The biology of obesity

The biology of obesity
A review in Proceedings of the Nutrition Society (2005), 65, 31-38 Trayburn P

Obesity is a preoccupation of modern nutrition. The founding fathers of our science would never have believed that the eradication of some major nutritional problems would lead to this particular epidemic.
The biology of obesity includes]
The fundamental mechanisms of energy balance and its regulation, genes, appetite, endocrine factors.
The biological basis for the development of obesity
Adipose tissue function
The biological description of the obese state ( particularly physiological adaptations)
The pathological consequences of obsess, i.e. associated disorders
The physiological basis of treatment strategies
Energy balance
It has always been axiomatic that obesity is fundamentally a problem of energy balance. That obesity can only develop when energy intake is in excess of energy expenditure, differences in input and output being buffered primarily by changes in fat stores.
There are two immutable “ Laws of Obesity”.
That for obesity to develop, intake must be in excess of expenditure
obese subjects have a higher energy expenditure and therefore a higher average energy intake than lean subjects. They have a larger relative mass to move about.
Appetite. It is understood that the central hypothalamus controls food intake. Several peripheral signals are recognised in the regulation of food intake eg ghreli, peptide YY and leptin. Leptin is secreted from the white adipose tissue.
The attractive work on thermogenesis of 20 to 30 years ago, has not stood the examination of time. That is the uncoupling of oxidative phosphorylation by brown adipose tissue mitochondria.
White Adipose tissue. The buffering of energy intake and expenditure is through triacylglycerol deposition in White Adipose Tissue. Obesity is due the laying down of white fat mass ( >85%). Adipose tissue is the source of endocrine signals e.g. leptin. There is a rich array of different glucose transporters more than 8 different types.
White Adipose Tissue is also an important endocrine system. Secreting adipokines.
Inflammation A number of inflammation related proteins e.g. nerve growth factor (NGF) are released by white adipocytes. It has been suggested that obesity and diabetes are associated with chronic low grade inflammation. This tissue related inflammation may play a role in the development of insulin resistance and associated pathologies.
Several thoughts come to mind in reading this very interesting review albeit somewhat tardily
There has always been the aphorism that within every fat person is a thin person struggling to get out. Maybe that within every thin person there is a fat person at risk of struggling in. Are we all at risk or only certain people.
If one goes round a super market , the fattest people are to be found in the crisp and confectionary isles tossing goodies into their trolleys. Cheap delicious high energy foods.. Greed has been carefully cultivated in our society either for readily eaten food or alcohol
The concept of low grade inflammation is fascinating. I was reared in Gastroenterology where the pre-occupation was duodenal ulcer disease. Everyone knew that this was a result of too much acid produced by the stomach. Everyone knew that this was due to stress. Reduce acid and stress and all would be ok. The chronic low grade inflammation in the stomach duodenum was ignored until the Helicobacter that causes gastric and duodenal inflammation was found. Eradication of the helicobacter led to a disappearance of duodenal ulceration. Maybe there is a message here for diabetes and obesity.
Appetite preferences are also important. The heavy consumption of sweets, crisps and alcohol is an exaggeration of appetite needs. Who are those who can so indulge themselves.?
That exercise is so important. The reduction of the involvement of schools in games and the reduced time given to energy expending games eg soccer, rugby and running cannot be good. Playing fields being lost for housing developments cannot be good for exercising children.

vitamin B12 biosynthesis in bacteria

Vitamin B12 is a complex molecule synthesised solely by bacteria. The chemistry of B12 proved to be a difficult task and during the elucidation of its chemistry and biochemistry four Nobel prizes have been won. One fragment of the vitamin has defied understanding until recently ( Ealick and Begely Nature 446, 22nd March 2007 pp 387-8 ) . This is the dimethylbenzimidazole ligand. ( DMB). reaction
There are several structurally related compounds of B12, only two have major recognised biological activity, methyl cobalamin ( a methyl donor in methionine biosynthesis ) and 5-deoxyadenosylcobalamin ( Ado B12) which is the source of the adenosyl radical, important in catalysing reactions with the removal of a hydrogen atom from a compound.
Ado B12 is the only organometallic compound used by living systems. The biosynthesis of which requires the destruction of vitamin B2., riboflavin. The enzyme is a flavin destructase ( BluB) , a reaction requiring oxygen. The enzyme catalyses the conversion of reduced flavin mononucleotide ( FMN ) to dimethylbenzimidazole ligand. ( DMB). The cannibalisation of one vitamin to create another, an interlinking system.
The writers of this fascinating article are surprised that this happens. But biochemistry is about the destruction of one chemical to form another. The fact that a vitamin is lost surely underlines why we have to continuously to stock up with more of the vitamin. .

muscle loss and ageing

Muscle loss ( sarcopenia ) and ageing.
As people grow older their muscle mass declines. There is a loss of muscle mass of 3-5% each decade which accelerates after the age of 60. The causes of this are not known
Prominent aetiological possibilities include altered endocrine function or changes in tissue response to nutrients. It is not clear whether declining physical exercise is cause or effect.
It has been shown that essential amino acid , but not non-essential amino acids stimulates muscle anabolism in the elderly. Whether this is feasible in the elderly or cost effect has yet to be demonstrated
Nutrition Research Reviews (2004) 17, 69-76 Fujita and Volpi.

Domestic toxic substances

An important subsidiary issue in nutrition is toxic substances which may be ingested, possibly along with food. This is a vast field but a recent and very well reviewed book is
How everyday products make people sick: Toxins at home and in the workplace
By Paul D Blanc.
University of California Press 2007
reviewed in Nature by Robbins ( Nature 446, 22nd March 2007 p377 )

The emphasis is on the limited manner that the body can respond to poisons and pathogens. There are such variables as length of exposure, amount of toxin exposed to, the mode of ingestion and the metabolism of the toxin. Examples of toxins are mercury poisoning, asbestosis, bleaching compounds, glue solvents, carbon disulphide and organic manganese compounds.

age and mastication

Influence of age on mastication : effects on eating behaviour.
Nutrition Research Reviews 2004, 17, 43-54 Mioche et al

During the process of eating food is first chewed. This is process wherein the food is broken down by rhythmic movement of the jaws up and down. The teeth break up the food and saliva is added which facilitates the swallowing of the cohesive wet mass the bolus. This is a complex process which involves the teeth, jaw muscles, temporo-mandibular joints, tongue, lips, cheeks, palate and salivary glands. There are considerable differences in the time that various people and peoples take over chewing. There are cultural differences between peoples, such as the rapid eating of meals which some Chinese enjoy and the prolonged time that the French take as they enjoy their food. The Victorian British Prime Minister Gladstone was said to chew each mouthful 30 times. The Buddhists ask us to eat slowly and mindfully. Fast food, fast eating .
The amount of time spent chewing will determine the bolus properties, but the end result tend to be the same in most people.
Chewing is part of the pleasure of eating and enjoying the taste and texture of the food. The condition of the teeth can effect the chewing process.
What are the effects of ageing on chewing and Mastication variables?
Teeth. Loss of teeth may reduce mastication efficiency.
Muscle activity. With senescence the muscles decline in strength and speed and hence the bite.
The tongue. The tongue musculature is peculiar to the tongue to allow the tongue to move in all the directions it is capable of in eating, talking etc.
Oral sensitivity. The sensitivity of the mouth declines with age and presumably the enjoyment of food with sensory stimuli.
Salivary secretion. Normally 1-1.5 litres of saliva are produced each day. Dry mouths are complained in a quarter of institutionalised elderly. Medication can however reduce salivary flow. Good salivary flow is important for swallowing and also enjoying food.
Swallowing. Impaired swallowing is common in the elderly.

Eating function.
Chewing pattern and texture. Texture is the sensory manifestation of food structure, and will influence chewing. The chewing cycle pattern may be affected by age.
In general healthy ageing has only minimal effects on oral physiology. Disease process may affect chewing and swallowing in many ways.

Breast feeding, sugar and pain in babies

Suckling and sugar educe pain in babies Shann in Lancet 369, March 3 2007-03-28
Babies are very aware of painful procedures and events. One such is blood sampling by heel prick. Babies who at the same time are being breast fed and given a cuddle appear to be more comfortable than babies without this support. More recent studies suggest that giving sucrose in addition to breast feeding increases the effectiveness of this regime. One ml of 30% sucrose in addition to breast feeding was better than 30&% glucose.
This simple safe strategy is important. It also raises the thought of fractious babies and feeding. Does the content of the milk help sooth the baby? Or do women who have unhappy babies produce insufficient or weak milk? Or none of these.

stunted children and body mass composition

Prolonged under nutrition during inter uterine and early child hood development is common in developing countries and causes stunting. ( Martin et al British J Nutrition , 92, 819-825 ,2004 ) . The prevalence in stunting world wide is 33%. Stunting in adults reflects the adequacy of nutrition during the pregnancy, breast feeding and subsequent feeding. Stunting paradoxically is related to increased body fat and overweight. . The metabolic response of stunted children is different to normal build children with diets when fed a diet with a higher fat content . The result is a greater increase in weight and waist:hip ratio.
In the study of Martin et al 2004, they analysed changes in body composition of stunted children during a fellow up period in poor children in Sao Paulo Brazil.. The stunted girls developed with less lean mass and greater body fat than normal controls.
One explanation is a preferential utilisation of protein stores as an energy store. The problem is one of biological adaptation to better metabolic efficiency.
It also raises an interesting point for our own populations. There has been a impoverished population in our society for ever. There is at the present time a more bountiful provision of cheap food. The impoverished now have ready access to cheap food and this is leading to obesity in a population metabolically ill prepared for the present abundance.

Retaining independence in Clinical Trials

There is a very thoughtful and important commentary in Nature 446, 8th March 2007 p 137 on Keeping Faith with Trial Volunteers by Piccart and Goldhirsch and colleagues The article discusses the concept of clinical trails from the point of view of the volunteers. They give of themselves to very varying extent. From the giving of a sample of blood to full scale studies. It is only reasonable that they have the best of study design, data collection analysis and full publication of results. I suspect that the animals used in experiments should ask the same as they give everything of themselves and die.
The article talks of the large clinical trials which require huge financial resources, in excess of the moneys available to academic researchers. This means partnership with industrial sources of money. The article suggests that pharmaceutical companies may structure the trials to answer important questions for their own needs for their drugs. Which is very reasonable. Except that academics might and should want to use the trial to test hypotheses that would be important in developing new strategies. For example length of follow up.
They suggest that academic investigators negotiate with industry before committing themselves to trials in the following areas
data control. The important academic quest is to look at the data from every point of view. The funding company may not wish to do this and may withdraw financial support. That is the company is looking to control trial data.
the use of the companies statisticians to look at the data and not to give the raw material to the academics.
They suggest that the academics have first look at the data and then hand it on to the company which can then use the data for their own benefit.
All the time it is important to remember the trial subjects and their contribution. It is kind to contact the subjects after the trial is complete and to inform them of the outcome.

These big trials are less common in nutrition. They should happen and when they do, ,please define the rules of engagement with the funders.

proton movements

The meanderings of the proton may appear a long way from standard understanding of nutrition but my belief is that Nutrition is a science based in Chemistry, Physiology and Biochemistry. It is important to retain an sense of basic sciences so as not to be overwhelmed by spurious claims.
Proton transfer is central to the chemistry of acids and bases in solution, enzyme activity , and transport mechanisms in biological membranes and photosystems ‘ . Our understanding of how protons are transferred between acids and bases in aqueous solutioncame from studies in the 1950s and 1960s,. Now Mohammed et al add more detail. They have shown more of the myriad, sometimes indirect, molecular pathways between acid and base that a proton can follow.
An acid is a substance that donates protons; a base is a substance that accepts them. Mohammed et a!, used laser excitation to ‘trigger’ the movement of a proton from the light-sensitive acidic molecule pyranine. This acid can be written ROH, where R is an organic group and OH a hydroxyl group. As a proton is simply a hydrogen atom stripped of its electron, its progress can be tracked by identifying, through spectroscopv, where the ‘H’ appears in the chemical products of the subsequent reactions.
Using spectroscopy the authors could follow the movement of the proton after leaving ROH, leaving behind the base RO~, and travelling to the negatively charged base molecule, BH . Protonation to form BH is incomplete even after 700 picoseconds — more than 1,000 times longer than it takes for ROH to be deprotonated. The proton appears to make intermediate stops at water molecules, Evidently, ROH is losing protons through more complicated, time-consuming pathways than just the simple confinement of the proton in a loose complex. . It seems that the proton is not transferred directly to the base R in the loose complex, but follows an indirect route to its final destination, shuttling stepwise over one or more additional water molecules in its quest for the base. This process is termed a solvent switch . A meandering proton passing through assorted pathways.
You may ask what has all this to do with anything related to nutrition, who knows butI find it interesting and it will encroach on us some day. .
James T. Hynes Nature 446, March 2007, pp 270-273
And Mohammed O Angew Chem Int Edn 46, 1458-1461 , 2007

prison and essential nutrients

I live in a very socially deprived region of Britain. The communities are wonderful to live in but there is not a very high level of prosperity.
Yesterday I went to the local shops and there were a crowd of men in their twenties , aggressive, loud and threatening. Unsmiling and not nice.
This brought to mind a reference that I saw recently which I have lost which is a shame. This article referred to a study in a British prison where inmates where fed well but I think given vitamin and trace element supplements. The benefit was to reduce the re offending rate. A significant proportion of men in prison are intellectually disadvantaged. This has clearly a multifaceted aetiology but insufficient essential nutrients is a good start for nutritionists.
Maybe the aggressive men would have done better with tomato juice rather than cigarettes.

The adverse side of the outdoors

It is approaching the summer. Anticipation is increased by the clocks going forward
The sun for nutritionists is associated with increased vitamin D metabolism and other benefits and also a sense of well being. There is the down side of potential skin malignancies.
A further down side is the suicide rate in people who work out of doors . This is in part seasonal affect disorder but also there is a sense of despair in poor areas of the world with hopeless poverty. Also in women being forced into humiliating roles as a universal support . In many rural communities suicide is by the use of pesticides and it is estimated that there are 300,00 deaths a year using this method.
Another important source of suicide is alcoholism and this is a real problem in sportsmen. The prevalence of suicide in Cricketers is more than in the general population and may as in other sports be a consequence of alcoholism.

human cancer genome

Many claims have been made that nutrition has a causative or preventive role in the aetiology of cancer. . Some of these claims can be seriously considered, others dismissed as fabrications of fertile imaginations. Unfortunately this is a complex area and one to be looked at with care. However some silly claims turn out to be well founded and the reverse.
The prospect of the entire cancer genome being described offers a basis for rational thoughts and experiments for nutritionists
Abnormalities in some 350 genes have been shown to be associated with human cancer.
.A recent paper in Nature ( Greenman Nature 446, 153-158, 2007 ) has identified mutations in protein kinases, regulators of proteins through adding a phosphate and another in Science has identified the whole cancer genome in breast and colorectal cancer ( Sjoblom Science 314, 268-274, 2006 ) .
The variety of defects underlying human cancer include
Activating intragenic mutations
Gene amplification
Gene translocations
Epigenetic silencing
Gene deletions
Inactivating mutations

By the time that a cancer is diagnosed billions of cells carry the DNA abnormality which initiated the malignant transformation plus others accumulated along the way. Some of these secondary mutations are due to selective pressures ( drivers ) others incidental ( passengers). Passengers are the chance result of mutation exposures, genome instability, or through the rapid rate of proliferation.
It is the drivers that are the initiators and the subject of significant research. Mind you the passengers may turn out to be important in giving malignancy some of the significant characteristics.
Kinases have a probable role in cancer development eg BCR-ABL in chronic myeloid leukaemia. Cellular kinase mutations are common in cancer of the lung, stomach, ovary, colon and kidney and rare in breast and testes.
Each cancer genome carries many singular abnormalities and not all mutations identified contribute to the manifestations of the associated cancers.
Drivers and passengers.
From Haber and Settleman Nature 446, 145-146, 2007

Metabolomics: an emerging tool for nutrition

Metabolomics: an emerging post-genomic tool for nutrition
Metabolomics is the study of the raw materials and products of the body’s biochemical reactions. Metabolomics is concerned with the analysis and measurement of global sets of low-molecular-weight compounds in urine, blood or some other body fluid, scanned in a NMR spectroscopy or Mass Spectrometer and to provide a profile of tens or hundreds of chemicals that can predict whether an individual vulnerable to a disease, or may develop side-effects from a particular drug. Such profiles may provide a more comprehensive view of cellular control mechanisms in man and animals, and raise the possibility of identifying surrogate markers of disease. Researchers are already trying to identify whether a person will develop specific diseases by measuring levels of gene expression or proteins, but supporters of metabolomics say they should be able to do it better. Small changes in the activity of a gene or protein (which may have an unknown impact on the workings of a cell) often create a much larger change in metabolite levels. The approach has already proved its worth: cholesterol and glucose have long been chemical indicators for heart disease and diabetes. Metabolomics has been made possible by the development of technologies that allow the function of cells and whole organisms to be explored at the molecular level. metabolites
Metabolomics has already been used to study toxicological mechanisms and disease processes and offers enormous potential as a means of investigating the complex relationship between nutrition and metabolism. Examples include the metabolism of dietary substrates, drug-induced disturbances of lipid metabolites in type 2 diabetes mellitus and the therapeutic effects of vitamin supplementation in the treatment of chronic metabolic disorders.
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But realising this vision isn’t straightforward. One of the first tasks is to create a catalogue of compounds in the human body, and this is proving hard to define. David Wishart at the University of Alberta, Edmonton, and his colleagues have taken an initial step forward by producing the first draft of the human metabolome. They searched the published literature for known human metabolites, and have collected around 2,500 of them into a public database (www.hmdb.ca).
However this may be an oversimplification. When the effect of age, gender, food physical makeup and chemical composition of diets rich in soya phyto-oestrogens on the absorption of the isoflavones was studied, urinary excretion of the metabolites was influenced by the isoflavone chemical make up of the diet , the sex of the person ingesting the food but not their age.
Nevertheless this is an exciting new area in Nutrition.
Terminology
Metabolomics The comprehensive analysis of the whole melabolome under a given set of conditions
Metabonomics: The quantitative measurement of time-related multiparametric metabolic responses of multicellular systems to pathophysiological stimuli or genetic modification
Metabolome The full set of low-molecular-weight metabolites within, or that can be secreted by, a given cell type or tissue
Metabolic fingerprinting The application of any technological approach whose output is processed with pattern-recognition software and without differentiation of individual metabolites
Lipidomics The characterisation of chemically distinct lipid species in cells and the molecular mechanisms through which they facilitate cellular function
Phillip D. Whitfield et al in British Journal of Nutrition 2004, 92, 549-555
Pearson H in Nature, 2007, 446, 8
Faughan MS et al in British Journal of Nutrition 2004, 91, 567-574

strokes and the role of nutrition

According to WHO, 87% of the 57 million people who die from stroke each year live in low-income or middle-income countries, which are unlikely to be able to afford stroke units or new drugs. Worryingly, because of changing demographics, 7-8 million people will die each year of stroke by 2030 unless national governments in poorer countries start to implement population-based primary prevention strategies that are proven to work. Kathleen Strong and colleagues from WHO, writing in the February issue of The Lancet Neurology, propose a worldwide goal for stroke: "a 2% reduction [in stroke death rates] each year over and above that which may happen as a result of better case management and treatment." Achieving this worthy goal would result in 64 million fewer deaths from stroke between 2005 and 2015-
But this target will only be possible if governments and international agencies realise that stroke is neither solely a disease of affluence nor does it selectively affect older people who are nearing the end of their lives. A third of all stroke deaths are in people younger than 70 years of age, with 94% of those deaths taking place in low-income or middle-income countries. Implementation of interventions that reduce hypertension, poor diet, and tobacco use will save more lives than all the thrombolytics, antiplatelets, and neuroprotectants combined. There is little doubt that for stroke, prevention really is better than cure.
This is an important role for nutrition. Weight control, blood cholesterol and sugar control , a diet containing the ideal components especially in my view plenty of varied fruit and vegetables and exercise.
This is real nutrition.

Diet of pregnant adolescents

A systematic review of dietary assessments of pregnant adolescents in industrialised countries
Victoria Hall Moran
British Journal Nutrition 2007, 97, 411-425
‘In the world’s rich nations, more than three quarter of a million teenagers will became mothers each year Adolescent pregnancy is a major public health challenge for many industrialised countries. In the most up-to-date and comprehensive survey of adolescent birth rates in the industrial­ised world, it was reported in 1998 that the USA had the highest adolescent birth rate, whilst the UK had the highest adolescent birth rate in Europe. Rates of adolescent births (the number of births per 1000 adolescents aged 15-19 years) in the USA were 52-1 per HHK) births - about four times the European Union average. Adolescent birth rates in the UK were 30-8per 1000 births - approximately five times those of The Netherlands, three times those of France and twice those of Germany -
Adolescent pregnancy is associated with significant medical, nutritional, social and economic risk for mothers and their infants. There is evidence lo suggest that the medical risk is particularly severe for young adolescents. Infants born to young adolescents (< 15 years) are twice as likely to be low birth weight and three times as likely not lo survive the neonatal period compared wiih infants bom to adult mothers 2000). Recent UK data confirm that children born to adolescent mothers have the highest infant mortality rate of 7-9per 1000 live births. This contrasts with a rate of 4-3per 1000 live births in women aged 30-34 years (the lowest risk group)
Rates of spontaneous miscarriage, very preterm birth (< 32 weeks) are highest in those aged 13-15 years . Young adolescent mothers are at higher risk for maternal health complicalions than adult mothers..
Poor pregnancies may result from these mothers being with being young, and with poor socio-economic status, lifestyle and adequacy of prenatal care
Relatively little is known about the nutrient intakes of adolescents during pregnancy. This reviewed dietary assessments of pregnant adolescents living in industrialised countries. Seven of which were conducted in the USA.
The nutrient intakes of pregnant adolescents were below the DRI for energy, iron, folate. calcium, vitamin E and magnesium, nutrients important for foetal growth and development during pregnancy.
The research was limited by sampling and measurement bias, and research is urgently required to address these limitations. These are young girls who have already in a sense defied conventional practice by becoming pregnant, Socio economic conditions and cultural practices are important. Extremely important is that the young girls are growing and physically maturing themselves.
In many ways, whatever is the role of the professional services the intelligent support of the girls family is of paramount import. Not always easy.

prevention of neural tube defects.

Neural tube defects and oral clefts are among the most common congenital malformations with prevalences of 10-15 per 10 000 and 20 per 10 000 live births, Periconceptional supplementation with folic acid reduces the risk of neural tube defects. What has been less defined is the effect of folic arid supplementation on other birth defects, such as cleft lip. with or without cleft palate.
, Wilcox and colleagues report a population based case-control study from Norway, which shows that supplementation with folic acid in the periconceptional period reduces the risk of cleft lip, with or without cleft palate, in newborn. Supplementation with 100 ug of folic acid for three months around conception was associated with a 40% reduction in the prevalence of cleft lip, with or without cleft palate, at birth. . The study supports findings from other recent studies, including a large meta-analysis.’
400 ug folic acid per day may well prevent a large proportion ot neural rube defects. even suboptimal fortification (for example. 180 ug/day in the US) greatly reduces neural tube defect rates.’
Three public health policies have been suggested.
1. for women to eat a diet rich in naturaJ folates. However, it is difficult to reach this dose with diet alone, and folate in the diet has lower bio-availability than synthetic folic acid.
2. The second is for women to take supplements of folic acid in the periconceptual period. But low compliance and high rates of unplanned pregnancy limit this approach, fewer than 50% of women followed the recommendations.
3. The third fortification of staple foods (such as wheat, corn flour, or rice).
The World Health Organization has recommended supplementation with 400 ug of folic acid in the peri-conceptual period. Fortification of food is mandatory in an increasing number of countries Countries differ substantially ) in their choices of preventive strategy.
”Further support for mandatory fortification of food comes from a cohort study showing that simply recommending women planning pregnancy to take folic acid is not enough to substantially reduce the prevalence of neural tube defects at birth.
However, in many European countries mandatory fortification has been limited by theoretical concerns. These include the potential of masking symptoms of vitamin B12 deficiency, interactions with certain drugs (amifolales). and other unrecognised adverse effects such as idiosyncratic reactions to folic acid even in small amounts
But mandatory folic acid fortification to achieve around 180 rig/day on average and 1000 pg/day at maximum appears to holds little risk of complications.
Fortification could also reduce the burden of major disorders such as cardiovascular diseases and dementia. The risks of these disorders increase with high plasma concentrations of homo-cysteine, which folic acid supplementation can reduce in humans. The definitive evidence in large long standing controlled trials studying the benefits of supplements in cardiovascular disease and dementia have yet to be obtained .
The underlying problem is a lack of knowledge of what basic defect is involved in the aetiology of these birth defects. Karen Liu has shown that in mice with a glycogen synthase kinase ( GSK-3β) defect developed defective fusion of the palate and sternum. Giving Rapamycin at an early stage in development prevented cleft palate.and later in the pregnancy the sternal defects. Rapamycin stabilizes the glycogen synthase kinase.
Another problem is the population at risk. The potential mother of a wanted baby is likely to follow this advise.
Nature 2007, vol 446, pp xi and 79
BMJ 2007, vol 334, pp433-4
Wilcox et al BMJ 2007 , vol 334, 464-467

diet and longevity

It is well established that reducing food intake increases life expectation.
Studies of longevity in simple organisms have helped an understanding of how caloric restriction might increase life-span. In the budding yeast Saccharomyces cerevisiae, nutrient withdrawal extends longevity through a pathway that requires the enzyme Sir2. Overproducing this enzyme can prolong the life of yeast grown under normal nutrient condition-. Similarly, in the evolutionary more advanced worm Caenorhabditis elegans, increased expression of the worm's version of Sir2 has also been shown to extend lifespan.
The Sir2 enzyme belongs to a large family of evolutionary conserved molecules called sirtuins. In lower organisms, such as yeast and worms, these enzymes regulate a wide range of cellular activities that affect lifespan, including modulating how tightly DNA is packaged inside cells.
In mammalian cells, sirtuins act as regulators of programmed cell death and differentiation (cell maturation). Sirtuins exert their effects on these cellular processes by removing acetyl groups from specific target proteins. Deacetylase function depends on the intracellular concentration of nicotinamide adenine dinucleotide (.NAD), and the oxidized form greatly enhances Sir2 activity. In yeast, caloric restriction may regulate Sir2 activity, and hence prolong life, by shifting the ratio of oxidized to reduced NAD or by altering the level of the NAD derivative nicotinamide . Together, these findings suggest a potential mechanism by which metabolic activity and lifespan might con-verge.
Building on the knowledge that caloric restriction prolongs longevity through Sir2, Howitz et al searched for a small molecule that could activate this enzyme directly. These investigators discovered two related compounds that each stimulated Sir2 activity. Both compounds belong to a family of polyphenols secondary metabolites in plants. One uf the most widely studied of these compounds is resveratrol ,a plant polyphenol that is abundant in red wine . and is the most potent Sir2 activator of all of the plant polyphenols tested. The authors showed that this chemical prolonged the lifespan of yeast by approximately 70%.
The concentration-dependent effects of resveratrol as observed by Howitz et al /, were complicated. At relatively low doses these molecules stimulated sirtuin activity, but, at least in certain assays, higher doses had the opposite effect. This is not an ideal character­istic for a pharmaceutical drug. Second, and more importantly, life extension in yeast is a long way from life extension in higher organ­isms. Indeed, how sirtuins function in mammalian ageing is not yet known.
All of which illustrates a fundamental difference between those who would have us following a pharmaceutical path to longevity or a dietary. A diet containing a wide range of plants varied each day may well appeal to nutritionists. In contrast to a fast food diet and pills. The latter would appeal to the Pharmaceutical industry to food related route to agriculture and nutrition.
Finkel T Nature 425, 11 September 2003, pp 132 – 133
Howitz KT et al 425, 11 September 2003 191-196

RNA control of genes

RNA interference, or RNAi. When a gene is to be expressed, it sends instructions to the cell’s protein synthesis machinery. The intermediary is messenger RNA (mRNA), which has a structure complementary to that of the gene. In their paper, published in Nature in 1998, Fire and Mello, and colleagues, demonstrated that these mRNAs can be targeted for destruction by specific double-stranded forms of RNA (A. Fire et al , Nature 391,806-811; 1998).
It was already known that ‘antisense’ RNA — an artificial molecule whose sequence complements the mRNA could silence specific genes when taken up by a cell. But the effect was modest and inconsistent. And, to complicate the picture the same effect was obtained with ‘sense’ RNA.
In a series of experiments on a muscle gene in the nematode worm Caenorhabditis elegans Fire and Mello showed that a powerful and consistent effect required the sense and antisense RNAs to be stuck together, as double-stranded RNA. When injected with the double-stranded RNA, the worms twitched awkwardly, just like mutant worms lacking the muscle gene. The researchers also showed that mRNA was destroyed by the treatment, rather than being masked as others had believed. And they showed that the double stranded RNA can cause more copies of itself to be made, can spread between cells and can even be inherited by progeny. It is now known that organisms use this mechanism to control the expression of their genes. RNAi is an important way to control genes which insert themselves throughout the genome, jumping genes and disrupt gene function .
This mechanism of RNAi is a universal mechanism throughout all the species studied.
Nature collection December 2006

vegetarianism and IQ

In a study of 8170 thirty year old men and women a possible link between IQ and vegetarian practice was examined. Only 366 were vegetarian, ( 4.5 % ) and even within this group 123 ate fish or chicken.
Vegetarians were more likely to be female, of a higher social class throughout their life and to have a good education. A higher IQ at 10y of age was likely to result in a vegetarian food intake. Though the odds ratio is not too high,( ≈1.38 )
A most intriguing result, where much is allowed for in the calculations.
The basic question is why do young people become vegetarian , health or unwillingness to kill animals for food.. Are girls more sensitive to this concern ? Are more intelligent girls more sensitive to animals being killed for food.
Or does vegetarian practice enhance IQ.?
Gale et al 2007, BMJ, vol 334, pp 245-8

sunscreen and vitamin D.

Many people use sunscreens to protect themselves and their children against the most lethal effects of UVR. Unsettlingly, data so far have failed to show that the use of sunscreen protects against melanoma, the deadliest form of skin cancer (see page 851). This and associated controversies have produced responses tanging from deep epidemioiogical curiosity to a recently filed class-action lawsuit against the sunscreen industry83.

Sunscreens are widely used as protection against developing skin cancers. The evidence for protection against melanoma is as yet to be proven. With keratinocyte-derived skin cancers such as squamous-cell carcinoma are , the association between Ultra Violet Radiation and carcinogenesis has been clearly established Correspondingly, sunscreens, when applied correctly, are effective at reducing the incidence of squamous-cell carcinoma and its precursor.

Sunscreens are defined according to ‘sun protection factor’ (SPF), which is measured by calculating the minimal dose of UVR necessary to cause confluent redness at 24 h after exposure on protected skin compared with unprotected skin. At present, the SPF measurement is based mainly on protection against UVB radiation (wavelengths 290-320 nm), although newer sunscreens may also shield UVA radiation (wavelengths 320-400 nm). UVB can cause DNA damage, and there is growing evidence that UVA might also have carcinogenic effects8”. Another question raised is whether sunscreen inhibits vitamin D production. However, there is little evidence to suggest that sunscreen prevents adequate vitamin D production, or that low vitamin D levels are associated with increased melanoma risk.
Nature, vol 445 22nd Feb 2007 p846.