Caloric Restriction

A popular topic on living longer is to maintain a 25-30% reduced calorie diet all year long.  This is the only approach that reliably lengthens the life of various animals from fruit flies to to dogs to monkeys.  There is some new evidence that alternative day caloric restriction helps humans.  Every day restriction is an extremely difficult diet to maintain because of the chronic hunger it causes.  Perhaps, the alternate day approach is doable and possibly even better.

Caloric Restriction Helped Overweight Adults: Prolonged calorie restriction increases life span in rodents. In a random assignment study of 48 overweight sedentary adults, participants were randomized to 1 of 4 groups for 6 months: control; calorie restriction (25% calorie restriction); calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet). Weight loss was: controls, -1.0%; calorie restriction, -10.4%; calorie restriction with exercise, -10.0%; and very low-calorie diet, -13.9%. Fasting insulin levels were reduced from baseline in the intervention groups (all P<.01), whereas DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie restriction and calorie restriction with exercise groups (both P<.05). After adjustment for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction (-135 kcal/d), calorie restriction with exercise (-117 kcal/d), and very low-calorie diet (-125 kcal/d) groups (all P<.008). These "metabolic adaptations" (~ 6% more than expected based on loss of metabolic mass) were statistically different from controls (P<.05). Protein carbonyl concentrations were not changed from baseline to month 6 in any group, whereas DNA damage was also reduced from baseline in all intervention groups (P <.005).

Protein Restriction Might Be Key: 40% protein restriction without strong caloric restriction also decreases Mitochondrial ROS generation and oxidative stress. It also increases maximum longevity (although to a lower extent than CR) and is a much more practicable intervention for humans than CR. An 80% methionine restriction also decreases MitROS generation in rat liver. Thus, methionine restriction seems to be responsible for the decrease in ROS production observed in caloric restriction. This is interesting because it is known that exactly that procedure of methionine restriction also increases maximum longevity. Methionine levels in tissue proteins negatively correlate with maximum longevity in mammals and birds. Mitochondrial oxidative stress, aging and caloric restriction: The protein and methionine connection. Pamplona R, et al. University of Lleida, Spain. Biochim Biophys Acta 2006 Feb 24. Ed: At least some human research has found some elderly eat too little protein and die sooner. Neither fat nor carbohydrate restriction decrease mitochondrial ROS and oxidative stress. J Bioenerg Biomembr 2006 Dec;38(5-6):327-33.

Caloric Restriction Minor Benefit for Humans: With mice, if you restrict their caloric intake by 10 percent, they live longer than if they have unlimited access to food.  If you restrict their intake by 20 percent, they live even longer, and restrict them to 50 percent, they live longer still; but restrict their intake by 60 percent and they starve to death. However, for humans, caloric restriction is not a panacea. While caloric restriction is likely to be almost universal in its beneficial effects on longevity, the benefit to humans is going to be small, even if humans restrict their caloric intake substantially and over long periods of time. Using a mathematical model demonstrating the relationship between caloric intake and longevity, using representative data from controlled experiments with rodents, as well as published studies on humans, diet and longevity, people who consume the most calories have a shorter life span, and that if people severely restrict their calories over their lifetimes, their life span increases by between 3 percent and 7 percent. The trade-off between calories and longevity appears to be close to a linear relationship, but the slope isn't very steep. Do you want to spend decades severely limiting what you eat to live a few more years? You will be unhappy and then your life will end shortly after mine ends. When you restrict the caloric intake of rodents, the first thing they do is shut off their reproductive system. A normal rodent reaches maturity at one month of age, and begins reproducing its body weight in offspring every month and a half. If humans shut off reproduction by severely limiting calories, the reduction in wear and tear on the body is minimal. The rodents placed on severely restricted diets bit people who tried to hold them, and had an unpleasant demeanor, unlike the more docile animals given more "normal" amounts of food. The human data factored into the mathematical model include the caloric intake of people in Japan, and their longevity, compared with sumo wrestlers, who consume more than twice the normal male diet, and men in Okinawa, Japan, who consume less than the average Japanese male. John Phelan, et al. UCLA. Why dietary restriction substantially increases longevity in animal models but won't in humans. Ageing Research Reviews 8/05.

Human Evidence of Benefit: Restricting caloric intake to 60-70% of normal adult weight maintenance requirement prolongs lifespan 30-50% and confers near perfect health across a broad range of species. Every other day feeding produces similar effects in rodents, and profound beneficial physiologic changes have been demonstrated in the absence of weight loss in ob/ob mice. Since May 2003 we have experimented with alternate day calorie restriction, one day consuming 20-50% of estimated daily caloric requirement and the next day ad lib eating, and have observed health benefits starting in as little as two weeks, in insulin resistance, asthma, seasonal allergies, infectious diseases of viral, bacterial and fungal origin (viral URI, recurrent bacterial tonsillitis, chronic sinusitis, periodontal disease), autoimmune disorder (rheumatoid arthritis), osteoarthritis, symptoms due to CNS inflammatory lesions (Tourette's, Meniere's) cardiac arrhythmias (PVCs, atrial fibrillation), menopause related hot flashes. In an article from 1957 in the Spanish medical literature, subjects were eating, on alternate days, either 900 calories or 2300 calories, averaging 1600, and that body weight was maintained. Thus they consumed either 56% or 144% of daily caloric requirement. The subjects were in a residence for old people, and all were in perfect health and over 65. Over three years, there were 6 deaths among 60 study subjects and 13 deaths among 60 ad lib-fed controls. Study subjects were in hospital 123 days, controls 219, highly significant difference.

Fish Oil Helps: Influence of food restriction (40% overall reduction in intake of all dietary components) combined with substitution of fish oil for corn oil in a factorial design. Autoimmune-prone (NZB x NZW)F(1) (B/W) mice, which develop fatal autoimmune renal disease, were used. The food-restricted/fish oil diet maximally extended median life span to 645 d (vs. 494 d for the food-restricted corn oil diet). Similarly, fish oil prolonged life span in the ad libitum-fed mice to 345 d (vs. 242 for the ad libitum/corn oil diet). Increased life span was partially associated with decreased body weight, blunting renal proinflammatory cytokine (interferon-gamma, interleukins-10 and -12 and tumor necrosis factor-alpha) levels and lower nuclear factor-kappaB (NF-kappaB). Reductions in NF-kappaB were preceded by enhanced superoxide dismutase, catalase and glutathione peroxidase activities. These findings demonstrate the profound additive effects of food restriction and (n-3) fatty acids in prolonging life span in B/W mice. J Nutr 2001 Oct;131(10):2753-60

Dogs: Caloric Restriction by 25% Lengthens Life: 48 dogs from 7 litters were paired, and 1 dog in each pair was fed 25% less food from 8 weeks of age until death. Median life span was significantly longer for the group that was fed 25% less food, whereas causes of death were generally similar. High body-fat mass and declining lean mass significantly predicted death 1 year prior to death, and lean body composition was associated with metabolic responses that appeared to be integrally involved in health and longevity. Lawler DF, et al. Nestle Purina, St Louis, MO. J Am Vet Med Assoc. 2005 Jan 15;226(2):225-31

Caloric Restriction May Be Better CR delayed the onset and reduced the incidence of seizures at both juvenile and adult ages and was devoid of adverse side effects. Furthermore, mild CR (15%) had a greater antiepileptogenic effect than the well-established high-fat ketogenic diet in the juvenile mice. The CR-induced changes in blood glucose levels were predictive of both blood ketone levels and seizure susceptibility. CR may reduce seizure susceptibility in EL mice by reducing brain glycolytic energy. Preclinical findings suggest that CR may be an effective antiseizure dietary therapy for human seizure disorders.

Food Restriction Helps Mice: Breast cancer survival is markedly improved with moderate food restriction vs. eating at will with 5% corn oil.  But substitution of 20% corn oil with 2% fish oil in ad libitum diets didn’t help. Proc Natl Acad Sci ’95;92:6494

Caloric Restriction in Monkeys Helps: CR (30%) monkeys have slightly lower body temperature and initial energy expenditure following onset of restriction, and better glucose tolerance and insulin sensitivity. The latter suggest a reduced predisposition towards diabetes as the animals age. Other potential anti-disease effects include biomarkers suggestive of lessened risk of cardiovascular disease and possibly cancer. Candidate biomarkers of aging, including the age-related decrease in plasma dehydroepiandrosterone sulfate (DHEAS), suggest that the CR animals may be aging more slowly than controls in some respects, although sufficient survival data will require more time to accumulate. In summary, nearly all CR effects detected in rodents, which have thus far been examined in primates,

Caloric Restriction Increases Melatonin: Food deprivation doubles melatonin in GI tract. It is a very potent scavenger of free radicals that has increased lifespan of mice in several studies. Bubenik, U Guelph, Science News 7/6/02.

Helps Mice Late in Life Against p53: Caloric restriction or a 1 day/week fast suppressed carcinogenesis even when started late in life in mice predestined to develop tumors due to decreased p53 gene dosage-support efforts to identify suitable interventions influencing energy balance in humans as a tool for cancer prevention. Carcinogenesis 2002 May;23(5):817-822

Exercise, Moderate Alcohol Good: Exercise was predictive of fewer IADL limitations and greater longevity, positive affect, and meaning in life 8 years later. Avoiding tobacco was predictive of longevity. Before controlling for health conditions, exercise predicted decreased risk of basic activities of daily living limitations and having more goals; moderate alcohol use predicted longevity; annual health checkup predicted more IADL limitations. Case Western, Kahana, Psychosom Med 2002 May-Jun;64(3):382-94

Caloric Restriction Every Other Day Better for Mice DM & Dementia: Mouse study suggests fasting every other day can help fend off diabetes and protect brain neurons as well as or better than either vigorous exercise or caloric restriction. Reduced meal frequency produced these beneficial effects even if the animals gorged when they did eat, National Institute on Aging. Proceedings of the National Academy of Sciences Online April 28, 2003, Dr. Mattson. Mice that were fasted every other day but were allowed to eat unlimited amounts on intervening days had lower blood glucose and insulin levels than either a control group, which was allowed to feed freely, or a calorically restricted group, which was fed 30 percent fewer calories. Also better resistance to a neurotoxin.

Caloric Restriction Did Not Help Decrease Rat Dementia: At 24 months, no difference between those on 60% calories vs. ad libitum (at will). Neurobiol Aging 3/99

Caloric Restriction Decreased Dementia in Presenilin- Mutant Mice: In mice. Zhu, Univ Kentucky, Brain Res 9/99 842:224

Melatonin: Caloric Restriction Increases Melatonin; Increases Mouse Lifespan: Food deprivation doubles melatonin in GI tract. It is a very potent scavenger of free radicals that has increased lifespan of mice in several studies. Bubenik, U Guelph, Science News 7/6/02. The pineal gland is smaller in obesity.

Vegans Lowest Cholesterol, Lowest Mortality: In the Oxford 12 year follow-up study of 6000 vegetarians and 5000 of their fish or meat eating friends (meat Qwk or more), HDL was slightly higher for fish eaters. Total cholesterol and LDL was lowest for vegans and highest for meat-eaters. All groups in study had much lower mortality than English average. Standardized mortality ratios lower for non-meat eaters: .80 all causes, .70 cardiac, .61 cancer. Animal fat consumption strongly linked to ischemic cardiac mortality. Eggs and cheese positively linked with cardiac mortality. Fish, fiber, alcohol no protective effect. All cause mortality was inversely linked to nuts and had a U-shaped relationship with milk and eggs suggestive. More appendectomies in meat eaters. Amer J Clin Nutr 01

Caloric Restriction Helps Even Elderly Rats: Rats demonstrated that DR initiated later in life (26.5 months old) restored the activities of proteasomes that have been implicated in removal of altered proteins. Thus, DR initiated even relatively late in life appears to have beneficial effects, restoring an animal's youthful condition in terms of the age-related accumulation of altered proteins. Toho Univ. Effect of dietary restriction beyond middle age: accumulation of altered proteins and protein degradation. Takahashi R, Goto S. Microsc Res Tech 2002 Nov 15;59(4):278-81

Caloric Restriction May Work in Monkeys Via Increased Insulin Sensitivity: rhesus monkeys studied over approximately 25 years (8 dietary-restricted [DR] and 109 ad libitum-fed [AL] monkeys). During the study, 49 AL monkeys and 3 DR monkeys died. Compared with the DR monkeys, the AL monkeys had a 2.6-fold increased risk of death. Hyperinsulinemia led to a 3.7-fold increased risk of death (p <.05); concordantly, the risk of death decreased by 7%, per unit increase in insulin sensitivity (M). There was significant organ pathology in the AL at death. The age at median survival in the AL was approximately 25 years compared with 32 years in the DR. Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction. Bodkin NL, Alexander TM, Ortmeyer HK, Johnson E, Hansen BC. U Maryland. J Gerontol A Biol Sci Med Sci 2003 Mar;58(3):212-9

Total Calories, Not Protein, Effects Longevity: Even with protein as high as 83%, mice lives were markedly prolonged by caloric restriction. Proc Natl Acad Sci USA ’86;41:126. Environ Health Perspec 2/98;106 Suppl 1:313

Thomas E. Radecki, M.D., J.D.

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