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October 25, 2014

Who wants to live forever?

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'Monkey business: rhesus monkeys Canto (left) and Owen (right) were among the oldest subjects in a 20-year study that found calorie restriction could slow ageing. Canto, 27, was on a restricted diet. Owen, 29, was on a normal diet'

Dr John B Carrigan examines the debate surrounding caloric restriction and looks at some of the potential drugs in development that aim to extend the human lifespan.

Conflicting views have long accompanied the concept and practice of caloric restriction (CR). Is it an anti-ageing elixir that has always existed right beneath our noses? Or is it a dangerous pseudoscience being developed and marketed in a world where we hear seemingly contradictory messages regarding diet and where both obesity and eating disorders are on the rise?

The answer may not be clear cut. While scientific evidence exists that would seem on the surface to suggest that caloric restriction is no pseudoscience, there would also appear to be a shortage of the ‘full story’. There is little doubt that many unsubstantiated claims and potentially serious issues around caloric restriction also exist.

The theory that intentionally depriving the body of the energy it needs may actually be of benefit dates back to 1935. Dr Clive McCay, a nutritionist at Cornell University, discovered that mice that were fed 30 per cent fewer calories lived about 40 per cent longer than their free-grazing laboratory mates. The dieting mice were also more physically active and far less prone to the diseases of advanced age.

Dr McCay’s experiment has been successfully recapitulated in a variety of species — such as fruit flies, roundworms and mice. These studies have concluded that the practice has been shown to switch biochemical pathways on or off, resulting in higher insulin sensitivity, decreased inflammation, enhanced cardiovascular functioning, reduced muscle-wasting with age and improved resistance to cellular stress. In addition to normal ageing being retarded, the incidence of age-related diseases such as diabetes and cancer has been shown to be much more reduced in these studies. The overall result is estimated to be an approximate 30 per cent increase in lifespan.

The practice of caloric restriction was popularised in diet books by Dr Roy Walford, a renowned pathologist at the University of California, Los Angeles, who spent much of the last 30 years of his life following a calorie-restricted regimen. Incidentally, he died of Lou Gehrig’s disease in 2004 at the age of 79. Rather ironically, work recently published has reported that long-term caloric restriction hastens the clinical onset, disease progression and shortened lifespan in the amyotrophic lateral sclerosis (Lou Gehrig’s disease) mouse model.
Weight loss
Largely as a result of Walford’s advocacy, several thousand people are thought to currently adhere to the practice of caloric restriction in the United States, according to Brian M Delaney, President of the Calorie Restriction Society. The Society’s website differentiates CR from regular weight-loss diets: “Weight-loss diets are aimed at shedding excess pounds, either for aesthetic reasons or to avoid the toxic health impacts of obesity. These diets only make sense for people who are overweight.

“The goal of CR is slower ageing and extended lifespan. Weight loss is a side effect. In fact, CR’s anti-ageing effects manifest themselves even in organisms with a ‘healthy’ weight,” it claims. “Increasing exercise, losing weight and keeping calories unchanged is not what CR is about. An exercise regimen that keeps you slim and leaves calorie intake unchanged is not CR, but simply a health programme for weight control to slim down.”

CR practitioners would typically aim to cut their calorie intake from the daily amount recommended by the Federal Drug Administration by about 20-30 per cent, while ensuring that adequate nutrition is maintained.

Dr Walford maintained that a body mass index of below 20 was a good aim. This is the lower end of the normal BMI range, according to traditional guidelines (the International Statistical Classification of Diseases states that the ‘normal’ range is between 18.5 to 25). Supporters of caloric restriction in the scientific world include Dr Luigi Fontana, Director of the Division of Nutrition and Aging at Istituto Superiore di Sanitá (Italian National Institute of Health) in Rome and Research Associate Professor of Medicine at Washington University in St Louis.

He studied members of the CR Society and published a very positive report in Proceedings of the National Academy of Sciences back in 2004, suggesting that most of the metabolic adaptations to CR as mentioned above could clearly be observed and the members had essentially a zero risk of developing stroke or cardiovascular disease.

Furthermore, the best CR animal study ever conducted, involving 20 years of applied CR to our near genetic neighbours, the rhesus monkeys, revealed some headline-grabbing results, not to mention pictures. According to the 2009 study, normally fed monkeys had a 50 per cent survival rate compared to 80 per cent of the CR-treated monkeys, while the appearance of the monkeys was even more astonishing. The non-treated set was reported to look visibly older, even to the untrained eye.

Despite all the positivity surrounding CR, the practice has its detractors while the science behind it also has its shortcomings. Critics point to the current epidemiological data, which does not consistently show that those who are thinnest live longest. Even as recently as two years ago, a long-term study of middle-aged and elderly people by the Tohoku University’s Graduate School of Medicine showed that people who were a little overweight at age 40 lived six-to-seven years longer than very thin people, whose average life expectancy was a good five years shorter than that of obese people.

Canto (left) and Owen

These findings mirrored many earlier results, but in addition, they addressed one controversy that previously held that thin people’s lives were short because many of them were either sick or they smoked. But the difference was almost unchanged, even when these factors were eliminated, as they were in this study. There is also a great suspicion of the unknown, specifically the dangers of what caloric restriction might mean to those at various stages in the life cycle and to those who carry other conditions such as, for example, the condition of Lou Gehrig’s disease, as already mentioned.

The CR Society warns that the diet regimen can also “attract people attracted to the extreme, who may push the limits of safe or healthy CR practice”. It mentions some anecdotal reports of CR-induced psychological disturbances, including anorexia, bingeing, excessive food thoughts and fantasies, although these have not been shown in peer-reviewed publications.
CR theory
There is some science that postulates the ‘how’ of CR treatment. The late American physicist, molecular biologist and behavioural geneticist Seymour Benzer’s laboratory at California Institute of Technology has evidence that modulation of TOR (target of rapamycin) signalling may make all the difference. TOR is a serine/threonine protein kinase (it adds phosphates to other proteins to activate them) that regulates cell growth, proliferation, motility and survival, protein synthesis and transcription in response to nutrient availability. This missing link is partially proposed on the basis that flies with mutations that reduce TOR signalling did not get further benefits by caloric restriction.

Furthermore, in 2009, Richard A Miller of the University of Michigan and co-workers reported that rapamycin (a bacterial natural product), which inhibits the TOR kinase, extends the life span of mice. Experts now believe that when TOR is blocked — whether from genetic mutation, rapamycin treatment or caloric restriction — cells put the brakes on growth by decreasing protein synthesis, ribosome production and amino acid transport.

Simultaneously, the organism becomes more resistant to some forms of stress. Autophagy, or the recycling of damaged cellular components, increases, leading to a fitter, more efficient cell.

While the TOR pathway has garnered much of the attention in recent years, other factors such as the insulin-like growth factor (IGF-1), a hormone similar in molecular structure to insulin (which plays an important role in childhood growth and continues to have anabolic effects in adults) are also involved. Many studies have also shown that it too is attenuated in CR-treated micro-organisms.

Intriguingly, Fontana observed this attenuation in mice but he did not observe it in the CR advocates, with the exception of vegetarians and those on low-protein diets. This raises the possibility that not only caloric restriction but also protein restriction might be important for slowing ageing in humans.
Mimetics
On foot of these studies, its not too surprising that drug development of mimetics is seen as hugely lucrative. CR mimetics are supplements that one could take that would potentially provide some or all of the benefits of CR without the reduction in calories. Currently, several molecules have been considered as CR mimetics but, as of yet, there is no strong evidence that they lead to longevity in humans.

Chief among these is resveratrol. This is by far the most popular purported CR mimetic in the media, despite a lack of conclusive evidence that it actually increases life span in mammals.

There is pretty good evidence that resveratrol can protect laboratory mice from toxicity associated with a high-fat diet, leading to about a 20 per cent increase in lifespan. But, amid the sensation of this report some years back, very few in the media highlighted that it did not provide any benefit to mice on a normal diet.

Positive human trials reportedly do exist courtesy of the work of Sirtris Pharmaceuticals, which created extremely high doses (3–5g) of resveratrol in a proprietary formulation designed to enhance its bioavailability. These have shown such quantities as necessary to significantly lower blood sugar. However, the study itself has never been published in a peer-reviewed scientific publication.

Despite generally being considered safe, there are also some concerns about side effects associated with resveratrol. Derived from red grapes, blueberries and peanuts, this drug can influence the way in which prescription drugs are metabolised. Considering the high percentage of people over 60 taking one form or another of prescription drugs, this is not a good feature to have in any CR mimetic.

There is little doubt that CR remains controversial. The promise of a longer and healthier life, whether from altering our eating patterns or taking a pill, will continue unabated to intrigue and attract us. However, in the midst of our battle to fight obesity and eating disorders through promoting healthy eating and exercise, the radical message of controlled starving is likely to cause huge confusion. There is, of course, also the question of whether a longer life brought about by avoiding steak and peppercream sauce is really worth living.

References available on request.