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.)

Fish really is brain food

Everyone has heard that eating fish is good for the brain. This notion goes back at least a century; the famous humorist and novelist P.G. Wodehouse often mentioned it in his books. In one scene, after Jeeves (the butler) describes a clever scheme to escape a ticklish problem, Bertie Wooster reacts:

I stared at the the man.
'How many tins of sardines did you eat, Jeeves?'
'None, sir. I am not fond of sardines.'
'You mean, you thought of this great, this ripe, this amazing scheme entirely without the impetus given to the brain by fish?'
'Yes, sir.' [From Very Good, Jeeves, (c) 1930 by P.G. Wodehouse]

A century ago, the evidence that fish is brain food was virtually nonexistent. Researchers have been looking at this question ever since, and the evidence has been mixed. Even if fish is good for the brain, the mercury content in some fish might have the opposite effect.

A new study that appeared last week in JAMA answers this question: fish is indeed good for the brain. More precisely, eating fish regularly was associated with a reduced risk of Alzheimer's disease. This benefit occurred despite the fact that people who ate more fish did have higher levels of mercury in the brain. Apparently, the levels of mercury were too low to cause harm, and the benefits of eating fish easily outweighed any risks.

The new study, by Martha Clare Morris and colleagues at Rush Medical Center in Chicago, looked at 554 Chicago residents, all part of a long-term aging study, who died over a ten-year period. The scientists conducted autopsies to look directly in the brain for physiological changes such as neuritic plaques, which are signs of Alzheimer's or other disease. They used questionnaire data, which they collected for everyone in the study, to measure how much fish people had been eating–an imperfect way to measure eating habits, but it's often the only realistic way to gather this information.

Here's what they found: people who ate seafood at least once per week had lower levels of three different physiological signs of Alzheimer's, but only in people with a genetic marker known as APOE ε4, which itself carries an increased risk of Alzheimer's. (None of the people in the study had dementia when they first enrolled, starting in 1997.) Somehow, then, eating fish seems to counteract the effects of this harmful genetic mutation.

Bad news for fish oil supplement makers: the study found that "fish oil supplementation had no statistically significant correlation with any neuropathologic marker." In other words, people who took supplements got no benefit. You just have to eat fish.

This isn't the first study to show a positive benefit to brain health from eating fish. The authors cite 13 previous studies that reported "protective relations between seafood consumption and n-3 fatty acids with cognitive decline and incident dementia." The JAMA study is the first to include mercury levels, brain changes associated with Alzheimer's, and diet all in the same study. It's reassuring to learn that despite the increased mercury caused (probably) by eating more fish, the overall effect is beneficial.

The authors also pointed out that as we age, our brains lose DHA, a critical lipid in the brain, and that therefore "fish consumption may be more beneficial with older age." The FDA already recommends that pregnant women and young children eat more fish for its nutritional benefits. Now there's evidence that older people should eat fish regularly too.

So it seems that Wodehouse's character Bertie Wooster might have been right: fish really is brain food.

Those fish oil supplements might cause cancer

Eating fish is good for you, especially fish that contain omega-3 fatty acids.  So I was surprised last week to read a new study in the Journal of the National Cancer Institute that found that omega-3 fatty acids increase the risk of prostate cancer.  The risk for both high-grade and low-grade cancer was increased with higher levels of omega-3 fatty acids.  This is a carefully done study, and the results should make anyone who is taking fish oil pills reconsider.

One reason this study caught many people off guard is that there has been much evidence showing that a diet rich in fish that contain omega-3 oils is good for you.  The Mayo Clinic says that  "eating fish helps your heart", especially fish like salmon that contain omega-3 fatty acids.  The American Heart Association (AHA) elaborates:

"Omega-3 fatty acids benefit the heart of healthy people, and those at high risk of — or who have — cardiovascular disease. Research has shown that omega-3 fatty acids decrease risk of arrhythmias (abnormal heartbeats), which can lead to sudden death. Omega-3 fatty acids also decrease triglyceride levels, slow growth rate of atherosclerotic plaque, and lower blood pressure (slightly)."

This all sounds great.  Because of the evidence about the benefits of fatty fish, supplement manufacturers have been marketing and selling fish oil pills for years, with great success.  As I described back in 2010, GlaxoSmithKline even created a high-dose omega-3 fatty acid pill called Lovaza that has FDA approval.

But the evidence for that you can get the same benefit from supplemental omega-3 fatty acids — taking a pill, that is — is much weaker.  In fact, a large review published last year in the Journal of the American Medical Association found no connection at all between supplemental omega-3 and a lower risk of heart attacks, strokes, or death in general.  Other studies have reported similarly negative results.  So it appears that fish oil pills may not have any heart benefits.

And now, with this new study, we learn that supplemental fish oil might increase the risk of prostate cancer.

The bottom line: the AHA recommendations about eating fish are probably still good ones.  The AHA website says:

"We recommend eating fish (particularly fatty fish) at least two times (two servings) a week. Each serving is 3.5 oz. cooked, or about ¾ cup of flaked fish.  Enjoy fish baked or grilled, not fried." 

But popping a fish oil pill is not going to cut it. As we've seen before, supplements often fail to show the benefits that a healthy diet offers.  So save your money and stop buying those fish oil pills — and fire up the grill and throw on a few salmon fillets for this weekend's barbecue.

Scientists build a better salmon

Salmon may soon be the first genetically modified animal to hit our dinner plates. We've been eating GMO foods for years, mostly without noticing it, but until now all the genetically modified organisms have been plants.

The new salmon was developed by AquaBounty Technologies, a company in Massachusetts, and here╒s how it works: start with Atlantic salmon, add a growth gene from the Pacific Chinook salmon, and add another gene from the ocean pout (Trisopterus luscus). In combination, these two genes make the Atlantic salmon grow to maturity in just 18 months, instead of the normal 3 years. The new salmon have the potential to make salmon farming much more efficient. The Washington Post reported this week that the FDA is close to approving the fish for human consumption.

This is cool science. So why are all the reports, both in the mainstream media and the blogosphere, making it sound like a frightening development?

Let's get one thing straight: we have to learn how to farm our fish. The human race is rapidly depleting the stocks of almost every wild fish that we like to eat, and many traditional fisheries are already wiped out. Others have been depleted so badly that severe fishing limitations have been imposed in a desperate attempt to allow stocks to recover. This can't go on.

Think about it: we farm all the other animals that we eat. Imagine that we only ate wild cows, or chicken, or pigs. The human race can't be fed by wild animals alone - we're too numerous and too hungry. Sooner or later, we will drive wild fish to extinction, unless we make the switch to farmed fish.

And as I wrote recently, oily fish like salmon contain omega-3 fatty acids, which appear to carry health benefits, especially when compared to the fats contained in other meats. We should all eat more salmon.

Okay, but what about the downsides of GMO salmon? The anti-GMO forces have issued statements warning of dire consequences if these "Frankenfish" are allowed on the market. Wenonah Hauter, the director of Food and Water Watch, a nonprofit whose goals I generally support, issued a statement that is full of misinformation. For example, she claims that the salmon are "toxic", which sounds pretty scary. As evidence, she says "a recent study commissioned by the European Union revealed that fish that have been modified to grow faster also have a higher tolerance to the toxins in their environment."

I looked up the EU study, by by Fredrik Sundström at the University of Gothenburg, to learn what it actually said. Although the university's press release says that "transgenic fish can be more resistant to environmental toxins," the study itself didn't provide any evidence for this claim. In fact, it didn't even study toxins. Instead, Prof. Sundström looked at what might happen if GMO fish escaped into the wild, and he concluded that they might survive better than wild fish. He didn't conclude anything about toxins.

Hauter of Food and Water Watch isn't the only one to get this wrong. Reporter Paulina Reso at the New York Daily News got it just as wrong, reporting that "A study commissioned by the E.U. found that these engineered fish have a higher tolerance to toxins, putting consumers at risk." She cites the same press release from the University of Gothenburg.

Not only is the claim about toxins unfounded, but it ignores the very real (and widely documented) danger of mercury accumulating in wild fish, including salmon. If you're truly concerned about toxins in fish, you would support fish farming, not oppose it.

The Center for Food Safety's George Kimbrell, quoted in The Post article and elsewhere, threatened to sue the FDA if they approve the new transgenic salmon. He says they are concerned about "catastrophic consequences like the gulf oil spill." Wow, that sounds awful! Transgenic salmon will be as bad as the largest oil spill in U.S. history? Is he kidding? Rather than spend time on breathless hyperbole, Kimbrell should be worried about the very real possibility of driving wild salmon to extinction. He doesn't explain what his concern is based on, and it seems that his group simply opposes any genetically modified organisms on principal. Their opposition is not based on science, nor on any well-thought-out concern about nature or the environment.

And yes, I know that fish farming itself can be harmful to the local environment. But our response can't be to abandon fish farming and continue overfishing until all wild fish are extinct. As the saying goes, don't let the perfect be the enemy of the good. We should work on ways to improve fish farming techniques and make them more sustainable.

Transgenic technology is cool. Of course it can be used in ways that don't benefit consumers - but so can traditional genetic techniques (which don't require any FDA approval, by the way). Take tomatoes: I can't remember the last time I found a tasty store-bought tomato in the U.S. They look great but taste like cardboard, all thanks to selective breeding that makes them easier to pack and transport. If someone creates a transgenic tomato that tastes good, I'll be the first in line to buy it. Meanwhile, I'm looking forward to the day when I can taste the new transgenic salmon.

Fish oil salesmen

Well, they’re not quite the modern-day equivalent of snake-oil salesmen, but the parallels are irresistible. In the 19th century, snake oil was promoted as a cure for joint pain and other ills, and the figure of the snake-oil salesman was widely ridiculed. (Ironically, snake oil is still used as a treatment in China today, despite the lack of any evidence for its efficacy.)

Today we have a new figure: the fish oil salesman. This modern figure, though, is no joke: he is a polished, sophisticated figure with the full weight of the FDA behind him. Should we buy his product?

Last week, while watching a major sports event, I was treated to a new commercial for a product called Lovaza, which I learned “helps to lower very high triglycerides in adult patients.” It’s a beautiful commercial, with an actor in a lab coat (am I supposed to think he’s a scientist?), carrying a clipboard and walking through a lab surrounded by blue aquariums. (Apparently the lab is under water.) You can see the ad here.