fade, leading to mitochondrial dysfunction and all the ill effects that go with it.

Test-tube and rodent studies also suggest that pterostilbene is more potent than resveratrol when it comes to improving brain function, warding off various kinds of cancer and preventing heart disease.

the rest comes from his multiple real world examples illustrating exactly why even the most reluctant mathophobe is well advised to achieve a personal understanding of the statistical underpinnings of life, whether that individual is watching football on the couch, picking a school for the children or jiggling anxiously in a hospital admitting office.

And while we’re talking about bias, let’s not forget publication bias: studies that show a drug works get published, but those showing a drug does nothing tend to disappear.

The same trade-off applies to the interpretation of medical tests. Unproven disease screens are likely to do little but feed lots of costly, anxiety-producing garbage into your medical record.

Given the poor quality of the typical American diet, this fortification is far from superfluous. In fact, for products like milk and flour, where fortification and enrichment have occurred for so long that they’ve become invisible, it would be almost irresponsible not to add synthetic vitamins.

synthetic vitamins are as essential to food companies as they are to us. To be successful in today’s market, food manufacturers must create products that can be easily transported over long distances and stored for extended periods.

They also need to be sure that their products offer some nutritional value so that customers don’t have to go elsewhere to meet their vitamin needs. But the very processing that’s necessary to create long shelf lives destroys vitamins, among other important nutrients. It’s nearly impossible to create foods that can sit for months in a supermarket that are also naturally vitamin-rich.

Today, it would be easy to blame food marketers for using vitamins to deceive us into buying their products. But our blindness is largely our own fault.

we’ve entered into a complicit agreement with them: They depend on us to buy their products, and we depend on the synthetic vitamins they add to those products to support eating habits that might otherwise leave us deficient

extra vitamins do not protect us from the long-term “diseases of civilization” that are currently ravaging our country, including obesity, heart disease and Type 2 diabetes — many of which are strongly associated with diet.

natural foods contain potentially protective substances such as phytochemicals and polyunsaturated fat that also are affected by processing, but that are not usually replaced. If these turn out to be as important as many researchers suspect, then our exclusive focus on vitamins could mean we’re protecting ourselves against the wrong dangers. It’s as if we’re taking out earthquake insurance policies in an area more at risk for floods.

And adding back vitamins after the fact ignores the issue of synergy: how nutrients work naturally as opposed to when they are isolated. A 2011 study on broccoli, for example, found that giving subjects fresh broccoli florets led them to absorb and metabolize seven times more of the anticancer compounds known as glucosinolates, present in broccoli and other cruciferous vegetables

And yet we refuse to change our eating habits in the ways that would actually protect us, which would require refocusing our diets on minimally processed foods that are naturally nutrient-rich.

The popularity of dietary supplements and vitamin-enhanced processed “health” foods means that even those of us who try to do right by our health are often getting it wrong.

we mustn’t let it distract us from an even more fundamental question: how we’ve allowed the word “vitamin” to become synonymous with “health.”

As a result, our microbiomes are better at helping us store fat than those of our ancestors.

Antibiotics aren’t the only force shifting our internal ecology. Modern diets are full of processed foods and low in fiber, the kind of hard-to-break-down carbohydrates found especially in vegetables, legumes, and whole grains that are crucial for a healthy microbiome.

The vast majority of our internal microbes live in the far reaches of our digestive tract, the colon, explains Justin Sonnenburg, an associate professor of microbiology and immunology at Stanford. Because of their location, these microscopic critters “really only get access to the dregs of what we eat”—the dietary fiber that our organs can’t digest. The microbes have evolved to process that fiber by fermenting it with enzymes.

feeding this fermentation process appears to be crucial for averting weight gain and diseases like obesity and Type 2 diabetes

fiber supplements might also trigger liver cancer.

“Right now, the only useful advice I could give somebody would be to eat foods naturally rich in fiber,” he says, like bran cereal and every kind of bean you can think of. Other winners included pears, avocados, apples, seeds, and nuts.

The Institute of Medicine recommends that women eat 25 grams and men 38 grams of fiber every day, but Americans only get about 15 grams on average.

The choice of whether to lunch on a cup of black beans or five chicken nuggets—which both contain about 220 calories—just got a whole lot easier.

Discokeryx xiezhi was an early relative of today’s giraffes, but more like a cousin and not a direct ancestor.

“To the best of our knowledge, D. xiezhi exhibits the most optimized head-butting adaptation in vertebrate evolution,” the researchers write in the paper.

The discovery of Discokeryx xiezhi suggests this fighting style and competition for mates may be a contributing factor in their long-neck evolution.

“In reality, it was likely a combination of natural selection ... for a particular dietary preference and sexual selection in that lineage that drove the evolution of modern giraffe necks and limbs,” Advait Jukar, a paleobiologist at Yale University who was not involved in the study tells Scientific American’s Rachel Nuwer.