Fight Aging!

Can caloric restriction extend human lifespan?

Copyright © Ian Williams Goddard

Only one intervention has been proven to extend both the average and maximum lifespan of all animal species tested: reducing the consumption of dietary calories, or caloric restriction (CR). [1-2] While widely recommended, exercise and nutritional supplementation have not been shown to extend maximum lifespan. [3-5] Because CR extends maximum lifespan, scientists believe it actually slows the process of aging. CR is therefore used as a means to study the process of aging. [6,7]

The graph to the left shows the lifespans of four groups of mice, illustrating the dramatic life extension induced by life-long CR. [8] The first group (green) were controls who ate freely without restriction and define normal lifespan. The other three groups were subjected to different degrees of CR initiated at one month of age, which is equivalent to a 2 year old child. Such early onset CR results in stunted growth and is therefore not acceptable for humans. The results found that more CR resulted in more life extension -- a pattern that holds until CR becomes actual starvation, whereupon it shortens lifespan. [9] The graph is a two-frame animation. The second frame shows equivalent human lifespan.

Adult-onset CR: Only adult-onset-CR data are relevant for human consideration, and life extension is less when CR is initiated in midlife, approaching nil when initiated in late life. [10] The next graphs show the lifespans of two long-lived mouse types gradually subjected to 44% (B10) and 27% (B6) CR starting at 12.5 months of age versus controls. B10 mice started CR at a human-age equivalence of 30, while B6 mice started CR at a human-age equivalence of 40. [11] Note: Adult-onset CR extends animal life only when phased in gradually (over a period equivalent to 2.5 years in humans) and when augmented with a nutrient-enriched diet.

Caloric Restriction initiated in adult mice vs controls, and human lifespan equivalence.
Adult-onset CR extends life only when phased in gradually including a nutrient-enriched diet.

CR not only extends the lifespan of laboratory animals but also reduces the incidence of virtually all diseases of aging such as cancer, [12-15] heart disease, [16,17] diabetes, [18-20] osteoporosis, [21,22] auto-immune disorders, [23-25] neurological decline [26-30] and diseases such as Alzheimer's [31] and Parkinson's. [32-34] Those references are linked to abstracts at the National Library of Medicine, please follow them for further details. While CR has failed to extend some cognitive functions in the Fisher-344 rat, [35,36] overall, CR has been shown to dramatically extend both the life and health of all animal species tested to date.

From Mice to Men?

The question that matters is: Will CR do for humans in real life what it does for animals in the lab? Because we humans live so long, no CR lifespan experiments have been conducted on humans. However, if CR can extend human lifespan one would expect to find a correlation between low body weight and longevity, since eating less is associated with lower weight. The fact that such a correlation does exist tends to support the hypothesis that CR will do for humans what it does for other mammals.

While early studies suggested that lower body weight was associated with increased mortality, once researchers accounted for factors such as smoking and illness-induced weight loss, the data showed a correlation between lower weights and increased longevity. [37] Several examples:

* In 1985, the National Institute of Health, Centers for Disease Control, and the Department of Health and Human Services published a "special report" stating: "[S]tudies based on life insurance data, the American Cancer Society Study and other long-term studies, such as the Framingham Heart Study and the Manitoba Study, indicate that the weights associated with the greatest longevity tend to be below the average weights of the population as long as such weights are not associated with concurrent illness or a history of medical impairment." [38]

* In 1993, the Journal of the American Medical Association published a study that concluded: "In these prospective data, body weight and mortality were directly related. After accounting for confounding by cigarette smoking and bias resulting from illness-related weight loss or inappropriate control for the biologic effects of obesity, we found no evidence of excess mortality among lean men. Indeed, lowest mortality was observed among men weighing, on average, 20% below the US average for men of comparable age and height." [39]

* In 1995, a study published in New England Journal of Medicine concluded: "Among women who never smoked, the leanest women ... had the lowest mortality, and even women with average weights had higher mortality. Mortality was lowest among women whose weights were below the range of recommended weights in the current U.S. guidelines. Moreover, a weight gain of 10 kg of more since the age of 18 was associated with increased mortality in middle adulthood. These data indicate that the lowest mortality rate for U.S. middle- aged women is found at body weights at least 15 percent below the U.S. average for women of similar age." [40]

* In 1997, the American Journal of Clinical Nutrition published a study on body weight and mortality stating: "We conclude that when appropriate adjustments are made for effects of smoking and underlying disease, optimal weights [for longevity] are below average in both men and women; this appears to be true throughout the adult life span." [41]

While such studies based on epidemiological data establish correlation, not causation, the weight of these findings among human populations in addition to laboratory proof that CR extends the lifespan of other mammals tends to favor the hypothesis that CR will also extend human lifespan.

Okinawa: Less Calories More Life

The Japanese district of Okinawa has the longest average lifespan in the world [42] and the highest percentage of centenarians -- people living to a 100 or more -- ever documented from reliable records. [43] Consistent with CR-induced life extension, Okinawans also eat up to 40 percent fewer calories than Americans [44] and 17 percent fewer calories than the Japanese average. [45] The caloric intake of Okinawan children is 36 percent below the Japanese recommended intake. [45] And yet, satisfying a necessary ingredient for CR-induced life extension, Okinawans have adequate nutrition. [45]

Not only do Okinawans have reduced mortality, but also consistent with animal CR research, they enjoy reduced morbidity from a range of causes. For example, these findings were presented at the annual meeting of the American Geriatrics Society (2001) [44]:

Compared to Americans, Okinawan elders

are 75% more likely to retain cognitive ability
get 80% fewer breast and prostate cancers
get 50% fewer ovarian and colon cancers
have 50% fewer hip fractures
have 80% fewer heart attacks

While many factors may contribute to Okinawan lifespan, researchers tend to favor the CR theory as the best explanation. [44] Even without explicit human CR research, available data tends to favor the hypothesis that CR-induced life extension may be a universal effect that applies to all species including humans. Perhaps the next best thing to human research is CR research on primates, which is currently underway.

Primate CR Research

Since 1987, the National Institute on Aging has been conducting a long-term study of CR on rhesus monkeys. In 1999, the NIA researchers stated: "[E]merging data from studies of CR in rhesus monkeys show promise that the model is working in a manner similar to that seen in rodents thereby strengthening the possibility that the well known effects of CR on lifespan, disease, and aging processes may be generalizable to all species." [46]

More recently, I contacted NIA researcher George Roth, who told me: "Morbidity and mortality appear to be lower in CR monkeys." He stated further that this difference from controls is approaching statistical significance. [47] About the NIA study, Modern Maturity states: "The incidence of diabetes ... is greatly reduced in monkeys on a restricted diet. The monkeys also show fewer signs of spinal arthritis, a common condition they share with humans." [48] These monkeys show other signs of reduced aging, such as a prevention of age-associated decline in melatonin levels. [49]

This table shows other bio-markers in the CR monkeys and comparison to findings in CR rodents. [46]

Findings in NIA Primate CR Study	Matches Rodent Data
(-) Body weight	yes
(-) Fat and lean mass	yes
(-) Time to sexual maturation	yes
(-) Time to skeletal maturation	yes
(-) Fasting glucose/insulin	yes
(-) Metabolic rate (short-term)	yes
(*) Metabolic rate (long-term)	yes
(-) Body temperature	yes
(*) or (+) Locomotion	yes
(-) Triglycerides	yes
(+) IGF-1/growth hormone	yes
(-) Il-6	yes
(*) Wound closure rate	yes
(*) Clonal proliferation	yes/?
(*) B-gal senescent cells	?
(-) Lymphocyte number	yes
(*) Lymphocyte calcium response	no

(-) = decrease, (+) = increase, (*) = no change

While researchers at the Wisconsin Regional Primate Center found different gene-expression changes between CR primates and rodents, [50] the overall body of evidence cited above suggests that CR is doing for primates -- and thus may do for humans -- what it does for all other animal species tested. Considering the long duration of human lifespan, data derived from primate research in addition to human body-weight data and examples such as Okinawa may be as close as we will come to answering the question: Will CR do for humans what it does for all other animals tested?

Discussion

Having reviewed the available data, one might be inclined to consider embarking upon a CR regime. The correlation between below-average body weight and longevity is by itself sufficient to suggest the wisdom of such. But there are several things one must first consider. For example, any CR regime should (a) be implemented gradually over time, (b) include only highly nutritious foods and supplementation to avoid malnutrition, and (c) be supervised from the beginning by a knowledgeable physician.

An article recently published in Scientific American implies that only extreme near-starvation CR will result in appreciable health benefits. [1] However, the data indicate that deriving benefits from CR is a matter of degree, not all-or-nothing. In other words, some CR is likely to result in some health benefits, while progressively more may result in progressively more benefits that fall off only as CR becomes malnutrition, whereupon CR becomes harmful. Merely cutting out junk foods, virtually all of which are high-caloric, by itself could result in moderate CR.

Initiating CR in mice during adulthood extended average lifespan but failed to extend maximum lifespan until researchers implemented adult-onset CR gradually and provided a nutrient enriched diet for the rest of their lives. In the first study to shown that -- illustrated in the second graphs above -- CR was initiated at an incremental level for one month, followed thereafter by a higher level of CR. [11] That one month phase-in equals approximately 2.5 human years. In a more recent study, caloric intake in mice was reduced by 16% for two weeks, followed by 45% CR thereafter. [51] Those two weeks equal around 1.3 human years. A gradual phase-in also makes CR easier, allowing appetite to adjust. In my own experience, CR has increased my enjoyment of food.

Another other key to CR is optimal nutrition. Many third-world countries have lower caloric intake and yet do not live longer due in large to inadequate nutrition. Okinawa on the other hand is an example of low caloric intake with adequate nutrition, which researchers believe may be why Okinawans live so long. [44] However, while CR prolongs cognitive functions into old age in animals, researchers at the USDA found evidence of cognitive impairment during CR in obese women [52] probably associated with reduced levels of iron despite the fact that the women were still consuming twice the recommended daily allowance of iron. [53] The same research found significantly improved word recall. [52] But before taking iron supplements consider that excess iron may promote diseases such as cancer [54,55], Alzheimer's [56], and Parkinson's. [57]

The fact that the women doing CR had reduced iron levels despite consuming twice the recommended amount of iron highlights the wisdom of consulting a physician before embarking upon a long-term CR program in order to establish baseline blood measures of as wide a range of nutrients and other health bio-markers as possible. This way the effects of CR on your health can be monitored to detect and correct any deficiencies that might result. Despite the extensive medical literature on CR-induced life extension, some physicians may not be aware of it, especially of its exploratory application in humans. It might therefore be wise to seek out a physician knowledgeable in preventative and anti-aging medicine. [58] It would also be wise to consult resources on CR, such as the website of one of the leading CR experts, Dr Roy Walford. [59]

This is not the end of this report, just the beginning. The following references are not there to look impressive but to serve as an open door to a wide body of information on CR and all the details cited above. Enjoy...

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References

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[1] Taubes, G. (2000). The Famine of Youth. Scientific American, June.

[2] Study that discovered caloric restriction extends animal lifespan: McCay CM, et al. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size. Journal of Nutrition, 10(1), pages 63-79.

[3] Skalicky M, & Viidik A. (2000). The collagen biomarker of aging can be influenced by physical exercise also in senescent rats. Experimental Gerontology, August, 35(5), pages 595-603.

[4] Holloszy JO. (1993). Exercise increases average longevity of female rats despite increased food intake and no growth retardation. Journal of Gerontology, May, 48(3), pages B97-100.

[5] Meydani M, et al. (1998). The effect of long-term dietary supplementation with antioxidants. Annals of the New York Academy of Sciences, November, 20;854, pages 352-60.

[6] Merker K. (2001). Proteolysis, caloric restriction and aging. Mechanisms of Ageing and Development, May 31, 122(7), pages 595-615.

[7] Weindruch R. (2002). Gene expression profiling of aging using DNA microarrays. Mechanisms of Ageing and Development, January, 123(2-3), pages 177-93.

[8] Weindruch R, et al. (1986). The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. Journal of Nutrition, April, 116(4), pages 641-54.

[9] Weindruch R, & Sohal RS. (1997). Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. The New England Journal of Medicine, October 2, pages 986-94.

[10] Lipman RD, et al. (1998). Effects of caloric restriction or augmentation in adult rats: longevity and lesion biomarkers of aging. Aging (Milano). December, 10(6), pages 463-70.

[11] Weindruch R, & Walford RL. (1982). Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science, March 12, 215(4538), pages 1415-8.

Cancer

[12] Kritchevsky D, & Klurfeld DM. (1986). Influence of caloric intake on experimental carcinogenesis: a review. Advances in Experimental Medicine & Biology, 206, pages 55-68.

[13] Albanes D. (1987) Caloric intake, body weight, and cancer: a review. Nutrition & Cancer, 9(4), pages 199-217.

[14] Kritchevsky D. (1997). Caloric restriction and experimental mammary carcinogenesis. Breast Cancer Research & Treatment, Nov-Dec, 46(2-3), pages 161-7.

[15] Kritchevsky D. (2001). Caloric restriction and cancer. Journal of Nutritional Science and Vitaminology (Tokyo). February, 47(1), page 13-9.

Heart Disease

[16] Swoap SJ. (2001). Altered leptin signaling is sufficient, but not required, for hypotension associated with caloric restriction. American Journal of Physiology, Heart & Circulatory Physiology, December, 281(6):H2473-9.

[17] Keenan KP, et al (1994). The effects of overfeeding and dietary restriction on Sprague-Dawley rat survival and early pathology biomarkers of aging. Toxicologic Pathology, May-June, 22(3), pages 300-15.

Diabetes

[18] Stern JS, et at. (2001). Calorie restriction in obesity: prevention of kidney disease in rodents. Journal of Nutrition, March, 131(3), pages 913S-917S.

[19] Fujioka K, et al (2000). Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus. Diabetes, Obesity & Metabolism, June, 2(3), pages 175-87.

[20] Okauchi N, et al. (1995). Is caloric restriction effective in preventing diabetes mellitus in the Otsuka Long Evans Tokushima fatty rat, a model of spontaneous non-insulin-dependent diabetes mellitus? Diabetes Research and Clinical Practice, February, 27(2), pages 97-106.

Osteoporosis

[21] Kalu DN. (1984). Aging and dietary modulation of rat skeleton and parathyroid hormone. Endocrinology, October, 115(4), pages 1239-47.

[22] Kalu DN. (1984). Lifelong food restriction prevents senile osteopenia and hyperparathyroidism in F344 rats. Mechanisms of Ageing and Development, July, 26(1), pages 103-12.

Auto-immune disorders

[23] Fernandes G. (1983). Influence of diet on vascular lesions in autoimmune-prone B/W mice. Proceedings of the National Academy of Sciences, February, 80(3), pages 874-7.

[24] Nandy K. (1982). Effects of controlled dietary restriction on brain-reactive antibodies in sera of aging mice. Mechanisms of Ageing & Development, February, 18(2), pages 97-102.

[25] Fernandes G, et al. (1976). Influence of diet on survival of mice. Proceedings of the National Academy of Sciences, April, 73(4), pages 1279-83.

Neurological decline

[26] Means LW, et al.(1993). Mid-life onset of dietary restriction extends life and prolongs cognitive functioning. Physiology & Behavior, September, 54(3), pages 503-8.

[27] Pitsikas N, & Algeri S. (1992). Deterioration of spatial and nonspatial reference and working memory in aged rats: protective effect of life-long calorie restriction. Neurobiology of Aging, May-Jun, 13(3), pages 369-73.

[28] Pitsikas N, et al. (1990). Effect of life-long hypocaloric diet on age-related changes in motor and cognitive behavior in a rat population. Neurobiology of Aging, July-August, 11(4), pages 417-23.

[29] Eckles-Smith K, et al. (2000). Caloric restriction prevents age-related deficits in LTP and in NMDA receptor expression. Brain Research, Molecular Brain Research, May 31, 78(1-2), pages 154-62.

[30] Lee CK, et al. (2000). Gene-expression profile of the ageing brain in mice. Nature Genetics, July, 25(3), pages 294-7.

Alzheimer's

[31] Mattson MP. (2000). Existing data suggest that Alzheimer's disease is preventable. Annals of the New York Academy of Sciences, 924, pages 153-9.

Parkinson's

[32] Roth GS, et al. (1984). Delayed loss of striatal dopamine receptors during aging of dietarily restricted rats. Brain Research, May 21, 300(1), pages 27-32.

[33] Levin P, et al. (1981). Dietary restriction retards the age-associated loss of rat striatal dopaminergic receptors. Science, October 30, 214(4520), pages 561-2.

[34] Ingram DK, et al. (1987). Dietary restriction benefits learning and motor performance of aged mice. Journal of Gerontology, January, 42(1), pages 78-81.

Other topics

[35] Markowska AL. (1999). Life-long diet restriction failed to retard cognitive aging in Fischer-344 rats. Neurobiology of Aging, March-April, 20(2), pages 177-89.

[36] Campbell BA, & Gaddy JR. (1987). Rate of aging and dietary restriction: sensory and motor function in the Fischer 344 rat. Journal of Gerontology, March, 42(2), pages 154-9.

[37] Manson JE. (1987). Body weight and longevity. A reassessment. Journal of the American Medical Association, January 16, 257(3), pages 353-8.

[38] NIHNC, CDC, & DHHS. (1985). Body weight, health and longevity: conclusions and recommendations of the workshop. Nutrition Reviews, February, 43(2), pages 61-3.

[39] Lee IM. et al. (1993). Body weight and mortality. A 27-year follow-up of middle-aged men. Journal of the American Medical Association, December 15, 270(23), pages 2823-8.

[40] Manson E. et al. (1995). Body wight and mortality among women. New England Journal of Medicine, September 14, 333(11), pages 677-85.

[41] Solomon CG. (1997). Obesity and mortality: a review of the epidemiologic data. American Journal of Clinical Nutrition, October, 66(4 Suppl), pages 1044S-1050S.

[42] Investigating the world's longest-live people. Okinawa Centenarian Study.

[43] Willcox BJ, et al. (2001). Evidence-based Extreme Longevity: The Case of Okinawa, Japan. Presidential Poster Session of the American Geriatrics Society Annual Meeting.

[44] Okinawa Centenarian Study data presented at the American Geriatrics Society annual meeting, 2001; cited by McCord H, & McVeigh G, (2002). NutritionNews: "Magic" Appetite Shutoff from the Orient. Prevention, January, pages 52-3.

[45] Kagawa Y. (1978). Impact of Westernization on the nutrition of Japanese: changes in physique, cancer, longevity and centenarians. Preventive Medicine, June, 7(2), pages 205-17.

[46] Lane MA. (1999). Nutritional modulation of aging in nonhuman primates. Journal of Nutrition, Health & Aging, 3(2), pages 69-76.

[47] Email response from NIA researcher George Roth (geor@vax.grc.nia.nih.gov), January 1, 2002.

[48] Warshofsky F. (1999). The Methuselah Factor. Modern Maturity, November-December.

[49] Roth GS. (2001). Dietary caloric restriction prevents the age-related decline in plasma melatonin levels of rhesus monkeys. Journal of Clinical Endocrinology & Metabolism, July, 86(7), pages 3292-5.

[50] Kayo T, el al. (2001). Influences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys. Proceedings of the National Academy of Sciences, April 24, 98(9), pages 5093-8.

[51] Shelley X, et a1. (2001). Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice. Proceedings of the National Academy of Sciences, September, 98(19), pages 10630-35.

[52] Kretsch, MJ, et al. (1997). Cognitive effects of a long-term weight reducing diet. International Journal of Obesity and Related Metabolic Disorders, January, 21(1), pages 14-21.

[53] Kretsch MJ, et al. (1998). Cognitive function, iron status, and hemoglobin concentration in obese dieting women. European Journal of Clinical Nutrition, July, 52(7), pages 512-8.

[54] Blanc JF, et al. (2000). Iron overlaod and cancer. Bulletin de l'Academie Nationale de Medecine, 184(2), pages 355-63.

[55] Nunez MT , et al. (2001). Iron-induced oxidative damage in colon carcinoma (Caco-2) cells. Free Radical Research, Jan;34(1), pages 57-68.

[56] Jeanie D. (2000). High Iron Levels Identified in Brains of Alzheimer's Patients. WebMD Medical News, February, 28.

[57] Levites Y. (2002). Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures(1). Biochemical Pharmacology, January, 63(1), pages 21-29.

[58] Search for a Physician or Practitioner, American Academy of Anti-Aging Medicine.

[59] http://www.walford.com/