Can You Improve Your Memory With A Jellyfish Protein?

Some colleagues of mine recently asked me about Prevagen, a supplement that is being advertised heavily on television as a memory booster. It's everywhere, they said–but what is it? And does it work?

Both questions are pretty easy to answer. On the first question, the TL;DR version is that Prevagen's primary ingredient is a protein called apoaequorin, which is found in a species of jellyfish that glows in the dark. These jellies produce two proteins, apoaequorin and green fluorescent protein (GFP), that help them fluoresce. It’s an amazing biological system, and the three scientists who discovered and developed the chemistry of GFP were awarded the 2008 Nobel Prize in chemistry.

Cool science! But what does this have to do with human memory? Not much, it turns out.

First let's examine what Prevagen's manufacturers, Quincy Bioscience, say about it. Their website claims that:
"Prevagen Improves Memory* 
Prevagen is a dietary supplement that has been clinically shown to help with mild memory loss associated with aging.* Prevagen is formulated with apoaequorin, which is safe and uniquely supports brain function.*"
Sounds pretty clear, right? But note the asterisks by each of these claims: if you scroll all the way down (or read the small print on their packages), you'll find out that:
"*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease."
You may recognize this language: it's what all supplement manufacturers use to avoid getting in trouble with the FDA. It means, essentially, that the government hasn't approved Prevagen to treat anything, including memory loss.

Despite Quincy’s claims, I see no reason why eating this protein would have any effect at all on brain function. First of all, it’s not even a human protein, so it's unlikely to work in humans. Second, even if it did work in humans, eating it would not deliver it to our brains, because it would be almost certainly be broken down in the stomach. And third, the connection between any protein and memory is very complex, so simply having more of a protein is very, very unlikely to improve memory.

Quincy's website points to a single study that they themselves conducted, which they argue showed benefits for people with mild memory impairment. However, others have pointed out that the experiment (which was never published in a scientific journal) didn't show any such thing: overall there was no difference between people who took Prevagen and those who took a placebo, but the manufacturer's did some p-hacking to extract a subgroup that appeared to get a benefit. As Dr. Harriett Hall and others have pointed out, this kind of p-hacking is bogus.

And what about my observation that the jellyfish protein will simply be digested in the stomach, and never make it to the brain? It turns out that the company itself admits that I'm right. On their website, they have a "research" page pointing to several safety studies, designed to show that Prevagen won't cause an immune reaction. One of these studies explains that
"Apoaequorin is easily digested by pepsin."
Pepsin is the chief digestive enzyme in your stomach. So Prevagen's main ingredient never gets beyond the stomach, which is why it's probably quite safe. (Joe Schwarcz at McGill University recently made the same point.)

Back in 2015, I asked Ted Dawson, the Abramson Professor of Neurodegenerative Diseases at Johns Hopkins School of Medicine, what he thought of Prevagen’s claims.
“It is hard to evaluate Prevagen as to the best of my knowledge there is no peer-reviewed publication on its use in memory and cognition,” said Dawson. “The study cited on the company’s web site is a small short study, raising concerns about the validity of the claims.”
Finally, a word to those who are still tempted to try Prevagen: it isn't cheap. Their website charges $75 for a bottle of 60 pills, each containing 10 mg of apoaequorin, or $90 for 30 pills of the "Professional formula," which contain 40 mg. (Note that there's no evidence that taking a higher dose will work any better.)

The FTC sued Quincy Bioscience in 2017 for deceptive advertising, arguing that claims that Prevagen boosts memory are false, and that claims it can get into the brain are also false. Just a few months ago, a judge ruled that the case can proceed. Meanwhile, though, the advertising and sales of Prevagen continue. The FTC case states that Quincy sold $165 million worth of Prevagen in the U.S. from 2007 to 2015.

So the bottom line is: jellyfish proteins are very cool, but eating them won't improve your memory. If you're interested in brain food, perhaps you just eat more fish, which might actually work.

(Note: I wrote about Prevagen in 2015, and some elements of this article are based on my earlier one.)

How to live longer: eat less red meat and more nuts. And be optimistic.

Will eating more red meat kill you? It just might–but there's something you can do about it.

Red meat has long been implicated in some very bad health outcomes, especially heart disease and colon cancer. And yet people keep eating it, for the simple reason that it tastes good (though not to everyone, of course).

A recent study out of Harvard and Fudan University, published in the BMJ, put some numbers on the risk of eating red meat. The authors used two very large studies, one of men and one of women, to ask a simple question: does eating red meat make it more likely that a person will die?

The answer is yes: in the study, men and women who ate more red meat–half a serving more per day–had about a 9% greater risk of death (from any cause), over the course of an 8-year followup period. Processed meats were worse: an increase of half a serving per day led to a 17% higher risk of death.

In case you're wondering, "processed" meats are foods like hot dogs, bacon, and sausages. And if half a serving per day sounds like a lot, it's not: the scientists defined a serving as just 85 grams of beef, pork, or lamb, or a single 45-gram hot dog, or 2 slices of bacon. By comparison, a quarter-pound hamburger is 115 grams. So an extra half-serving isn't very much.

(But smoked salmon lovers needn't worry: as I wrote back in August, smoked salmon is not processed meat. It's fish, which is far healthier than red meat.)

Can you lower our risk of death by reducing red meat consumption? The study looked at this question too, and the answer was, again, yes: if you replace one serving of red meat per day with whole grains, vegetables, or nuts, your risk of dying goes down, as much as 19%.

Even better is to replace one serving per day of processed meat (bacon, sausages, etc) with nuts:
"A decrease in processed meat and a simultaneous increase in whole grains, vegetables, or other protein sources was even more strongly associated with lower total mortality, with the largest reductions in risk seen with increases in nuts."
That led to a 26% reduction in the risk of death over eight years. The authors found similar results when they looked at benefits over different time spans.

The conclusion is pretty clear: replace some of the red meat in your diet with vegetables, whole grains, or nuts, and you'll probably live longer.

There's another thing you can do to avoid dying of a heart attack: be optimistic. In a completely independent study published just last week in JAMA, scientists conducted a meta-analysis of 15 earlier studies, asking whether optimism is associated with better heart health. They found that over a 14-year period, optimistic people had a 35% lower (relative) risk of cardiovascular problems and 14% lower (relative) risk of dying than pessimistic people.

There are many caveats about this study–first, it's a meta-analysis, meaning that it combines the data from many other studies. That can lead to biases, but the authors acknowledged this problem and seem to have been pretty careful to avoid it. Second, how do you measure optimism? Turns out there's a questionnaire for that, dating back 25 years, and it appears to be reliable and reproducible. Most of the studies used the same method for measuring optimism, and the benefits were quite consistent across all the studies. And it's possible that sicker people are more pessimistic, so the cause-and-effect could go either way here.

So there you have it: cut down on red meat, eat nuts instead, and stay positive. You'll live longer.





Is this drug combo a true fountain of youth?

Is rejuvenation of the thymus a key to restoring youth? Maybe it is.

A very surprising result appeared last week in a journal called Aging Cell. A team of scientists published the first results of a study that showed, in a small group of older men, that some signs of aging could be reversed with a 3-drug combination.

Not just slowed down. Reversed.

If this holds up, it could literally be life-changing for millions of people. I was initially very skeptical, having read countless claims of anti-aging treatments over the years, virtually all of which turned out to be wrong. Anti-aging treatments are a huge commercial market, full of misleading promises and vague claims. Youth-restoring skin treatments (which don't work) are a particular favorite of cosmetics companies.

But this new study is different. The scientists decided to explore whether recombinant human growth hormone (rhGH) could help to restore the thymus gland. Your thymus is in the middle of your chest, and it is part of your immune system, helping to produce the T cells that fight off infections. As we age, the thymus shrinks and starts to get "clogged with fat," as a news story in Nature put it. Hints that rhGH could help restore the thymus goes back decades, but it had never before been tested in humans.

The scientists leading the study added two more drugs, DHEA and metformin, because rhGH does carry some increased risk of diabetes. Both of these drugs help to prevent diabetes, and both might also have anti-aging benefits, although neither of them is known to affect the thymus.

Amazingly, in 7 out of 9 men in the study (it was a very small study), the thymus showed clear signs of aging reversal, with new thymus tissue replacing fat. The side effects of rhGH are very mild, and none of the men in this study had any significant problems from it or from the other two drugs.

Equally remarkable was another, unanticipated, sign of anti-aging. The study measured "epigenetic age" in all the subjects by four different methods. "Epigenetic age" refers to markers at the cellular level that change as we age, and as the study explains:
"Although epigenetic age does not measure all features of aging and is not synonymous with aging itself, it is the most accurate measure of biological age and age‐related disease risk available today."
After 9 months of treatment, the epigenetic age of the men in this study was 2.5 years younger. The treatment didn't just slow aging–it reversed it. The effects persisted in a followup 6 months later: one and a half years after the study began, the men's epigenetic age was 1.5 years younger than at the beginning. This is truly remarkable.

Any study has limitations, so I should mention a couple here. First, the study was very small, just 9 men, but the effects were strong and significant. Second, the lead scientist of the study, Gregory Fahy, is the co-founder of a company called Intervene Immune that plans to market anti-aging treatments. The authors also include scientists from Stanford, UCLA, and the University of British Columbia.

A few years ago I wrote about another drug combination, dasatinib and quercetin, which showed great promise in reversing aging, but only in mice. We're still waiting to hear more about that treatment, although a test in humans showed some promise earlier this year.

The new 3-drug combination is the most promising I've seen yet. The possible benefits are enormous: as the study points out, they include lower risks for at least 8 types of cancer, heart disease, and stroke. Unlike many other anti-aging treatments, this one has genuine plausibility, and the effects on the thymus can be measured almost immediately. Let's hope this one works out; we'll all be better off if it does.

College football season is starting up. Why do universities support a sport that harms their student athletes?

For those of us in academia, September means a new school year, and all of the excitement and energy that students bring as they return to campus. Strolling around, you can feel the energy in the air.

September is also the beginning of the college football season (in the U.S.). For many students, alumni, and other fans, watching the game each week is one more fall activity they look forward to.

But now, thanks to a rapidly growing body of new research, we know that football can severely harm and even kill its players. Not right away, but years later, through a brain disease called CTE, or chronic traumatic encephalopathy. This is a frightening disorder that gradually destroys brain cells, causing memory loss, confusion, impaired judgment, and progressive dementia. Many former players die very young, in their 40s or 50s, after first suffering for years.

CTE is caused by repeated blows to the head, events that are common to football. It has grown worse in recent decades as the players have gotten bigger and stronger. Improvements in helmet technology haven't helped, and they might even have made CTE even worse, because the helmets allowed players (by their own admission) to use their heads as battering rams.

Two years ago now, a large medical study of football players' brains showed that an appallingly high percentage of those players had CTE. In that study, Boston University scientists led by Jesse Mez and Ann McKee found CTE in the brains of 110 out of 111 former NFL players (99%), and 48 out of 53 college players (91%).

As the BU scientists themselves pointed out, the former players and their families may have suspected something was wrong, and that may have motivated them to participate in the study. Thus the extremely high proportion of deceased players showing CTE in this study is certainly an overestimate. But as I wrote at the time:
"is it okay to ask young men to play football if the risk of permanent brain damage is only 50%? What if it's just 10 or 20%? Is that okay? Is football that important?"
Clearly, the answer should be no. University presidents are constantly, even obsessively, worrying about the safety of their students. Campuses have many programs in place to protect students from crime, from sexual harrassment, from emotional distress, and more. And yet every fall, they willingly–no, enthusiastically–subject the 100 or so students on their football teams to a serious risk of lifelong, life-threatening brain damage. This simply should end.

For an especially poignant story, watch this short video about Greg Ploetz, who played on the 1969 national championship football team at the University of Texas, and who died in 2015 after years of worsening dementia:
As his daughter says in the video,
"If [today's football players] knew what he went through, and what we went through as a family, there's no way that people would decide to keep playing." 
Perhaps universities could take a cue from former Baltimore Ravens player John Urschel, widely considered the smartest player in the NFL, who was pursuing a Ph.D. in mathematics at MIT while simultaneously playing pro football. Two years ago, Urschel quit, because he was worried that brain damage would destroy his ability to think clearly. And just one week ago, Indianapolis Colts' star quarterback Andrew Luck retired early because football had "wrecked his body and stolen his joy."

Brain damage may be happening to much younger players too. A study from the University of Washington last year found that 5% of youth football players aged 5-14 had experienced concussions each season. Three years ago, a mother sued the Pop Warner youth football organization after her son committed suicide at age 25. An autopsy showed that he had CTE, and the mother argued that his brain damaged was caused by his years playing youth football. The Pop Warner organization settled the suit for close to $2 million, but other lawsuits have been filed since.

As I and others have written, football and its promise of big-money television contracts has corrupted our universities. While universities build ever-bigger football stadiums and pay coaches exhorbitant salaries, they force the players to play for free. Now we know that players face a much more direct threat: long-term brain damage.

Let me ask university presidents this question as bluntly as I can: how much brain damage is acceptable for your football players? If your answer is "none," then it's time to get football out of our universities.

$545 million wasn't enough for chiropractors. Now they're lobbying Congress for much more.

Medicare currently wastes more than $545 million a year on chiropractors, as I revealed in an article last year. Wasteful as this is, it's not enough for chiropractors, who have successfully lobbied to have two Congressmen propose a new bill, HR3654, that will require Medicare to pay chiropractors for the full range of services that real doctors offer.

The American Chiropractic Association is practically rubbing its (metaphorical) hands together with glee. As they proudly point out, this endorsement of quackery is bipartisan: the bill is sponsored by two New York Congressman, Democrat Brian Higgins and Republican Tom Reed.

The idea of having chiropractors function as regular physicians is very troubling. Chiropractors do not receive proper medical training: they get their Doctor of Chiropractic (D.C.) degrees from one of a very small number of special chiropractic schools, which do not provide the full medical training that real medical schools do. Their curriculum also includes a heavy dose of pseudoscience, especially the training around subluxations.

For a detailed discussion of why chiropractors are not competent to be family physicians, I recommend this article by an experienced physician, Dr. Harriett Hall, titled "Chiropractors as family doctors? No way!" Dr. Hall goes into considerable detail explain why many of the medical practices of chiropractors are non-standard, not evidence-based, and possibly harmful. Or see this lengthy takedown of chiropractic subluxations by Sam Homola, a former chiropractor.

Many chiropractors are also anti-vaccine, unfortunately, as documented just two weeks ago in this article by attorney Jann Bellamy. Among other things, Bellamy points out that a major chiropractic conference this fall will feature a keynote talk by anti-vaccine activist Robert Kennedy Jr. (about whom I've written before).

Even more alarming, as I've explained before, is that chiropractic neck manipulation has been shown to carry a small but real risk of stroke, because it can create a tear in your vertebral arteries. For example, this report from 2016 documented a case of cerebral hemorrhage apparently caused by chiropractic manipulation. The patient in that case was a 75-year-old woman, which puts her squarely in the class of patients eligible for Medicare.

And to those chiropractors who've read this far: I'm sorry that you were hoodwinked into spending 3-4 years in a chiropractic school, paying nearly $200,000 in tuition and fees, with the promise that you'd be a legitimate medical professional. You were scammed, and I'm sorry about that. And I understand that most (perhaps all) chiropractors want to help their patients. The problem is, the training offered by chiropractic colleges is far short of a proper medical degree.

If the chiropractors' lobbying association get its way, this $545 million (annually) in wasted Medicare dollars will soon become a far higher amount–to the detriment of patients. The bill will allow chiropractors to bill Medicare for pretty much any service that a bona fide physician offers.

It's also worth noting that in 2018, Medicare's Inspector General issued a report titled "Medicare needs better controls to prevent waste, fraud, and abuse related to chiropractic services," which revealed that almost half of Medicare spending on chiropractic care from 2010-2015, between $257 million and $304 million per year, was likely wasted or fraudulent. One wouldn't think this is a time to expand Medicare's coverage of chiropractic.

Congress, don't be fooled by arguments that this proposed new law will lower medical costs, or give patients what they need: it won't. Instead, it will dramatically increase the amount of funds wasted on ineffective treatments. The U.S. does need a better health care system, but this bill would be a big step in the wrong direction.

Hey, NY Times: Keep your hands off my smoked salmon

For lovers of smoked salmon, the New York Times featured an alarming headline last week: "Do Lox and Other Smoked Fish Increase Cancer Risk?" The article reported that the American Institute for Cancer Research, a respected nonprofit organization, considers smoked fish (including lox) to be in the same category as "processed meat." The Times answers its own question with "it might."

The Times is wrong. If anything, smoked salmon is good for you. Let me explain.

Where does the concern come from? In 2015, a major report from the International Agency for Research on Cancer (IARC) concluded that red meat and processed meat probably cause cancer, especially colon cancer. To be precise, they wrote that
"there is sufficient evidence in human beings for the carcinogenicity of the consumption of processed meat."
And what, you might ask, is processed meat? According to the IARC:
"Processed meat refers to meat that has been transformed through salting, curing, fermentation, smoking, or other processes to enhance flavour or improve preservation."
Although the 2015 IARC report didn't mention smoked fish, the NY Times reporter, Sophie Egan, points out that smoked salmon (lox) is also transformed through salting and smoking (or curing, if you consider gravlox). To support this concern, Egan quotes Alice Bender, a dietitian (with a master's degree but not a doctorate) from the American Institute for Cancer Research. According to Bender, who was not involved in the IARC report,
"Even though it’s possible that processed fish and even chicken and turkey could be better alternatives [to processed meats], for now we have to look at all of it as processed meat."
No, we don't.

I read the IARC report, and it doesn't mentioned smoked fish. It states that processed meats usually "contain pork or beef, but might also contain other red meats, poultry, offal (eg, liver), or meat byproducts such as blood." And an earlier report gave these examples of processed meats: ham, bacon, sausages, blood sausages, meat cuts, liver paté, salami, bologna, tinned meat, luncheon meat, and corned beef. Nothing about fish.

However, I wanted to be certain, so I dug down into the original research. The IARC report is based on a whole raft of earlier studies, which they combined and summarized, and it turns out that some of those studies did indeed look at smoked fish.

In particular, this IARC study from 2007–one of the studies that the 2015 IARC report relied upon–looked at both meat and fish and how they affected the risk of colon cancer. The 2007 study found that consumption of fish reduced the risk of cancer. And most important for today's discussion, they stated explicitly that
"Fish included fresh, canned, salted, and smoked fish."
There you have it. Consumption of fish, including smoked fish, reduces the risk of colon cancer. (A minor caveat: smoked salmon does have a high level of salt, which can be a concern for people with high blood pressure.)

So my response to the NY Times: keep your hands off my bagels and lox. Really, you should know better.

The US will try treating opioid addiction with fake medicine

If you can't afford to offer real medical care, why not offer fake medicine? The U.S. Medicare system is about to give this strategy a try, for treating back pain.

Last week, Medicare announced that it wants to start paying for studies of acupuncture as a treatment for low back pain, as reported by the Washington Post and Stat. The government's reason, according to Secretary of Health and Human Services Alex Azar, was that we need this option to help solve opioid addiction:
“Defeating our country’s epidemic of opioid addiction requires identifying all possible ways to treat the very real problem of chronic pain, and this proposal would provide patients with new options while expanding our scientific understanding of alternative approaches to pain.”
If you break down HHS Secretary Azar's statement, it's mostly correct. Yes, treating opioid addition should explore all methods for treating chronic pain. And yes, this program will provide "new" options, even though the option in question is nonsense.

But (3) no, studying acupuncture will not expand our scientific understanding of "alternative approaches" to pain. Why not? Because thousands of studies have already been done, and the verdict was in, long ago, that acupuncture is nothing more than an elaborate placebo.

The problem is, acupuncture proponents never give up. Every time a study shows that acupuncture fails (and this has happened, repeatedly), they claim it wasn't done properly or make another excuse. I've even seen proponents argue that studies in which acupuncture failed were in fact successes, because acupuncture and placebo treatments both outperformed the "no treatment" option.

(Aside: we use placebo treatments because we've known for decades that any treatment, even a sugar pill, may show a benefit as compared to no treatment at all. Acupuncture research has created placebos by using fake needles that don't actually pierce the skin, or by placing needles in random places rather than the so-called acupuncture points. Scientifically speaking, if a treatment doesn't outperform a placebo, then the treatment is a failure.)

To make matters worse, the new HHS program will fund "pragmatic" clinical trials rather than the usual, gold-standard randomized trials (RCTs). Without going into details, let's just say that pragmatic trials are much less well-controlled than RCTs, allowing more room for mistakes and misinterpretation. This is a bad idea even when the intervention being studied is legitimate. It's an even worse idea here, where trials have shown, over and over, that acupuncture doesn't work.

Secretary Azar might be confused because the acupuncture industry has managed to get hundreds of studies published, many of them positive–but most of them are poorly designed, and who has time to read all that bad science? (The rare well-designed studies always show that acupuncture doesn't work.) Acupuncturists have even created pseudoscientific journals devoted entirely to acupuncture, as I wrote about in 2017. Some of these journals are published by respected scientific publishers, but they are still little more than fake journals.

Not surprisingly, with entire journals trying to fill each issue with acupuncture articles, last week's Medicare announcement noted that
"the agency [CMS] recognizes that the evidence base for acupuncture has grown in recent years". 
No, it hasn't. What has grown is the number of articles. Adding more garbage to a pile doesn't make it smell better.

For those who aren't familiar with the claims of acupuncture, let's do a very quick summary: acupuncturists stick needles in a person's body at specific points in order to manipulate a mystical life force that they call "qi" (proounced "chee"). This idea is "a pre-scientific superstition" that has no basis in medicine, physiology or biology, and has never had any good scientific evidence to support it.  Acupuncturists don't even agree on where the acupuncture points are, which should make it impossible to do a scientific study. It's not at all surprising that acupuncture doesn't work; indeed, if it did work, modern medicine would have to seriously examine what mechanism could possibly explain it.

But wait, argue proponents, what about all the wise traditional doctors in China who developed acupuncture over thousands of years? Well, it turns out that acupuncture wasn't popular in China until the mid-20th century, when Chairman Mao pulled a fast one on his population because he couldn't supply enough real medical care. Mao didn't use acupuncture himself and apparently didn't believe in it. I highly recommend this expose of Mao's scam, by Alan Levinovitz in Slate.

So rather than spend millions of dollars on yet another study of acupuncture for pain, I have a better suggestion for HHS: invest the funds in basic biomedical research, which has had a flat budget for more than a decade now. As long as it goes through proper peer review, almost any research will be far better than wasting the money on acupuncture.

Now, I'm not naive enough to think that Medicare will take my advice, but I can tell them right now what their new "pragmatic" trials will reveal. Acupuncturists will happily take the money, treat people suffering from back pain, and report that some of them experienced reductions in pain. Some of the patients will invariably agree, because back pain comes and goes, and it's hard to know why it went away.

Then the acupuncturists will say, "look, it works! Now please cover acupuncture for all Medicare patients." Then we'll spend more tax dollars on pseudoscience, and patients will be in just as much pain as ever. If Medicare falls for this (and I fear they will), then Chairman Mao will have fooled the U.S. government, just as he fooled many of his own people half a century ago.