Calorie restriction for longevity ~ For mice, not man

Work in any field long enough and you get a “nose” for the job. It is an instinctive reaction to some new event or idea, built on decades of the passive accumulation of knowledge in ones chosen field. I’ve acquired such a nose an did so quite early on. Instinctively, I could spot a good, original and potentially new area of interest among a forest of dross. Equally, I could sniff a no-hoper, a line of research rapidly going nowhere. I first heard a lecture on calorie restriction over 15 years ago, appropriately at a hotel affiliated to the Orlando Disney Park. Rats, whose energy intake was restricted to 15 - 25% of caloric intake, lived longer than rats given as much as they liked to eat of standard rat chow. I neither like nor dislike rats but it remains that I really have no feelings for them of any substance. The fact that the caloric restriction made them live longer was really of no interest to me, other than to wonder how rats feel about longevity in a captive and restricted, if not slave-like existence. However, translating this to humans really made me titter. We live in an extraordinarily obesogenic environment with overweight and obesity abounding and growing in prevalence to every corner of the globe and with quack diets and trash books for every desirable attribute, including weight loss and aging, dominating the mass media. So, it appears from the rat handlers, that  we are to think about adding caloric restriction as an additional string to our public health nutrition bow to beat the grim reaper and steal a few more mortal years. As one of my teachers used to say in exasperation in class at daft responses: “Ye gods and little fishes.”

The effect of caloric restriction on longevity was first reported in 1935 and has now been studied in yeast, worms, flies and rodents and a 15-15% restriction in energy intake in the latter can increase longevity by up to 60%. Such is the wealth of data on these  diverse species that one must accept the literature that caloric restriction prolongs life expectancy. The big question is the translation of that concept to man. Relative to these species, we mature far more slowly and have a longer life span. People often talk about human equivalents of “dog years” but in absolute terms, we outlive dogs by at least 8 fold.

The Calorie Restriction Society^[1] boasts 7,000 members. One such member is described in a journalistic piece on the web site. This member is 48 years old, is fit as a fiddle, weighs 118 pounds which is 7 pounds less than the minimum recommended for his height, he confines his energy intake to 1,500 calories a day and although his energy expenditure is not described, he would appear to be very physically active. He first got interested in caloric restriction as a tool to longevity when he was faced with his first manifestation of aging, a receding hairline. Poor guy!!!

The whole are of calorie restriction took a hit recently when the National Institute on Aging published its long term study of energy restriction on longevity in rhesus monkeys, a species far closer to man than yeast, flies, worms and mice^[2].   A 20 year study examined the effects of caloric restriction introduced to rhesus monkeys at varying stages of life. No statistically significant differences were observed between control monkeys fed ad libitum and those calorie-restricted (10-40% restriction). The latter did achieve a longer life span than would normally be expected for this species but the authors point out that they lived a privileged life of good husbandry and veterinary care. The main causes of death did not differ between the two groups:cancer, cardiovascular disease and general organ deterioration. However, generally recognised beneficial biomarkers of health increased in the caloric restricted monkeys but this did not translate into a longer life. In fairness to the literature, another colony of monkeys elsewhere (different diet, management and breeds)  did respond but in the world of science, it only takes one black swan to demolish a theory. The recent Nature paper is that black swan.

From a practical point of view, I can see a few dedicated enthusiasts sharing the necessary skills via social networks to achieve successful caloric restriction but I fail to see how it would be dealt with the great majority of the people. Leaving aside the ever-present obesogenic food supply, how is the average person to know exactly what their energy requirements are and then how to pare that down by 20% or more of that to achieve the required level of calorie restriction? How, especially with increasing age, do we ensure that caloric restriction does not drift into malnutrition which in the older population is so strongly associated with increased admission to hospitals, increased complications hen there, longer stays and more frequent re-admissions. Professor James Hill of the University of Colorado in his excellent book “The Step Diet” ^[3], recommends 25,000 steps per day plus rejection of 25% of the food served at every meal, just to maintain weight loss. For the many fatties among us, moi included, there is (a) the need to shed pounds to an appropriate avoirdupois a la James Hill and (b) having done so, to then hit a 25% calories restriction.

It ain’t going to happen. My nose was right!

Finally, apologies for the late post of this blog but that happens. Also next two mondays are in Asia and a lot of teaching at China Agricultural University in Beijing and Honk Kong University so I’ ll try but please be understanding!

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^[1] http://www.crsociety.org/

^[2] Mattison JA et al (2012) Nature, 489 (7415), 318-321

^[3] http://tinyurl.com/9pbpbh3

Genes, memes and obesity

I have blogged several times about the uniqueness of obesity to the human race. Notwithstanding the fact that we share 98% of our genes with our nearest biological relatives, the chimpanzees, we alone get fat. It therefore follows that our obesity has origins in the basic biology of energy metabolism and storage but that it also has origins in the society we have constructed. For hard-nosed reductionist biologists, sniffing around the causes of obesity outside the laboratory is most unattractive because it brings us into the world of psychology, of human behaviour and of social organisation and these are all seen as “soft sciences”. If this view persists, then the so-called ‘hard sciences” of genetics and its associated disciplines, will wane in importance. Consider the brouhaha that greeted the discovery of cafeteria feeding of rats to induce obesity, the discovery of genetically obese rodent models, the incredible discovery of the appetite regulating plasma protein leptin and now, the flavour of the month, the gut microbiota. All have hit the front covers of Nature and Science and all have been the flavour of the months at key scientific conferences. But when all of these are added up, the best they can do is explain bits and pieces of the “how” of obesity. They cannot some of the “why” such as genetic predisposition but they cannot explain the “why” of individual obesity and overweight.

What makes humans so different from other species is that we alone have mastered the ability to learn from one another by imitation. This imitation can be vertical such as what we learn from our parents. It can be horizontal such as what we see others doing. Of course, we actually don’t have to see others doing something to imitate it. A third party can describe what he or she saw and we can have a shot at it, maybe getting it right first time, maybe having to go back for another look at the person who has mastered this act and eventually, we will be able to do it. These acts of imitation spread through society at a rate vastly greater than that of natural selection of genetic potential. To the biological scientist, this is interesting but seriously wooly. It is poorly defined, poorly characterised, impossible to measure and impossible to attribute origins of imitated acts.

In 1976, Richard Dawkins wrote a book which to this day remains a best seller entitled the ‘Selfish Gene’. Dawkins did not mean that there was a gene for selfishness but rather that all genes were utterly selfish in competing with other genes to be included in the blue print of the next generation, the one after that and so on. The human body is the vehicle and the gene is the “replicator”. But Dawkins stepped boldly out of biology in coining the term ‘meme” to explain the basic unit that is involved in the vertical and horizontal transmission of human knowledge. The exact quote is thus: “ We need a name for a new replicator, a noun that conveys the idea of a unit of cultural transmission, or a unit of imitation. ‘Mimeme’ comes from a suitable Greek root, but I want  a monosyllable that sounds a bit like ‘gene’. I hope my classicist friends will forgive me if I abbreviate mimeme to meme^[1]”.

A meme is any concept or idea that is replicated by imitation. It can be verbal (rote, word-of-mouth, sung or chanted), written (prose, verse or music) and it can be an action (the Maori Haka, the handshake, the Christian blessing). The private thoughts and fantasies you have lying in bed or day dreaming on the bus to work are not memes since there is no expectation of transmission to others. Dawkins saw memes as being identical to genes in their characteristics with the three prerequisites of the latter: replication, variation and selection. Memes compete with one another for retention within our brains and there are far more meme than there is storage space in our brains  for them so the memes that win out to to be transmitted  vertically are no different from the genes that win out for retention in the next generation.

The development of obesity is a passive event over time since nobody really sets out to gain weight. But once we gain weight, we access memes that are implanted in our brains: “Fat isn’t pretty”; “Being fat is bad for health”. But when it comes down to the decision to “do something”, what is the behaviour we imitate? For some, especially among young professionals, the imitated behaviour fights the passive gain in weight, a life-time commitment of watching and weighing, of eating carefully and of exercising diligently. This behaviour is also true for some who lost weight and who want to imitate that behaviour that retains weight loss. For others, and it is a fact of life that it is the majority, the imitated behaviour is to do nothing. The meme to do something about overweight has to compete with memes that govern other activities in daily life and the modeled meme is one of the status quo. Fat people don’t die on the streets. They grow old. They are no sadder and no happier, no poorer and no richer and no more loved or feared than lean people.

The future of cell biology will reside in the cell since the latter is the raison d'être of cell biology. Human obesity can be studied by the geneticists and the memeticists on different planets as is presently the case. Those who bring these disciplines together will be the future. Memes are neither angels nor demons, which flit around some unique ethereal space entering our head for good or bad. Memes are ultimately connected to a neuronal network in the brain, unique to that meme. Thus they do have a biological base but not a genetic base. The biological base must connect to the phenotype. I wish I could sing like the late Luciano Pavarotti or swing my golf club like Tiger woods but I cant. Why not? I can cut the grass and I’m good at figuring out complex scientific concepts and at designing experiments to test these theories. Why so? Is our phenotype where our genotype meets our ‘memotype’? Complex questions indeed but valid complex questions.

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^[1] For those of you who would like a quick tour of memes, try the review by McNamara in Frontiers of Evolutionary Neuroscience May 2011 (volume 3): “Can we measure memes”. For a truly fantastic introduction to memes, buy Susan Blackmore’s book “the Meme Machine”, Oxford University Press.

Media reporting of food related health claims

In 2009, the World Cancer Research Fund (WCRF)^[1] conducted a survey of 2,400 UK subjects to ascertain their views as to the evidence linking diet and physical activity to cancer. WCRF argue that the advice linking diet and physical activity to cancer is both robust and relatively unchanged in the last decade. However, what they found was that in the 55+ group, 60% felt that scientists were always changing their mind and that 30% thought that the best advice was to avoid health advice and eat what you want. The figure for the sample as a whole were marginally lower. A group of London scientists decided to follow this up with a survey of material appearing in the UK press in one week covering food and health and to examine this the media representation to determine the accuracy or otherwise of the coverage. Their paper was published in the journal “Public Understanding of Science”^[2].The lead authors were Professor Tom Sanders, a world authority on diet and cardiovascular function and Dr Ben Goldacre, best known for his book “Bad Science”, but he is also a research fellow at the London School of Hygiene and tropical medicine. They were joined by Ben Cooper a medical student and William Lee an MRC Training Fellow in Psychiatry.

Overall, the top 10 best selling newspapers in the UK are read daily by about 10 million people so print media has a very big audience. The study was carried out in the first week of November and the focus was on articles that recorded an actual health claim to a food in some way. Stories about GM or about waste or other issues were excluded - the story had to involve a health claim as defined by the European Food Standards Agency. A total of 111 such stories were reported in the week. The next stage was to subject the reported new story to two grading systems specifically designed to grade scientific evidence. The first of these is called the Scottish Intercollegiate Guidelines Network (SIGN)^[3] and that of the WCRF. As the authors point out, each might have its flaws but “..taken together, these tools represent robust and widely recognised measures of relative evidence of quality”.

I have averaged the scores of the two grading systems since they were generally similar. The single most important figure was that only 10% fell into the category “convincing”. All the rest fell into shades of doubt such as 15% “probable and 7% “possible” or 4% “unclassifiable”. By far the biggest figure of 64% is for “insufficient” evidence. In effect the general take home message is that 1 in 10 media stories involving linking some aspect of diet to health is true. For two thirds, the evidence is non-existent and the rest fall in between. Where does the blame lie?

 Journalists rely quite a lot on press releases and the nature of press releases is that the releasing body, be it a company, an NGO, a university or a trade organisation want the media to take up the press release. Ideally, the journalist should use the press release as the starting point to make contact with the researcher and to develop the story from there. But quite often, it is the press release alone which makes it to the print edition. One of the main culprits in this communication change in my view are university communications units. They are constantly looking for press coverage in an ever increasing academic environment and they have a captive audience of academics who enjoy their moment of glory in the media. 

I would go further back in the communication chain to the actual research process and bemoan the growth and dominance of unchallenged data on food and health. Fine, I understand that certain associations between diet and health are not readily amenable to testing in intervention studies. But these are few and far between. What is exasperating is the rush to publicise the relationship observed between serum whatever and some wonderful health attribute in some cross sectional study without any direct evidence from human intervention studies that the relationship stands up to this test. One area which is without doubt the most culpable these days is the great news that “scientists have discovered a link between some nutrient intake profile, a relevant common genetic variation and some disease”. These triangular links of diet, phenotype and disease (e.g. the gene for some lipoprotein, high blood cholesterol and olive oil intake) are ten-a-penny and each worth more or less nothing without some verification with an intervention study. So rapid is the expansion of this unholy triangle that the funding to establish an intervention study is never likely to be extensive. Which of the putative claims do you spend your money on?

An exception is the work done by scientists at the University of Ulster and Trinity College Dublin who showed that if low riboflavin status was corrected in persons on medication for hypertension, those with a common (ca 30%) genetic variation showed a dramatic reduction in blood pressure^[4]. So they set out to recruit equal numbers of the three genetic classes (the less common genetic variation being absent or inherited from one parent or both) and they carried out an intervention study (riboflavin supplement versus placebo) which proved that those with the less common genetic variation responded very positively with dramatically reduced blood pressure. They went back then four years later and those that had been randomized to the placebo were now given the riboflavin and vice versa and again they proved the association. This is darn hard work but it is what is needed to take an “association” to a “verification”. Sadly, the moment of glory in the media seems to satisfy most scientists and most universities. It is easy to be critical of journalists for not following press releases in more depth getting a second and their opinion but those in glass houses......

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^[1] http:www.wcrf-uk.org/audience/media/press_release.php?recid=63

^[2] Cooper BEJ et al (2011) The quality of the evidence for dietary advice given in UK national newspapers. Public Understanding of Science, May, 1-10

^[3] http://www.sign.ac.uk

^[4] Wilson et al (2012) Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up. Am J Clin Nutr.  Mar; 95(3):766-72. Epub 2012 Jan 25.