Calorie restriction

From Longevity Wiki

Aging, the physical and physiological decline of an organism, is inevitable. External stressors such as excess food intake, poor fitness, or certain diseases can accelerate biological aging. Reducing calorie intake significantly below that of feeding without restriction is called calorie restriction (CR).[1]

A number of studies have indicated that CR increases the lifespan (50-300%) and reduces the onset of age-related diseases in a variety of organisms (e.g. rats, mice, flies, worms, and yeast).[2] There is some evidence from human epidemiological and clinical trial data suggesting that CR could increase healthy lifespan by 1 to 5 years.[2]

Care should be taken in using CR as a means to increase lifespan and prevent age-related diseases. It is important to recognize that scientists refer to CR as caloric restriction with adequate nutrition. Nutrient deficiencies are associated with various health deficits, and taking less calories than ideal can also be detrimental. There is also concern that reductions in fat mass in the body could affect muscle, bone, and tissue functionality.[2] Thus, it is important to have good nutrient quality intake along with CR.

Additionally, there are risks related to impaired immune function with CR, which is an example of a psosible tradeoff.[2] There may be utility in combining CR with other interventions to maximize healthy longevity, but data is lacking in both animals and humans.

Several mice studies show that different genetic backgrounds may substantially influence the response to CR.[3] This means that while some strains of mice obtain lifespan benefit, others may attain no benefit or even experience harm.

Evidence

CR is the most widely researched intervention for slowing aging and preventing age-related diseases. A scientist, Clive McCay, first published his groundbreaking research in 1935 – his experiments demonstrated that rats with restricted diets experienced a 33% increase in lifespan.[4] Similar experiments have since been carried out on a vast number of species, from worms, mice, primates to humans.

Worms

Caenorhabditis elegans, a commonly studied roundworm, have been found to develop mutations in “eat” genes upon partial starvation. Those mutations lengthened lifespan by up to 50%. In another study, it was found that when C. elegans experience dietary restriction early in development, proteostasis is enhanced, and the adult lifespan is increased.

Mice

A caloric-restriction experiment was conducted on wild mice to see if the mice would experience similar results as genetically bred lab mice. The longest-lived wild mouse in the CR test group died at 1601 days old. Comparatively, the oldest wild mouse in the control group died at 1403 days. It is also worth noting that there was no robust longevity difference between the groups but there was an anticancer effect in the CR group. No differences in longevity between both groups were noted, possibly because wild animals have genetic variation in CR effect, wild animals ate less than ad libitum (without constraint), and wild animals may not have the same CR effect as lab animals.

In another study, it was noted that caloric restriction increased working memory in mice. Male mice that experienced long periods of fasting between meals were found to live longer, healthier lifespans, regardless of what kinds of food they ate.

Primates

The Restrikal study, initiated in 2006, studied the effect of 30% CR in the grey mouse lemur primate, Microcebus murinus.[5] Results of the study indicated that CR prolonged the lifespan by 50%, from 6.4 to 9.6 years, but affected brain structural integrity.[5] It was observed that gray matter integrity in the cerebrum was compromised by CR, yet importantly, this did not result in any apparent changes to cognitive function. Other studies on rhesus monkeys have also reported an overall positive effect of CR, discussed below.

Wisconsin primate study

Rhesus monkeys subjected to long term 30% restricted diet had significantly improved age related and survival compared to control group monkeys.[6]

NIA primate study

In contrast to the Wisconsin primate study, the NIA study showed no differences between survival of monkeys fed control versus calorie restricted diets.[7]

Given that both the Wisconsin and NIA primate studies aimed to investigate calorie restriction as an intervention to slow aging, researchers have attempted to determine why slowed aging was only demonstrated in the Wisconsin study. The observed difference between these two studies is particularly controversial because the control primates in the NIA study lived longer than the CR group in the Wisconcsin study, suggesting potential differences in methodology played an important role.

Some have suggested that diet composition is important, due to clear differences in feeding quality and composition between the Wisoncsin and NIA studies.

Humans

There is currently no evidence that calorie restriction extends healthy human lifespan.[3] However, there is early clinical evidence suggesting that CR without malnutrition may lead to various health benefits related to aging, based on several randomized controlled trials. In these human studies, CR is defined as a restriction of calories of ≥10% compared to feeding without restriction (ad libitum).

The Population of Okinawa

Studies into certain populations known for their exceptional longevity, such as in Okinawa - a small island of Japan - have provided some insights into lifestyle determinants of longevity. Okinawans have long been recognized as one of the most long-lived people groups on the planet, and this is typically attributed to their diet (fish and vegetables). However, as of late, some attention in the scientific community has deviated from the contents of Okinawan’s diets and focused, instead, on their caloric deficits. Six generations of Okinawans aged 65+ were studied; their diet composition, energy intake and expenditure, and survival patterns were analyzed, among many other factors. The results lent support to the wide-ranging health benefits of caloric restriction in humans. Some researchers have speculated that the introduction of Westernized diets may in part explain recent decreases in Okinawan population lifespan.[2]

Biosphere II - human experimentation

Biosphere II experiment was an involuntary experiment that gave an opportunity to observe CR effects. Volunteers were kept in an ecological ecosystem for two years and allowed to harvest 85% of their food. The food consisted mainly of fruits, vegetables, grains and minimal protein. During the experiment, because of food scarcity, the energy intake of the volunteers decreased by 38% for 6 months. After leaving the experiment the volunteers had a 6% slowing of metabolism which lasted for another 6 months.[2]

CR Society International is a group of volunteers that have chosen to restrict their energy intake for a period of 3 to 15 years. Individuals of the CR society are leaner, have lower body fat, have better cardiometabolic health, and lower inflammation.[2]

CALERIE trials

The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) research network has produced the most rigorous clinical study conducted in humans. Over a period of nine years, three pilot trials were conducted followed by a randomized study (CALERIE 2).[8][9]

During phase 1 of the trial, three differing degrees of CR (20%, 25%, and 30%) were tested on a variety of age groups with an overweight BMI status. The trial lasted for 6 – 12 months, and the studies were used to develop and advance the following Phase 2 trial.

In Phase 2 of CALERIE, participants were able to restrict caloric intake by 11.9% and experienced ~10% weight loss over two years, despite the identified target of 25% CR. It must be noted that the level of CR achieved in this study required intensive intervention, involving personalized treatments, algorithmic/computer tracking, and various educational initiatives.[9] Therefore, the feasibility of such a CR intervention in the real world is something that remains uncharacterized. However, despite participants in the CR group achieving a lower CR target than intended, various improvements to health were noted. The trial resulted in lower levels of T3 and TNF- ɑ, while also reducing certain cardiometabolic risk factors.[8]

Additional analyses suggested a slow down in biological aging rate, and found that weight loss did not appear to account for these effects.[10] The authors highlight that, based on prior knowledge that a divergence in biological aging trajectories can be observed as early as early adulthood, CR may be more effective in humans when started young.[11] Moreover, potential CR-related toxicities were posited to be better tolerated in younger adults.[10]

CR and immune function - randomized controlled trial

One clinical study investigated moderate CR versus ad-libitum feeding over 2 years. It was found that CR without malnutrition may induce health benefits without impairing cell-mediated immunity or increasing infection risk in non-obese humans.[12]

Underlying biological mechanisms

Taking extra calories can lead to cellular glycotoxicity and lipotoxicity which causes inflammation and oxidative stress and thus increasing the risk of age-related diseases (e.g. cancer, diabetes, cardiovascular disorders)[2]. Caloric restriction could have a number of positive effects including preservation of cognition, protects colon health, protection against arthritis amongst other benefits (Figure 1).

  • Decrease in the systemic risk factors for cardiovascular disease (glucose levels, blood pressure, plasma lipid levels)
  • Alteration in the sympathetic nervous system, as well as the neuroendocrine system in lab animals and, sometimes, humans.
  • Reduces oxidative damage, as it causes a decrease in the production of Reactive Oxygen Species.
  • Increase in CoQ-dependent reductases within the plasma membrane, thus protecting phospholipids and preventing the lipid peroxidation reaction progression.
  • Inhibits the mTOR pathway, which induces autophagy, a specific process that recycles cellular waste
  • Activates known pro-longevity pathways such as FOXO/AMPK/SIRT that are evolutionarily conserved across various species

Controversies of calorie restriction research

There are several criticisms against CR, some of which are highlighted by Sohal and Forster (2014) in “Caloric Restriction and the Aging Process: A Critique.”[13] The authors highlight that there is a large disparity in CR-related longevity increases: namely, that longevity effects are not universal and sometimes are not shared by different genetic strains of the same species. Moreover, the control animals in the widely-cited caloric restriction studies were fed ad libitum, causing them to become overweight and vulnerable to disease and early deaths. Therefore the relative benefit in the CR group was exaggerated compared to control subjects. In other words, animals with CR diets appear to live relatively longer because the control animals were dying from complications of excess feeding.

Another challenge related to CR as an effective intervention for human aging is the difficulty in compliance over long periods of time.[2] Concerns over mental and sexual health have also been raised with more severe CR. There are concerns over the loss of weight and fat mass in younger people practicing CR. Exercising along with CR and good nutrition (high protein diet) appears to be highly beneficial for loss of free fat.[2] New nutritional approaches such as intermittent fasting have emerged. However, there is comparatively limited research on the topic, with CR being the most well-studied nutritional intervention for healthy aging. Furthermore, worms that were treated with Allantoin, rapamycin, TSA, and LY-294002 had a reduced decline in pharyngeal pumping, which indicates a slower rate of aging. Thus, the study uncovered that not only could drug treatments increase longevity but they could also improve the organism’s healthfulness.

Similar to non-human primates the effects of CR on lifespan remain controversial in humans. However, it is clear from obesity research that eating too much results in poor health and decreased longevity. Combining different strategies to delay age-related disease might be the best option.[14]

  1. Bales, C. W., & Kraus, W. E. (2013). Caloric restriction: implications for human cardiometabolic health. Journal of cardiopulmonary rehabilitation and prevention, 33(4), 201.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Flanagan, E. W., Most, J., Mey, J. T., & Redman, L. M. (2020). Calorie Restriction and Aging in Humans. Annual Review of Nutrition, 40, 105-133.
  3. 3.0 3.1 Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. Science, 374(6570), eabe7365.
  4. McCay, C. M., Crowell, M. F., & Maynard, L. A. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size: one figure. The journal of Nutrition, 10(1), 63-79.
  5. 5.0 5.1 Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., ... & Aujard, F. (2018). Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. Communications biology, 1(1), 1-8.
  6. Colman, R. J., Beasley, T. M., Kemnitz, J. W., Johnson, S. C., Weindruch, R., & Anderson, R. M. (2014). Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nature communications, 5(1), 1-5.
  7. Mattison, J. A., Roth, G. S., Beasley, T. M., Tilmont, E. M., Handy, A. M., Herbert, R. L., ... & De Cabo, R. (2012). Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature, 489(7415), 318-321.
  8. 8.0 8.1 Kraus, W. E., Bhapkar, M., Huffman, K. M., Pieper, C. F., Das, S. K., Redman, L. M., ... & CALERIE Investigators. (2019). 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. The lancet Diabetes & endocrinology, 7(9), 673-683.
  9. 9.0 9.1 Rickman, A. D., Williamson, D. A., Martin, C. K., Gilhooly, C. H., Stein, R. I., Bales, C. W., ... & Das, S. K. (2011). The CALERIE Study: design and methods of an innovative 25% caloric restriction intervention. Contemporary clinical trials, 32(6), 874-881.
  10. 10.0 10.1 Belsky, D. W., Huffman, K. M., Pieper, C. F., Shalev, I., & Kraus, W. E. (2018). Change in the rate of biological aging in response to caloric restriction: CALERIE Biobank analysis. The Journals of Gerontology: Series A, 73(1), 4-10.
  11. Belsky, D. W., Caspi, A., Houts, R., Cohen, H. J., Corcoran, D. L., Danese, A., ... & Moffitt, T. E. (2015). Quantification of biological aging in young adults. Proceedings of the National Academy of Sciences, 112(30), E4104-E4110.
  12. Meydani, S. N., Das, S. K., Pieper, C. F., Lewis, M. R., Klein, S., Dixit, V. D., ... & Fontana, L. (2016). Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans. Aging (Albany NY), 8(7), 1416.
  13. Sohal, R. S., & Forster, M. J. (2014). Caloric restriction and the aging process: a critique. Free radical biology & medicine, 73, 366–382. https://doi.org/10.1016/j.freeradbiomed.2014.05.015
  14. Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., Chahory, S., Cordonnier, N., Desquilbet, L., Hurion, M. and Zahariev, A., 2018. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. Communications biology, 1(1), pp.1-8.