Can calorie restriction really extend lifespan?

Each time the media proclaims “Eat Less and Live Longer” people may ponder the question of whether increasing their health and lifespan by reducing calories is a good option. Is eighty more years of daily rabbit food-fuelled misery a good trade off for fifty years of dietary delight (with a possible few miserable ones at the end)?
Well this agonising choice may be unnecessary thanks to our friends at big Pharma.
There are novel therapeutic compounds in the pipeline that could mean you don’t have to forego that pastry after all.

Amid much Shylock-like hand rubbing and Porsche catalogue perusing, the scientists are wetting their proverbial Armani underpants at the prospect having created a highly lucrative magic pill that will simulate calorie restriction and exercise – without having to deny yourself a single morsel or getting off your pizza-encrumbed comfy chair. It’s called SRT501 and it’s already in Phase 2 clinical trials in patients with type 2 diabetes.

Should we just accept that calorie restriction or its pharmaceutical equivalents increase health and longevity at face value?

I would like to mention some reasons why we shouldn’t.

All the studies conducted thus far have involved only laboratory animals. This research needs to be taken with a pinch of low-calorie salt because extrapolating animal studies to humans is particularly problematic in this instance.

Rodents in the laboratory hardly simulate human real life. Rats don’t have to pry themselves out of bed in the morning, negotiate rush hour traffic and spend 8+ hours dealing with irritating customers, lazy colleagues or ogre bosses. They don’t return after a gruelling day to a house full of noisy, selfish teenagers, patronising, bossy mother in laws or screaming colicky infants. No, they laze about in their cages contemplating their navels.

Rats and mice fed fewer calories do appear to live longer - but don’t step away from the donut just yet. Rat chow is the standard laboratory diet in these studies, and judging by its composition, living longer would not be a welcome prospect; if these animals could talk they would plead to be euthanised.

Most of the energy provision in rat chow is from processed cornstarch; it has a high glycaemic index, is anti-thyroid and promotes weight gain – not exactly a health food and certainly not a natural diet for a rat. So the less calories angle could easily be interpreted as ‘feeding less crap food to rats promotes longer life’.

Glucose metabolism in rodents is different to human glucose metabolism. This difference is allegedly why the compound alloxan (it’s added to our flour) produces diabetes in these hapless furry creatures but apparently leaves our own pancreatic beta cells relatively unscathed.
There have been cell studies in human tissue in test tubes, but that doesn’t convincingly simulate real life either. To be convincing (to me at any rate), large-scale human trials need to be conducted in age-, socio-economic status-, rotten boss-, traffic conditions-, unruly teenagers-, baby-shrieking-, unreasonable mother-in-law-matched subjects who would be randomised to eat a normal diet or a calorie restricted one, and followed up for over 50 years to analyse which group lived the longest and healthiest.

The ‘fountain of life’ enzymes in the body that fasting (and the magic pill) induce are called sirtuins. These sirtuins rejuvenate the mitochondria (little energy burning furnaces) in every cell allowing them to be more efficient and long-lived. Not a great deal is known about these enzymes apart from the possibility of generating vast amounts of revenue because they have only recently been discovered.
SIRT1 is necessary in the fasted state (lower blood glucose) to allow the mitochondria to switch from burning glucose to burning fatty acids as fuel. So in conditions of low blood glucose, sirtuin-1 is increased. The magic pill SRT501 increases sirtuin-3 and sirtuin-4. SIRT3 is responsible for protecting the mitochondria during cellular stress and in brown fat it increases thermogenesis [1], theoretically contributing to the armchair-assisted weight loss. SIRT4 produces an insulin-degrading enzyme and depletion leads to a greater insulin response to glucose [2, 3].

So it appears that the sirtuins are an integral mechanism in insulin response (but there are many others; nothing in physiology is that simple). Insulin at low levels is necessary for life, but at continually high levels (as we have with Western diet) it is extremely damaging. The take-home message could then be “eat less crap and live longer” rather than the simple “eat less – period”.

All the enzymes, hormones, minerals, proteins and lots of other factors in the human body are regulated by a complex loop-feedback mechanism (this is why so little of the brain is concerned with conscious thought – regulation of the body needs a lot of brain power). They are finely tuned on a moment-by-moment basis to do their respective jobs; too little or too much either way and you may find you are suffering a horrible disease or have even dropped dead on the spot. Increasing or blocking the actions of these substances with synthetic molecules that override this fine-tuning is a recipe for disaster. Notable molecule-meddling tragedies include Vioxx, thalidomide and several diabetes drugs. When scientists find a substance in the body with a ‘good’ action they want to increase it because they figure more is better. The converse is also true. But the fact is they haven’t fully explored what other actions the substance has. Vioxx caused an increase in heart attacks is because it blocked COX-2, an enzyme involved with inflammation. They decided COX-2 was bad so it had to be stopped at all costs. What they hadn’t bothered to discover was that COX-2 protected the heart.
Meddling with glucose and fat metabolism can increase the risk of all sorts of nasty diseases - SIRT3 levels are much higher in breast cancer [4]. One review entitled Sirtuins: critical regulators at the crossroads between cancer and aging [5] admitted “By participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers.” Tinkering with your sirtuins sounds like a game of Russian roulette.

Here’s a whacky idea – instead of traipsing down the rabbit food road, or spending the kids’ college funds on an expensive, potentially toxic pill, a cheaper, safer option (well, free actually, unless you want to pay me for this advice) – is to eat…less…carbohydrate – especially sugar.


1. Shi, T., et al., SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem, 2005. 280(14): p. 13560-7.
2. Ahuja, N., et al., Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J Biol Chem, 2007.
3. Haigis, M.C., et al., SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell, 2006. 126(5): p. 941-54.
4. Ashraf, N., et al., Altered sirtuin expression is associated with node-positive breast cancer. Br J Cancer, 2006. 95(8): p. 1056-61.
5. Saunders, L.R. and E. Verdin, Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene, 2007. 26(37): p. 5489-504.