Calorie restriction

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Calorie restriction or Caloric restriction (CR) is the practice of limiting dietary energy intake in the hope that it will improve health and retard aging. In human subjects, CR has been shown to lower cholesterol, fasting glucose, and blood pressure. Some consider these to be biomarkers of aging, since there is a correlation between these markers and risk of diseases associated with aging. Except for houseflies (below), animal species tested with CR so far, including primates, rats, mice, spiders, Drosophila, C. elegans and rotifers, have shown lifespan extension. CR is the only known dietary measure capable of extending maximum lifespan, as opposed to average lifespan. In CR, energy intake is minimized, but sufficient quantities of vitamins, minerals and other important nutrients must be eaten. To emphasize the difference between CR and mere "FR" (food restriction), 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.

Contents

[edit] Research history

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 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 0-398-05496-7).

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. Among the most notable are the members of the Calorie Restriction Society.

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.”

[edit] Effects of CR on different organisms

[edit] Primates

Researchers at New York's Mount Sinai School of Medicine found that compared to monkeys fed a normal diet, squirrel monkeys on a life-long calorie-restrictive diet were less likely to develop Alzheimer's-like changes in their brains. Since squirrel monkeys are relatively long lived, definitive conclusions regarding whether or not they are aging slower are not yet available.

[edit] Rats

Seventy years ago, McCay CM, et al., discovered that reducing the amount of calories fed to rats nearly doubled their lifespan. For the last seventy years, scientists have proposed hypotheses as to why. Some explanations included reduced cellular divisions, lower metabolism rates, and reduced production of free radicals generated by metabolism. Recently, Harvard professor David A. Sinclair has conducted research that provides a new explanation for the lifespan extension caused by calorie restriction. It involves the activation of a gene called Sirt1. When Sirt1 gene activity is increased by genetic manipulation, caloric restriction does not increase it any further. Knocking out the Sirt1 gene also eliminates any beneficial effect from caloric restriction. Resveratrol has been demonstrated to increase the activity of the Sirt1 gene the same way caloric restriction does.[citation needed] When resveratrol increased the subject's lifespan, caloric restriction failed to increase it any further.

[edit] Mice

Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic hypothalamus as they grow old. The female mice that were given a calorically restricted diet during the majority of their lives, maintained higher levels of ERα in the pre-optic hypothalamus than their non-calorically restricted counterparts.[1] Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice.[2]

[edit] Spider

[edit] Drosophila

Research in 2003 by Mair et al. ([8]) showed that calorie restriction has an instantaneous effects on death rates in fruit flies of any age.

[edit] C. elegans

[edit] Rotifer

[edit] 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.

[edit] Hormesis hypothesis

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 protect 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.

[edit] Sir2/SIRT1

Sir2 or "silent information regulator 2" is a longevity gene in baker's yeast cells that extends lifespan by suppressing DNA instability (see Sinclair and Guarente, Cell, 1997)[3]. In mammals Sir2 is known as SIRT1. 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. David Sinclair at Harvard Medical School, Boston, showed that in mammals the SIRT1 gene is turned on by a CR diet, and this protects cells from dying under stress[4]. An article in the June 2004 issue of the journal Nature showed that SIRT1 releases fat from storage cells [5] See also SIRT1 in the Ensembl genome browser. Sinclair's lab reported that they have found small molecules (e.g. resveratrol) that activate Sir2/SIRT1 and extend the lifespan of yeast[6], nematode worms, fruit flies[7], and mice comsuming a high caloric diet[8]. An Italian group headed by Antonio Cellerino showed that resveratrol extends the lifespan of a vertebrate fish by 59%[9]. In the yeast, worm, and fly studies, resveratrol did not extend lifespan if the Sir2 gene was mutated. A group of researchers headed by Matthew Kaeberlein and Brian Kennedy at the University of Washington Seattle believe that Sinclair's work on resveratrol is an artifact and that the Sir2 gene has no relevance to CR[10].

[edit] DHEA

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).

[edit] 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.

[edit] 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 the first, they show that calorie restriction does not increase respiration in yeast (in contrast with the model proposed by Lenny Guarente). In the second, calorie restriction decreased the activity of TOR, a nutrient-responsive signaling protein already known to regulate aging in worms and flies. This paper is the first to directly link TOR to calorie restriction.

[edit] Objections to Calorie Restriction

[edit] 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 calorie 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.

[edit] Catabolic damage

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.

[edit] 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.

[edit] 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.

[edit] Benefits only the young

There is evidence to suggest that the benefit of CR in rats might only be reaped in early years. A study on rats which were gradually introduced to a CR lifestyle at 18 months showed no improvement over the average lifespan of the Ad libitum group[11]. This view, however, is disputed by Spindler, Dhahbi, and colleagues who showed that in late adulthood, acute CR partially or completely reversed age-related alterations of liver, brain and heart proteins and that mice placed on CR at 19 months of age show increases in lifespan[12].

[edit] Possible contraindications

Both animal and human research suggest CR may be contraindicated for people with amyotrophic lateral sclerosis (ALS). Research on a transgenic mouse model of ALS demonstrates that CR may hasten the onset of death in ALS. Hamadeh et al therefore concluded: "These results suggest that CR diet is not a protective strategy for patients with amyotrophic lateral sclerosis (ALS) and hence is contraindicated." [13] Hamadeh et al also note two human studies[14][15] that they indicate show "low energy intake correlates with death in people with ALS." However, in the first study, Slowie, Paige, and Antel state: "The reduction in energy intake by ALS patients did not correlate with the proximity of death but rather was a consistent aspect of the illness." They go on to conclude: "We conclude that ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake." (PMID 8604660)

Previously, Pedersen and Mattson also found that in the ALS mouse model, CR "accelerates the clinical course" of the disease and had no benefits.[16] Suggesting that a calorically dense diet may slow ALS, a ketogenic diet in the ALS mouse model has been shown to slow the progress of disease.[17] More recently, Mattson et al opine that the death by ALS of Roy Walford, a pioneer in CR research and its antiaging effects, may have been a result of his own practice of CR. [18] However, as Mattson et al acknowledge, Walford's single case is an anecdote that by itself is insufficient to establish the proposed cause-effect relation.

[edit] Negligible effect on larger organisms

Another objection to CR as an advisable lifestyle for humans is the claim that the physiological mechanisms that determine longevity are very complex, and that the effect would be small to negligible in our species. [19]

[edit] Note on Terminology: Calorie Restriction vs. Caloric Restriction

Most believe that "calorie restriction" is the better 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."

[edit] Intermittent fasting as an alternative approach

Studies by Mark P. Mattson, Ph. D., 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 60% of the calories given to a control group. A third group was fasted for 24 hours, then permitted to free-feed. [9] 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."

In a television interview with Meredith MacRae c. 1984, Roy Walford mentions intermittent fasting and its dramatic effects on animal life span through "undernutrition without malnutrition".

[edit] See also

[edit] Notes

  1. ^ Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H., 2005. "Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice". Neuro Endocrinol Lett. 2005 Jun; Vol. 26(3):197-203. PMID 15990721
  2. ^ F. Yaghmaie, O. Saeed, S.A. Garan, M.A. Voelker, A.M. Gouw, W. Freitag, H. Sternberg and P.S. Timiras, "Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice." Int J Dev Neurosci. 2006 Nov; Vol. 24(7):431-436. PMID 17034982
  3. ^ Sinclair DA, Guarente L. Extrachromosomal rDNA circles--a cause of aging in yeast. Cell. 1997 Dec 26;91(7):1033-42. PMID: 9428525[1]
  4. ^ Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004 Jul 16;305(5682):390-2. Epub 2004 Jun 17. PMID: 15205477[2]
  5. ^ Picard F, Kurtev M, Chung N, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004 Jun 17;429(6993):771-6. PMID 15175761. Letter in Nature
  6. ^ Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24. PMID: 12939617[3]
  7. ^ Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004 Aug 5;430(7000):686-9. Epub 2004 Jul 14. Erratum in: Nature. 2004 Sep 2;431(7004):107. PMID: 15254550[4]
  8. ^ Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. Epub 2006 Nov 1. PMID: 17086191[5]
  9. ^ Curr Biol. 2006 16:296[6]
  10. ^ Kaeberlein M, Kirkland KT, Fields S, Kennedy BK. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol. 2004 Sep;2(9):E296. Epub 2004 Aug 24. PMID: 15328540[7]
  11. ^ Lipman RD, Smith DE, Bronson RT, Blumberg J. Is late-life caloric restriction beneficial? Aging (Milano). 1995 Apr;7(2):136-9. PMID 7548264
  12. ^ Spindler SR. Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction. Mech Ageing Dev. 2005 Sep;126(9):960-6. Review. PMID: 15927235
  13. ^ Hamadeh MJ, Rodriguez MC, Kaczor JJ, Tarnopolsky MA. Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse. Muscle Nerve. 2005 Feb;31(2):214-20. PMID 15625688.
  14. ^ Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ. Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death. Am J Clin Nutr. 1996 Jan;63(1):130-7. PMID 8604660.
  15. ^ Slowie LA, Paige MS, Antel JP. Nutritional considerations in the management of patients with amyotrophic lateral sclerosis (ALS). J Am Diet Assoc. 1983 Jul;83(1):44-7. PMID 6863783
  16. ^ Pedersen WA, Mattson MP. No benefit of dietary restriction on disease onset or progression in amyotrophic lateral sclerosis Cu/Zn-superoxide dismutase mutant mice. Brain Res. 1999 Jun 26;833(1):117-20. PMID 10375685.
  17. ^ Zhao Z, Lange DJ , Voustianiouk A, et al. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neuroscience 2006, 7:29. (PMID 16584562). Media report on Zhao et al.
  18. ^ Mattson MP, Cutler RG, Camandola S. Energy intake and amyotrophic lateral sclerosis. Neuromolecular Med. 2007;9(1):17-20. PMID 17114821.
  19. ^ Phelan JP, Rose MR. Why dietary restriction substantially increases longevity in animal models but won't in humans. Ageing Res Rev. 2005 Aug;4(3):339-50. PMID 16046282

[edit] References

  • The Retardation of Aging and Disease by Dietary Restriction Richard Weindruch, Roy L. Walford (1988). ISBN 0-398-05496-7
  • 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.
  • 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.
  • 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.

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