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Calorie Restriction

Calorie restriction or Caloric restriction (CR) is the practice of limiting dietary energy intake to improve health and retard aging. In human subjects, CR is known to slow the signs of aging, as indicated by biomarkers such as cholesterol and blood pressure. Every animal species tested with CR so far, including monkeys, rats, spiders and rotifers, has shown corresponding lifespan extension. CR is the only known dietary measure capable of extending maximum, as opposed 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, or 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.

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 revisited in an experimental trial conducted by 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 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.

Why does CR increase longevity?

There have been many theories as to how CR works, and many of them have fallen out of favor or been outright disproved. These include reduced metabolic rate, developmental delay, the control animals being gluttons, and decreased steroid glucocorticoid production.

A small, but rapidly growing number of respected 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 accumulation of fatty 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 extension of these findings to human nutrition and longevity is as noted above still in progress. 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. 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. David Sinclair showed that in 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. 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 does 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.

Calorie restriction has also been shown to increase DHEA in primates (Exp Gerontol. 2003 Jan-Feb; 38(1-2):35-46).

"To lengthen thy life, lessen thy meals." - Benjamin Franklin, "Poor Richard's Almanack", June 1733

 

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."

References

* Ageless Quest. Lenny Guarente, Cold Spring Harbor Press, NY. 2003.

* 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.

* 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.

* Eat more, weigh less, live longer, New Scientist, January 2003.

* Extended longevity in mice lacking the insulin receptor in adipose tissue. Bluher, Khan BP, Kahn CR, Science 299(5606): 572-4, Jan 24, 2003.

* 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, 20th October 2003.

* 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.

* 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.

* Interview, Longevity and Genetics, Matt Kaeberlein, Brian Kennedy.


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