Calorie restriction
In the 1930s, biologists conducted calorie restriction (CR) experiments on mice, reducing their food intake by 30%, but leaving the nutrient composition unchanged. The experimental mice were much healthier, living 50% longer on average, increasing lifespan from two to three years, and showing no signs of the diseases that normally plague old mice.
There were other differences, CR mice were smaller than their control counterparts, with fewer offspring, and possibly distressed by their constant hunger. Puzzled by this mysterious increase in longevity, scientists tried but failed to reach any definite conclusions until the advent of a theory of aging that could properly account for it and the advent of gene technology that could confirm it.
In 1977, Tom Kirkwood published his disposable soma theory of species lifespan, an evolutionary theory of longevity, positing that species lifespan is crafted by natural selection, with lifespan depending centrally on the link between soma and germ-line. Soma is the physical body of the organism, configured in turn by its genes - its germ-line. According to Kirkwood, any organism has two primary biological tasks: ensuring the survival of the soma by consuming energy from its environment, and ensuring the survival of the germ-line by reproduction. The survival of the germ-line is dependent on the survival of the soma, but once the germ-line has been passed on via offspring the soma is disposable, the organism is redundant and can be allowed to die.
This theory runs counter to the popular view, with many believing that we inevitably age and die to make room for the next generation, to avoid being a burden, to avoid competition for resources, or possibly to avoid new forms of music. Not so, says Tom Kirkwood, we age and die because our lifespans have evolved that way, in evolutionary terms there is nothing inevitable about aging and death.
According to Kirkwood, indefinite healthy longevity can be achieved – some animals such as the hydra for example are biologically immortal. But longevity is very expensive, demanding continuous error free, protein replication, consuming significant amounts of energy. Therefore, it makes no sense to invest in potential longevity when it’s not needed, if it involves producing expensive potential lifespans that cannot be realised in the wild because of accidents or predators. An organism faces many challenges to its mortality – disease, accidents, predators and famines, very few organisms die of old age in the wild. Consequently an organism’s longevity will be governed by the time needed to reach maturity and the period needed for reproduction; beyond that it’s not expected to survive natural predation and deprivation in any event. So repairs and maintenance are set just to cover the expected lifespan, and the balance of the resources and energy are reallocated to reproduction.
Firstly, ageing is likely to happen because genes treat organisms as disposable: they invest enough in maintenance to enable the organism to get through its natural expectation of life in the wild environment in good shape, but more than this is a waste. Secondly, there may be design constraints that favour the interests of the organism in its youth at the expense of its long term durability. Finally, natural selection in the wild is not much concerned with late-acting mutations, which may accumulate unchecked in the genome (Kirkwood, T. ‘The Time of Our Lives’, Phoenix 1999, page 79).
Eventually, scientists discovered why their half-starved mice lived longer: semi-starvation switches off the growth and reproduction genes of the mice, but switches on the repair and maintenance genes. Biologists concluded that semi-starvation – the laboratory equivalent of hard times – causes the animal to postpone growth and reproduction, concentrating instead on repairs and maintenance, on keeping itself alive and well until times improve, until there is more food available to support itself and a larger family.
This ability to switch between biological modes depending on environmental circumstances seems to be common across many species – mice, nematode worms, yeast, fruit flies, monkeys, and possibly humans, although none of these informal, long-lived human experiments are yet completed, and nor will they be for many years.
Hence, we seem to face a difficult choice, semi-starving ourselves and living a long healthy, but miserable, half-starved life; or eating, being merry, and having lots of kids but degrading rapidly and dying young. But, possibly not, maybe we can trick our biological system into believing we are living in hard times, allowing us to reap all the benefits of higher repairs and maintenance, enjoying longer healthier lives, while experiencing all of the joys of eating, merriment and procreation along the way. The key to this intriguing possibility is insulin.
Insulin is the metabolic index of feast or famine, high insulin levels signalling feast, low insulin signalling famine. Feast, in turn, signalling growth and reproduction, and famine signalling repairs and maintenance. This biological signalling system evolved over millions of years and is common across many species. As for humans, our paleolithic ancestors evolved over this period eating mostly fatty meats and fruit and edible vegetable matter when available, and insulin is sensitive to the glucogenic proteins in meat and to the carbs in fruit and veg. That’s how we evolved, our metabolic signalling system centred on insulin, hard wired into us.
However, the idea that aging itself can be regulated by targeting insulin is very recent. Cynthia Kenyon, a US biologist, has made some interesting discoveries:
Inhibiting insulin/IGF-1 signaling extends lifespan and delays age-related disease in species throughout the animal kingdom. This life-extension pathway, the first to be defined, was discovered through genetic studies in the small roundworm C. elegans.
In spite of the fascinating qualities of the aging process, such as its remarkably different pace in different species, until the last few decades aging was not thought to be subject to any active regulation. Now we know that the rate of aging is indeed subject to regulation, by classical signaling pathways. These pathways link the aging rate to environmental and physiological cues, and may even underlie its diversification during evolution. At the heart of these pathways are stress and metabolic sensors such as insulin and IGF-1 hormones, TOR kinase and AMP kinase, whose up- or down-regulation can trigger a variety of cell-protective mechanisms that extend lifespan.
So there it is: humans and many other organisms have an intrinsic ability to switch between biological modes from growth and reproduction to repairs and maintenance, from disease and short life span to health and long life span using nothing more than a simple signalling system based on insulin ostensibly linked to the organism’s circumstances of feast or famine. And here's the trick: insulin only responds to glucose and other sugars in the diet, so not all foods produce insulin. Carbohydrates, especially refined carbs, produce the most, proteins except leucine and iso-leucine can be metabolised into glucose but rarely are, and fat produces no insulin at all. So the insulin signalling system can be tricked into believing it's in the middle of a famine by consuming a low carb, high fat diet - the ketogenic diet.
The ketogenic diet
The parallels between CR and the ketogenic diet have been noted and researched:
Both calorie restriction and the ketogenic diet possess broad therapeutic potential in various clinical settings and in various animal models of neurological disease. Following calorie restriction or consumption of a ketogenic diet, there is notable improvement in mitochondrial function, a decrease in the expression of apoptotic and inflammatory mediators and an increase in the activity of neurotrophic factors.
Maalouf, M. ‘The neuroprotective properties of calorie restriction, ketogenic diet and ketone bodies.’ Brain Research 2008.
The effects are summarised in the following table
As Kenyon indicates the actual CR mechanism operates through an evolutionarily conserved signalling mechanism involving a reduction in insulin and related insulin-induced hormones such as Insulin-like growth factors (IGF-1) brought about by a reduction of carbs and protein as a part of the overall reduction in food. As insulin levels fall a whole array of stress genes are increasingly expressed whose function is to conduct repairs and maintenance on the organism, to conserve the organism until better times.
Kenyon quickly became a convert when she found that putting sugar in her experimental worm food shortened the worm’s lifespan. The following is an extract from a New Scientist interview with Kenyon in 2003:
But for now, caloric restriction seems the one proven way to extend lifespan.
Is that why you've virtually given up carbohydrates?
That's not necessarily why I do it. I do it because it makes me feel great and keeps me slender. And I don't feel really tired after a meal. But I think if I wanted to eat in a way that extended lifespan this is how I would do it. In fact, I stopped eating carbohydrates the day we found that putting sugar on the worms' food shortened their lifespans.
How does it work?
I eat a diet that keeps my insulin levels low. So, for example, at breakfast I have bacon and eggs with tomatoes and avocados. It's bit like the Atkins diet. I don't actually know if I eat fewer calories, but I feel great and I weigh what I did in high school. I certainly wouldn't want to be hungry all the time, but I'm not, I'm never hungry. I tried caloric restriction just for two days but I couldn't stand it, being hungry all the time.
Kingsland, J. ‘I Want to Live Forever’ Interview with Cynthia Kenyon, New Scientist, 2003.
Of course, it would be nice if humans could take advantage of this calorie restriction mechanism, living beyond 150 years healthily would be commonplace, but as the Kenyon quote illustrates, the struggle against semi-starvation is just too much for most people – they are beaten almost every time by the agony of hunger.
But CR seems to be an unnecessarily painful way to go about limiting insulin when it is not calories as such that promote insulin, but carbohydrate calories (and, to a lesser extent, protein calories). Hence if you want to increase your healthy lifespan possibly by as much as 50% then move onto the ketogenic diet and lifestyle.
The ketogenic diet dramatically lowers insulin, automatically turning off the hunger switch, allowing individuals to consume their own fat, and often producing a mild state of euphoria, a far from unpleasant experience.
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