Caloric Restriction is one of the longevity protocols that has the strongest supporting evidence from research studies. Here we give you an overview of the definition of Caloric Restriction (CR); the mechanisms by which it is thought to act on the hallmarks of aging; the most compelling research studies we found; and some concrete tips on how, when, and if CR should be part of your longevity strategy.
Caloric Restriction vs. Fasting
With the growing popularity of intermittent fasting, time-restricted feeding and caloric restriction there is growing confusion on what each is and how different from each other. So a good starting point is to make a distinction between fasting and CR:
- Fasting refers to the voluntary abstention from all food and/or drink for a period of time (usually measured in days) and is primarily concerned with restricting the frequency or timing of meals. Like fasting, time-restricted feeding aims to abstain from any food intake during a large window (i.e. 16 hours) in a 24-hour period.
- Caloric restriction in contrast, refers to the intentional reduction of normal food intake (usually by 20-50%) without total nutrient deprivation and risk of malnutrition. While the ideal application of CR is adopting a consistent pattern of lower calorie consumption, in practice, the difficulty of sustaining lower intake indefinitely dictats that most CR applications on 5-7 day windows, repeated periodically.
Go deeper into the distinction between fasting and CR in this video interview of Dr. Valter Longo, director of the Longevity Institute at the University of Southern California and author of the popular book “The Longevity Diet: Slow Aging, Fight Disease, Optimize Weight.”
How Does Caloric Restriction Improve Lifespan?
In our research we found that there are four main hypotheses for how CR may function to slow the cellular aging process. These four mechanisms all address different aspects of the hallmarks of aging:
- Attenuation of damage from oxidative stress. This hypothesis is based on the fact that increased caloric intake has been shown to result in a greater accumulation of reactive oxygen species (ROS) inside the cell. High levels of ROS promote genomic instability and accelerate cellular aging. The reverse has also been observed: under a situation where caloric intake is limited, the rate of accumulation of ROS decelerates resulting in higher genomic stability. Specifically, CR is thought to increase the expression of enzymes that protect the cell against ROS thus reducing oxidative stress and DNA damage
- Growth hormone (GH) and insulin-like growth factor (IGF-1) axis. According to this hypothesis, increased caloric intake results in higher circulating levels of GH and IGF-1. This in turn promotes cell proliferation. Under CR, circulating levels of GH and IGF-1 are reduced, thus discouraging cell proliferation and shifting the body’s efforts to cell repair and maintenance
- A third avenue by which CR is thought to slow aging is by inducing cellular hormesis. When the cell’s nutrient sensing mechanisms detect a lower availability of energy sources, they trigger a stress response that causes the body to shift from growth to energy conservation. Specifically, the hormetic response upregulates and prioritizes cell repair and maintenance processes (e.g., autophagy) and downregulates energy-intensive ones such as cellular division and growth
- Insulin and glucose reduction. Ad libitum, non-restricted diets result in increases in insulin production and blood glucose levels as the body works to break down food. By contrast, CR has been shown to significantly reduce insulin levels and to attenuate the glycemic response to meals. This reduction in insulin and glucose in turn improves cellular nutrient sensing and signaling resulting in greater cellular health
Here is a very useful graphic summarizing the four mechanisms by which CR improves cellular health:
What Does the Current Research Say About CR?
Research on CR has been performed across various types of animal models from yeast to primates and has been consistently shown to delay the onset of age-related diseases as well as extend lifespan. One indication of the potential effectiveness of a longevity protocol is its ability to induce a consistent response across a wide swath of the evolutionary scale. CR checks the box on this one, given that the research has spanned such a broad range of species.
Here are some of the highlights:
- Yeast: studies of the yeast species S. cerevisiae aimed to trigger a form of CR by reducing the glucose concentration in the growth medium. In these studies, yeast grown on the reduced glucose showed a substantial extension in lifespanvs. controls.
- Roundworms: restriction of the food source in this species increased their lifespan by 150%.
- Fruit flies: surprisingly we share many genetic similarities with fruit flies, particularly in genes related to many diseases. Research in fruit flies has shown that CR has varying effects depending on diet composition and quality. For example, this study compared two forms of CR on flies: yeast and carbohydrate restriction. It found that the magnitude of the “effects on lifespan when the caloric content of the food was changed via altering yeast concentration far exceeded that seen when calories were changed to the same extent via manipulation of sugar levels.” These results suggest that protein/lipid levels have a greater effect on survival than carbohydrates”.
- Mice: of the animal models used so far, the ones using rodents provide some of the best clues as to the type of benefits that might be derived when CR is applied in human subjects. Rat and mouse models presented some of the first experiments examining the beneficial effects of CR, with the first study suggesting that CR may result in longer life published in 1935. More recently, this 2009 study suggests that CR in rodents yields a 60% increase in lifespan when compared with controls.
- Primates: two studies performed on rhesus monkeys appear to be the most cited when it comes to CR and lifespan, even though they showed contradictory effects. The first study performed by researchers from the University of Wisconsin examined the effect of CR on Rhesus macaques (N=76) over a 20-year follow-up. Monkeys were split evenly and randomized to either treatment or control groups. In the treatment group, baseline intakes were reduced by 10% per month for 3 months in order to achieve a 30% restriction in daily intakes; controls were fed ad libitum with no restrictions in daily calories. Over a 20-year period, controls were more than 2x more likely to die during the experiment than the treatment monkeys. At follow-up, the authors found that the risk of age-related disease was nearly 3x times lower (HR=2.9) when compared to controls.
The second study performed by researchers from the National Institute of Aging also examined the effects of CR in rhesus monkeys (N=121) over a period of 20 years. Monkeys were split evenly and randomized to either treatment or control groups. In the treatment group, CR monkeys received 30% less food than height-, age- and sex-matched control monkeys; controls were allotted food based on data published by the National Research Council to provide approximate ad libitum intake without overfeeding. In this casel, researchers saw no significant impact of CR on survival between treatments and controls. Furthermore, while treatment monkeys experienced small improvements in biomarkers, they were nonsignificant. Researchers attribute these inconsistent results to differences in study design, husbandry and diet composition.
Go Deeper: Read additional studies related to this data set”
- Caloric restriction improves health and survival of rhesus monkeys
- Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys
CR studies in humans have proven to be more complicated than those performed using animal models. Ethical concerns and experimental limitations have slowed research in human subjects. Still there are a number of observational and even one clinical study shedding light on the feasibility of CR in humans.
Of the observational studies, religious groups provided some of the preliminary data on the effects of regular CR. Observational studies of Muslims during Ramadan revealed no significant changes to biomarkers following prolonged periods of CR. Studies in Greek Orthodox congregations have shown reductions in BMI, total cholesterol, and LDL post-CR when compared to baseline (pre-CR). Similarly, Christians practicing the 21-day Daniel Fast saw improvements to biomarkers including total cholesterol, LDL, blood pressure, insulin, and C-reactive protein.
Observational studies have also included artificial living conditions such as those created during the Biosphere 2 study (N=8). During this study, 4 men and 4 women lived in a sealed environment for 2 years. Study participants were subjected to CR and fed a low calorie, nutrient dense, mostly vegetarian diet (approximately 1800–2000 kcal/day). The authors observed significant weight loss and improvements in blood pressure, blood glucose, insulin levels, cholesterol, LDL, and triglycerides among participants. Unfortunately, these effects were transient and study participants returned to their pre-study weights and reestablished pre-study biomarkers after the conclusion of the experiment.
Okinawa, Japan has also provided a home base for researchers interested in studying the effects of CR in human populations. Okinawa is one of five Blue Zones where people experience extreme longevity. One epidemiologic study in Okinawa found that among elderly Okinawans, lower caloric intake and negative energy balance earlier in life resulted in a lower BMI, decreased risk for age-related diseases and longer lifespan when compared to mainland Japanese citizens and Americans.
Randomized clinical trials have been rare in humans so far, but the Comprehensive Assessment of the Long Term Effects of Reducing Intake of Energy (CALERIE) trials are among the first ongoing research studies examining the feasibility and effects of CR in a clinical setting. During CALERIE 1 (N=225), pilot studies conducted at multiple sites randomized participants to 20–25% CR diet or weight maintenance diet for 6 or 12 months. Results from these preliminary studies showed that energy expenditure, core body temperature, fasting insulin, bone mass, muscle size and strength, and markers of oxidative stress and DNA damage all decreased while insulin sensitivity and mitochondrial DNA synthesis and mass increased.
During CALERIE 2 (N=218), participants were randomized to a 25% CR diet or their usual diet for a period of 2 years. Study results indicated that CR adults had significantly lower total cholesterol, LDL-cholesterol, triglycerides, C-reactive protein, TNF-α, and blood pressure at the end of the study period when compared to controls. Additionally, HDL-cholesterol and insulin sensitivity increased. It is important to note however, that during the 2-year study period none of the CR participants achieved a full 25% reduction in calories for a sustained period of time. The average reduction among CR participants was 12%.
Go Deeper: Read this awesome review from Rhonda Patrick to learn more about the different results of CR research studies.
How Should I Use CR as Part of my Longevity Protocol?
Based on what we found in our search, CR is an effective, while not always feasible, method for reducing energy intake and controlling biomarkers. To practice CR, the rule of thumb we kept seeing is to aim to reduce your daily intake by 20% or more (although the majority of experiments we saw both in animals and in humans utilize a reduction of 20-30%, and the effective intake reduction observed in CALERIE 2 was only 12%). This means that if you ordinarily consume 2000 kcal/d, a 20% reduction implies consuming only 1600 kcal/d. The reality is that for most of us, this level of intake reductions are hard to sustain indefinitely. However, many of the benefits of CR can be achieved through periodic practice.
While the evidence of CR producing favorable results for your BMI and other key age-related markers seems to be quite robust, its practice needs to come with precautions. Individuals with a pre-existing condition (e.g. diabetes), those who are taking prescription medications, or those above age 70 should consult with their primary care before adding CR to their longevity protocol.
Additionally, some research suggests that prolonged CR can disrupt the gut microbiome and even increase the number of harmful bacteria. Another reason that suggests CR may be best practice in cycles, rather than making it your primary dietary pattern. in order to avoid damage to your gut. There is also the option to skip CR in favor of an alternative CR mimetic.
Our search for alternatives to straight-up CR turned up some interesting options:
The Fast-Mimicking Diet
Prolon is a fasting mimetic diet that utilizes CR to achieve its health effects. The Prolon program, designed on the research of Dr. Valter Longo, consists of 5-day cycles during which an individual consumes a very-low calorie diet of pre-packaged foods provided by the company. The foods included in the program are optimized to provide a balance of macro and micronutrients to avoid nutrient deficiency. Prolon has three packages to choose from—First Time Single User ($199), 3 Box Bundle ($565), or Monthly Subscription ($189/mo). Click here to learn more about Prolon, how to order and use the products, and get the answers to user FAQs.
Supplements and Medications
Certain supplements and medications have also been shown to mimic the effects of CR on the body without requiring an individual to actually alter their energy intake. Three common CR mimetics include:
- Rapamycin—An immunosuppressant drug that inhibits mTOR and has been shown to reverse age-related decline in animal models. Studies have shown that part of the mechanism of action of this drug mirrors the effect of fasting and very low calorie diets, which improve insulin sensitivity and reverse type 2 diabetes. You can learn more about this lifespan-extending compound here.
- Metformin—An anti-diabetic medication that has been shown to slow aging in animal models and reduce age-related neurodegenerative disease like Alzheimer’s and cancer in humans. Listen to Joe Rogan talk with David Sinclair about the use of metformin as an anti-aging drug.
- Resveratrol—A natural phenol present in the skins of purple grapes and other foods. Resveratrol is a SIRT1 activator and seems to reduce diseases resulting from abnormal metabolic control, inflammation, and cell cycle defects. Supplementing resveratrol may also neutralize the detrimental effects of free radicals and oxidative stress on our cells, decreasing systemic inflammation, and delaying aging and disease. Check out our deep dive into resveratrol and see our top picks for supplementation.
Time and Feeding Frequency Restriction
Altering the time or frequency of meals is another way to mimic the effects of long-term CR. Some methods you might want to consider are:
- Intermittent Fasting—Limiting meals to a certain number of hours of the day. Intermittent fasting can help reduce inflammation and lower your risk for chronic disease. Click here to learn about how intermittent fasting affects the body.
- Alternate-day Fasting—Fasting a full 24-hours every other day while eating normally on non-fasting days.
- 5:2 Eating--Consuming a regular, non-restricted diet 5 days per week and fasting for 2 days per week.
- Prolonged Fasting—Fasting for more than 48 hours.
Go Deeper: Learn more about CR mimetics with these papers:
- Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential
Based on all the evidence we’ve poured through, CR seems to present a viable strategy for extending healthspan. As usual, the caveat that additional research is required to prove its efficacy in humans applies. While we can’t predict that CR will add years to your life, based on what is already in the research, we do know that CR provides tangible health benefits that can help mitigate your risk for age-related disease and decline.
Go Deeper: See What Some of Our Favorite Gurus Are Saying About CR and Fasting
- Peter Attia: Nutritional Biochemistry Calorie Restriction Archive
- Rhonda Patrick: Time-restricted Eating & Fasting
- Valter Longo: The Fast Mimicking Diet and the Keys to Longevity
Have you tried calorie restriction? Let us know about your experience firstname.lastname@example.org
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