to average lifespan. Energy intake must be minimized, but sufficient quantities of vitamins, minerals and other important nutrients must still be ingested. To emphasize this, CR is often referred to by a plethora of other names such as CRON or CRAN (calorie restriction with optimal/adequate nutrition), or the "high-low diet" (high in all nutrients aside from calories, in which it is "low"). Other names for the diet emphasize the goal of the diet, such as CRL (calorie restriction for longevity), or simply The Longevity Diet, as in a recently published book by that name.
In 1934, Clive McCay and Mary Crowell of Cornell University observed that laboratory rats fed a severely reduced calorie diet while maintaining vital nutrient levels resulted in life spans of up to twice as long as otherwise expected. These findings were explored in detail by a series of rigid experiments with mice conducted by Roy Walford and his student Richard Weindruch. In 1986, Weindruch reported that restricting the calorie intake of laboratory mice proportionally increased their lifespan compared to a group of mice with a normal diet. The calorie-restricted mice also maintained youthful appearances and activity levels longer, and showed delays in age-related diseases. The results of the many experiments by Walford and Weindruch were summarized in their book The Retardation of Aging and Disease by Dietary Restriction (1988) (ISBN 0398054967).
The findings have since been accepted, and generalized to a range of other animals. Researchers are investigating the possibility of parallel physiological links in humans (see Roth et al below). In the meantime, many people have independently adopted the practice of calorie restriction in some form, hoping to achieve the expected benefits themselves.
Washington University trials were set up in 2002 and involved about 30 participants. Dr. Luigi Fontana, clinical investigator, says CR practitioners seem to be ageing more slowly than the rest of us. “Take systolic blood pressure,” he says. “Usually, that rises with age reliably, partly because the arteries are hardening. In my group, mean age is 55, and mean systolic blood pressure is 110: that’s at the level of a 20-year-old.
“Of course, I can’t tell you if my subjects will live to 130. So many uncontrollable factors affect length of life. I don’t have enough evidence to prove these people are ageing more slowly, but it looks like it.”
Why might CR increase longevity?
There have been many theories as to how CR works, and many of them have fallen out of favor or been disproved. These include reduced basal metabolic rate, developmental delay, the control animals being gluttons, and decreased glucocorticoid production.
A small, but rapidly growing number of researchers in the CR field are now proponents of a new theory known as the "Hormesis Hypothesis of CR". In the early 1940s, Southam & Ehrlich, 1943 reported that a bark extract that was known to inhibit fungal growth, actually stimulated growth when given at very low concentrations. They coined the term "hormesis" to describe such beneficial actions resulting from the response of an organism to a low-intensity biological stressor. The word "hormesis" is derived from the Greek word "hormaein" which means "to excite". The Hormesis Hypothesis of CR proposes that the diet imposes a low-intensity biological stress on the organism, which elicits a defense response that helps protects it against the causes of aging. In other words, CR places the organism in a defensive state so that it can survive adversity, and this results in improved health and longer life. This switch to a defensive state may be controlled by longevity genes (see below).
Recent research has suggested (see Matthias Bluher, C. Ronald Kahn, Barbara B. Kahn, et al.) that it is not reduced intake which influences longevity. This was done by studying animals which have their metabolism changed to reduce insulin uptake, consequently retaining the leanness of animals in the earlier studies. It was observed that these animals can have a normal dietary intake, but have a similarly increased lifespan. This suggests that lifespan is increased for an organism if it can remain lean and if it can avoid any excess accumulation of adipose tissue: if this can be done while not diminishing dietary intake (as in some minority eating patterns, see e.g. Living foods diet or Joel Fuhrman) then the 'starvation diet' anticipated as an impossible requirement by earlier researchers is no longer a precondition of increased longevity.
The extent to which these findings may apply to human nutrition and longevity is as noted above under investigation. A paper in the Proceedings of the National Academy of Sciences, U.S.A. in 2004 showed that practitioners of a CR diet had significantly better cardiovascular health (PMID 15096581). Also in progress are the development of CR mimetic interventions.
Recent discoveries have suggested that the gene Sir2 might underlie the effect of CR. In baker's yeast the Sir2 enzyme is activated by CR, which leads to a 30% lifespan extension in test subjects. David Sinclair showed that in test mammals the Sir2 equivalent gene known as SIRT1 is turned on by a CR diet, and this protects cells from dying under stress. Leonard Guarente showed that SIRT1 releases fat from storage cells. This work was published in the June 2004 issues of the magazines Nature and Science (PMID 15175761). See also ENSEMBL gene database for information on SIRT1. Sinclair's lab reported that they have found small molecules (e.g. resveratrol) that activate Sir2 and can extend the lifespan of yeast.
More recent discoveries by Matt Kaeberlein and Brian Kennedy at the University of Washington have demonstrated that CR may not act through Sir2. Kaeberlein and Kennedy have also largely discredited Sinclair's work with resveratrol, demonstrating that the findings in Sinclair's Nature paper are an artifact of the Biomol Fluor de Lys assay (PMID 15684413).
While calorie restriction has been shown to increase DHEA in primates (PMID 12543259), it has not been shown to increase DHEA in post-pubescent primates (PMID 15247063).
Free radicals and glycation
Two very prominent theories of aging are the free radical theory and the glycation theory, both of which can explain how CR could work. With high amounts of energy available, mitochondria do not operate very efficiently and generate more superoxide. With CR, energy is conserved and there is less free radical generation. A CR organism will be less fat and require less energy to support the weight, which also means that there does not need to be so much glucose in the bloodstream. Less blood glucose means less glycation of adjacent proteins and less fat to oxidize in the bloodstream to cause sticky blocks resulting in atherosclerosis. Type II Diabetics are people with insulin insensitivity caused by long-term exposure to high blood glucose. Obesity leads to type 2 diabetes. Type 2 diabetes and uncontrolled type 1 diabetes are much like "accelerated aging", due to the above effects. There may even be a continuum between CR and the metabolic syndrome.
In examining Calorie Restriction with Optimal Nutrition, it is observed that with less food, and equal nutritional value, there is a higher ratio of nutrients to calories. This may lead to more ideal essential and beneficial nutrient levels in the body. Many nutrients can exist in excess to their need, without side effects as long as they are in balance and not beyond the body's ability to store and circulate them. Many nutrients serve protective effects as antioxidants, and will be at higher levels in the body as there will be lower levels of free radicals due to the lower food intake.
Calorie Restriction with Optimal Nutrition has not been tested in comparison to Calorie Excess with Optimal Nutrition. It may be that with extra calories, nutrition must be similarly increased to ratios comparable to that of Calorie Restriction to provide similar antiaging benefits.
Stated levels of calorie needs may be biased towards sedentary individuals. Calorie restriction may be more of adapting the diet to the body's needs.
Although aging can be conceptualized as the accumulation of damage, the more recent determination that free radicals participate in intracellular signaling has made the categorical equation of their effects with "damage" more problematic than was commonly appreciated in years past.
Papers on CR in yeast: dismissing increased respiration
In late 2005 Matt Kaeberlein and Brian Kennedy published two important papers on calorie restriction in yeast. In a paper published in PLoS Genetics they show that Lenny Guarente's model for calorie restriction increasing respiration is wrong. In a potentially much more important paper published in Science they tell us what might actually be happening with calorie restriction - decreased TOR activity. TOR is a nutrient-responsive signaling protein already know to regulate aging in worms and flies, and this paper is the first to directly link TOR to calorie restriction.
Objections to Calorie Restriction
No benefit to houseflies
One of the most significant oppositions to caloric restriction comes from Michael Cooper, who has shown that caloric restriction has no benefit in the housefly PMID: 15319362. Michael Cooper claims that the widely purported effects of caloric restriction may be because a diet containing more calories can increase bacterial proliferation, or that the type of high calorie diets used in past experiments have a stickiness, general composition, or texture that reduces longevity.
A major conflict with calorie restriction is that a calorie excess is needed to prevent catabolizing the body's tissues. A body in a catabolic state promotes the degeneration of muscle tissue, including the heart. It also makes gaining muscle tissue difficult. Loss of muscle tissue is a strong indicator of aging.
Physical activity testing biases
While some tests of calorie restriction have shown increased muscle tissue in the calorie-restricted test subjects, how this has occurred is unknown. Muscle tissue grows when stimulated, so it is possible that the calorie-restricted test animals exercised more than their companions on higher calories. The reasons behind this may be irrelevant, as in any case it would be a bias in testing. Such tests need to be monitored to make sure that levels of physical activity are equal between groups.
Insufficient calories and amino acids for exercise
Exercise has also been shown to increase health and lifespan and lower the incidence of several diseases. Calorie restriction comes into conflict with the high calorie needs of athletes, and may not provide them adequate levels of energy or sufficient amino acids for repair.
Benefits only the young
Furthermore there is evidence to suggest that this benefit can only be reaped in early years. Lipman, Smith, Bronson and Blumberg published a study on Long Evans rats which were gradually introduced to a CR lifestyle at 18 months. This population showed no improvement over the median lifespan of Ad Libitum group. PMID: 7548264
Negligible effect on larger organisms
Another objection to CR as a lifestyle would be that the effect is small to negligible in larger organisms. John Phelan published an article PMID: 16046282 postulating that the CR case is vastly oversimplified when applied to larger mammals.
Note on Terminology: Calorie Restriction vs. Caloric Restriction
Most believe that "calorie restriction" is the best term for this diet. The adjective "caloric" is inappropriate for the same reason that the theory of music is not called "musical theory," but rather "music theory." A musical theory is a theory of a musical nature, not a theory of or about music. The CR diet is not a "restriction of a caloric nature." Likewise, the restriction of protein in the diet is referred to as "protein restriction," not "proteinic restriction." Nonetheless, many researchers still say "caloric restriction."
Intermittent fasting as an alternative approach
Studies by Mark P. Mattson, PhD, chief of the National Institute on Aging's (NIA) Laboratory of Neurosciences, and colleagues have found that intermittent fasting and calorie restriction affect the progression of diseases similar to Huntington's disease, Parkinson's disease, and Alzheimer's disease in mice (PMID 11119686). In one study, rats and mice ate a low-calorie diet or were deprived of food for 24 hours every other day (PMID 12724520). Both methods improved glucose metabolism, increased insulin sensitivity, and increased stress resistance. Researchers have long been aware that calorie restriction extends lifespan, but this study showed that improved glucose metabolism also protects neurons in experimental models of Parkinson's and stroke.
Another NIA study found that intermittent fasting and calorie restriction delays the onset of Huntington's disease-like symptoms in mice and prolongs their lives (PMID 12589027). Huntington's disease (HD), a genetic disorder, results from neuronal degeneration in the striatum. This neurodegeneration results in difficulties with movements that include walking, speaking, eating, and swallowing. People with Huntington 's also exhibit an abnormal, diabetes-like metabolism that causes them to lose weight progressively.
This NIA study compared adult HD mice who ate as much as they wanted to HD mice who were kept on an intermittent fasting diet during adulthood. HD mice possess the abnormal human gene huntingtin and exhibit clinical signs of the disease, including abnormal metabolism and neurodegeneration in the striatum. The mice on the fasting program developed clinical signs of the disease about 12 days later and lived 10 to 15% longer than the free-fed mice. The brains of the fasting mice also showed less degeneration. Those on the fasting program also regulated their glucose levels better and did not lose weight as quickly as the other mice. Researchers found that fasting mice had higher brain-derived neurotrophic factor (BDNF) levels. BDNF protects neurons and stimulates their growth. Fasting mice also had high levels of heat-shock protein-70 (Hsp70, which increases cellular resistance to stress.
Another NIA study indicates that intermittent fasting may be more beneficial than cutting calorie intake. The researchers fed one group of mice 40% of the calories given to a control group. A third group was fasted for 24 hours, then permitted to free-feed. According to an Associated Press article ( 29 April 2003 ), the fasting mice "didn't cut total calories because they ate twice as much on days they weren't fasting. Both the fasting mice and those on a restricted diet had significantly lower blood sugar and insulin levels than the free-fed controls. A toxin that damages hippocampal cells was injected in all of the mice. Hippocampal damage is associated with Alzheimer's. Interestingly, the scientists found less damage in the brains of the fasting mice than in those that ate either a restricted or a normal diet. The NIA is planning a human study that will compare a group eating three meals a day with a group eating the same diet and amount of food within four hours and then fasting 20 hours."
- Genes & Development ; Koubova,J; 17(3):313-321 (2003) Review of maximum lifes span extension by calorie restriction
- The Retardation of Aging and Disease by Dietary Restriction Richard Weindruch, Roy L. Walford (1988). ISBN 0398054967
- Ageless Quest. Lenny Guarente, Cold Spring Harbor Press, NY. 2003. ISBN 0879696524.
- The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. Journal of Nutrition, 116(4), pages 641-54.Weindruch R, et al.,April, 1986. PMID 3958810.
- Caloric Restriction and Aging Richard Weindruch in Scientific American, Vol. 274, No. 1, pages 46--52; January 1996.
- 2-Deoxy-D-Glucose Feeding in Rats Mimics Physiological Effects of Caloric Restriction. Mark A. Lane, George S. Roth and Donald K. Ingram in Journal of Anti-Aging Medicine, Vol. 1, No. 4, pages 327--337; Winter 1998.
- Biomarkers of caloric restriction may predict longevity in humans. Roth GS, Lane MA, Ingram DK, Mattison JA, Elahi D, Tobin JD, Muller D, Metter EJ.: 297: 811, Science 2002. PMID 12161648.
- Eat more, weigh less, live longer, New Scientist, January 2003. http://www.newscientist.com/article.ns?id=dn3303
- Extended longevity in mice lacking the insulin receptor in adipose tissue. Bluher, Khan BP, Kahn CR, Science 299(5606): 572-4, 24 January 2003 . PMID 12543978.
- Interview,I want to live forever, Cynthia Kenyon Professor of Biochemistry and Biophysics at the University of California , San Francisco , by James Kingsland. New Scientist online, 20 October 2003 . http://www.newscientist.com/channel/opinion/mg18024175.300
- Sir2-independent life span extension by calorie restriction in yeast, Kaeberlein, M., K.T. Kirkland, S. Fields, and B.K. Kennedy. 2004. PLoS Biol 2: E296. PMID 15328540.
- Substrate-specific Activation of Sirtuins by Resveratrol, Kaeberlein, M., T. McDonagh, B. Heltweg, J. Hixon, E.A. Westman, S.D. Caldwell, A. Napper, R. Curtis, P.S. Distefano, S. Fields, A. Bedalov, and B.K. Kennedy. 2005. J Biol Chem 280: 17038-45. PMID 15684413.
- Interview, Longevity and Genetics, Matt Kaeberlein, Brian Kennedy. SAGE Crossroads
- Increased Life Span due to Calorie Restriction in Respiratory-Deficient Yeast, Kaeberlein M, Hu D, Kerr EO, Tsuchiya M, Westman EA, Dang N, Fields S,Kennedy BK. PLoS Genet. 25 November 2005 ;1(5):e69
- Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients, Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK. Science. 18 November 2005 ;310(5751):1193-6.