The Science Of Calorie Restriction

If you ever wished to affect longevity and ageing in the most potent natural way possible, eating less might be the answer.

Around 500 years ago a young and wealthy Venetian merchant Alvise “Luigi” Cornaro believed he had bottled the brew for extending ‘health span’. In his thirties, after suffering from a “train of infirmities,” as he put it Luigi sought medical attention. The prescription from his physicians? To eat less. After several unsuccessful tries, once he did manage to stick with it for over the course of a year, he found himself “freed from all … complaints.” Limiting himself to 350 grams of food (consisting of soup with egg yolk, bread, and meat, fish, or fowl) and 414 mL1 of wine a day, he became “exceeding healthy.”

Some people argued that perhaps caloric restriction (CR) can increase healthspan, but surely it can’t increase lifespan? “To this, I answer, that experience proves the contrary; and that I myself am a living instance of it.” (Cornaro reportedly died at age 98.)

What we today call caloric restriction (meaning eating fewer calories without malnutrition) was nothing new, Cornaro noted (in the mid 16th century, mind you). Galen, the Greek physician—born in 129 AD—was extolling the same virtues. Ben Franklin wrote in 1733 “To lengthen thy life, lessen thy meals.”

It was only in the last century that CR was put to the test in more experimental settings. It is hard to conduct life-long well-controlled studies on humans, but if we see similar effects in a diverse range of species that span a remarkable amount of time (about a billion years of evolution from the time yeast arrived on the scene to mammals), it increases the chances that what we’re looking at in a petri dish, or cage, is relevant to humans.

It should be noted that not all species respond to CR by living longer, according to the literature. The study on lemurs showed a median and maximum life extension but it also caused a significant decrease in the grey matter of the brain. This goes to show that extended CR without periods of growth might cause more harm than good in some species including humans concludes Dr Rhonda Patrick.

It also looks like more than just calorie restriction, it is the specific nutrient restriction that might play a bigger role. Jon Ramsey, a professor and researcher of molecular biosciences at UC Davis found a 13 per cent increase in median life span for the mice on a high-fat versus high-carb diet. In humans, that would be seven to 10 years. But equally important, those mice retained quality of health in later life.

“From ancient Greek physicians to mid-16th-century Venetian merchants, to Ben Franklin, what we now know as the caloric restriction was observed to extend the quality of one’s life well into the old age. Only in the last century did we put it into a proper scientific study. Surprisingly, restricting calories without malnutrition proved to extend the life and the quality of it for a whole range of species from yeast, flies, worms and spiders, to fish, rats, mice, dogs, and monkeys. Not all species responded with a longer life, however. More and more it looks like the restriction of specific nutrients might be even more important.”

When we talk about slowing down ageing it’s not the wrinkles on our face that are the main concern. All the diseases are the product of ageing itself. Slowing down that clock by exercising, fasting, eating the right foods, having enough good quality sleep, water and meaningful activities will stop the formation of diseases and in many cases even reverse them. Think about this for a minute. Just by making the right choices, you can literally reverse your biological age!

There are various ways of practising fasting and numerous benefits it brings from fat loss to improved cognitive performance and mental resilience to dramatically improved relationship to food. This article will focus on the science of calorie restriction from the longevity perspective.

The biochemistry of life extension

There is a genetic pathway that gets triggered when energy intake is low. These genes are called sirtuins they react to hormetic stressors like heat, cold, low energy input, etc. They take care of the DNA repair and stabilisation of the epigenome.

The famous life-extension research scientist Dr David Sinclair explains that when you are hungry a gene called NAMPT is activated that produces NAD, which is the fuel for sirtuins to enable them to do their job. There are two ways to synthetically boost NAD. One is to take resveratrol (the ingredient in red wine, btw pinot noir has the most) with some other plant chemicals, and the other option is something that is taking over the market now, the NAD precursor supplements.

But we can also boost the performance of sirtuins naturally, by simply lowering the energy input. It is a natural protection mechanism that evolved with us over millions of years to enable us to survive times of scarcity and actually perform better while we hunt for food.

mTOR is another gene that affects your longevity when fasting by being turned off. It is a protein complex within a cell that registers amino acids. In the presence of amino acids (after a protein-rich meal) it is turned on and allows cells to build things like muscles. But having it turned on constantly is not a recipe for longevity. Studies are now conclusive that if you downregulate this gene you get longer life.

All this is because this downregulation activates a process called autophagy which is a process where proteins are recycled and that is really important for longevity. We want the body to do this regularly otherwise we end up with dysfunctional proteins accumulating in the body. For example, if that happens in the brain it is known to cause Alzheimer's disease.

This accumulation is reversible by fasting and also by simply having lower levels of certain amino acids (namely leucine, isoleucine, and valine or the so-called BCAAs) for at least part of the week, suggests Dr Sinclair. Just by downregulating mTOR and stimulating autophagy, the researchers were able to extend the life of flies and mice by a staggering 30%!

Human growth hormone (HGH) has been shown to increase dramatically during fasting. One study found that 3 days into a fast, HGH levels increased by over 300%. After 1 week of fasting, they had increased by a massive 1,250%. HGH is an important hormone produced by your pituitary gland. It plays a key role in growth, body composition, cell repair, metabolism, and recovery from injury and disease. During fasting having elevated HGH levels places your metabolism in fat-burning mode while maintaining muscle mass.

Another process occurs when you skip your meals. AMPK (AMP-activated kinase) an enzyme that responds to low energy is activated. The main thing that it does is it makes more mitochondria says Dr Sinclair. We lose mitochondria as we age, but when we exercise or fast, we get more. Mitochondria is not only important to metabolise things but to create chemical energy. So when we activate AMPK we feel better, have more energy and slow down ageing.

FOXO3 is also an important component of longevity. This is a transcription factor that regulates a whole host of genes, many of which have to do with DNA repair, autophagy, stem cell function, production of antioxidants, and anti-inflammatory pathways. Periods of refeeding and growth are, of course, extremely important and they stimulate a growth factor IGF-1 (a hormone with anabolic effects). Both IGF-1 and insulin inhibit FOXO3. Many studies confirm that when FOXO3 is downregulated the life extension is gone.

Apoptosis is a process of programmed cell death. Your body carries around a lot of cells that it doesn’t need. During fasting, this cellular program that causes the damaged cells to kill themselves is enhanced.

Lastly, let’s mention senescent cells. These cells have lost the ability to proliferate and they resist apoptosis. They cannot participate in standard tissue preservation and tissue repair. Rather, senescent cells disrupt the milieu by producing a plethora of bioactive factors that cause inflammation and impede regeneration. So basically, these zombie cells just wander around wreaking havoc and causing inflammation. It is a natural part of ageing, but with an unhealthy lifestyle, we can quickly exacerbate the situation. Fasting has been shown to effectively reduce the amount of these cells.

“Eating less or having big gaps of non-calorie consumption activates a whole host of processes in the body that are beneficial for longevity. Sirtuins are genes that get activated and take care of DNA repair. Autophagy is a process that recycles old cells while AMPK is an enzyme that helps create more mitochondria. Growth hormone is dramatically increased during fasting preserving your muscle mass while burning fat. Senescent cells are zombie cells that lost the ability to proliferate and refuse to die. Fasting dramatically cleans up these cells too.”

Prefer to take a pill?

Rapamycin is a drug that successfully downregulates mTOR and mimics the benefits of fasting, while Metformin, a drug used for type 2 diabetes activates AMPK. Both have been shown to slow down the recurrence of all diseases of ageing.

Drugs called senolytics are meant to fight the accumulation of senescent cells, slow down aging and maintain better function during old age. A study on mice showed that senotherapy (the use of senolytics) prolonged lifespan, rejuvenated the function of bone marrow, muscle and skin progenitor cells improved vasomotor function and slowed down atherosclerosis progression.

“As always there are pills that can mimic the effects of fasting. Many biohackers opt to use the pills in combination with actual fasting to further increase the effects. Rapamycin downregulates mTOR - a protein that registers the presence of amino acids - and this enables autophagy to ramp up. Metformin is a drug that activates AMPK.

Fasting has been shown to help with certain diseases like type 1 diabetes, multiple sclerosis, and cancer.”

Conclusion

Let’s call a spade a spade: fasting is not fun, it requires a certain discipline, eating is much more enjoyable. But fasting is the cheapest and one of the most accessible and potent practices anyone can implement to improve their overall health, wellbeing and mental resilience. It is one of the rare practices that can be in some shape or form recommended to anyone that wants to extend their life and be healthier. Not just humans, animals too!