Amino Acids and Longevity —

Dietary restriction – reduced food intake without malnutrition prolongs life span in yeast, worms, flies, rodents, monkeys and possibly humans.

But dietary restriction also often impairs fecundity, possibly because maintenance of the overall body mass (the non -germline parts of an organism), and thus long life, do not give space for reproductive activity.

Biologists have long thought that an organism’s response to food shortage is an evolutionary device that allows individuals to survive a famine by diverting resources away from reproduction and reallocating them to essential functions for survival

Grandison et al in Nature 2009 report that this idea is almost certainly wrong. They find that dietary amino acids are responsible for shortening lifespan and increasing reproduction in the fruitfly Drosophila mela¬nogaster, but that both longevity and fecundity can be maximized when intake of these nutrients is finely tuned.

It has become clear that rich diets shorten life, not because of excess calories but rather because of dietary imbalance, with lifespan and fecundity being maximized at different nutritional optima, Specific nutrients are implicated in dietary restriction, especially amino acids, Reducing the intake of casein, a major amino-acid source, extends lifespan but decreases fecundity in Drosophila. Similarly, methionine restriction promotes lon¬gevity in flies, rats and mice.

In a series of painstaking experiments, Grandison et al fed female flies a restricted diet that extends lifespan at the expense of fecundity, and then tried to restore the short¬life and high- fecundity characteristics of fully fed flies by adding back specific nutrients. Adding carbohydrates, lipids or vitamins made no difference. But adding amino acids short¬ened lifespan and increased egg production to the level observed under full feeding.

Grandison et al. found that adding all non-essential amino acids only marginally shortened lifespan and did not change fecundity, whereas adding all essential amino acids decreased lifespan and increased egg production as much as combining all aminoacids or full feeding.

Methionine alone increased fecundity as much as full feeding but without reducing lifespan. Methionine together with one or several other essential amino acids is responsible for the life span-shortening effect of full feeding.

The benefits of methionine might be through the IIS-insulin /insulin-like growth factor (IGF) pathway .

If the present results’ in the fly are gener¬ally applicable, even mammals might be able to enjoy a long life without loss of fecundity by virtue of a suitably balanced diet.

Flat 2009 Diet and longevity in the balance Nature vol 462 pp989-990

Grandison et al 2009 Amino acid imbalance explains extension of life span by dietary restriction in Drosophila.Nature vol 462 pp 1061-1064

Bone Density Measurements —

Accurate measurements are critical to any scientific exercise. Bone mineral density monitoring is by dual energy x ray absorptiometry which is costly. A well recognised method. Bisphonate treatment( alendronate ) reduces the risk of fractures, does not relieve pain from existing fractures and may have side effects. A side product of a trail of the effectiveness of bisphonate treatment was an evaluation of dual energy x ray absorptiometry and its ability to show significant change in bone mineral density and predict if any changes in bone mineral density were valuable in predicting fractures.

The results for an individual over time were so variable and the results did not allow prediction of fracture risk.

Another variable is that compliance with treatment is not god.

Bell et al 2009 Value of routine monitoring of bone mineral density after starting bisphonate treatment : secondary analysis of trail data. BMJ vol 338 1553

Compston 2009 Monitoring bone mineral density during antiresorptive treatment for osteoporosisisBMJ vol 338 1511-1513

Bone Formation —

Bone modelling and remodelling are the final common pathways expressing all genetic and environmental factors affecting the attainment, maintenance, and decay of bone’s material and structural strength.’ During growth, this cellular machinery assembles the size, shape, and architecture of bone by depositing and removing material from the outer (periosteal) surface and the three (endocortical, intracortical, and trabecular) components of the inner (endosteal) surface

At completion of growth, periosteal apposition slows and remodelling of the three inner surfaces maintains bone strength by removing and replacing old or damaged bone with an identical volume of new bone. Around midlife, remodelling becomes unbalanced so that every time bone matrix is remodelled, whether initiated for damage repair or adaptation to loading, more bone is removed than is replaced by cells of the basic multicellular unit, producing one loss and structural decay. Although this negative balance of a few percent can worsen as age advances, the driving force producing bone loss and structural decay is the remodelling intensity, the birth rate of the many new basic multicellular units arising on these surfaces after menopause in women and in both sexes late in life.

The amount of bone loss and structural decay also relies on accessibility of the bone matrix to remodelling. This accessibility depends in part oft how a volume of bone is designed in space. Remodelling is initiated on a bone surface. A volume of bone with a large exposed surface will be remodelled rapidly by the large number of basic multicellular units that can access and erode bone matrix beneath the surface. A volume of trabecular or spongy bone has a larger surface than does an equal volume of cortical or compact bone and is thus exposed to more remodelling and is lost more rapidly than is cortical bone. For this reason, trabecular bone loss and fractures of the vertebral body, which is a structure containing large amounts of trabecular bone, have dominated thinking and research into the structural basis of bone fragility for almost 70 years.”

Which neglects the role of decay of cortical bone in pathogenesis of bone fragility, which is an omission that is difficult to reconcile with the epidemiology of fractures. About 80% of all fractures in old age are non-vertebral, arise at sites that are mainly cortical, and occur after age 60 years when the rate of trabecular bone loss decelerates.” Moreover, only 20% of bone is trabecular-80% is cortical.

Zebaze et al 2010 Intracortical remodelling and porosity. in the distal radius and post-mortem femurs of women: a cross-sectional study . The Lancet vol 375 pp 1729-1736

Bone Formation —

Atfi and Baron( 2010) PTH battles TGF-ß in bone Nature Cell Biology 12, 205 – 207 (2010)

Bone remodelling in vertebrates is coordinately regulated by the opposing effects of parathyroid hormone (PTH) and transforming growth factor-beta (TGF-ß). PTH couples the processes of bone resorption and formation by enforcing simultaneous internalization of TGF-ß type II receptor (TßRII) and PTH type 1 receptor (PTH1R), which attenuates both TGF-ß and PTH signalling in vivo.

Skeletal development and homeostasis are regulated by a signaling network that balances bone formation by osteoblasts with bone resorption by osteoclasts1. Perturbations of this network are associated with skeletal disorders such as osteoporosis, and an inherent risk of fracture and associated morbidity and mortality

Bone Health —

Bailey and Brook-Wavell have written an interesting review on exercise and bone mineral density in the Proceedings of the Nutrition Society.

Physical activity is a major physiological method for increasing and maintaining bone mineral density and geometry. With an important role in maintaining peak bone mass and strength, and reducing the risk of future osteoporotic fracture. However, not all exercise is effective, so a prescription in terms of optimal type, intensity, frequency and duration is required.

Studies using animal models suggest that loading that is high in magnitude, rapidly applied and novel is most effective, whilst duration is less important beyond a threshold number of cycles.

In human subjects cross-sectional studies comparing different athletic populations suggest that those who participate in high or odd-impact sports have higher bone mineral density; whilst impact exercise, strength training and brief high-impact-jump training interventions increase bone mineral density in pre-menopausal women. Brief hopping exercises were shown to be feasible for sedentary pre-menopausal women, producing ground-reaction forces as high as those from jumping. Regularly performing these hopping exercises over 6 months was found to increase femoral-neck bone mineral density of the trained leg relative to the control leg. women.

Bailey and Brook-Wavell 2008 Exercise for optimising peak bone mass in women Proceedings of the Nutrition Society vol 67, pp9-18

Bones and Vegetarianism —

A diet that is outside the accepted norm may raise concerns for its adequacy in terms of nutrients and whether or not this diet has inbuilt deficiencies

The vegetarian diet is one such concern. The Oxford cohort of the European Prospective Investigation into Cancer and Nutrition ( EPIC-Oxford ) conducted a survey of vegetarians and non vegetarians in Oxford for bone fracture.

They studied vegetarians, vegans, meat eaters and fish eaters for self reported bone fractures. Spontaneous bone fractures are a rough and ready estimate of bone fragility eg osteoporosis.

The conclusion is that there is no difference in fracture rate between vegetarians, meat eaters and fish eaters but is very slightly greater for vegan.

At the end of the day the conclusion was that the differences was that calcium intake rather than the prime strategy of the diet mattered.

Appleby et al (2007) Comparative fracture risk in vegetarians and non-vegetarians in EPIC-Oxford. European Journal of Clinical Nutrition vol 62, 1400-1406

Ethnicity and UK children’s diet —

In the UK, South Asian adults have increased risks of CHD, type 2 diabetes and central obesity. Black African-Caribbeans, in contrast, have increased risks of type 2 diabetes and general obesity but lower CHD risk. There is growing evidence that the risk differences emerge in early life and that nutritional factors may be important. This study looks at the variations in nutritional composition of the diets of South Asian, black African-Caribbean and white European children, using 24h recalls of dietary intake collected during a cross-sectional survey of cardiovascular health in eighty-five primary schools in London, Birmingham and Leicester.

In all, 2209 children aged 9-10 years took part, including 558 of South Asian, 560 of black African-Caribbean and 543 of white European ethnicity. Compared with white Europeans, South Asian children reported higher mean total energy intake; their intake of total fat, polyunsaturated fat and protein (both absolute and as proportions of total energy intake) were higher and their intakes of carbohydrate as a proportion of energy (particularly sugars), vitamin C and D, Ca and haem Fe were lower.

These differences were especially marked for Bangladeshi children. Black African-Caribbean children had lower intakes of total and saturated fat (both absolute and as proportions of energy intake), Dietary Fibre , vitamin D and Ca. The lower total and saturated at intakes were particularly marked among black African children. Appreciable ethnic differences exist in the nutritional composition of children’s diets, which may contribute to future differences in chronic disease risk.

Donin et al 2010 Nutritional composition of the diets of South Asian, black African-Caribbean and white European children in the United Kingdom: The Child Heart and Health Study in England (CHASE) British J Nutrition vol 104 276-285

Genistein and Bone Mineral Density —

A reduction of bone mineral density of less than 0.795g/cm3 is called osteopenia and is associated with increased spontaneous bone facture. This is found more frequently in post menopausal women.

The phytoestrogen genistein has been shown to significantly increase bone density in a trial reported in the BMJ 2007, vol 335, p 299 from the original paper ( Marini et al Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women : a randomised trial Ann Intern Med 2007; 146: 839-47).

The women in the trial took 54 mg of genistein each day, 20% withdrew because of gastrointestinal effects ( constipation and dyspepsia ) .

Bone metabolism improved in the women who took the genistein and bone mineral density improved by at least 20%.

Another example of the role that plant secondary metabolites can have in humans. However it would be better to find a low dose primary nutritional source eaten over a life time than a larger dose with unknown as yet potential complications ( maybe , maybe not)

Longevity —

The process of ageing and longevity may be controlled biologically by specific alterations in chromatin state. The link between chromatin and ageing has mostly focused on histone deacetylation by the Sir2 family, but less is known about the role of other histone modifications in longevity.

Histone methylation has a crucial role in development and in maintaining stem cell pluri¬potency in mammals.

In this paper Greer et al identify the ASH-2 trithorax complex, which trirnethylates histone H3 at lysine 4 (H3K4), as a regulator of lifespan in Caenorhabditis elegans in a directed RNA interference (RNAi) screen in fertile worms.

Deficiencies in members of the ASH-2 complex-ASH-2 itself, WDR-5 and the H3K4 methyltransferase SET-2–extend worm lifespan.

Conversely, the H3K4 demethylase RBR-2 is required for normallifespan, consistent with the idea that an excess ofH3K 4 trimethylation-a mark associated with active chromatin¬is detrimental for longevity.

Lifespan extension induced by ASH-2 complex deficiency requires the presence of an intact adult germline and the continuous production of mature eggs. ASH-2 and RBR-2 act in the germline, at least in part, to regulate lifespan and to control a set of genes involved in lifespan determination.

These results indicate that the longevity is regulated by an H3K4 methyltransferase/demethylase complex acting in the C. elegans germline.

Greer et al ( 2010 ) Members of the H3K4 trimethylation complex regulate llfespan in a germ line-dependent manner in C. elegans Nature vol 466 pp 383-387

Memory and female shape —

A woman’s body shape may influence how good her memory is, according to US researchers. Although carrying excess weight anywhere appears to impair older women’s brains, carrying it on the hips may make matters worse.

The Northwestern Medicine team found “apple-shaped” women fared better than “pears” on cognitive tests. But depositing fat around the waist increases the risk of cancer, diabetes and heart disease, experts warn. They said the findings, in the Journal of the American Geriatrics Society, highlighted the importance of maintaining a healthy weight for both body and mind. Some of the health risks associated with obesity, such as vascular disease and inflammation, may explain why people who are overweight appear to be at higher risk of dementia.

The study involved 8,745 post-menopausal women aged 65 to 79. These women were asked to complete a memory test that doctors use to judge brain function. They were also weighed and their BMI calculated. BMI. Over two-thirds of the women were overweight or obese.

The researchers found that for every one point increase in a woman’s BMI, her memory score dropped by one point. And pear-shaped women – those with smaller waists but bigger hips – scored particularly poorly.
The researchers say this is likely to be related to the type of fat deposited around the hips versus the waist. Different kinds of fat may release different hormones and have varying effects on insulin resistance, lipids and blood pressure.

BBC web site

Osteoporosis and Polyphenols —

In Nutrition Research Review 2007 , 20, 89-105, T. P. al write on Bone mineral density, polyphenols and caffeine: a reassessment

In an ageing society, the maintenance of good bone health with age is important. In osteoporosis, bone becomes increasingly porous, resulting in both greater chance and severity of bone fracture at the hip. spine, forearm and shoulder. Bone fractures result in reduced mobility, discomfort and a higher risk of early mortality. Osteoporosis can cost the UK over £1-7 billion for the treatment of hip fracture.

Elderly women are at risk from osteoporosis, because they can lose between 10 and 15 % of their bone every decade after the menopause. Women lend to have lower peak bone mass than men, and that levels of oestrogen (a hormone with a positive effect on bone health) are decreased during and after menopause and tend to live longer than men.

Bone tissue is in a constant state of flux. The skeleton has obvious mechanical roles and is also a Calcium depository for the rest of the body, with calcium being removed and replaced as required. The state of bone flux within an individual can be described in terms of bone mineral density. Bone metabolism is controlled by a variety of growth hormones, sex steroid hormones (such as oestrogens), thyroxine. corticosteroids and insulin. Three hormones play vital roles, 1.25-dihydroxycholecalciferol. parathyroid hormone and calcitonin. As well as affecting dietary calcium adsorption efficiencies, these hormones also influence the three cell types relevant to bone formation and metabolism osteoblasts (hone formation), osteocytes (bone maintenance) and osteoclast (bone resorption). The balance between the formation and resorption of bone tissue is affected by genetic and environmental (for example, diet and lifestyle) factors.

Several studies have shown benefit from drinking tea and bone mineral density and fracture risk. This could be due to the fluoride and polyphenol components of tea. Caffeine consumption has been seen as a potential risk factor for low bone mass density and high fracture risk.

Fruit and vegetable intake which includes increased polyphenols intake may also contribute positively to bone health.

In this review the evidence surrounding the function(s) of poly phenol-rich foods in bone health is examined, along with more recent studies challenging the relevance of caffeine consumption to in vivo Ca balance. Plant foods rich in polyphenols such as tea. fruit and vegetables, as significant factors in a healthy diet and lifestyle, may have positive rules in bone health, and the negative role of caffeine may have been overestimated.

Osteoporosis —

Osteoporosis is a progressive disabling bone condition where the bones soften as a result of bone resorption exceeding bone formation. Tang et al in a careful review of the prescription of calcium and vitamin D concluded that calcium ( 1200 mg / day ) or calcium plus 800 iu of vitamin D in addition to the calcium significantly and beneficially decreased bone loss and decreased fractures.

Notes of caution.

Many people fail to last the course of treatment and it is essential to take this supplement for years

It is better to start aged between 50-70 than older.

Be careful of too much calcium , we are talking of grammes per day can lead to hypercalcaemia, the milk alkali syndrome. Rare but exists. ( Kaklamanos and Perros 2007 Milk alkali syndrome without the milk , BMJ vol 335 397-8

(Tang et al 2007 Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta analysis Lancet vol 370 pp 657-66 and comment Reginster J-Y 2007, Calcium and vitamin D for osteoporotic fracture risk Lancet vol 370, 632-3)

Sirtuin and Ageing —

Sirtuins are members of a class of enzyme, deacetylases which remove acetyl groups from proteins. Sirtuin activators increase yeast life span by 70%.

It is possible but not absolute that a compound resveratrol may activate sirtuins. A possible mechanism for the putative activity of resveratrol is similar to caloric restriction.

It is rumoured that resveratrol is the component f red wine that has health benefits.

Ledford 2010 Much ado about ageing Nature 464 pp 481-2

Vitamin D and Osteoporosis —

Fractures due to with falls is an important cause of morbidity and mortality in elderly people. Some 30% of active old people aged over 65 years and 50% of those cared for in institutions fall each year. Ninety percent of hip fractures in the elderly happen during falls and about 5% of the elderly population suffers a fall related fracture each year. This vulnerability is increased by osteoporosis which also increases with advancing age. Osteoporosis primarily affects postmenopausal women, due to the decline in bone mass and changes in bone architecture with oestrogen deficiency

Osteoporosis is an under-diagnosed and under-treated condition. In American women less than 15% of American women with osteoporosis receive treatment. Most high-risk patients, e.g. after a hip fracture, are not treated for their osteoporosis; As the population ages, osteoporosis will become more prevalent with attendant costs of preventing and treating the disease rising

Effective methods of reducing or preventing falls and fractures in older people are needed, and vitamin D supplementation is highly recommended as a standard preventative measure in osteoporosis management. Vitamin D is essential for the maintenance of calcium homeostasis. It is synthesized in the skin after exposure to sunlight, and is also obtained through the diet. Vitamin D inadequacy is common in elderly people, particularly in countries where it is not commonly added to food.

Serum 2 5-hydroxy vitamin D (25(OH)D), reflects vitamin D status, and levels

However, the independent effect of vitamin D is less well understood for osteoporosis or for falls. A study by Jackson et al QJM 2007, vol 100 pp 185-192 used a meta-analysis to evaluate how supplementation with vitamin D alone affects the risk of falling, and sustaining vertebral and non-vertebral fractures, primarily in postmenopausal women. All had reduced 25(OH)D serum concentrations and subsequently received 300 to 800 IU each day.

There is some benefit from taking vitamin D3 supplements in reducing the incidence of falls which must be reflected in reduced harm to these older individuals.

Jackson et al QJM 2007, vol 100 pp 185-192

Vitamin D Status —

This paper Andersen et al ( 2008 ) Pakistani immigrant children and adults in Denmark have severely low vitamin D status Eur J Clin Nutr 62: 625-634

is an important paper in that here is further underlining of th need to monitor the health of immigrants. Especially in this case where the climate is so different to the country of origin. Further more the immigrants may congregate in Cities , live indoors and avoid sun life. The mal effects of sun light deprivation and reduced vitamin D levels are profound.

Vitamin D in the Elderly —

This is a good review by Oudshoorn et al on the important subject of vitamin D in the elderly.

Vitamin D is a pleiotropic hormone. Besides the effects on classical tissues like bone and intestine, vitamin D has an effect on many more tissues. Effects of vitamin D metabolites can occur via endocrine, paracrine or autocrine mechanisms.

Ageing increases the risk of vitamin D deficiency and is associated with vitamin D resistance and less efficient intestinal Ca absorption and renal reabsorption. Vitamin D supplementation doses needed to treat vitamin D deficiency and secondary hyperparathyroidism vary considerably between individuals. This makes it necessary for clinicians to give tailored advice to patients when treating hypovitamino¬sis D, taking into account these age-related effects and other characteristics that influence vitamin D status and Ca homeo¬stasis.

In general, mobile, Caucasian community-dwelling elderly, who have a varied diet, need vitamin D supplementation of 10-20 µg (400 IU – 800 IU ) /d to reach serum vitamin D levels of 50-75 nmol/l. Frail or institutionalised elderly on the other hand are suggested to need up to 50 ug (2000 IU)/). The effectiveness of this high-dose vitamin D supplementation in raising serum 250HD3 levels adequately has been demonstrated in several clinical trials. However, good evidence for the optimal dose of vitamin D supplementation in specific high-risk groups is still lacking.

Oral supplementation is the most effective intervention to treat vitamin D deficiency. Ergocalciferol is equally as effec¬tive as cholecalciferol in raising serum 250HD3 levels. Daily dosing is the most efficient interval to raise serum 250HD3 concentrations when compared with weekly or monthly administration.

Although vitamin D supplementation therapy is generally regarded as safe, cases of iatrogenic and accidental overdose with cholecalciferol have been reported. . Most safety data concerning the use of high-dose cholecalciferol sup¬plementation come from observations in relatively young indi¬viduals. Few studies have used high-dose cholecalciferol supplementation for longer periods in frail, older patients. Frail old people, particularly the institutionalised, often have poor daily fluid intake, use diuretics and have less thirst sensation than younger persons.

All clinicians who frequently treat older patients should take a proactive approach to screening at-risk individuals for vitamin D deficiency, as this condition is still very prevalent. When treating patients for vitamin D deficiency, Ca intake should be assessed. Possible unwanted effects of long-term vitamin D supplementation and the effects of hypervitaminosis D should be studied in forthcoming trials.

Oudshoorn et al Ageing and vitamin D deficiency : effects on calcium homeostasis and consideration or vitamin D supplementation .

Zoledronic Acid and Osteoporosis —

This is strictly not nutrition but the concepts are very relevant to nutrition and important slowly evolving disease conditions.

Black et al looked at the use of Once yearly infusions of zoledronic acid for the treatment of postmenopansal osteoporosis. N Engl Med. 2007:356:1809-22

Oral bisphosphonates help prevent fractures in postmenopausal women, but they can be inconvenient to take and many women stop their treatment. These authors wanted to test whether a more convenient yearly infusion of intravenous zoledronic acid would also reduce the risk of fractures.

7765 postmenopausal women with osteoporosis took part in a randomised, double blind trial, sponsored by the manufacturers of zoledronic acid. Participants were given three infusions of zoledronic acid (5 mg) or a placebo at yearly intervals. They were followed up for 12 months after their last infusion. The authors looked for vertebral fractures in yearly spinal radiographs. Other fractures, including hip, were reported by participants and confirmed by radiographs. The authors monitored participant’s bone mineral density using dual energy x ray absorptiometry and used serum markers to monitor bone turnover.

Zoledronic acid is a third-generation bisphosphonate. .Analogues of pyrophosphate. the bisphosphonates bind to calcium hvdroxyapatite in the skeleton blocking calcium release. They inhibit osteoclast formation and osteoblast proliferation and induce osteoclast apoptosis. These agents also block skeletal calcium release induced by various factors released by tumours Both zoledronic acid and pamidronatc have been shown to have direct anti tumour effects in vitro, Zoledronic acid induces cell apoptosis and inhibits proliferation in human breast, prostate. and myeloma cell lines. ( Dunham D Journal of Pharmacy Society of Wisconsin Jan/Feb 2003, – 9-13)

3.3% (92/2822) of the women given zoledronic acid had a vertebral fracture, a reduction of 70% compared with the 10.9% (310/2853) of those given placebo Zoledronic acid also significantly reduced the risk of hip fracture (1.4% v 2.5%, ), all non-vertebral fractures, all clinical fractures, and clinical vertebral fractures. It also significantly increased women’s bone mineral density at the hip, lumbar spine, and femoral neck compared with placebo (by 6%, 6.7%, and 5.1%) and reduced bone turnover.

The down side is that an infusion of zoledronic acid was associated with a higher incidence of fever, myalgia, flu-like symptoms, headache, and arthralgia. It was also associated with a higher risk of serious atrial fibrillation (5% v 1.3%,), but no long term renal toxicity. One woman in each group developed osteonecrosis of the jaw, a rare side effect of intravenous bisphosphonates given in high doses to patients with cancer.

A single yearly infusion of 5 mg zoledronic acid helped prevent important osteoporotic fractures in this vulnerable population of postmenopausal women. The excess of atrial fibrillation is a worry and needs further investigation. Some women might find a yearly infusion easier and more convenient than regular oral drugs, and it’s possible the two routes are equally effective.

Reported in the BMJ 7th July 2007 p 36

It seems extraordinary that an annual infusion at a dose of 5 mg can have such a sustained effect.


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