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umerous studies have shown that a diet of reduced calories, also known as caloric restriction (or CR) promotes lifespan extension by up to 50% in a wide range of organisms, including yeast, worms, flies and mice. (1) However there are some exceptions, including wild mice and houseflies. (2,3) In mammals CR triggers physiological changes that improve glucose control; in rodents and humans CR decreases insulin and glucose levels and improves insulin sensitivity. These metabolic changes are relevant to aging because decreasing insulin signaling is implicated in the longevity of most organisms. (4) It has long been known that if you want to study premature aging study diabetics.

Does CR lengthen life... or just make it seem interminably longer?

Traditionally, the benefits of CR have been attributed to a class of genes known as sirtuins. Activation of sirtuins, either by restricting calories or by pharmacological means, extends the lifespan and/or promotes the health of a wide variety of organisms from yeast to mammals. The most-studied sirtuin is SIRT1, and multiple studies provide support for the strong role for SIRT1 in the beneficial effects of CR. Rodent studies show that CR upregulates SIRT1 expression in a variety of tissues, such as brain, kidney, liver, white adipose, and skeletal muscle (5). Nonetheless, SIRT1 induction is not observed in all CR studies, and it may be induced in a tissue-specific manner or even decreased. (6)

The discovery that sirtuins can also be modulated directly by small molecules has opened up the possibility of mimicking the benefits of CR without having to restrict calories. SIRT1-activating compounds (STACs) include resveratrol, quercetin, fisetin (3,7,3’,4′-tetrahydroxyflavone), butein (3,4,2”,4′-tetrahydroxychalone) and analogs of the B vitamin nicotinamide. These molecules have been shown to extend life span in a wide variety of organisms from yeast to flies to obese mice, (7–11) however, some labs report little or no life span extension. (12,13)

Wheeling into Longevity City

A just-published study from the journal Functional Ecology may shed new light on the mechanisms of caloric restriction and point to potential benefits yet unanticipated. (14) Shugo Watabe at the University of Tokyo experimented with rotifers, microscopic or near-microscopic creatures known as “Wheel Animals’ and typically found in fresh water. Like many other studies Watabe found that CR increased their lifespan. However what was especially interesting is that fact that Watabe also observed that the offspring of the rotifers in question also lived longer than normal. In other words, caloric restriction of the parent produced inheritable changes in the metabolism of the offspring.

New research may help keep Rotifers out of old age homes.

Rotifers are virtually all-female and reproduce by a process known as parthenogenesis, the result being (give or take the odd mutation) that a rotifer’s daughters are genetically identical to her. This makes rotifers convenient subjects for studies of epigenetic inheritance. Professor Watabe looked at the expression levels of two antioxidant enzymes, catalase and manganese superoxide dismutase (Mn SOD) in the rotifer Brachionus plicatilis during two consecutive generations.

Without CR the animals lived for an average of 8.8 days. With it they lived for 13.5 days. However, things got interesting when Watabe did the same thing with the rotifers’ offspring. The daughters of those rotifers which had been fed as much as they could eat lived for 9.5 days if treated likewise and 14.4 if put on CR. However, those born of calorie-restricted mothers lived for 12.7 and 16.8 days respectively. Something in the calorie restricted mother had programmed a function in the daughter that allowed it to live longer even if it was fed as many calories as it desired.

It appears that the daughters from the CR-treated mothers were endowed at birth with a higher ability to resist oxidative stress due to increased levels of the enzyme catalase in their messenger RNA (mRNA). This was not observed for manganese SOD, the other anti-oxidant studied.

The enemy.

Biochemists love catalase because it is darn near close to a ‘perfect enzyme’. All known animals use catalase in every organ, with particularly high concentrations occurring in the liver. Its major job is to break up hydrogen peroxide (H2O2) into water and oxygen. Hydrogen peroxide is a harmful by-product of many normal metabolic processes, and has been implicated in the causation of many problems, from grey hair and the skin condition vitiligo. So to prevent damage, it must be quickly converted into other, less dangerous substances. Catalase has the amazing dual-function ability to take hydrogen peroxide and any number of toxins, smash them together and inactivate them both.

Finally, catalase is a textbook example of enzyme efficiency: It is claimed that catalase is at the upper limit of what is known as a diffusion-controlled limit –basically the frequency of how often enzymes and their substrates bang into each other. In short, it is amazingly efficient at what it does. One molecule of catalase can convert millions of molecules of hydrogen peroxide to water and oxygen per second.

Potential and Pratfalls

If inherited epigenetic changes were causing daughter rotifers to produce more catalase, it would raise the question of whether a similar thing happens in other species and, if so, whether it might be induced therapeutically, without all the tedious business of a lifetime’s starvation. That would certainly be worth looking at. According to a report by the Rand Corporation, such a drug would be among the most cost-effective breakthroughs possible in medicine, providing Americans more healthy years at less expense (an estimated $8,800 a year) than new cancer vaccines or stroke treatments. (15)

One possible complication comes to mind which, if nothing else, demonstrates the complexity of the problem. If caloric restriction yields such metabolically efficient offspring why did the children of caloric-deprived mothers during the Dutch ‘Hongerwinter‘ wind up instead with diabetes and obesity? One could always argue that there is a distinct difference between caloric restriction using nutrient-dense foods and starvation, and that may indeed be true. Only time will tell.

An area of considerable debate is the role of sirtuins in tumor causation and cancer cell proliferation, for which there is a large and often contradictory literature. One of the confusing aspects of SIRT1 is that it plays a dual role in cell survival and cell death and can be modulated in different directions by a variety of different stimuli. Although CR is arguably the most effective way to prevent cancer in rodents and primates, which some view as an indication that sirtuins are tumor suppressors, some sirtuins, such as SIRT1, have prosurvival functions, which could be a sign that they promote tumorigenesis. (16)

Sirtuins like SIRT1 bind to and deacetylate a number of important gene regulaotry factors—such as the PPARs and FOXO family of transcription factors —which themselves drive metabolic responses such as insulin secretion, gluconeogenesis, and fatty acid oxidation. Histone deacetylation is a hallmark of epigenetic control of gene expression, and probably implies that there are multiple epigenetic effects that result from CR.

Post-genomic, transgenerational epigenetic inheritance certainly does a much better job of explaining the tendencies for longevity to run in certain families than the traditional genetic determinism theories.

1. Sinclair DA. Toward a unified theory of caloric restriction and longevity regulation. Mech. Ageing Dev. 2005;126:987–1002
2. Harper JM, Leathers CW, Austad SN. Does caloric restriction extend life in wild mice? Aging Cell. 2006;5:441–449.
3. Cooper TM, Mockett RJ, Sohal BH, Sohal RS, Orr WC. Effect of caloric restriction on life span of the housefly, Musca domestica. FASEB J. 2004;18:1591–1593.
4. Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature. 2000;408:255–262.
5. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004;305:390–392.
6. Chen D, Bruno J, Easlon E, Lin SJ, Cheng HL, et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 2008;22:1753–1757.
7. Yuan Z, Seto E. A functional link between SIRT1 deacetylase and NBS1 in DNA damage response. Cell Cycle. 2007;6:2869–2871.
8. Lavu S, Boss O, Elliott PJ, Lambert PD. Sirtuins—novel therapeutic targets to treat age-associated diseases. Nat. Rev. Drug Discov. 2008;7:841–853.
9. Bauer JH, Goupil S, Garber GB, Helfand SL. An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA. 2004;101:12980–12985.
10. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430:686–689.
11. Jarolim S, Millen J, Heeren G, Laun P, Goldfarb DS, Breitenbach M. A novel assay for replicative lifespan in Saccharomyces cerevisiae. FEMS Yeast Res. 2004;5:169–177.
12. Viswanathan M, Kim SK, Berdichevsky A, Guarente L. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev. Cell. 2005;9:605–615.
13. Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L. Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech. Ageing Dev. 2007;128:546–552.
14. Kaneko, G., Yoshinaga, T., Yanagawa, Y., Ozaki, Y., Tsukamoto, K. and Watabe, S. , Calorie restriction-induced maternal longevity is transmitted to their daughters in a rotifer. Functional Ecology, no. doi: 10.1111/j.1365-2435.2010.01773.x
15. One for the Ages: A Prescription That May Extend Life (www.nytimes.com/2006/10/31)
16. D’Adamo PJ. ‘Sirtuins’ in: Fundamentals of Generative Medicine, Volume I (2010) Drum Hill Books, Wilton CT USA

Tags: caloric restriction | catalase | epigenetics | lifespan | sirt1 | sirtuins

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t would be tidy if all people who were blood group O lived in one part of the world, and all blood group A in another. But this does not happen. The various blood groups are found pretty much all over the planet. However they are not found in the same frequency everywhere. It was this difference in the frequency between the blood groups that gave the early blood group detectives their first insights into a tangible form of human individuality.

The Austrians referred to the dismal conditions of the Allied Army of Salonika as the 'world's largest concentration camp.'

Soon after the ABO blood groups were discovered by Karl Landsteiner in the early 1900’s, scientists began to think about using them as a tool to help study the differences between different populations. One of the first to begin using blood group in this manner was a husband and wife team, Ludwik and Hanka Hirszfeld. During World War I, they took blood samples from the soldiers of three continents then assembled in the area of Greece called Macedonia as “The Allied Army of the East.” In reality this army was a hodgepodge of battered contingents and survivors from various Allied nations that did little more than stay put in camp and suffer from constant epidemics. However the Hirszfelds realized that the international nature of this army presented opportunities of examining the serological properties of the blood of a large number of soldiers or civilians belonging to very different races.

They established three categories: One marked by a high percentage of subjects of blood group A and a low percentage of blood group B, which seemed to include the majority of European races (European type); a second showing, on the contrary, a high percentage of blood group B and a low one of blood group A, comprising Asians and Ethiopians (Asian-African type); and a last category containing approximately equal quantities of blood groups A and B made up of Russians, Turks, Arabs and Jews, which they called an intermediate type.

Hirschfeld Biochemical Index showing difference in gene frequencies. The figures given are the percentages of positive reactions with anti-A and anti-B reagents. Red bar is the percentage of B white bar is the percentage of A.

The Hirszfelds invented an interesting and useful tool called the Hirszfeld Biochemical Index and which conveniently lets us express the ratio of blood group A to B in any population. The formula is very simple; you add up the number of blood group A and AB individuals in a population and then divide it by the number of blood group B and AB individuals. As so:

Hirszfeld Index = (A + AB) /(B + AB)

Thus, the higher the Hirszfeld Biochemical Index of a population, the more blood group A people in that population over blood group B people in it; the lower, the more blood group B over A. The highest number in the Hirszfeld Biochemical Index (most As, least Bs) was found among the English troops (4.5); the lowest (most Bs, least As) were found in the Indian (0.5) and Vietnamese troops (0.8).

Ludwik Hirschfeld

The work of the Hirszfelds would look crude in comparison to later, more sophisticated methods, and it suffers from the problems of all single-gene examinations of human diversity, that is there are no “pure races” to be identified by a single marker. But their discovery, published in 1919, did give rise to a considerable number of subsequent investigations, producing an enormous mass of documents of varying merit.

The Hirszfelds themselves were a parable of how fluid ethnic affiliations can be: Polish Jews who were attached to the Serbian army through the University of Zurich. They later converted to Catholicism, but were nonetheless confined to the Warsaw Ghetto, where Ludwik gave illegal lectures on medical topics including one on blood groups and race. Yet they managed to survive into a world in which, due to the recent oppressions having been based solely on grounds of ‘blood’, race was a guilty and discredited notion.

1. Excerpted from: D’Adamo PJ. ‘Archeogenetics’ in: Fundamentals of Generative Medicine, Volume I (2010) Drum Hill Books, Wilton CT USA
2. Ludwik Hirschfeld on the Individualist

Tags: anthropology | blood groups | Ludwik Hirschfeld

A

fugue is a musical composition in which one or two themes are repeated or imitated by successively entering voices and developed in a continuous interweaving of the voice parts. It is a much used device in classical music, where often one section of the orchestra will start a melodic line, to which other sections enter in contrapuntal fashion, each starting at the beginning and producing an often hypnotic and undulating melody.

Our African legacy is a similarly fugue-like story, as at different times and in different groupings, humans struck out of Africa, one at a time, with fractions of the group returning and new groups setting out again and again.

We belong to a species group called Homo sapiens sapiens (“modern wise man”). We are possibly descendants of Homo erectus (“upright man”), who lived in Africa at least about two million years ago, although like everything in anthropology, there are arguments pro and con.

Homo erectus would bear a striking resemblance to modern humans, but he had a smaller brain, about 75% of our modern day version. Despite his more modern looks, evidence suggests that he could not produce the complex sounds of our present day speech. H. erectus was probably the first true hunter-gatherer, or maybe more accurately hunter-scavenger. Migrating into Asia, probably following the herds of great mammals such as the mammoths, he left evidence of his existence as far as China (“Peking Man”). He was a great tourist; evidence suggests that he spent time on the French Riviera and remains dating over one million years old have been found in India, Pakistan, China and Indonesia. His presence in Asia initially baffled early anthropologists, and led more than a few to conclude that Asia, not Africa, was the birthplace of modern man.

Ashes to ashes..

However, for reasons not really known, once out of Africa Homo erectus seemed to have stagnated and died out. However, some anthropologists believe that the Homo erectus that stayed in Africa continued to evolve and eventually became Homo sapiens; however other experts do not concur. This had led to two opposing theories. The Multiregional Hypothesis holds that evolution has occurred through a single widespread human species –Homo sapiens– changing and evolving as it spread throughout the world. This idea directly challenges the Out of Africa Model, which claims Homo sapiens evolved recently as a new species in Africa, and then dispersed throughout the Old World, replacing the existing human populations without mixing with them. The genetic evidence seems to support the Out of Africa Model better than the Multiregional Hypothesis, though the jury still out.

The word Paleolithic is Greek for “Old Stone Age” and it extended from the point from where we began to use simple stone tools to roughly the point where we began to harness the power of food domestication and agriculture, at which time begins the Neolithic or “New Stone Age.”

We’ll pick up the story again about 90,000 years ago, when the grandfather of all modern people was born in Africa. As we will see later on, this does not mean that he was the only man alive at the time; it just means that he is as far back as we can go to find a most common ancestor. Certainly, there were thousands of other humans around; however, over the ages their genetic lines just died out. As old as that is, he’s a whippersnapper next to our genetic grandmother, who clocks in at a robust 150,000 years ago.

Although the oldest, or Lower Paleolithic Period is thought to extend almost two million years into the past, most modern type human development took place from about 300,000 years ago to about 10,000 years ago, during the Middle and Upper Paleolithic Periods, a time that may have witnessed the beginnings of a full-featured use of language and branching off much of our current day physical and genomic distinctions. At this time, although it is not completely certain, the early proto-languages may have begun.

Fire and language: Quite the combination.

At archeological sites, tools are often more abundant than bones. Humans have only about 200 bones, and many of these contain edible substances, such as marrow or brain, so you don’t see very many of them, but stones you do see; especially tools made of very hard materials, such as quartz and obsidian. The techniques of making these tools were handed down from generation to generation and the sequences of these techniques became a trademark of that group. A similarity of tool-making techniques among groups of people tells us that knowledge as well as genes was exchanged.

Fire is a discovery rather than an invention, and prehistoric humans certainly knew about it. They may have even witnessed lightning striking an old tree, causing it to burst into flames –or even the sun, shining on dry leaves, causing them to smolder and ignite.

Fire could be considered a tool, since it frightens off predators, keeps people warm and dry, helps cook food, and provides a center for the home territory of a group of people. Here our early ancestors could sit at night, warm and secure, talking over the day’s events, seeing each others faces reflected in the fire. As one classical anthropologist put it:

Human beings convert energy drawn from outside their own bodies into social structure, and the greater the amount of energy consumed, all things being equal, the more complex the social structure.

Stone tools and fire gave our early ancestor a more complex social structure, and all three combined to provide a control over the environment that his ancestors could never have dreamt about. But it gave him something even greater than simple control of his immediate world. It gave him the confidence to explore the far reaches of his curiosity. And that meant travel.

Excerpted from:

1. D’Adamo PJ. ‘Archeogenetics’ in: Fundamentals of Generative Medicine, Volume I (2010) Drum Hill Books, Wilton CT USA

A

lthough almost everyone knows that fingerprint ridge patterns remain constant and unchanging throughout life (which is why they are so useful to law enforcement) even professionals involved in dermatoglyphics research are often unaware of the changeable nature of the actual height of the ridges themselves. There are a series of surprising correlations between changes to the height of the ridge pattern and links to gluten intolerance found in diseases such as celiac and to certain sensitivities to proteins in the diet called lectins.

Ridge height appears to be linked to many of the same cell processes that control glycosylation in the gut. Proper ridge height equates with a patent digestive track, while a worn appearance may signal digestive problems. Known as ridge hypoplasia, this is a situation in which the fingerprint ridges are reduced in height, giving them a “worn-off” appearance. These areas of worn off ridges are also covered with an unusual number of fine secondary creases that become visible, producing what are called “white lines.” (1)

Normal and low ridge height

White lines and celiac disease

Typically, the number of white lines increases with age and with subsequent deterioration of gut integrity. Research dating back to the early 1970’s has linked the appearance of white lines to adults who suffer with celiac disease. (2-6) Ridge height is the only aspect of fingerprints that can actually change with health status. Most interestingly, these white lines often improve with the maintenance of a gluten free diet, and researchers suggest that improvements to ridge height and disappearance of white lines could be used as an indicator of the patient’s response to diet therapy, although complete improvement of the fingerprints could often take as long as two years.

Ridge height of a 54-year-old man with celiac disease

At the left is a series of fingerprint from the right little finger of a 54-year-old man with celiac disease. Left to right: A newly-diagnosed showing almost complete ridge atrophy. Middle: After one-month treatment with gluten free diet. Shows partial ridge atrophy with appearance of white lines. Right: After 11 months on a gluten free diet prints show an almost complete regeneration of the dermal ridges, with disappearance of most white lines. (2)

There is no widespread agreement about the frequency of white lines in the general population. The most extensive study indicated that they are found in the fingerprints of 11-13% of the population, although the study used police records and so would have been made up predominantly of males. (6) Other figures, with broader subject bases, seem to indicate that they can be seen in about 22-30% of all northern Europeans. White lines appear to be more common on the left hand and more commonly on the third and fourth digits. (7-8)

1. D’Adamo PJ. ‘Dermatoglyphics’ in: Fundamentals of Generative Medicine, Volume I. 2010. Drum Hill Books, Wilton CT USA
2. Schauman and Alter, Dermatoglyphics in Medical Disorders, Springer Verlag. New York- Heidelberg. 1976
3. Mylotte M, Egan-Mitchell B, Fottrell PF, McNicholl B, McCarthy CF. Fingerprints in patients with coeliac disease and their relatives. Br Med J. 1972 Oct 21;4(5833):144-6
4. David TJ, Ajdukiewicz AB, Read AE. Dermal and epidermal ridge atrophy in celiac sprue. Gastroenterology. 1973 Apr;64(4):539-44
5. David TJ, Ajdukiewicz AB, Read AE. Fingerprint changes in coeliac disease. Br Med J. 1970 Dec 5;4(5735):594-6.
6. Cherill FA. Fingerprints and disease. Nature 166: 581. 1950
7. Wendt GG. Kranheit in “weisse Linien” der fingerliesten. Artzl. Forsch. 6. 227; 1952 (referenced in 2)
8. Wendt GG. Uber weisse im abdruck der menschlichen Fingerbeere. Homo. 6. 180; 1955 (referenced in 2)
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Tags: celiac | diet | fingerprint | gluten | leaky gut | lectins | white lines

S

alacia is a genus of plants in the family Celastraceae. One species in particular, Salacia oblonga, used for thousands of years in Ayurvedic medicine, is increasingly becoming the subject of considerable medical interest because of its potential as an anti-diabetic agent. The herb is a native of India and Sri Lanka and has been used in traditional Indian medicine and Ayurveda successfully for years. The active constituents, salacinol and kotalanol, inhibit alpha-glucosidase and aldose reductase. The inhibition of these substances decreases the breakdown of carbohydrates into absorbable monosaccharides and therefore decreases postprandial (after meal) blood glucose levels. (1)

Alpha-glucosidase inhibitors are used to establish greater glycemic control over hyperglycemia in diabetes mellitus type 2, particularly with regard to the postprandial hyperglycemia. They may be used in conjunction with an appropriate diabetic diet and exercise, or they may be used in conjunction with other anti-diabetic drugs. Inhibition of these enzyme systems reduces the rate of digestion of complex carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into the simpler, rapidly assimilable glucose molecules. In diabetic patients, the short-term effect of these drug therapies is to decrease current blood glucose levels: the long term effect is a modest reduction in hemoglobin A1c level.

Those Ayurvedic guys knew their herbs.

In a randomized, double-blinded crossover study of sixty-six patients with diabetes were studied to evaluate the effect of an herbal extract of Salacia oblonga on postprandial glycemia and insulinemia in patients with type 2 diabetes after ingestion of a high-carbohydrate meal. The study was divided into three groups: a control meal with a high dose (480mg) of Salacia extract, a control with a lower dose (240mg) of Salacia extract, and a control group given just the meal.Both doses of the Salacia extract significantly lowered the postprandial positive area under the glucose curve (14% for the 240 mg extract and 22% for the 480 mg extract) and the adjusted peak glucose response (19% for the lower dose and 27% for the higher dose of extract) compared to the control meal. In addition, both doses of the herbal extract significantly decreased the postprandial insulin response, lowering both the positive area under the insulin curve and the adjusted peak insulin response (14% and 9%, respectively, for the 240 mg extract; 19% and 12%, respectively, for the 480 mg extract) in comparison with the control meal. (2)

Salacia oblonga extract functions as a PPARα activator, providing a potential mechanism for improvement of postprandial hyperlipidemia and hepatic steatosis in diabetes and obesity. (3)

Salacinol

The PPARs (peroxisome proliferator-activated receptors) receptor family is comprised of three closely related isotypes (PPARα, β/δ and γ, which have been identified in various species and are structurally homologous. PPARα and PPARγ are found predominantly in liver and adipose tissue, respectively, and PPARβ/δ is ubiquitously expressed. PPARs can be activated by fatty acids, fatty acid derivatives, and synthetic compounds, heterodimerize with retinoid x receptors (RXRs), and bind to peroxisome proliferator response elements (PPREs) located in the promoter region of their target genes. Each member of the PPAR family plays a distinct role in lipid metabolism. PPARα enhances fatty acid combustion in liver by inducing genes that encode enzymes involved in β-oxidation. PPARα, the first PPAR identified, is activated by natural lipophilic ligands, like fatty acids and their derivatives, certain leukotriene products, and synthetic ligands, such as fibrates. PPARα regulates lipid metabolism and transport, fatty acid oxidation, and glucose homeostasis. In addition, PPARα exerts anti-inflammatory effects. (4)

Like most alpha-glucosidase inhibitors, Salacia extract can cause a temporary increase in breath hydrogen excretion. (5) There is often a bout of flatulence that occurs during the early stages of treatment. (6)

Salacia extracts were determined not to be genotoxic under the conditions of the reverse mutation assay and mouse micronucleus assay, and weakly positive for the chromosomal aberrations assay. However even these mild genotoxic changes were deemed insignificant due to the enormous amount of plant material needed to produce the genetic changes. (7) Salacia extract, in a medical food consumed for 2 weeks in amounts estimated at 10-fold greater than proposed for human intake, did not result in clinical chemistry or histopathologic indications of toxic effects in male Sprague-Dawley rats. (8)

1. Benalla W, Bellahcen S, Bnouham M. Antidiabetic medicinal plants as a source of alpha glucosidase inhibitors. Curr Diabetes Rev. 2010 Jul 1;6(4):247-54.
2. Williams JA, Choe YS, Noss MJ, Baumgartner CJ, Mustad VA. Extract of Salacia oblonga lowers acute glycemia in patients with type 2 diabetes. Am J Clin Nutr. 2007 Jul;86(1):124-30. [full text]
3. Huang TH, Yang Q, Harada M, Uberai J, Radford J, Li GQ, Yamahara J, Roufogalis BD, Li Y. Salacia oblonga root improves cardiac lipid metabolism in Zucker diabetic fatty rats: modulation of cardiac PPAR-alpha-mediated transcription of fatty acid metabolic genes.Toxicol Appl Pharmacol. 2006 Jan 1;210(1-2):78-85
4. D’Adamo PJ. ‘Network Medicine’ in: Fundamentals of Generative Medicine, Volume I. 2010. Drum Hill Books, Wilton CT USA
5. Collene AL, Hertzler SR, Williams JA, Wolf BW.Effects of a nutritional supplement containing Salacia oblonga extract and insulinogenic amino acids on postprandial glycemia, insulinemia, and breath hydrogen responses in healthy adults.Nutrition. 2005 Jul-Aug;21(7-8):848-54.
6. Collene AL, Hertzler SR, Williams JA, Wolf BW. Effects of a nutritional supplement containing Salacia oblonga extract and insulinogenic amino acids on postprandial glycemia, insulinemia, and breath hydrogen responses in healthy adults.Nutrition. 2005 Jul-Aug;21(7-8):848-54.
7. Flammang AM, Erexson GL, Mecchi MS, Murli H. Genotoxicity testing of a Salacia oblonga extract.Food Chem Toxicol. 2006 Nov;44(11):1868-74.
8. Wolf BW, Weisbrode SE. Safety evaluation of an extract from Salacia oblonga. Food Chem Toxicol. 2003 Jun;41(6):867-74.

Tags: alpha-glucosidase inhibitors | Ayurvedic | blood sugar | diabetes mellitus | PPAR | Salacia oblonga | type 2 diabetes

R

ead of a fantastic new initiative on The Edge website that proposes to study cancer by involving physical scientists (in this case informatics titan Danny Hillis) in collaboration with biomedical investigators. The leaders of the National Cancer Institute are very keenly aware of how little progress has actually been made in the treatment of cancer. They’re thinking very laterally in giving funding to people like Hillis (whose historical basis has been in the engineering and computational sciences) to work on cancer. From the sounds of the announcement Hillis has clearly embarked on a systems approach.

From the Edge article:

We misunderstand cancer by making it a noun. Instead of saying, ‘My house has water’, we say, ‘My plumbing is leaking.’ Instead of saying, ‘I have cancer, we should say, “I am cancering.’ The truth of the matter is we’re probably cancering all the time, and our body is checking it in various ways, so we’re not cancering out of control. Probably every house has a few leaky faucets, but it doesn’t matter much because there are processes that are mitigating that by draining the leaks. Cancer is probably something like that.

It will take a village to beat cancer.

NCI is creating a program where physical scientists can be the principle investigators, partnered with the co-investigators who are clinicians and biological scientists. Giving money to physical scientists is a pretty radical idea and apparently it is very controversial within the biological community. Of course, no research biologist or pharmacologist wants to turn over the rudder to an information guy. But there are some good reasons to be at least open to the possibilities of the idea.

In his autobiography, Surely You’re Joking Mr. Feynman!, Richard Feynman makes a rather telling observation about the difference between physicists and biologists. He was quite struck by the sheer amount of information that biologists felt compelled to keep in their heads at all times, unlike physicists, who often carried much less information, and felt quite comfortable about it, knowing that there were ample opportunities to use reference materials as needed.

That, in my opinion, constitutes the divide between the traditional, reductionist ways of researching the life sciences, versus the newer ways of system biology and informatics via complexity and information theory: One assumes that you have to be smart to get smarter, whilst the other assumes that you can get smarter by being more stupid.

Hillis again:

In order to understand what’s actually going on, we have to look at the level of the things that are actually happening, and that level is proteomics. Now that we can actually measure that conversation between the parts, we’re going to start building up a model that’s a cause-and-effect model: This signal causes this to happen, that causes that to happen. Maybe we will not understand to the level of the molecular mechanism but we can have a kind of cause-and-effect picture of the process.

Here we diverge a bit, although perhaps only in choice of syntax. Granted, we cannot possibly conceive of an approach to cancer that doesn’t involve protein coding. But an exclusively ‘first-intentional’ frame of reference (DNA to RNA to proteins) risks overlooking already established secondary and tertiary feedback and control mechanisms (post-translational modifications such as protein folding and epigenetic alterations) that inevitably factor into the transcription of cancer genes, the inhibition of apoptosis (cell death) and the development of metastatic potential.

Crick’s Central Dogma and reductionist parsimony got us this far (and for that there is much to be thankful for) but from here on in, I suspect that they will be critical parts of the error-trapping subroutines, but will not drive new discovery.

Glycans (complex chains of sugars, often bonded to proteins or lipids) are also important cellular determinants and carriers of information. For example, the simple sugar galactose serves as a recognition marker that determines the survival time of many serum glycoproteins in the circulatory system of man, the rabbit and the mouse. In bird and reptile species the recognition marker appears to be primarily n-acetylglucosamine. Clearance systems in which fucose and mannose are the markers have also been found. Notch receptors are highly conserved intercellular signaling pathways that direct embryonic cell-fate decisions. These receptors are regulated by ‘Fringe’ proteins. Recent evidence shows that Fringe is a fucose-specific GlcNAc-transferase. (1,2)

Changes in N-linked glycosylation are known to occur during the development of various diseases. Increased branching of oligosaccharides, in particular fucosylation, has been associated with cancer metastasis and has been correlated to tumor progression in human cancers of the breast, colon and melanomas. Numerous clinical studies have shown a clear correlation between changes in the makeup of cell surface sugars (aberrant glycosylation) status of primary tumors and invasive/ metastatic potential of human cancers, as reflected by 5- or 10-year survival rates of patients. (3)

Sugar changes even appear to influence the energetic changes in cell polarity. Many epithelial cells normally become polarized, with at least two distinct plasma membrane surfaces. In the case of the intestinal epithelium, proteins are oriented either basolaterally (toward the blood) or apically (toward the lumen). Hepatocytes (liver cells) are unusual in that they polarize in three dimensions rather than as a two dimensional sheet. The basolateral surface is in contact with the blood, while the apical surfaces of the cells form the bile canaliculi. Glycoproteins directed to these surfaces may be selective or even specific for the apical or basolateral surface, and thus maintenance of this polarity depends upon the continuous sorting of newly made proteins and membranes. (4)

Recently, it has been suggested that fucosylation of N-linked glycan within polarized hepatocytes directs glycoproteins to the apical surface and into the bile, and as a consequence, fucosylated glycoforms are normally rare in the blood, and are enriched in the bile. Thus, if cancer cells become “depolarized”, it is reasoned that fucosylated glycoforms would rise in abundance in the blood. (5)

These are single, tiny examples, describing a challenge of mind-numbing complexity. Many other classes of glycoconjugates impact metastasis, such as the proteglycans, mucins and glycosphingolipids.

I will eagerly await the developments from such a imaginative mind and the creative tensions that will inevitably result from its academic juxtapositions.

Yet when I hear ‘cancering’ I still think about glycans.

1. Brückner K, Perez L, Clausen H, Cohen S. Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature. 2000 Jul 27;406(6794):411-5.
2. Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P, Irvine KD, Haltiwanger RS, Vogt TF. Fringe is a glycosyltransferase that modifies Notch. Nature. 2000 Jul 27;406(6794):369-75.
3. Hakomori S. Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)-lipid metabolism. Cancer Res 1996;56:5309-5318
4. Mehta A, Block TM. Fucosylated glycoproteins as markers of liver disease. Dis Markers. 2008;25(4-5):259-65.
5. T. Nakagawa, N. Uozumi, M. Nakano, Y. Mizuno-Horikawa, N. Okuyama, T. Taguchi, J. Gu, A. Kondo, N. Taniguchi and E. Miyoshi, Fucosylation of N-glycans regulates the secretion of hepatic glycoproteins into bile ducts, J Biol Chem 281(40) (2006), 29797–29806.

Tags: glycans | glycobiology | molecular oncology | proteomics

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new study on the role of mucosal immunity and host genetics in defining intestinal commensal bacteria indicates that basic elements of gut immunity, such as antibody class known as secretory IgA (sIgA) exert profound effects on the composition of the bacterial flora that inhabit the gut. This reinforces the prior observations about the influence of ABO and secretor genetics on the microbiome. It has been known since the 1950’s that ABH secretor status correlates with sIgA levels (non-secretors having lower levels), while some strains of enteric bacteria are up to 50,000 time more likely to be found in on ABO blood group versus another.

Bus, bugs, everywhere.

Human feces contain enzymes produced by enteric bacteria that degrade the A, B, and H blood group antigens of gut mucin glycoproteins. The autosomal dominant ABH secretor gene together with the ABO blood group gene control the presence and specificity of A, B, and H blood group antigens in human gut mucin glycoproteins. There is evidence that the host’s ABO blood group and secretor status affects the specificity of blood group-degrading enzymes produced by his fecal bacteria in vitro. ( Free Text) Comparatively small populations of fecal bacteria produce blood group-degrading enzymes but their presence is highly correlated with the ABO /secretor phenotype of the host: Fecal populations of B-degrading bacteria were stable over time, and their population density averaged 50,000-fold greater in blood group B secretors than in other subjects. In fact, the large populations of fecal anaerobes may be an additional source of blood group antigen substrate for blood group antigen degrading bacteria: antigens cross-reacting with blood group antigens were detected on cell walls of anaerobic bacteria from 3 of 10 cultures inoculated. (Free Text)

Although it is well recognized that blood group antigens can serve as points of attachment for microbial adhesins, perhaps less appreciated (at least with regard to the ABO group) is the sheer destructive potential of the opposing blood group antibodies (isohemagglutinins.)

When an isohemagglutinin antibody encounters a foreign antigen, a reaction called agglutination occurs. This means that the antibody attaches to the antigen and makes it very sticky. When cells, viruses, parasites and bacteria are agglutinated, they stick together and “clump up,” which makes the job of their disposal much easier. As microbes must rely on their slippery powers of evasion, this is a very powerful defense mechanism. It is rather like handcuffing criminals together; they become far less dangerous than when allowed to move around freely.

Unlike IgG class antibodies, which require the assistance of the immune system to do their business, these isohemagglutinins kill things all by themselves, which is why getting the wrong blood group in a transfusion is so dangerous.

It is an interesting dichotomy that polymorphisms such as the blood groups that are capable of producing such a toxic reaction to the presence of an opposing blood group antigen but are themselves really just non-lethal mutations. Nobody dies just because they are one blood group or another, although there are many physiologic distinctions and consequences.

It is difficult to understand how agglutinins are produced in individuals who do not have the respective antigenic substances in their red blood cells. However, group A and B antigens are believed to enter the body in the food, in bacteria, or by other means, and these substances presumably initiate the development of anti-A or anti-B agglutinins.

—Arthur Guyton, Textbook of Medical Physiology

Although most scientists are aware of the relationship between the blood group antigens and antibodies that are the determining factor behind the classic transfusion relationships discovered by Landsteiner in 1900. However not very well known is the fact that foods and bacteria that possess many of these same opposing ABO blood group antigens are the source of induction for these IgM class antibodies.

Tags: abh secretor status | abo bood groups | microbiome

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reviously, Dohan (Acta Psych Scand 1966, 42(2):125-152) observed a decrease in hospital admissions for schizophrenia in countries that had limited bread consumption during World War II, which suggested a possible relationship between bread and schizophrenia.

That bread may be bad for your head.

Early work with lectins clearly showed that the brains of schizophrenics bind lectins differently than the brain tissue of non-schizophrenics, which appears to make sense in that the carbohydrate content of schizophrenic brain tissue (in addition to dementia and a few other illnesses) revealed the existence of spherical deposits in the inner and middle molecular layers of the dentate gyrus in the hippocampal formation which contained fucose, galactose, n-acetyl galactosamine, n-acetyl glucosamine, sialic acid, mannose and chondroitin sulfate; many of these blood group active carbohydrates with known lectin binding affinities (link).

We report the unexpected resolution of longstanding schizophrenic symptoms after starting a low-carbohydrate, ketogenic diet. After a review of the literature, possible reasons for this include the metabolic consequences from the elimination of gluten from the diet, and the modulation of the disease of schizophrenia at the cellular level.(link)

Tags: gluten | lectins | schizophrenia

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atching Bill Clinton discuss his recent weight loss on CNN, I was struck by just how sallow and unhealthy he appeared. Clinton is apparently following a extremely low fat, plant based diet in hopes of reversing some of the atherosclerosis he has developed that may be complicating his shunt.

While Clinton’s 20+ pound weight loss is certainly a move in the right direction, evidence suggests that simple, extreme and rapid weight loss may only address part of the problem, and may indeed leave certain individuals open to entirely new susceptibilities.

A recent  article in the International Journal of Obesity would appear to indicate that the toxins that accumulate in the fat tissue of overweight people persist after weight loss even though their body fat concentration is lower.

Bill Clinton at the recent wedding of his daughter Chelsea.

Does this explain why so many folks who rapidly lose weight often look worse than before?

Clinton, who is apparently following the precepts of Caldwell B. Esselstyn Jr appears to be on a rather draconian diet: No oil (including olive oil or peanut butter); no dairy products, poultry or meats whatsoever. Perhaps typical of most (but not all) exponents of this type of eating, there can be a rather unnerving element of evangelism to their message, which can be counter-productive in many individuals and circumstances.

Although there is considerable evidence that plant-based diets can be therapeutic in many individuals, to consider them to be any sort of broad panacea would be an over-extrapolation, to say the least. In in some cases, such as a widely hyped ballyhooed China Study, one might want to slow down a bit and take a closer look at the data.

Tags: Bill Clinton | China Study | persistent organic pollutants (POPs) | Plant-based diet | Rapid weight loss

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elcome to (n=1). a new blog in which I hope to detail new developments and discoveries in the rapidly evolving field of genetic medicine, nutrition, complexity theory and popular culture.