Saturday, December 29, 2012

The Nutrition Debate #81: Calorie Restriction in Humans

My 12/15/12 column, “Calorie Restriction and Longevity” (#79 here), dealt with one aspect of the first part of a scientific paper, “The Neuroprotective Properties of Calorie Restriction, The Ketogenic Diet, and Ketone Bodies.” This NIH Public Access article published in 2008 is, frankly, very technical, so to make the subject a little more “accessible” (for us both), I also included in the column several Gary Taubes quotes from “Good Calories – Bad Calories.” Taubes is an award-winning science writer, but that book is also pretty dense.  I call it a “tough slog”, but I underlined about one-third of the 560 page text. It’s a very compelling read, and I strongly recommend it to all open-minded and serious health readers.

In #79 I took the subject of Calorie Restriction only far enough to establish some of the health and longevity benefits. Unfortunately, they were limited to yeast, worms, fruit flies and mice. And I did not address the “potential pitfalls and health concerns” of calorie restriction in humans. Taubes, by the way, calls conventional calorie restricted diets in humans “semi-starvation” diets, because they are! But I am not advocating Calorie Restriction (CR) per se.  That will be clear next week when I lay out what I think is perhaps a new dietary paradigm. But first, the pitfalls and concerns.

“CR has many consequences, the majority of which are unknown at this time,” wrote Barbara Hansen in The Journal of Nutrition. This now dated 2001 Introduction to “Calorie Restriction: Effects on Body Composition, Insulin Signaling and Aging,” can be seen here. The data she presents, from a 1995 paper by Bodkin, is also dated, but prescient: “Neither the mechanisms by which life extension takes place (in rodents) nor the mechanisms by which the complex features associated with insulin resistance and Metabolic Syndrome are prevented by CR, are understood. Clearly advancements in this area will lead to better understanding of this powerful nutritional tool.” Indeed, as we have seen, they did.

Quoting Hansen and Bodkin from 1993: “CR produces altered pathways of nutrient disposal, including reduced plasma glucose, insulin and leptin levels” (emphasis mine); and Hansen (1996): “CR carried out for 10 to 15 years in adult rhesus monkeys has been shown to result in sustained alteration in glycogen metabolism, despite apparent retention of normal insulin-stimulated glucose uptake, normal glucose tolerance and normal fasting glucose and insulin levels.”

Hansen cites another research paper (Ortmeyer, 2000) to demonstrate the effect of CR on insulin action by the “rate-limiting enzyme of glycogen storage, glycogen synthase.” Ortmeyer reported, “CR appeared to unveil a predisposition in approximately one half of the CR monkeys toward metabolic abnormalities in response to insulin” (again, my emphasis). Continuing, “Although glycogen content remained normal in all CR monkeys, we suspect that the induction of abnormal insulin action on glycogen synthase by long-term CR may represent a pointer toward the underlying defect that, under ad libitum conditions, would lead to obesity, insulin resistance, and eventually Type 2 diabetes in approximately one half of aging rhesus monkeys.” This is all very important, if, of course, it translates from non-human primates to humans.

A cautionary note, though: A 2006 ncbi.nih abstract in PubMed here, “Calorie Restriction in Humans: Potential Pitfalls and Health Concerns,” makes two very good points that illustrate the proper skepticism of the scientific mind. 1) “In humans, several studies investigating short-term calorie restriction or ‘weight-loss’ programs suggest beneficial outcomes on parameters of cardiovascular disease.” “However, few studies are currently investigating the quality of life and potential pitfalls of long-term calorie restriction in humans. It is likely that some of the physiological and psychological effects of calorie restriction that occur in animals may impact the human life very differently.” And 2) “For certain, calorie restriction has a plethora of health benefits in mammals, such as a reduction in age-related diseases such as cancer. However, despite the ‘magic’ of CR, this intervention in humans may present itself with a number of health concerns, which may not be applicable to or impact the life of experimental animals, but may do so in humans.” Now this may sound like the perfunctory disclaimer one sees in all ‘objective’ research papers, but it is worth keeping in mind.

The closing paragraph of Hansen’s piece above reveals what she regards as a “missed opportunity.” For me, it reveals the myopic vision of an out-of touch research biologist unable to see a clinical approach informed by nutrition: “The power of CR to mitigate, delay or prevent this clinical development of disease, despite the presence of underlying defects in insulin action, points to the critical need for effective CR mimetic approaches to slow or halt the consequences of the underlying genetic predisposition toward obesity and Type 2 diabetes in humans (and in non-human primates).”

That’s a touching sentiment toward her aging rhesus monkey colony, but it calls for a pharmacological approach to address the genetic predisposition to a metabolic disorder of fat regulation affecting perhaps half of humankind, at least in the context of the Western Diet. A pill to pop! How absurd this is, especially when the solution is staring us all right in the face. It couldn’t be clearer or more apparent to me. If you haven’t figured it out yet, you’ll have to wait ‘til next week for me to spell it out for you.
© Dan Brown 12/29/12

Saturday, December 22, 2012

The Nutrition Debate #80: Obesity Caused by Gut Bacterium!

A few days ago, the Health page of the Financial Times online ( here) led with the banner headline, “Scientists Link Obesity to Gut Bacteria.”Call me a skeptic, if you like, or even a “conventional thinker” (pulleesse, don’t call me that!), but I’ll have to “wait and see” on this one. I know, a lot of serious scientists have been talking and writing about this in the blogosphere lately, but this is the first that I have seen it in the “mainstream” media.

So far, I have been dismissing this talk as too “edgy” and too esoteric for my non-scientific brain to wrap around. Besides, I have just gotten comfortable with – in fact, fully embraced Gary Taubes’s alternative Carbohydrate Hypothesis. This theorem places the action – or rather the “broken” action, of the hormone insulin at the center of the obesity epidemic. And now some cutting edge thinkers are moving on to another frontier – the human gut.

I suppose it’s a good thing that science is “advancing” quickly, but scientists would be the first to say that caution is and should be the “order of the day.” And I have no doubt it will. Everything will be “peer reviewed” (for what that’s worth!), and replicated with double-blind, prospective, trials, etc, etc. But journalism is not so constrained, and journalists often get it wrong. And, as a result, so does the public. And then the processed and packaged food industries pick-up on it, and all of a sudden a box of Cheerios cereal is a cholesterol-lowering drug.

But this rant is not about the gut bacterium “discovered” by the Chinese scientists at Shanghai Jiao Tong University, as reported by Professor Zhao Liping in the FT.  It is about the response of Dr. David Weinkove, lecturer in biological sciences at Durham University in Durham, England. Durham, for my non-British readers, is listed third after Oxford and Cambridge in many rankings of institutions of higher learning in the UK. I gave a hearty guffaw when I read his reaction to the news. He said, according to the FT, “If obesity is caused by bacteria, it could be infectious and picked up from some unknown environmental factor, or a parent. IT MIGHT NOT BE BEHAVIORAL AT ALL” (emphasis mine).

I apologize for “shouting” but I just couldn’t believe that he said this. I accept that the vast majority of the lay public believes that nearly 50% of all the adults in the U.S. and the UK are obese because we eat too much and exercise too little. But, for a lecturer in biological science at a leading UK center of research and learning to say it?!! Give me a break!

In an email exchange I had with Gary Taubes on the day before I wrote this, he related to me that he was preparing a rebuttal to the British Medical Journal (BMJ) on a piece they had just published about how low fat diets were associated with weight loss. I read the piece and decided that it was beyond my ken. I replied to him that I would leave the BMJ to him, and I would continue to fight “the good fight” on a different level. But when I am reminded how far we (all of us with an open-minded view of the science) have to “climb” to overcome such ignorance, it is indeed a daunting prospect.

Anyway, if the “gut bacteria” news had escaped your notice by the time this post hits the blogosphere, let me bring you up to speed. Dr. Zhao, the lead scientist and spokesman for the study, asserted, “This is a very important phenomenon. It is the last missing piece of evidence (that) bacteria causes (sic) obesity.” I laughed again at this as I could imagine Dr. Weinkove (of Durham) salivating at the prospect of what that breakthrough news portends. I saw a vision of sugar plums dancing in his head when he said, as the FT reported, “Dr. Zhao’s research paved the way to intervene in obesity and could allow new drugs to be developed for treatment.” It reminded me of the researchers and drug developers who first  came up with the statin compounds to lower LDL lipoproteins, and thus Total Cholesterol (TC,) because LDL was the only sub-component of TC that they could easily and effectively lower with a drug. This led to world-wide sales today of well over $20 billion, and to dubious health benefits and myriad risks. But it was a boon to the bottom line of big pharma.  Billions in profits and decades of grants for the “research community” ensued, both in academia and industry.

So, while I am skeptical by nature, and that is a good thing both in science and in general, I am still open-minded. I can also hope that this is “a very important phenomenon” and that it is “the last missing piece of evidence” of what causes obesity. And just as cholesterol testing was developed in the 1980s and then evolved beyond LDL, let’s hope that gut bacteria research, whether relevant to obesity of not, evolves as well. After all, as everyone is fond of saying, “there are 10 times more microbes than human cells in our bodies and they can be beneficial.” So, as science advances, particularly with recent progress in the knowledge of the human genome, a “breakthrough” of this magnitude would be welcome. Semi-starvation on a “balanced” diet, and boring daily exercises, don’t work for most people. And my VLC Ketogenic Diet is certainly restrictive and requires discipline. And I like my sugar plums…and Christmas cookies too!
© Dan Brown 12/22/12

Saturday, December 15, 2012

The Nutrition Debate #79: Calorie Restriction and Longevity

People often ask me what motivated me to lose so much weight (170 lbs). I tell them: “I didn’t want to die; I looked around me and I didn’t see any morbidly obese old people, and I was getting old… and I wanted to live to be older.” I had been gaining weight, and my doctor had been urging me to lose for years. Then, for two visits I was unable to weigh in at his office because his scale only went to 350. So, on the way to work one day in NYC I stopped at the Fulton Fish Market and asked permission to weigh myself on a commercial scale. I was shocked. I weighed 375 pounds. The next week, as I entered my Doctor’s office, he saw me and said, “Have I got a diet for you!!!” I was motivated.

Of course, as I was losing weight (first on Atkins, and later on Bernstein – for diabetics), I wondered how low I would go. I had the luxury to fantasize about this because I was losing weight easily and without hunger. This will happen when you strictly follow a Very Low Carb (20g of carbohydrate a day) Way of Eating. I also remember reading about Calorie Restriction (CR) and longevity in Gary Taubes seminal 2007 book, “Good Calories – Bad Calories” (“The Diet Delusion” in the UK). This defining work is a “tough slog” but a “great read” too. Calorie Restriction and its positive association and correlation with longevity are covered in depth in Chapter 13, “Dementia, Cancer and Aging.” Are you motivated yet?

In 2008 the authors of “The Neuroprotective Properties of Calorie Restriction, The Ketogenic Diet and Ketone Bodies,” published online as a NIH Public Access peer-reviewed manuscript here, said, “Obesity is associated with an increased risk of dementia.” They continued, “Low dietary energy intake is associated with decreased incidence of Alzheimer’s and Parkinson’s diseases…and calorie restriction for 6 months improves biomarkers associated with longevity including reduced fasting insulin levels, body temperature and DNA damage.” And “Calorie Restriction might even reduce disease risk and increase lifespan in normal weight subjects.” Also, “Beneficial effects on mental health have been reported as well, with improved mood following calorie restriction of obese diabetic patients.” Each quote cites a study or studies.

The problem with the preceding paragraph is that “all the available information is derived exclusively from animal models.” “Calorie restriction prolongs the lifespan of yeast, roundworms, rodents and monkeys, even when initiated in midlife.” “Moreover, age-related deficits in learning and motor coordination are reduced by calorie restriction in rodents.” “Aged mice exhibited similar improvements in learning tasks…” And, “in parallel, calorie restriction also prevented age-related deficits in…a cellular correlate of memory.” “To date, however, clinical trials looking at the effects of calorie restrictions on brain aging and neurological disease have not been performed [on humans],” say the authors.

The authors continue, “the mechanisms that have been proposed to explain the neuroprotective effects of calorie restriction can be grouped into two general categories: 1) improved mitochondrial function, leading to decreased production or reactive oxygen species [free radicals] and increased energy output; 2) regulation of gene expression, resulting in decreased activity of pro-apoptotic factors and increased levels of neuroprotective factors such as neurotrophins.” In addition, “calorie restriction delays age-related oxidative damage to DNA, proteins and lipids” [the ‘antioxidant effect’], thus “decreasing the mitochondrial production of reactive oxygen species” [again,‘free radicals’].

Back to Taubes: “All this leads us back to the spectacular benefits of semi-starvation on the health and longevity of laboratory animals” (GC-BC: pg. 218). “The calorie-restricted animals live longer because of some metabolic or hormonal consequence of semi-starvation, not because they are necessarily leaner or lighter” (ibid. pg. 219). I’m thinking, that’s encouraging, and I reasonably conclude from this that it’s what I eat now, not how thin I am, that will (may?) determine my health outcome.

Taubes sums it up nicely this way: “The characteristics that all these long-lived organisms seem to share definitively are reduced insulin resistance, and abnormally low levels of blood sugar, insulin, and insulin-like growth factor (IGF). As a result, the current thinking is that a lifelong reduction in blood sugar, insulin and IGF bestows a longer and healthier life. The reduction in blood sugar also leads to reduced oxidative stress and advanced glycation end-products (AGEs) and all the toxic sequelae that follow. The decrease in insulin and IGF also apparently bestows on the organism an enhanced ability to protect against oxidative stress and to ward off other pathogens” (GC-BC pg. 220).

Quoting Taubes again (GC-BC pg. 220): “The most compelling evidence now supporting this hypothesis has emerged since the early 1990s from genetic studies of yeast, worms and fruit flies, and it has recently been confirmed in mice. In all four cases, the mutations that bestow extreme longevity on these organisms are mutations in the genes that control both insulin and IGF signaling.”  Then, Taubes quotes the cancer researcher J. Michael Bishop’s 1989 Nobel Prize lecture: “When reduced to essentials, the fruit fly and Homo Sapiens are not very different.” Next week: CR in humans.
 © Dan Brown 12/15/12

Saturday, December 8, 2012

The Nutrition Debate #78: Metabolic Syndrome and Risk of Cancer

If you have Metabolic Syndrome there is a greater risk that you will develop certain types of cancer, according to a systematic review and meta-analysis reported in Medscape on November 18, 2012. The retrospective study was performed by a group of physician-researchers and was published in Diabetes Care, the magazine of the American Diabetes Association. To be clear, the study reports an association with cancer risk, not a causal relationship.

If you are unfamiliar with Metabolic Syndrome, it is defined by a cluster of risk factors: 1) obesity, particularly central obesity, 2) dysglycemia (i.e. pre-diabetes or Type 2), 3) elevated blood pressure, 4) and dyslipidemia, specifically high triglycerides and low HDL. Between 35% and 40% of the adult population of the U. S. today has Metabolic Syndrome. The higher percentage applies if the criterion for inclusion is a smaller waist measurement:  37”vs 40” for men and 31.5”vs 35” for women.

In 1986, when I was first diagnosed as a Type 2 diabetic, I had the full cluster of risk factors for Metabolic Syndrome, but no one told me I had it, or Syndrome X as it was then called. In fact, to this day no one has told me. Why is that, I wonder? Especially since the implications go far beyond cancer risk. The risks of virtually all the so-called Diseases of Civilization (heart disease, stroke, Alzheimer’s, etc.) are associated with a diagnosis of Metabolic Syndrome. Do you have Metabolic Syndrome? If you don’t know or aren’t sure, take a look at the specific criteria in Nutrition Debate #9 here.

The results of the study (pg.1): “We analyzed 116 datasets from 43 articles, including 38,940 cases of cancer. In cohort studies in men, the presence of Metabolic Syndrome was associated with liver, colorectal and bladder cancer. In cohort studies in women, the presence of Metabolic Syndrome was associated with endometrial, pancreatic, breast postmenopausal, rectal and colorectal cancers. Associations with Metabolic Syndrome were stronger in women than in men for pancreatic and rectal cancers. Associations were different between ethnic groups: we recorded stronger associations in Asia populations for liver cancer, in European populations for colorectal cancer in women, and in U. S. populations (whites) for prostate cancer.”

The conclusions (pg. 1): “Metabolic Syndrome is associated with increased risk of common cancers; for some cancers the risk differs between sexes, populations and definitions of metabolic syndrome.”

Furthermore detailed conclusions from page 28 drive home the findings: “Our results from meta-analyses of prospective cohort studies indicate that metabolic syndrome is consistently associated with an increased risk of several cancers in adults. However, many of the reported associations are small (relative risk between 1.1 and 1.6) and might differ between sexes for some sites and also across populations. In particular, the associations were stronger in women for some cancers (pancreas and rectal), and the magnitude of the association was highest for sex specific cancers (endometrial and breast postmenopausal). Moreover, from analyses in which sufficient datasets existed, the association was stronger for colorectal cancer in European populations (relative risk 1.64).”

And this hit: “Given the widespread diffusion of Metabolic Syndrome and the increased cancer mortality associated with Metabolic Syndrome, the findings of the present meta-analysis may have clinical significance. At least for some common cancer sites (colorectal cancer in both sexes, liver cancer in men, and pancreas cancer in women), we are confident that the results are real, as the grading for study quality was moderate to high and overall risk of bias was low” ( pg. 28).

Finally this blow (pg. 28): “Findings from this meta-analysis, which includes many recently published studies, suggest that Metabolic Syndrome is associated with increased risk of common cancers. The excess risk of cancer conferred by Metabolic Syndrome is low to moderate and in part explained by accompanying obesity and hyperglycemia. Neverthe-less, the increasing prevalence of Metabolic Syndrome worldwide and the high incidence of some malignancies, particu-larly colorectal and breast cancers, imply that every year many cases of cancer are attributable to Metabolic Syndrome” (emphasis mine). Remember, this is a retrospective, meta-analysis – not a prospective double-blind clinical trial, but to use the words “attributable to” is pretty strong language to be sure. It certainly should give one pause for thought.

Thoughts like, “What can I do about it?” Well, you can change your diet, that’s what. You can lose weight easily and keep it off permanently by eating a Very Low Carb, ketogenic diet. With this diet your blood sugars will normalize, and with weight loss your blood pressure will come down. And this diet will raise your HDL and lower your triglycerides. These are all the risk factors for Metabolic Syndrome, and they can all go away. You will be free of Metabolic Syndrome. Ipso facto!
© Dan Brown 12/8/12

Saturday, December 1, 2012

The Nutrition Debate #77: Low Carb Dieting and Pauline Kale (sic)

My doctor stumbled upon Low Carb dieting on a Sunday morning in early July 2002. He opened The New York Times and saw on the cover of the Magazine a big juicy ribeye steak with a melting lump of butter on top. If his biochemistry is the same as the rest of the human race, his salivary glands began to secrete digestive juices and a signal went from his hypothalamus in the center of the brain to his pancreas to start secreting insulin. There was no olfactory stimulus. The visual image was enough to start this autonomic response. Even the idea of eating will do it. It tells us, “It’s time to eat!”

Of course, my doctor didn’t act on these impulses because another part of his brain told him 1) it’s just a picture and 2) it would be bad for his health to eat so much saturated fat and cholesterol. The rational mind overrode the autonomic. As an internist and cardiologist he had learned in medical school, and had had reinforced in continuing education throughout his professional life, that saturated fat and dietary cholesterol were verboten. They would clog his arteries. He had seen atherosclerotic patients every day in his practice. They were a constant reminder that eating saturated fats and cholesterol would be “the death” of him. We have that message drilled into us constantly as well. The DEATH of us.

But, that particular Sunday morning my doctor was relaxed at home and engaged in one of his favorite day-off indulgences – putting his feet up and reading his favorite newspaper. Besides, he was intrigued because the title of the cover story was, “What If It’s All Been a Big Fat Lie?” The author, Gary Taubes, is a highly regarded science writer who has won the National Science Writers “Science in Society” award 3 times (and 3 is the limit!) And the New York Times was at that time still “the old gray lady” of print journalism whose motto was “all the news that’s fit to print.” So… my doctor decided to read the story. It was a life-changing event (for me)!

Then, in the noble tradition of medical self-experimentation exemplified by Werner Forssmann, “inventor” of cardiac catheterization in the 1930s, my doctor decided to try the diet that Taubes outlined. And in about 6 weeks, he lost 17 pounds on Atkins Induction! I assume he tested his blood chemistry and lipid panel before and after, and his n=1 self-experiment proved to “do no harm” (and maybe even a little good?). So, soon afterwards, as luck would have it, as I walked into his office, my doctor saw me and said to me, “Have I got a diet for you!” I needed it too. I had just discovered (on a Fulton Fish Market scale) that I weighed 375 pounds!

So, where does Pauline Kael (correct spelling) come into this picture? According to Wikipedia, Pauline Kael was “a film critic who wrote for The New Yorker from 1968 to 1991. “She is often regarded at the most influential film critic of her day,” according to Harper’s, and she was known for her “witty, biting, highly opinionated and sharply focused” reviews. I read her every week, but I remember her best for a comment she reportedly made in a lecture to the Modern Language Association in December 1972. It was in the wake of Richard Nixon’s landslide victory in the 1972 presidential election:

“I live in a rather special world. I only know one person who voted for Nixon. Where they are I don’t know. They’re outside my ken. But sometimes when I’m in a theater I can feel them.”

I have to admit that that image is pretty funny, and certainly “witty, biting, highly opinionated and sharply focused,” but Wikipedia notes that Kael was widely criticized for this sentiment. It illustrated the isolation in which it is possible to live, if you are surrounded by like-minded people, especially if you think of yourself as being superior in education or intellect. In such cases it extends to beliefs as well. Such elitism is common among the intelligentsia. New York Post writer John Podhoretz once claimed that New Yorkers “can easily go through life never meeting anybody who has a thought different from their own.” Under such circumstances, wouldn’t any disparate thought be heresy?

The world of human nutrition today suffers from this same constrained view. “The Nutrition Debate” seeks, in a very modest way, to present another view and to encourage self experimentation. There’s lots of support for this alternative; it just doesn’t get much play in medicine or the media. Of course, there are other forces at work here (big agriculture and big food manufacturers, to name just two of the major stakeholders), but the medical and public health communities are where integrity and professionalism are supposed to mean something. That is where I think we can best make inroads and foment change.

So, when my doctor was willing to try something that goes against the teachings he had practiced (and lived) by – first on himself (like Forssmann, whose self experimentation led to the  Nobel Prize), and then on his non-compliant, heavily medicated, morbidly obese Type 2 diabetic patient (me), I think there’s hope. And if others try it, and it works for them too, maybe it won’t be as creepy as it was for Pauline Kael in that dark theater in 1972. That’s my hope anyway, and why I keep writing this blog.
© Dan Brown 12/1/12