It irritates me occasionally that people don’t understand how radically the biological sciences have changed in the last few decades. Obviously, the average person is unlikely to know what’s happening in research labs, but people in the financial business should at least be interested in the factors influencing the largest sector of our economy.
The biggest change is the advent of new and constantly improving biotechnological tools (at a rate faster even than Moore’s Law). These tools have yielded scientific advances that make obsolete the old assumptions about how new therapeutics are conceived and evaluated. This is not a small thing. The last decade of research has yielded more understanding of cellular and genomic functions than the entirety of the last century.
Back in the primitive days of late 20th century, medicine was mostly about drugs. And drug development consisted largely of guessing which molecules might produce a desirable effect in human subjects. These test compounds were given to animals, starting with rodents and moving up the scale of complexity to primates. If drug candidates yielded beneficial and profitable outcomes for the animal-testing process, they would then be tested in humans using escalating dosages. If the candidate did what it was supposed to do without too many side effects, it was categorized legally as a drug and made available to the public.
It’s actually somewhat amazing that we developed any effective drugs at all, given how unsophisticated the analytical tools were. A huge number of drugs, such as aspirin, were found only because natural versions were used in traditional folk medicine. Many drugs were found by accident when a drug approved for one purpose proved useful for something else. Tadalafil, now a billion-dollar erectile-dysfunction treatment marketed as Cialis, was originally investigated as a heart medicine. Now, it’s also prescribed for prostate and blood pressure problems.
The best-selling drug of all time, Lipitor, nearly didn’t make it into human trials because it was late to the statin market. Though it was shown to be more effective at lowering cholesterol than its competitors at the time, many doctors prescribed it for its unexpected benefits in other areas, such as cancers, probably due to their anti-inflammatory effects. Statins have even been shown to reduce mortality among influenza patients.
As more has become known about the underlying causes of aging and disease, new tools have arrived that increase the speed and accuracy of screening technologies that are used to identify useful molecules. This has led, in turn, to an increasing focus on naturally occurring molecules. I’ve been hearing this for years from established players inside the pharmaceutical industry, but there’s still condescension from mainstream financial analysts who simply don’t keep up with technology.
Those who misunderstand the importance of naturally occurring molecules may be conflating them with the alternative “natural” products sections of health-food stores. I’m okay with that, of course, because I’d just as soon be the one to break the big news, even if I’m doing it without the comforting presence of the financial media herd.
Among the biotech players who have pointed out the importance of naturally occurring molecules is billionaire philanthropist Dr. Phillip Frost, chairman of the big pharma company Teva Pharmaceuticals. In an interview for a past issue, Frost told me that naturally occurring molecules have important advantages that he is exploiting. First, a molecule that is found naturally in the human body is much less likely to be toxic than an invented molecule. Second, the regulators understand this, so the legal path to legal drug status is likely to be easier and faster. In the pharmaceutical business, time-to-market is immensely important as it directly determines the ROI of successful drugs.
One naturally occurring molecule that enjoys significant scientific attention is nicotinamide riboside (NR), which has successfully completed its first human clinical study carried out in the laboratory of Dr. Charles Brenner, the Roy J. Carver Chair of Biochemistry and Professor of Internal Medicine at the University of Iowa. Brenner, while a faculty member at Dartmouth College, discovered that NR is a critical precursor of nicotinamide adenine dinucleotide (NAD) in its oxidized form NAD+.
I’ve gone over this in previous issues, but I’ll briefly review. There has been an almost overwhelming amount of research in the past few years into the role of NAD+. Simply put, NAD+ is the charged or oxidized form of the NAD molecule. These critical molecules are found in every cell of your body, providing the electrochemical foundation for a wide range of cellular functions. Among them are the production of the only form of energy your body can use: adenosine triphosphate (ATP). The food you eat is useless until it’s converted into ATP, which drives all your biological systems.
ATP is manufactured in the mitochondria. The best way to think of mitochondria is a network of energy-producing bacteria inside your cells. In fact, they appear to be bacteria and even have, like bacteria, their own circular DNA plasmids. Unlike, bacteria, however, they don’t do well on their own. They can survive and operate on their own, but they have to communicate via chemical messaging with the DNA in your genome as well as each other to perform optimally.
Three-Parent Babies or a Failure to Communicate
You’ve probably noticed the raging debate about three-parent babies in the media. Personally, I think this term is incredibly irresponsible and misleading. What is really happening is that the gametes from the father and mother (sperm and ovum) join to form the new genome in the zygote. That doesn’t change at all. The genetic makeup of a child’s genome comes from the father and mother. Period.
So how do potentially fatal mutations in mitochondrial DNA appear in the first place? One way is directly related to NAD+. Mitochondria don’t have the sophisticated genetic repair mechanisms that our genomes do. With only 37 coding genes, compared to the tens of thousands in the genome, they deal with mutations differently.
In healthy, young individuals, mitochondrial DNA repair takes place, we now believe, by replicating intact plasmids to make new mitochondria and abandoning the bad plasmids. It’s a system that works well, but it deteriorates as we age. If, for some reason, communication between mitochondria and the master genome isn’t efficient, mutated plasmids can replicate to the point that they replace healthy versions.
Until recently, we didn’t understand how this failure to communicate happened. Now, it’s become clear that NAD+ levels fall as we age. This has two primary impacts. One is that our ability to convert food into ATP is compromised. One result of this is increased storage of food as fat, but the more important impact is that our cells lack the energy they need to perform optimally. Critical cellular maintenance function declines, which can hurt the genome itself.
Even worse, it has become apparent only recently that NAD+ is the energy substrate that genes rely on to perform remote functions. This means that genes can makes their incredible protein machines, but those machines fail to perform their intended function.
It’s not a great metaphor, but you can think of a gene protein as a robotic ambulance created to find and fix a problem. Without sufficient NAD+, that robotic ambulance is created but finds that the roads and phone system are in such a bad state of disrepair that they often can’t get to their targets.
In an advanced state of failure, it becomes a vicious circle. Low NAD+ levels cause cellular problems that result in even lower NAD+ levels. Our mitochondria are stranded and alone, lacking the ability to communicate with the central dispatcher, the genome. They do their best but, isolated, they degrade further.
Sometimes, mutated mitochondria may be passed on in the germ line of the mother. This can cause mitochondrial diseases associated with diabetes, deafness, blindness, multiple sclerosis-type diseases and a lot of other really awful disorders. Not only can they be passed down, they can worsen over subsequent generations.
An interesting thing about mitochondrial disease is that many of the same disorders occur with increasing frequency in older people as NAD+ levels fall. Diseases that are not caused by mitochondrial mutation can also be provoked by low NAD+ levels as well. Many neurodegenerative diseases are currently being investigated by major universities for treatment with NR. Animal studies have been extremely promising. For example, NR has been used to effectively treat animals with the accelerated aging disease Cockayne syndrome (CS). In those studies, NAD+ levels in the mitochondria of animals were restored. NR and another NAD+ precursor, a form of oxaloacetate, have also yielded significantly increased life spans in lower animal forms.
Obviously, we therefore want to know if NR increases NAD+ levels in humans. Now we know that it does. Read the entire press release here. The study also showed a very strong safety profile.
Will NR prove to be as effective in humans as it is in animals? We may never have proof, for two reasons. One is that different people live very different lives and aren’t subject to controlled double-blind tests. It’s conceivable that we could control for various lifestyle factors for a while, but the final data point in a longevity study is death. You don’t really know how something affects a life span until the test subject dies. Since humans are among the longest living species, any valid controlled study would take decades and necessarily include a lot of people.
Some top scientists, however, believe for reasons that I explained at the start of this article that we already know enough to warrant use of the molecule for purposes of life extension. MIT biologist Leonard Guarente is best known for his research into the sirtuin genes, which are activated via calorie restriction with optimal nutrition (CRON). This article, about his decision to formulate a nutraceuticals product line featuring NR got a lot of attention.
Guarente, along with other scientists, has concluded that the failure is connected to an insufficient energy substrate: NAD+. This is really interesting research and may mean that normal sirtuin activation is sufficient in a cellular environment with enough NAD+. Since Guarente is including pterostilbene, a phytochemical from blueberries known to activate the sirtuins, he is evidently hedging his bets. According to the MIT Technology Review article, he expects a synergistic effect with NR.
We don’t yet know if NR is going to be the kind of marketing success that resveratrol was, but it’s more likely, given Guarente’s entry to the market. Others in the same article believe so.
“NAD replacement is one of the most exciting things happening in the biology of aging,” says Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York, who has coauthored scientific papers with Guarente but is not involved in Elysium. “The frustration in our field is that we have shown we can target aging, but the FDA does not [recognize it] as an indication.”
Even skeptics quoted in the article are only partially so.
“There is enough evidence to be excited, but not completely compelling evidence,” said Brian K. Kennedy, CEO of the California-based Buck Institute for Research on Aging.
Personally, I’m about the same age as Guarente so I may not have time for “completely compelling evidence,” so I take both of the molecules in his product, as does the boss, John Mauldin. Guarente is absolutely correct when he complains about the lack of a regulatory path for extending health spans. The Japanese are much further along the way to solving this problem, by the way.
Unlike anatabine citrate, which was pressured off the market by the FDA, NR and pterostilbene do not usually cause immediate physiological changes noticeable to most people, though the recent study shows that important changes are taking place on the cellular level. This makes sense, however, as they work from opposite directions. Anatabine citrate shuts down the autoimmune feedback loop of inflammation caused by excess activation of the NF kappa B transcription factor. Based on animal tests, human trials, and the anecdotal reports of many thousands of people, it appears to help in conditions ranging from arthritis to IBS and Parkinson’s. I believe, based on current research into the inflammation-related causes of cancer, it will also reduce risk of that disease.
NR and pterostilbene seem to improve cellular functions and, over time, could accomplish the same thing, but that is yet to be seen. Certainly, you will never hear the company that owns the NR patents make statements to that effect due to the regulatory restrictions on scientific speech. They have, however, learned from watching the FDA deal with Rock Creek Pharmaceuticals. This puts them in a position to avoid the regulatory snares created only recently to force truly efficacious nutraceuticals under government control. If you haven’t watched the video of Dr. Fiona Crawford talking about traumatic brain injury and anatabine, by the way, you should. This is truly important science.Incidentally, Rock Creek Pharmaceuticals now has permission to begin human trials of anatabine citrate in Great Britain, but the hundreds of thousands of users who want continued access may have to wait for that approval. For many people I know, this is a serious problem, but I don’t think the company has a choice in the matter. Have I mentioned that the system needs serious reform?
Editor, Transformational Technology Alert
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