Aubrey de Grey (here, here and here) is an iconoclastic anti-aging researcher living in Cambridge, UK who approaches the science of anti-aging medicine from an engineering perspective (requires free registration). He lectures extensively and constantly pushes the boundaries of anti-aging research. He isn’t trained in biology or medicine, but as an engineer. His extensive knowledge of medicine and the biological sciences is pretty much self taught. He doesn’t subscribe to any particular medical or scientific ideology, i.e., alternative medicine verses mainstream medicine, or any specific dietary practices other than the idea that caloric restriction has been shown in animal studies to prolong life. But Dr. de Grey isn’t interested in the mere 20-30 percent increase in lifespan brought about by caloric restriction; he’s more interested in increasing lifespan 100 to 200 years or more. Which he believes can be done if we look at forestalling aging from an engineering point of view.
He has written (co-written, actually) a book titled, appropriately enough, Ending Aging, describing his theories of aging and discussing the problems that must be overcome to undo the forces of our own biochemistry and physiology that grind us down over time. I read the book when it first came out and found it fascinating. I wouldn’t think it’s a particularly an easy read for one not scientifically inclined. If you thought Gary Taubes’ book was difficult, I wouldn’t recommend this one. If you do get it and are prepared to spend some time really digging in, you will come away rewarded, if not in understanding (which you will certainly get), at least in the knowledge that there are many extremely clever people working to keep us living longer. If you just want to read a little of the book, I recommend Chapter 5, Meltdown of the Cellular Power Plants, which is a virtuoso piece of scientific reasoning. Dr. de Grey published his theory of mitochondrial survival of the slowest, the subject of this chapter, a few years back, and I thought it a brilliant piece of scientific detective work.
As I was reading this book last year I got to the chapter about advanced glycation end-products (AGEs) I came across something troubling. Dr. de Gray was describing the AGEing process, which, as most readers of this blog probably know, is the process whereby sugar irreversibly binds to proteins, causing the proteins to lose their functionality. The proteins so bound up by sugar also cross link with other such proteins, making them even less functional. One of the prime examples of this phenomenon that we have all witnessed is the formation of cataracts in the eyes of some elderly people. AGE cross-links accumulate on the clear crystalline proteins in the lenses of the eyes, making them opaque. These opaque lenses, cataracts, impair vision and require surgical removal for vision to be restored.
Another place this AGEing reaction is seen is in hemoglobin, the oxygen carrying molecule in blood. Glucose, fructose and other sugars bind to the hemoglobin protein giving us the hemoglobin A1c that is a measure of long-term elevated blood glucose in those with diabetics. But there is measurable Hgb A1c in all of us, which is an indicator that this process operates even at normal blood glucose levels. Granted, it’s significantly higher in diabetics, but it’s performing its evil handiwork on those of us without the disease.
The same goes for fats in the blood. One of the reasons that meats brown is the conversion of the fat to AGEs. So elevated triglycerides along with elevated blood sugar are a set up for the formation of AGEs, which is probably one of the reasons that those with diabetes tend to have accelerated aging and an increased incidence of the diseases of aging (high blood pressure, cardiovascular disease, etc.) as compared to those without diabetes. So, you would think that a low-carb diet, which reliably reduces blood sugar and triglycerides significantly, would be a good thing. Right?
Not according to Dr. de Grey who writes
…not all AGEs are even derived from glucose. Blood fats (triglycerides) can also cause the cross-linking of proteins, particularly if there’s a high level of oxidative stress: this is the chemistry that underlies the browning of a turkey skin as it roasts, even without a sweet, syrupy slather on its surface. As with blood sugar, diabetics usually have high triglyceride levels, and even many nondiabetic people would benefit from having their triglyceride levels brought down; but triglycerides also resemble blood sugar in being indispensable to normal function, so there’s only so far that such a strategy can be safely pursued.
LESS IS MORE…IS WORSE
And that’s not all: attempts to control levels of both these early precursors of AGEs, even by nonpharmacological means, can have perverse metabolic consequences.
For instance, one established effect of very low-carbohydrate diets of the Atkins type is to bring down both triglyceride levels and the body’s total exposure to carbohydrates, so some advocates have hypothesized that these diets would reduce a person’s AGE burden. Unfortunately, it turns out that the metabolic state that these diets induce (the notorious “ketosis”) has the unfortunate side effect of causing a jump in the production of the oxoaldehyde methylglycoxal, a major precursor of AGE’s that is also, ironically, produced within the cells of diabetic patients when they are forced to take in more glucose than they can immediately process. A recent study tested the size of this effect in healthy people who successfully followed the first two phases of the Atkins diet for a month, and who had the ketones in their urine to prove that they were sticking to the diet. These previously healthy people suffered a doubling of their methylglycoxal levels, leading to concentrations even worse than those seen in poorly controlled diabetics. Like other oxoaldehydes, methylglycoxal is far more chemically reactive than blood sugar (up to 40,000 times more reactive, in fact), and is known to cause wide-ranging damage in th body, of which AGE cross-links are but one example. This potentially makes the Atkins diet a recipe for accelerated AGEing, not a reprieve from it.
The study Dr. de Grey refers to was published a few years ago in a paper in the Annals of the New York Academy of Science. Aside from the fact that this is the only such paper in the literature showing this phenomenon, you must realize that the papers published in this journal are the print versions of talks given at NY Academy of Science meetings. These meetings are organized around specific topics and dozens of researchers present their work. These presentations are then written up and published in the Annals. As such, they really don’t go through the peer-review process that other such studies must before they appear in print in standard scientific journals. In fact, most papers that appear in the Annals of the NY Academy have been published elsewhere first because the published papers are what led the organizers of the particular meeting to seek out these researchers and ask them to speak. The fact that this paper has never been published elsewhere either before or after the publication in this journal makes me suspect that the work couldn’t pass the peer-review process. If you think about how slight the evidence needs to be in the mainstream medical press to publish negative data about low-carb diets, especially the Atkins version, it makes you wonder why this wasn’t published elsewhere if the data were even semi-worthwhile.
Virtually all of the other papers I’ve seen point to elevated glucose as the driving force behind the elevated levels of methylglyoxal in patients with diabetes. And the glucose levels are in such greater quantity wreaking their havoc than even a doubling (the increase implied by the Ann NY Acad article) of methygloxal would cause. It’s kind of the same situation we find with melanoma and colon, breast and prostate cancers. It has been shown that vitamin D is protective against colon, breast and prostate cancers so going out in the sun and getting vitamin D helps you avoid a host of common cancers. But, supposedly (I don’t believe it, but let’s accept it for this argument’s sake) sunlight causes melanoma. What no one ever tells you is that there is one melanoma for every 200 of these other cancers, so by avoiding the sun you increase your risk for common cancers to prevent an extremely uncommon one. Same goes for the glucose/methylglyoxal situation. If you worry about methylglyoxal, but let your glucose and triglycerides go up as a consequence, you’ll suffer much more damage than if you keep glucose and triglycerides down and let methylgloxal double simply because there is so vastly much more glucose and triglyceride. And that’s even if the methlygloxal levels double, which I seriously doubt. (If you want to read a little more on my thoughts on this subject, go to this post and scroll down to the comments (there are several) by Tim Lundeen and my responses.)
But, as it turns out, we probably don’t need to worry about the situation.
As part of his continuing quest to move the science of anti-aging medicine forward, Dr. de Grey took over as editor of the major journal of anti-aging medicine and renamed it Rejuvenation Research. Most of the articles this journal publishes are fairly technical and esoteric, of interest to only those in the biz of hardcore anti-aging research. But as I was going through a few back issues catching up on my journal reading, my eyes lit on an article titled Effect of Short-Term Ketogenic Diet on Redox Status of Human Blood. Hmmm, thought I, I’ll bet this is another article in the same vein as the one from the Ann NY Acad. In fact, I couldn’t remember the names of the authors of said article and thought it might be the original article finding the light of day in a strict peer-reviewed journal. When I downloaded the full text, however, I was delightfully surprised.
The authors of this paper had also seen the article in the Ann NY Acad and wanted to take a look for themselves. They wanted to see just what a low-carbohydrate, ketogenic diet would do to the oxidative stress levels and the anti-oxidant capacity of healthy subjects. Recall that in the lengthy quote above from de Grey’s book he states that
…blood fats (triglycerides) can also cause the cross-linking of proteins, particularly if there’s a high level of oxidative stress…
These researchers wanted to see if there really was an increase in oxidative stress as the other paper (and de Grey’s book) intimated.
They put 20 healthy normal weight females on a low-carbohydrate (55 g carb per day), high-fat (138 g per day) diets for two weeks.
The diet was based on animal products enriched in fat including pork, beef, butter, lard, cheese, eggs, and up to 100 g/d of vegetables and fruits.
After only two weeks on this diet significant changes came about in numerous parameters.
3HB TAS, UA, and SH content were significantly increased. MDA content was not altered. Activities of CAT and SOD remained unchanged.
What does all this mean? 3HB is 3-β-hydroxy-butyrate, a ketone body, which would be expected to be elevated since the subjects were following a ketogenic diet. It’s important to know that 3HB levels are elevated, however, because it lets us know that the subjects were following the diet. TAS is total antioxidant status, which is a measure of the ability of fresh plasma to inhibit oxidation. If TAS is up, then the body has more antioxidant capacity. UA is uric acid, which scavenges oxidative free radicals and protects against oxidative stress. SH is sulfhydryl group content, which is a measure of glutathione, a major home-grown antioxidant. Increased SH means the body is increasing its level of its own self-made antioxidants in the mitochondria where all the bad free radical activity takes place.
But what if all this increased antioxidant activity is because the diet is so inflammatory (as the section in de Grey’s book would have us believe is the case with low-carb diets)? That’s where the CAT and SOD measurements come into the picture. CAT and SOD are catalase and super oxide dismutase, both enzymes involved in the body’s defense against increased oxidation. If CAT and SOD are not elevated, that indicates that the body isn’t threatened with increased oxidative stress. MDA is the malondialdehyde levels, which were unchanged. MDA is another marker for oxidative stress. The fact that it’s unchanged also is just another indicator that the diet didn’t increase oxidative stress.
The dietary changes brought about an increase in antioxidant capacity without an increase in oxidative stress. In other words, the body isn’t simply producing more antioxidants because the diet is inflammatory. As the authors put it
Elevated antioxidative capacity was not an adaptive response to increased oxidative stress because no evidence was obtained indicating increased oxidative stress. Increased antioxidative capacity was also not due to inactivation of antioxidant enzymes because SOD and CAT activities were not decreased.
And all this in only 14 days in healthy, young subjects, who, one assumes, were in pretty good shape to begin with. Just imagine the improvement we might see in overweight middle-aged diabetics (or even non-diabetics) who have inflammation out the yang. Were I in that condition, I would gladly trade the results seen in these subjects for a doubling of methylgloxal, assuming such a change would actually occur.
Oh, and speaking of ketones and antioxidant capacity, when I was going through the medical literature looking for other papers on the subject, I came across a paper waiting to be published in the Journal of Neurochemistry showing that a ketogenic diet increases the levels of glutathione inside the mitochondria. For decades scientists have known that mitochondria throw off free radicals as they do their work of converting food energy to ATP, the energy currency of the body. And scientists have known that these free radicals damage the mitochondria. Long ago the assumption was made that taking antioxidants in the form of supplements should squelch the free radicals generated within the mitochondria and result in a prolongation of life. Problem is that it doesn’t work, apparently because antioxidants taken orally don’t penetrate into the mitochondria where the free radicals are. A zillion studies have shown that taking antioxidants doesn’t increase lifespan.
The only thing that reliably does increase lifespan is caloric restriction (CR) in lab animals, at least. CR is thought to work in great measure by decreasing the number of free radicals fired off in the mitochondria as a consequence of the mitochondria having less food that they have to process. The mitochondria make their own antioxidants – one of which is glutathione – to help protect themselves from the free radicals they generate. Anything that increases the glutathione within the mitochondria is going to help increase longevity and decrease many of the ravages of disease, many of which stem from excess mitochondrial free radical production. This study indicates that a ketogenic diet significantly increases the production of glutathione within the mitochondria, which is right where you want it, especially to protect the mitochondrial DNA.
Granted, this study was a rat study, and I’m not a big fan of extrapolating rat studies to human studies. But, rat mitochondria aren’t that different from ours so it’s a little easier to make the leap of faith. So, I would recommend for a long and healthy life that you ketonate as much as possible. Let those ketones do the job of blood sugar, keeping your blood sugar low. Lower sugar, lower AGEs, Lower AGEs, longer life.