Caloric restriction

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 minimised, but sufficient quantities of vitamins, minerals and other important nutrients must still be taken. To emphasise this, CR is often referred to as CRON or CRAN (caloric restriction with optimal or adequate nutrition.)

While scientists knew about the effects of CR since the 1930s, the first major demonstration of the benefits of caloric restriction was 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 generalised 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 caloric 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”. What is "hormesis"? 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 demonstrated (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 by two leading researchers in the field, Prof. Leonard Guarente (M.I.T.) and Prof. David Sinclair (Harvard University) have shown 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. 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. 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 (http://www.ensembl.org/Mus_musculus/geneview?gene=ENSMUSG00000020063) for information on SIRT1. Sinclair's lab has recently reported that they have found small molecules that activate Sir2, and these can extend the lifespan on yeasts, worms and flies. These molecules, known as STACs for "Sir2 activating compounds", only work in organisms that have a functional Sir2 gene. Experiments to extend the lifespan of mice by activating SIRT1 using genetic and chemical means are in progress.

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

References

• 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; Januarytits

• 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.

External links

• Calorie Restriction Society (http://www.calorierestriction.org/)
• Weight loss methods and classification of caloric restriction diets. (http://www.thedoctorslounge.net/centers/nutrition/weight_loss/index.htm)
• A study of the high rate of centenarians in Okinawa. (http://www.okinawaprogram.com/)
• Calorie Restriction with Optimum Nutrition Web site. (http://www.cron-web.org/)