Ageing and longevity

Longevity is a curious and important point. Does one want to live to old age. Does one want to die old and alert or become time expired and senile and old.
This question has been highlighted by two reports
One by the WHO who showed that in two districts of Glasgow that the expectation of live differed by 28 years. In the socially deprived area the radio interviewed several local people who just said one had to die sometime and why bother. That a diet of fish and chips was enjoyable. A formidable health problem, how can one help those who do not want help. Whose way of life is so poor that the need to prolong it is not great.
At the same time Vijg and Campis have written a review in Nature on the puzzle f ageing.
Ageing and death are inevitable. When we die depends on so many variables and the upper limit of expectation is not known. Different creatures live for a long time others briefly. At the moment the best expectation is 85 years of age though many parts of the world have no hope of this. Manipulations of single genes can extend life. These genes regulate growth, energy metabolism, nutrition , sensing and reproduction. Life expectation increases when activity of the gene is reduced.
Dietary restriction( not malnutrition ) is a potent extender of life expectation.
Three major pathways are involved the insulin receptor system, the mTOR pathway (mTOR) is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription., and mitochondrial pathways.
Easy then , eat less,
But smoking reduces life expectation by 11 years so no smoking and exercise.
Vijg and Campis 2008 Puzzles, promises and a cure for ageing Nature vol 454 pp 1065-71

Olympic athletes and nutrition

The wonders of the Beijing Olympics are now behind us
The implications for nutrition of the activities of these extraordinary people are immense.
Two asides
The great swimmer Phelps eats 12000 calories a day. This energy intake is presumably monitored by a nutrition team. What happens when he rests from swimming or retires? I hope that he is guided through this change of energy intake and utilisation whilst returning to normal activity.
Or Chris Holt the Scottish cyclist who has a thigh measurement of 26 inches, greater than Mrs Beckham’s waist. What happens when he retires?

carcinogenesis, p53 and stress

This is such an intriguing paper. Many lay people believe that there is a relationship between stress and the development of cancer. The tumour suppressor p53 is activated following stress and initiates a heterogeneous response in a cell-, tissue- and stress-dependent manner. This heterogeneity is reflected in the different physiological outcomes that follow p53 activation. One mechanism that may contribute to this variability is the promoter selectivity of p53 target genes. p53 is at the hub of numerous signalling pathways that are triggered in response to particular stresses, all of which can leave their mark on p53 by way of post-translational modifications and interactions with cofactors. The precise combination of these marks, much like the bars in a barcode, dictates the behavior of p53 in any given situation.
I am not sure what this tells us but there is the beginning of a revelation here.
Murray-Zmijewski et al 2008 A complex barcode underlies the heterogeneous response of p53 to stress
Nature Reviews Molecular Cell Biology 9, 702-712

brown and white fat tissue

Seale et al , Tseng et al and Cannon and Nedergaard write in three articles of brown and white fat This is not a popular topic and these authors bring new insights to this most important field.
They describe a revised model of the origins of fat cells. White fat cells accumulate energy from food within a large fat droplet for later use (or not). Certain developmental cues, such as BMP2 and BMP4, induce young white fat cells to differentiate into mature fat cells. By contrast, brown fat cells, which also take up food energy, use it up in their mitochondria through the activity of the UCPl protein. It emerges that brown fat cells share their predecessor cells with muscle cells. Some of these precursor cells — for example, those controlled by BMP.can be induced to express PRDM 16, a transcription factor that will direct them into the pathway to develop into brown fat cells. In the absence of PRDM 16, and possibly owing to the activity of myogenin, the precursor cells develop into muscle cells, which also contain many mitochondria and use energy, but here they use it for real work.
Cannon and Nedergaard 2008 Neither fat nor flesh Nature vol 454 pp 947-948
Searle et al 2008 PRDM16 controls a brown fat/skeletal muscle switch. vol 454 pp 961-967
Tseng et al New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature vol 454 pp 1000-1004

codeine and breast feeding

In the Lancet of August 23rd 2008 there is an fascinating debate on a report from 2006 also in the Lancet ( Lancet 2006 vol 368 p 704 . In the original case report the death of a neonate was attributed to the mother taking codeine . The mother was an ultra rapid converter of codeine to morphine and the morphine passed in the breast milk to the baby. The new letter by Bateman et al challenges their conclusions suggesting that the concentration and amount of codeine and morphine in the milk could never achieve lethal amounts to the baby. The original authors reply and disagree saying that the metabolism of the baby is different from the adult and that the infant war vulnerable to small doses of morphine.
They both make good case for their point of view.
For the nutritionist the important message is that the mother is the source of the constituents of the breast mil. Care and attention should be taken about what the breast feeding mother eats and drinks and is given in non nutritional substances, drugs, alcohol etc.
The baby is very dependent and vulnerable,
Lancet 2008 vol 372 pp 625-626
Ferner 2008, Did the drug cause death? codeine and breast feeding Lancet vol 372 pp 606-7

Ghrelin and appetite control

UCP2 mediates ghrelin’s action on NPY/ AgRP neurons by lowering free radicals
Zane B. Andrews et al 2008 Nature vol 454 pp 846-851
The gut-derived hormone ghrelin acts on the brain by regulating neuronal activity
Ghrelin is a hormone with widespread activity. This paper links its activity with appetite control in a complex action involving fatty acids as a hypothalamic fuel and also carbohydrate and energy intake. Anti oxidant status also has a role. No doubt in time this will become clearer.
Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). The authors show that ghrelin initiates changes in hypothalamic mitochondria! respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2.

epigenomes and nutrition

This paper in Nature 2008, vol 454 7th August p 711-2 is an easy read account of epigenomics, the physiology of molecular biology
Epigenomes, is all the epigenetic marks in a given cell type. Epigenetic processes are essential for packaging and interpreting the genome, are fundamental to normal develop¬ment and are increasingly recognized as being involved in human disease. Epigenetic mechanisms include, among other things, histone modification, positioning of histone variants, nucleosome remodelling, DNA methylation, small and non-coding RNAs. These mechanisms interact with transcription factors and other DNA-binding proteins to regulate gene-expression patterns inherited from cell to cell. The patterns underlie embryonic development, differentiation and cell identity, transitions from a stem cell to a committed cell and responses to environmental signals such as hormones, nutrients, stress and damage.
Although epigenomic changes are heritable in somatic cells, drug treatments and presumably nutrients could potentially reverse them. This has significant implications for the prevention, diagnosis and treatment of major human diseases and for ageing.

Obesity and shapes , Why ?

Where I live in Scotland obesity is a real problem. It is so sad to see young women waddling along with considerable difficulty.
What is odd to me is that the old fashioned fat woman was equally fat all over, this new epidemic seems to concentrate the fat around the bottom, and result in a very broad beam person. Often the grace and prettiness of the face is left intact.
Many believe the pandemic is due to a massive increase in the eating of processed food. Could this be that the other contents of the food eg the preservative sodium nitrate could play a role n in affecting the distribution of the fat by influencing body signals and distribution controls. Crisps come to mind though there may be other chemicals and does not explain the effect of soft drinks though these may just ad to the energy input.

Dietary Reference points for trace elements

There is a good review of methods of evaluating the status of trace elements in the body for Nutrition
Ed Fairweather-Tait and Harvey
Micronutrients status methods Proceedings of the EURRECA Workshop and working party on new approaches for measuring micronutrient status.
BJN vol 99 Supplement 3 pp S1-80

Biomarkers of copper status: a brief update
Harvey and McArdle
Copper (Cu) deficiency in humans is associated with anaemia, hypercholes-terolaemia and bone malformations. Despite significant effort over several decades a sensitive and specific Cu status biomarker has yet to be identified.
Current biomarkers include a range of cuproenzymes such as the acute phase protein caeruloplasmin and Cu-Zn-super-oxide dismutase all of which are influenced by a range of other dietary and environmental factors. A recent development is the identification of’ the Cu chaperone, CCS as a potential biomarker; although its reliability has yet to be established.
Merhods to assess iron and iodine status
Zimmermann
Four methods are recommended for assessment of iodine nutrition: urinary iodine concentration,1 the goitre rate, and blood concentrations of thy¬roid stimulating hormone and thyroglobulin. These indicators are complementary, in that urinary iodine is a sensitive indicator of recent iodine intake (days) and thyroglobulin shows an intermediate response (weeks to months), whereas changes in the goitre rate reflect long-term iodine nutrition (months to years). Spot urinary iodine concentrations are highly variable from day-to-day and should not be used to classify iodine status of individuals. International reference, criteria for thyroid volume in children have recently been published and can be used for identifying even small goitres using thyroid ultrasound. Recent development of a dried blood spot thyroglobulin assay makes sample collection practical even in remote areas.
Serum ferritin remains the best indicator of iron stores in the absence of inflammation. Measures of iron-deficient erythropoiesis include transferrin iron saturation and erythrocyte zinc protopor-phyrin, but these often do not distinguish anaemia due to iron deficiency from the anaemia of chronic disease. The serum transferrin receptor is useful in this setting, but the assay requires standardization. In the absence of inflammation, a sensitive method to assess iron status is to combine the use of serum ferritin as a measure of iron stores and the serum transferrin receptor as a measure of tissue iron deficiency.

Update on the assessment of magnesium statue
Arnaud
There is no simple rapid and accurate method, only serum magnesium and use of loading dosage methods.

Indicators of zinc status at the p[population level: a review of the evidence.
Gibson, Hess, Hotz, Brown

There are few reliable methods, only serum zinc and the clinical sign of clinical runting in children. of

Dietary reference intake for polyphenols

Gary Williamson * and Birgit Hoist
Dietary reference intake (DRI) value for dietary poly phenols: are we heading in the right direction?
Polyphenols are widely distributed in plant foods, and have been linked to improved human health through reduced risk of chronic diseases, especially cardiovascular. Although they do not cause classical deficiencies, recently they have been discussed as 'lifespan essentials because they are needed to achieve a full lifespan by reducing the risk of a range of chronic diseases. A recent meta analysis shows promising actions of polyphenols from cocoa, soya and tea on flow mediated dilation, blood pressure and LDL cholesterol. Many epidemiological studies support the action of polyphenols or polyphenol-rich foods on health, but there are still many gaps in our knowledge. More adequately powered, randomised, placebo controlled human studies are needed on polyphenols. There is a large number of structurally different polyphenols which are relevant for health, and obtaining enough information to set a DRI for each of these will not be feasible in the foreseeable future. A new approach is needed, and a new way of thinking, which would apply not only to polyphenols but also to other phytochemicals. Today, a target intake value of polyphenols as 'lifespan essentials' needs to be based on the amount of polyphenols in '5-a-day'. We are heading in the right direction towards a DRI, but bioavailability and dose-effects, including toxic levels, need to be established before DRIs can be considered.

Williamson and Hoist 2008 Dietary reference intake (DRI) value for dietary polyphenols : are we heading in the right direction? British Journal of Nutrition 99 suppl 3 S 555-S58

Our food, our future

I listened yesterday morning to a wonderful programme on BBC Radio 4 “ Our Food, our future” presented by Tome Hean. The participants included young mothers short of money and cooking skills and some very articulate and contributing Nutritionists and Dieticians. ( BBC Radio 4 Monday 9 am August 4th available to hear on the BBC web site ).
One contributor made a very good point. He differentiated between the value of food and the values of food.
The Value being the price at the shop
The Values being the whole of nutrition, the nutrition value of a food , its economic history and its ability to add to the well being of the consumer with minimal disturbance of the world’s being.
Added values being the cooking so that raw materials are presented as delicious food. Also the importance of sit down meals, not grazing. The importance of the communal family unit..
Many of the young women confessed to being ignorant of cooking skills. Also with their economies failing, the cost of made up food and less food for cooking had to be balanced against preparation costs and time and cooking costs.,

dietary cholesterol, fat and apolipoprotein sterols

This paper may at first sight appear to be too detailed and even boring. Far from it.
Cholesterol and coronary heart disease is such an important topic. Our understanding of the place of diet owes much to the patient meticulous studies of Grundy, Brown and Goldstein , Ahrens , Miettinen and others . Never easy reads but slowly an understanding of the complex process of cholesterol metabolism has emerged.
Always the question was being asked what if.
The studies are long winded , on volunteers in special metabolic areas and required much of the subjects and their studiers.
I t is of great interest to me to see that Tatu Miettinen is still publishing relevant work.
Apo E phenotypes E2, E3 and E4 are involved in the homeostasis of cholesterol metabolism, in its elimination as bile acids, in the removal of chylomicron remnants and in the hepatic clearance of dietary fat.
In addition, apo E phenotypes and cholesterol absorption efficiency are interrelated, so that the E4 isoform is associated with enhanced and e2 iso-form with low cholesterol absorption efficiency.
Interrelationship of apo E phenotype% with cholesterol absorption may in fact be a reason for the respective high and low levels of serum cholesterol. However, the association between apo E phenotypes and serum cholesterol level seems to be dependent on the amount of dietary fat and cholesterol.
Miettinen and colleagues has previously shown that during ad libitum home diet (HD) with high fat and cholesterol intake (38 % energy (E%)/d and 574mg/d, respectively), a positive association between apo E phenotypes and cholesterol absorption efficiency.
But not when the intakes of fat and cholesterol were reduced.
During low fat and cholesterol intake , the absorption efficiency and synthesis of cholesterol were apo E dependent, vanishing, however, after four-fold increase in cholesterol intake..
Accordingly, it seems evident that the interplay between apo E phenotypes and cholesterol metabolism is dependent on the dietary amount of cholesterol and fat.
apo E phenotype regulates the sensitivity of serum total cholesterol (TC) and LDL-cholesterol (LDL-C) levels in response to the amount of dietary cholesterol and fat..
From among small amounts of non-cholesterol sterols in serum and especially in LDL particles the most important are dietary phytosterols, cholestanol, a metabolite of cholesterol, and cholesterol precursor sterols..
In steady-state conditions, the non-cholesterol sterols reflect cholesterol metabolism such that cholestanol and the phytosterols campesterol and sitosterol reflect positively the fractional cholesterol absorption.
Whereas the cholesterol precursor sterols lathosterol and desmosterol parallel the changes in cholesterol synthesis and the activity of hepatic HMG-CoA reductase under normal conditions.
Nissinen, Gylling and Miettinen 2008 Effects of dietary cholesterol and fat on serum non-cholesterol sterols according to different apolipoprotein E subgroups among Healthy men. British Journal Nutrition vol 100. 373-379

Nutrition, logic and information

From time to time,one reads a truly exciting article. Such an article is printed in Nature written by Paul Nurse ( Nature 2008 Life, logic and information vol 454 pp 424-5) and has made me think how nutrition fits into his massive picture of the future.
Biology has over the recent decades learnt so much of how genes, cells and organisms function.
However the connecting networks, general cellular homeostasis, maintenance of cellular integrity, the generation of special and temporal order, inter and intra-cellular signalling , cell memory and reproduction are not fully understood.
Nutrition has lagged behind this revolution and has less to contribute than the central position of our science merits.
Nutrition has a central role in such thinking.
There is too much emphasis on the effects of nutrition on the aetiology of disease and not on normal function. Maybe the grant giving boards are to blame.
Living organisms are complex. To understand the interconnections of living systems we need a new language and logic, drawn from systems analyses of living organisms.
The needs are
To describe molecular interactions and biochemical transformations as logic circuits showing how information is managed. The cell is the basis for such a description.
Logic circuits need to broken down into individual segments , eg negative feed back loop and positive feed back loops. The control of the cells intake of nutrition and how it asks for more of this and that nutrient is important here. What happens in excess circumstances and in reduced circumstances.
Detailed biochemical descriptions are required for this. Knowledge of the anatomy of the cell, rate constants , strengths of integration allow interaction models to be built and differential equations to be created.
How these modules operate and link together allows us to understand the flow of information.
How is information gathered. For nutritionists this is a long path from the plant seed and animal foetus to the farm to the shop to the consumer to the table, to the mouth , intestine, to the storage and transport systems and then allocated to a cellular system.
The basis of the cellular systems are the nucleic acids information storage and the DNA and histone methylation , protein kinase and phosphatases which act antagonistically as switches.
Detailed modelling might show that certain molecules are associated together in particular ways. The interactions of vitamin B12 and folic acid is a good example.
This would enable pathways and the limiting factors and interactions to be identified.
Such logics have been used in other fields of endeavour eg transportation , flight routes
Biological systems are more flexible and constantly changing
The temporal organisation and dynamics of the biological process would then make more sense.
In nutrition this system analysis would be enriched by behavioural analysis.
A brilliant prospect. Which requires a group of thinkers akin to the splitting of the atom and to better purpose.

arsenic uptake by rice

Rice is very efficient in assimilating arsenic polluting paddy fields. The plant uses the same transport system as for silicon to achieve this , with two transporter proteins belonging to the aquasporin family.
As if polluted wells was not enough of a tragedy.
Proc.NatlAcad Sci . USA dol 10.1073/pnas. 0802361105 ( 2008)

Self perception of obesity , changing trends

In any Public Health programme that entails a change in life style it is important that the population at risk should need to recognise that their life style is contributing to real or potential ill health. This applies to alcohol, social behaviour , excessive sized families , smoking and drugs.
Alternatively there is the prospect of a charge of the Nanny State where Big Brother overlooks the population and dictates their way of life.
However if people who have lived in a particular way then throw themselves on the general population and expect help for their past life then the genera population has a .
say.
This is difficult. Some people have been forced or connived into a life threatening and health damaging life, coal miners, fishermen , armed forces who have worked for society in general and require support when the load is too much
However those who have lead a life devoted to alcohol, social behaviour , excessive sized families , smoking and drugs who may not justify the same support.
It is wrong to discriminate against any sufferer so there is a dilemma. Furthermore our concern about treating fat people with knee replacement is misplaced, the operation yields the same long term benefits as normal weight individuals. ( News 2008 Obesity does not limit benefits of knee replacement BMJ vol 337 p 2552 )
A interesting paper in the BMJ of 2nd August 2008 shows that in general perceived and reported weight do not accord and has deteriorated in he last 12 years
Most people believe that obesity is related more to personal behaviour than to broader society.
Perhaps nutritionists have inadvertently contributed to the current attitudes by emphasising hormones and genetics rather than self indulgence.
The problem may well be one of Public Health programmes
Editorial 2009 Public perception of overweight, underestimation has important implications for public health programmes BMJ vol 337, pp 243-4
Johnson et al 2008 Changing perceptions of weight in Great Britain : comparison of two population surveys BMJ vol 337 pp 270-272

Smoking in London

There is an exhibition at the Museum of London showing a history of smoking in London
Smoking cigarettes kills a Londoner every hour.
Cigarette butts account for 40% of the litter on London’s Streets.
Two million Londoners still regularly light up and smoke cigarettes.

World population

World population growth
The BMJ records an interesting description of how the world population has grown out of control.
The first modern human was about in about 160000 BC.
In AD 1 the world population was 250 million
1776 1 billion
1945 2.3 billion
2006 6.5 billion
The human population has quadrupled in less than 100 years.
The annual increase in population of the world is 79 million
This has profound implications for the future of the world
So we worry abut whether or not we eat too much of this and that. Or the millions of starving and quietly and surely we are driving the human race into extinction by over populating the globe
BMJ picture of the week 2008 vol 337, This week , Editorial and Research p 279

Arsenic pollution in SE Asia

Arsenic poisoning is a real problem in Bangladesh. A recent paper in Nature 2008, vol 454 p 263 indicates that many other areas in SE Asia may be troubled by arsenic pollution of the water.
A map of contamination indicates that the Myanmar Irrawaddy Delta may be contaminated by arsenic. Many of these countrey's wells are polluted. Arsenic poisoning can cause skin lesions and cancer.
The reason is that the deltas fill with relatively new sediments only 10,000 years old. These are more likely to release arsenic.
3.5 million people live in these regions.
Ledford 2009 Irrawaddy may be poisoned by arsenic Nature vol 454 pp 263

signalling nutrient entry to cells

Zinzalla and Hall have writen an important review on how cells sense nutrients to control growth. The selection of nutrients between cells whether they be in the brain, muscle or elsewhere is a knowledge desert.
When we eat a meal how does the food get distributed before the eventual cell receives the nutrient.
There is also the distribution of carbohydrate, amino acids and lipids as well as the essential trace elements and vitamins.
It is possible to understand that when the cell requires trace elements or vitamins,the deficit is sent as a message to the cell surface and then the receptor signals needy to the blood and things happen.
How does the cell signal that amino acids or sugars or lipids are needed?
In mammalian cells, nutrients (such as amino acids), growth factors and cellular energy together trigger a molecular signalling pathway, mediated by the protein TOR, that controls cell growth. TOR inhibition by the anticancer drug rapamycin prevents unruly cell growth.
TOR (‘target of rapamycin’) is protein kinase found in two functionally and structurally distinct multiprotein complexes: TORC1 and TORC2. TORC1 controls many cellular processes that ultimately determine cell growth, including protein synthesis, ribosome formation, nutrient transport and autophagy (a survival mechanism that kicks in in response to starvation).
Activation of TORC1 requires simultaneous availability of amino acids, growth factors and energy. Inputs from growth factors (such as insulin) and energy contribute to the determination of that amino acids trigger TORC1 activation. Amino-acid depletion results in rapid dephosphorylation of two molecules downstream of TORC1, S6K and 4E-BP, whereas addition of amino acids leads to rapid, TORC1 -dependent phosphorylation of these molecules. But what is the molecular link between the amino-acid signal and TORCl activation?
Rag GTPases, heterodimers of RagA or RagB and RagC or RagD are involved in TORCl activation in response to this nutrient signal. By binding to TORCl, Rag GTPases mediate its transfer to intracellular membranes that contain another GTPase, Rheb. There, other signals such as cellular energy and growth factors (insulin) integrate with the amino-acid signal, leading to Rheb-mediated activation of TORCl and phosphorylation of its downstream effectors S6K and 4E-BP, which ultimately lead to protein synthesis and cell growth.
An very interesting start to understanding a key elements of nutrition.
Zinzalla and Hall 2008, Linking nutrients to growth. Nature vol 454 pp 287-8