What Is Caloric Restriction?

In this review, we take a look at the practice of caloric restriction and how it differs from fasting.

What is caloric restriction?

In the broadest sense, caloric restriction can mean simply a reduction in the amount of calories consumed, relative to an individual’s typical diet or the average diet within a similar population.

In the context of longevity, it usually refers to a much more significant reduction than simply skipping dessert. It’s sometimes even referred to as “caloric restriction without malnutrition” in order to distinguish it from starvation or a diet that lacks necessary nutrients such as vitamins and minerals.

When scientists write about it, they often describe it with strong claims that are not typical of academic manuscripts.

“… the most effective non-genetic intervention to delay ageing.” – Ana Maduro et al, Porto Biomedical Journal, 2021 [1].

“… the only strategy that reliably extends healthspan in mammals including non-human primates.” – Frank Madeo et al, Cell Metabolism, 2019 [2].

 “… the most robust intervention known to increase maximal lifespan and healthspan.“ – Ana Napoleão et al, Nutrients, 2021 [3].

“… the most effective non-genetic intervention to delay aging phenotypes.” – Luigi Fontana et al, Mechanisms of Ageing and Development, 2018 [4].

Studies often compare the diet to one which is ad libitum (Latin for “at one’s pleasure”). Energy consumption is typically restricted by 25-30%, although much higher levels have been shown to be beneficial, especially in simpler organisms. However, much of the data we have on humans is in the 10-15% range due to the difficulty of getting subjects to adhere to higher restrictions.

What is the difference between caloric restriction, fasting, and the ketogenic diet?

Fasting and “keto” are two other longevity strategies commonly associated with caloric restriction. They have similar anti-aging effects and share similar biochemical pathways.

There are many different types of fasting (intermittent fasting, extended fasting, and any number of different configurations), but the main difference with caloric restriction is that fasting is time-restrictive, not calorie-restrictive.

Depending on the design, a fasting diet may also result in fewer calories consumed. In OMAD (one meal a day), for example, it’s quite difficult to eat the same amount as when food is available at all hours of the day.

In other configurations, such as incorporating a several-day-long fast once per month, mice and humans alike tend to make up for the calories they missed during their feeding windows [5].

The ketogenic diet is a high-fat, adequate-protein, and low-carbohydrate diet. It’s all about what you eat, not when or how much. In general, people do tend to also consume fewer calories when they have fewer options at their disposal. The unique aspect of the ketogenic diet is that it forces your body to consume fats for energy instead of carbohydrates and sugars, which are constantly available and easy to break down. This puts the body in a state of ketosis, which can also be achieved by fasting and calorie restriction and has various benefits throughout the body [6].

Fasting and ketogenic diets are easier to follow than caloric restriction. However, their effects are generally not as robust in terms of health and life extension in model organisms, although some research also opposes this.

What are the potential benefits of caloric restriction?

Maximum and median lifespan are greatly extended in simpler organisms, such as yeast, worms, and flies. In rodents, it has been shown to prevent or treat nearly all age-related diseases, including cancer, atherosclerosis, diabetes, cardiomyopathy, kidney disease, autoimmune diseases, and neurodegeneration.

It improves recovery from stressors such as surgery, radiation, and excessive heat, prevents the gaining (or causes the loss) of excess body fat, prevents frailty, and increases both healthspan and lifespan [7].

There are a myriad of physiological responses that have been shown to contribute to these benefits. Insulin sensitivity is increased. Hormones levels such as insulin, leptin, and norepinephrine decrease, while anti-inflammation hormones such as cortisol and ghrelin increase. DNA repair systems are upregulated.

Autophagy is also increased, making the body more efficient with its resources while repairing and removing damaged proteins, lipids, and mitochondria. Metabolism is decreased, resulting in less oxidative stress. Various inflammation factors are downregulated. Each of these effects would be powerful on their own, but combined, there’s little wonder how it could have such an impact on aging [1].

On a molecular level, these effects are carried out through many different pathways. The most well-established are the nutrient sensing pathways, mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 signaling (ISS), AMP-activated protein kinase (AMPK), and sirtuins (SIRT).

While a great deal of research has gone into studying these pathways, the incredible complexity of biology means that much is still unknown about the way it slows biological aging [8].

But do these benefits translate to humans?

First things first, diet interventions are notoriously difficult to conduct and interpret in humans. This is particularly true for diets that are hard to adhere to, such as moderate to high caloric restriction.

Non-human primates are drastically more reliable than mice for predicting results in humans, and two major, 30-year-long studies have been completed. Both studies showed a reduction in age-related diseases and a corresponding increase in healthspan based on a 30% reduction in calories.

However, the study conducted at the University of Wisconsin also found an approximately 10% increase in lifespan [9-10] while a similar study at the National Institute on Aging found no difference in delaying death [11].

The discrepancy between these studies has largely been attributed to their slightly different methodologies, but the NIA study nonetheless injects some uncertainty as to whether or not CR may be beneficial for extending lifespan in humans [12]. Restricting caloric intake by 30% also resulted in notable increases in healthspan, median lifespan, and maximum lifespan in the short-lived (maximum 12 years) mouse lemur [13].

The human data is limited

The human studies to date are much shorter, cross-sectional, or retroactive. This makes it difficult to parse confounding variables that could be contributing to differences between groups and to verify adherence. Human populations such as the Okinawans of Japan who tend to consume fewer calories have longer lifespans and fewer age-related diseases [14].

Individuals who have self-selected to practice caloric restriction independently of an experimental procedure have a variety of positive cardiovascular outcomes [15]. A 2-year study found a 15% reduction of calories resulted in weight loss, decreased energy expenditure, and lower levels of oxidative stress [16].

Other studies have followed up with individuals who were exposed to famine, such as during World War II. Although results have been mixed, extreme starvation seems to be associated with accelerated aging, while moderate exposure reduces the risk of age-related diseases such as breast cancer [17].

A multitude of growing evidence suggests that it may increase longevity in humans, but we are far from understanding to what extent. Various other questions also remain such as how much to restrict calories, the optimum ages and durations to restrict for, and what the chronic effects might be in humans.

The case against caloric restriction

Reducing calories in this way does not come without potential risks and side effects. Restricting too much can result in a slow starvation with a myriad of negative consequences. It can be difficult to adequately obtain non-calorie related nutrients while restricting calories, resulting in malnutrition. When done properly, less severe side effects have been noted, including hunger, fatigue, cold sensitivity, menstrual irregularities, anemia, edema, muscle wasting, weakness, dizziness, irritability, lethargy, and depression [18].

Aside from these side effects, the decrease in quality of life still cannot be ignored. Food is one of the universal joys of life. It is the centerpiece of social events from dinner parties to holiday feasts and first dates across the globe. Little in life can match a pint of ice cream or a bar of chocolate, at least in terms of dopamine.

It’s understandable that even research subjects consistently fail to adhere to the diet. Most individuals, even those intimately familiar with the research, choose a life which is a few years shorter rather than subject themselves to decades of caloric restriction.

Which isn’t even to say the science is irrefutable. Many of the benefits seen may in fact be the disguised negative consequences of ad libitum eating [19]. Depending on the species, strain, and diet, free feeding can result in a disastrously unhealthy diet.

Humans are no different in this regard, although we have added difficulty presented by the extremely unhealthy options available to us. While it’s near certain that restricting calories provides benefits over the ad libitum diet, whether it improves upon a more achievable, simple, health-conscious diet has yielded mixed results in the literature [5].

Can you mimic caloric restriction?

Due to the difficulty of restricting calories for long periods of time, researchers have looked for caloric restriction mimetics based on the knowledge behind the mechanisms by which it works.

This has fueled research behind ways to boost autophagy, DNA repair, insulin sensitivity, anti-inflammatories, and antioxidant molecules. As mentioned earlier, fasting and the ketogenic diet have significant overlap with caloric restriction.

Unsurprisingly, moderate exercise elicits many of the same responses as caloric restriction. Several drugs have had some success, most notably rapamycin, resveratrol, NMN, and metformin [2].

Does caloric restriction work, and is it worth it?

It was among the first discovered interventions to delay aging and extend lifespan. Remarkably, many of the pathways involved appear to be conserved from yeast, worms, flies, and mice to primates, although the magnitude of the effects on lifespan appear to diminish as the strategy is implemented in more complex organisms.

Even so, its effects are impressive compared to other anti-aging strategies, including drugs and behavior modifications that mimic the effects of caloric restriction.

There is some uncertainty regarding the best way to implement such a diet in humans, as no long-term study has been completed. It is also unclear how much of a benefit it provides over other healthy diets or if these benefits are outweighed by potential side effects or detractions from quality of life.

It has inspired several lines of longevity research that look into other drugs and behavioral modifications that take advantage of similar biochemical pathways.

Regardless of whether you choose to implement this diet into your lifestyle, it has served as an impactful way to study aging. It has been an excellent proof-of-concept strategy which has been among the first to show the aging process can be modified, inspiring a wealth of other research with similar goals. Without its discovery, the longevity field would not be where it is today.

Author: Greg Gillispie

Source: Lifespan.io is a nonprofit advocacy organization and news outlet covering aging and rejuvenation research.

Literature

[1] Maduro, A.T. et al. Ageing, cellular senescence and the impact of diet: an overview. Porto Biomedical Journal (2021), doi: 10.1097/j.pbj.0000000000000120

[2] Madeo, F. et al. Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Cell Metabolism (2019), doi: 10.1016/j.cmet.2019.01.018

[3] Napoleão, A. et al, Effects of Calorie Restriction on Health Span and Insulin Resistance: Classic Calorie Restriction Diet vs. Ketosis-Inducing Diet. Nutrients (2021), doi: 10.3390/nu13041302

[4] Fontana, L. et al. Caloric restriction and cellular senescence. Mechanisms of Ageing and Development (2018), doi: 10.1016/j.mad.2018.10.005

[5] de Cabo, R. and Mattson, M.P. Effects of intermittent fasting on health, aging, and disease. New England Journal of Medicine (2019), doi: 10.1056/NEJMra1905136

[6] Moreno, C.L. and Mobbs, C.V. Epigenetic mechanisms underlying lifespan and age-related effects of dietary restriction and the ketogenic diet. Molecular and Cellular Endocrinology (2017), doi: 10.1016/j.mce.2016.11.013

[7] Fontana, L. The scientific basis of caloric restriction leading to longer life. Current Opinion in Gastroenterology (2009), doi: 10.1097/MOG.0b013e32831ef1ba

[8] Carmona, J.J. and Michan, S. Biology of healthy aging and longevity. Revista de Investigación Clínica (2016), 68:7-16.

[9] Colman, R.J. et al. Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys. Science (2009), doi: 10.1126/science.1173635

[10] Colman, R.J. et al. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nature Communications (2014), doi: 10.1038/ncomms4557

[11] Mattison, J.A. et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature (2012), doi: 10.1038/nature114322

[12] Vaughan, K.L. et al. Caloric Restriction Study Design Limitations in Rodent and Nonhuman Primate Studies. The Journals of Gerontology: Series A (2018), doi: 10.1093/gerona/glx088

[13] Pifferi, F., et al. Promoting healthspan and lifespan with caloric restriction in primates. Communications Biology (2019), doi: 10.1038/s42003-019-0348-z

[14] Willcox, D.C., et al. Caloric restriction and human longevity: what can we learn from the Okinawans? Biogerontology (2006), doi: 10.1007/s10522-006-9008-z

[15] Fontana, L. et al. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proceedings of the National Academy of Sciences (2004), doi: 10.1073/pnas.0308291101

[16] Redman, L.M. et al. Metabolic Slowing and Reduced Oxidative Damage with Sustained Caloric Restriction Support the Rate of Living and Oxidative Damage Theories of Aging. Cell Metabolism (2018), doi: 10.1016/j.cmet.2018.02.019

[17] Vin-Raviv, N. et al. Severe caloric restriction in young women during World War II and subsequent breast cancer risk. International Journal of Clinical Practice (2012), doi: 10.1111/j.1742-1241.2012.02966.x

[18] Marzetti, E., et al. Cellular mechanisms of cardioprotection by calori restriction: state of the science and future perspectives. Clinics in Geriatric Medicine (2009), doi: 10.1016/j.cger.2009.07.002

[19] Smith, N.J.G., et al. A Comparison of Dietary and Caloric Restriction Models on Body Composition, Physical Performance, and Metabolic Health in Young Mice. Nutrients (2019), doi: 10.3390/nu11020350

Source Lifespan.io