Calorie restriction diet – a longevity intervention

Highlights

• Caloric restriction (CR) is a dietary intervention focusing on daily reduction in food intake by 30-40 %
• CR was proven to be connected with lifespan and healthspan prolongation through molecular pathways alteration and core body temperature decrease
• Lifelong caloric restriction can extend the life of rodents by up to 50 %, and the initiation time of the caloric restriction regime is crucial

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Introduction

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More and more research recommends a caloric restriction (CR) diet to reduce aging-related diseases, especially the ones induced by obesity, such as diabetes. Caloric restriction is suggested to be one if not the only non-genetic intervention that reliably prolongs health span and improves longevity in simple model organisms. Studies have shown that CR affects several hallmarks of aging, such as deregulated nutrient sensing, cellular senescence, or altered intercellular communication. It also causes a reduction in body temperature, which is proposed to contribute to changes increasing lifespan. Low body temperature was also shown to improve health and longevity independent of CR.

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What is the caloric restriction?

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Caloric restriction is a dietary intervention focusing on daily reduction in food intake. It is reached by a 30 to 40 % decrease in overall caloric intake without causing malnutrition. Effects of CR on longevity, healthspan, and cellular senescence have been studied in various species such as budding yeast, fruit fly, spiders, worms, or primates. It was published that CR can slow down aging and increase cognitive performance. It was also proven to protect against tissue structure and function deterioration and maintain stem cell function that usually deteriorates with age. Caloric restriction has different effects on different tissues, e.g., its cell protective responses are present in nearly all organs, including the brain.

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What is more, it reduces DNA damage. Few factors impact the effectiveness of a caloric restriction diet, e.g., the diet composition, the duration of the diet, and the time of its initiation. In the case of the composition, it was shown that specific lipid profiles and signals or amino acid composition might be the most crucial in aging delaying. Based on research, initiation of CR in the first or second half of life is more effective than application during both halves and speaking of duration; in general, the longer, the better (1).

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Body temperature drops during calorie restriction

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Reducing core body temperature in homeotherms such as humans is possible through only one intervention: calorie restriction (CR). CR can be obtained by specific dietary patterns such as intermittent fasting. In 1935 McCay suggested that caloric restriction can be used to increase the mean and maximum life span in rodents (2). The adaptive mechanisms during calorie restriction permit survival in conditions of limited resources by reducing metabolic demand for body temperature maintenance, which means conserving energy by lowering the body temperature. A controlled and balanced dietary regimen is, to date, the most effective way to prolong lifespan and slow down aging by also reducing body temperature (3). From a thermodynamic point of view, aging is proposed to result from a rise in molecular disorder and the dropping of metabolic stability. Temperature changes affect thermodynamics and may influence the aging process, with organisms aging faster at higher temperatures due to causing more molecular damage. It means that a calorie restriction regime that lowers the body temperature might extend the lifespan by lowering the metabolic rates and decreasing the rate of biochemical reactions in the body (4, 5). CR also involves a conversion between the state of growth and proliferation to the state of maintenance and repair. Until now, there is still no strong proof in human models of CR influence on longevity employing temperature lowering. However, preliminary results from research done in 2008 on a group of human participants being calorie-restricted for six months showed a ∼0.2 ◦C reduction in core temperature, similarly to observations in non-human primates (6).
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The molecular principles of calorie restriction

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Calorie restriction is involved in many crucial biochemical pathways in the organism such as insulin/IGF, PI‐3K/AKT, TOR, and FOXO signaling. CR is an intervention proven to extend both mean and maximum life span in mammals by reducing cytokine levels, adiposity, insulin/insulin-like growth factor (IIS) signaling, thyroid hormone levels, and increase of adiponectin. Because of those changes, downstream cellular pathways are impacted, such as SIRT1 activation, IIS/phosphatidylinositol 3-kinase (PI3K)/Akt signaling, AMPK/mTOR, and extracellular signal-regulated kinase 1/2 (Erk1/2) signaling.
The response of all these pathways to calorie restriction improves the fitness of cells and longevity thanks to the activation of autophagy, stress defense mechanisms, and survival pathways, as well as blocking pro-inflammatory mediators and cellular growth (7). TOR and insulin/PI3K pathways are known nutrient-sensing pathways that regulate longevity. Reducing insulin/PI3K signaling extends the lifespan in worms, flies, and rodents. Downstream of the insulin/PI3K pathways is the FOXO transcription factor family controlling the stress response, cell survival, and metabolism. In mammals, the sirtuin protein family influences cell survival and metabolism through both FOXO-dependent and FOXO-independent mechanisms. Whether TOR signaling regulates mammals' life span is unknown, but it is strongly suggested (8).

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Caloric restriction in rodent studies

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Lifelong caloric restriction can extend the life of rodents by up to 50 %, and the initiation time of the caloric restriction regime is crucial. Later the diet is started, shorter is the lifespan extension (9). Caloric restriction was also proven to delay the cancer onset and other age-related diseases in mice.  Based on genetic background differences, CR can also impact positively or negatively mouse longevity. Visible lifespan extension in mice was achieved through over-expression of the catalytic subunit of mouse telomerase (mTERT) in mice subsequently on CR diet  In TERT transgenic (TgTERT) mice, the prevalence of tumors was significantly reduced with CR, which also prolonged their lifespan. These results have proven that CR can attenuate the erosion of telomeres which prolongs the lifespan. Genetic background is an important distinction as mice derived from the wild did not show the same longevity benefits as their lab bred counterparts (10).  The caloric restriction might also increase metabolic efficiency and prevent cell damage. It impacts the lifespan of rodents by reducing insulin and glucose levels and the IGF-1 signaling pathway. CR is proven to increase the expression and activity of sirtuin proteins in many tissues, which are closely related to aging. CR was proven to positively affect inflammation and insulin resistance in a rat model by regulating GSH redox status and NF-kB, SIRT1, and FoxOs. CR alters the development of cardiovascular disease and diabetes thanks to controlling the mechanisms of maintaining cardiac activity, such as autophagy, apoptosis, or mitochondrial quality. It is suggested that CR regulates adult neuronal stem cells. It increases neurogenesis in young adult rats and reduces age-related declines in neurogenesis in older ones (11). CR can also have negative impact such as reduced fertility or risk of freezing. In mice in the CR group, exercise could cause bone loss and be harmful to the bones compared to the control group  (12).

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Eat less to live healthier and longer

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Ethnic groups from areas called Blue Zones are known for their longevity. Some of them like, e.g., the Okinawans from Okinawa islands of Japan, swear by the habit of eating less and believe it is the key to health. Their diet follows a saying, "hara hachi bu" - eat only till 80 % full (13). This diet protects from obesity, and if introduced to obese patients, it helps in weight loss. Weight loss significantly reduces the risk of developing type 2 diabetes.
Moreover, insulin sensitivity, blood glucose levels, and serum lipids have all been improved by caloric restriction. It appears that the risk of hypertension is also reduced by caloric restriction leading to a decrease in cardiovascular disease, stroke, and kidney failure. CR was also proven to prevent age-related neuronal loss and various age-related neurodegenerative disorders and induce neurogenesis (11). Long-term CR has adverse side effects in humans and animals, such as the constant hunger, coldness due to core body temperature drop, and lower libido. It leads researchers to look for a way to mimic the CR effect by the use of pharmaceuticals. Promising drugs from this family are rapalogues or metformin, already successfully used for diabetic patients (9, 14, 15){Speakman, 2011 #4894;Shi, 2021 #5238}.

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Should caloric restriction be suggested to everyone?

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According to Most et al., continuous CR in healthy, non-obese individuals may reduce the incidence of cardiovascular disease by 30 %. Long-term CR without malnutrition was also proven to enhance the efficiency of resting energy expenditure which reduces oxidative damage to tissues and organs, and this process suppresses inflammation. Not all effects of CR are positive in human subjects. With age, human resistance to stressors declines, and calorie restriction might be one of the stressors. Hence, CR should be introduced to the elderly with caution.  People with already low body mass index (BMI, less than 21 kg/m2) have higher risks of health problems due to CR.  CR was also shown to be able to decrease bone mineral density as well as increase the risk of osteoporotic fractures. That is why always before introducing CR as an anti-aging therapy, the patient's physical condition, mental state, and BMI should be thoroughly tested (12). Caloric restriction diet should focus not only on calorie amount but also on food quality and diet composition. CR should also pair with a longevity-oriented lifestyle, including regular exercise, good night sleep, and avoiding stress.


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