There is epidemiological data associating higher intake of calories and fats with increased risk of Alzheimer disease (AD), in particular among individuals carrying the apolipoprotein E4 (ApoE4) allele (Luchsinger et al., 2002). Moreover there is also experimental evidence suggesting that lowering dietary caloric intake may benefit AD through mechanisms involving the promotion of neurotrophic factors and reduction of oxidative stress cascades in the brain (Mattson, 2003). However, until now, there was no direct information if caloric reduction may beneficially influence AD pathophysiology.

Our recent study (see Wang et al., 2005) provides novel evidence for the potential beneficial role of caloric restriction in AD. Indeed, we found that a reduction in carbohydrate caloric intake (30 percent) may benefit AD by promoting the "non-amyloidogenic" a-secretase pathway of the amyloid precursor protein (APP) in the brain of Tg2576-AD mice. Our study suggests that a reduction in carbohydrate content in the diet, while maintaining normal protein, fat, cholesterol, vitamin, and mineral...  Read more

There is epidemiological data associating higher intake of calories and fats with increased risk of Alzheimer disease (AD), in particular among individuals carrying the apolipoprotein E4 (ApoE4) allele (Luchsinger et al., 2002). Moreover there is also experimental evidence suggesting that lowering dietary caloric intake may benefit AD through mechanisms involving the promotion of neurotrophic factors and reduction of oxidative stress cascades in the brain (Mattson, 2003). However, until now, there was no direct information if caloric reduction may beneficially influence AD pathophysiology.

Our recent study (see Wang et al., 2005) provides novel evidence for the potential beneficial role of caloric restriction in AD. Indeed, we found that a reduction in carbohydrate caloric intake (30 percent) may benefit AD by promoting the "non-amyloidogenic" a-secretase pathway of the amyloid precursor protein (APP) in the brain of Tg2576-AD mice. Our study suggests that a reduction in carbohydrate content in the diet, while maintaining normal protein, fat, cholesterol, vitamin, and mineral content, is sufficient for preventing AD-type neuropathology.

To date, studies on the interrelationship between dietary factors and AD have primarily been focused on the role of fat, cholesterol, and vitamins. Moreover, recent evidence also suggests that consumption of certain polyunsaturated fatty acids, such as n-3 fatty acids, may reduce risks for AD and experimental neurodegeneration. Our study is the first to demonstrate a direct link between the intake of an "individual" macronutrient and AD amyloidosis. However, we cannot definitively state that the decreased AD-amyloid neuropathology was the result of low carbohydrate intake per se, or was a more general consequence in response to a reduction in caloric intake.

References:
1. Luchsinger JA, Tang MX, Shea S, Mayeux R. (2002) Caloric intake and the risk of Alzheimer disease. Arch. Neurol. 59:1258-1263. Abstract

2. Mattson MP. (2003) Will caloric restriction and folate protect against AD and PD Neurology 60:690-695. Abstract

3. Wang J, Ho L, Qin W, Rocher AB, Seror I, Humala N, Maniar K, Dolios G, Wang R, Hof PR, Pasinetti GM. Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer's disease. FASEB J. 2005 Jan 13; Abstract

View all comments by Giulio Pasinetti

As noted in Deibel et al. [1996], Grant [1997, 1999a, 1999b] and Grant et al. [2002], one of the hallmarks of Alzheimer disease (AD) is the elevation of transition metal ions (Ag, Fe, Mn, Zn, etc.), aluminum and a decrease of base cations (Ca, Mg, etc.). This is very similar to what happens in forest soils under the action of acid deposition over a long period. The transition metal ions are associated with increased oxidative stress in the brain [Deibel et al., 1996]. It has been proposed that the dietary factors that increase the risk of AD—total fat and total calories—also increase the acid balance of the digestive system [Grant, 1997, 1999a]. A quick search of PubMed provides additional support for this hypothesis in that meat and protein increase the amount of Cu, Fe, and Zn and decrease the amount of Ca, while grains tend to reduce transition metal ion loading [Greger and Snedeker, 1980; Hallfrisch, et al., 1987; Johnson et al., 1992; Hunt et al., 1995, 1998; Reddy et al., 2002; Hunt, 2003]; dietary sugars also reduce Ca loading [Tjaderhane Larmas, 1998]. High-energy intakes...  Read more

As noted in Deibel et al. [1996], Grant [1997, 1999a, 1999b] and Grant et al. [2002], one of the hallmarks of Alzheimer disease (AD) is the elevation of transition metal ions (Ag, Fe, Mn, Zn, etc.), aluminum and a decrease of base cations (Ca, Mg, etc.). This is very similar to what happens in forest soils under the action of acid deposition over a long period. The transition metal ions are associated with increased oxidative stress in the brain [Deibel et al., 1996]. It has been proposed that the dietary factors that increase the risk of AD—total fat and total calories—also increase the acid balance of the digestive system [Grant, 1997, 1999a]. A quick search of PubMed provides additional support for this hypothesis in that meat and protein increase the amount of Cu, Fe, and Zn and decrease the amount of Ca, while grains tend to reduce transition metal ion loading [Greger and Snedeker, 1980; Hallfrisch, et al., 1987; Johnson et al., 1992; Hunt et al., 1995, 1998; Reddy et al., 2002; Hunt, 2003]; dietary sugars also reduce Ca loading [Tjaderhane Larmas, 1998]. High-energy intakes are generally associated with energy dense foods such as meat and sugar [Grant, 2004]. Thus, the risk of AD may be reduced by caloric restriction because it is generally associated with a better balance of nutritional factors and is, thus, less likely to adversely affect the trace mineral composition of the body and brain.

References:
Deibel MA, Ehmann WD, Markesbery WR. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress. J Neurol Sci. 1996 Nov;143(1-2):137-42. Abstract

Grant WB. Dietary links to Alzheimer's disease. Alz Dis Rev 1997;2:42-55.

Grant WB. Aluminum accumulates in body with high-acid diet, Townsend Letter for Doctors and Patients, June 1999a;191:92.

Grant WB. Dietary links to Alzheimer's disease: 1999 update, J Alz Dis 1999b;1197-201. Abstract

Grant WB. The primary role of sweeteners in the body mass indexes of women from developing countries: implications for risk of chronic disease. Am J Clin Nutr. 2004;80:527-8. Abstract

Grant WB, Campbell A, Itzhaki RF, Savory J, The significance of environmental factors in the etiology of Alzheimer's disease, J Alz Dis (Debates from Challenging Views of Alzheimer Disease) 2002;4:179-89. Abstract

Greger JL, Snedeker SM. Effect of dietary protein and phosphorus levels on the utilization of zinc, copper and manganese by adult males. J Nutr. 1980 Nov;110(11):2243-53. Abstract

Hallfrisch J, Powell A, Carafelli C, Reiser S, Prather ES. Mineral balances of men and women consuming high fiber diets with complex or simple carbohydrate. J Nutr. 1987 Jan;117(1):48-55. Abstract

Hunt JR. Bioavailability of iron, zinc, and other trace minerals from vegetarian diets. Am J Clin Nutr. 2003 Sep;78(3 Suppl):633S-639S. Review. Abstract

Hunt JR, Gallagher SK, Johnson LK, Lykken GI. High- versus low-meat diets: effects on zinc absorption, iron status, and calcium, copper, iron, magnesium, manganese, nitrogen, phosphorus, and zinc balance in postmenopausal women. Am J Clin Nutr. 1995 Sep;62(3):621-32. Abstract

Hunt JR, Matthys LA, Johnson LK. Zinc absorption, mineral balance, and blood lipids in women consuming controlled lactoovovegetarian and omnivorous diets for 8 wk. Am J Clin Nutr. 1998 Mar;67(3):421-30. Abstract

Johnson JM, Walker PM. Zinc and iron utilization in young women consuming a beef-based diet. J Am Diet Assoc. 1992 Dec;92(12):1474-8. Abstract

Reddy ST, Wang CY, Sakhaee K, Brinkley L, Pak CY. Effect of low-carbohydrate high-protein diets on acid-base balance, stone-forming propensity, and calcium metabolism. Am J Kidney Dis. 2002 Aug;40(2):265-74. Abstract

Tjaderhane L, Larmas M. A high sucrose diet decreases the mechanical strength of bones in growing rats. J Nutr. 1998 Oct;128(10):1807-10. Abstract

View all comments by William Grant

Caloric restriction has been shown to extend longevity and delay the onset of many age-related diseases in almost every species tested (Lane et al., 2002; McCay et al., 1935; Weindruch and Walford, 1988). Based on this, it would not be surprising, at least to these scientists, if CR slowed the progression of Alzheimer's disease. Since AD is just one of many diseases of aging, it is likely that all age-related diseases share a common thread.

The primary question is why and how does caloric restriction slow the rate of aging. Initially many thought that the benefits of CR were the result of a decrease in metabolic rate (Harmon, 1956). However, numerous examples of long lived organisms with extremely high metabolism cast serious doubt on the oxidative stress or "rate of living" hypothesis. The most notable of these papers is by Goodrick et al (1990) which showed that intermittent fasting extended longevity even though overall caloric intake was unchanged. Likewise, rats maintained under cold conditions live slightly longer than controls (Holloszy and Smith, 1986) despite...  Read more

Caloric restriction has been shown to extend longevity and delay the onset of many age-related diseases in almost every species tested (Lane et al., 2002; McCay et al., 1935; Weindruch and Walford, 1988). Based on this, it would not be surprising, at least to these scientists, if CR slowed the progression of Alzheimer's disease. Since AD is just one of many diseases of aging, it is likely that all age-related diseases share a common thread.

The primary question is why and how does caloric restriction slow the rate of aging. Initially many thought that the benefits of CR were the result of a decrease in metabolic rate (Harmon, 1956). However, numerous examples of long lived organisms with extremely high metabolism cast serious doubt on the oxidative stress or "rate of living" hypothesis. The most notable of these papers is by Goodrick et al (1990) which showed that intermittent fasting extended longevity even though overall caloric intake was unchanged. Likewise, rats maintained under cold conditions live slightly longer than controls (Holloszy and Smith, 1986) despite evidence that cold exposure in rats significantly increases oxidative stress (Kaushik and Kaur, 2003). The one thing that an inadequate food supply and an inconsistent food supply have in common is that they both represent hostile reproductive environments. And, like most interventions that extend longevity, fasting also decreases fertility (Holliday, 1989). We have proposed that the hormones that control reproduction also control aging and are suppressed in a hostile reproductive environment. This allows the organism to preserve its fertility and slow its rate of aging increasing the chances of it encountering a reproductive friendly environment at some future time.

We believe that reproductive hormones regulate aging by regulating cell cycle signaling and have put forth the "Reproductive-Cell Cycle Theory of Aging." (Bowen and Atwood, 2004). This theory states that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence. If true, then Alzheimer's disease and even aging itself could be affected by hormonal manipulation without subjecting individuals to near starvation. Clinical trials using leuprolide acetate to suppress luteinizing hormone are currently underway in patients with AD and should shed light on the validity of this new theory.

References:
Bowen, R.L. and Atwood, C.S. (2004). Living and Dying for Sex: A theory of aging based on the modulation of cell cycle signaling by reproductive hormones. Gerontology 50, 265-290. Abstract

Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider N. (1990) Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age. Mech Ageing Dev. 55, 69-87. Abstract

Harmon, D. (1956). Role of free radical and radiation chemistry. J Gerontol 11, 298-300. Abstract unavailable.

Holloszy JO, Smith EK. (1986). Longevity of cold-exposed rats: a reevaluation of the "rate-of-living theory". J Appl Physiol. 61, 1656-1660. Abstract

Holliday R. (1989) Food, reproduction and longevity: is the extended lifespan of calorie-restricted animals an evolutionary adaptation?Bioessays. 10, 125-127. Abstract

Kaushik S, Kaur J. (2003). Chronic cold exposure affects the antioxidant defense system in various rat tissues. Clin Chim Acta. 333, 69-77. Abstract

Lane, M. A., Mattison, J., Ingram, D. K., and Roth, G. S. (2002). Caloric restriction and aging in primates: Relevance to humans and possible CR mimetics. Microsc Res Tech 59, 335-338. Abstract

McCay, C., Crowell, M., and Maynard, L. (1935). The effect of retarded growth upon the length of the lifespan and ultimate body size. J Nutr 10, 63-79. No abstract available.

Weindruch, R., and Walford, R. L. (1988). The Retardation of Aging and Disease by Dietary Restriction (Springfield, IL, Charles C. Thomas).

View all comments by Craig Atwood
View all comments by Richard Bowen

Roy Walford, a scientist at the University of California, was willing to go to extreme lengths to extend his life. After finding that rodents fed an incredibly skimpy diet lived long lives, Walford put himself on equally bare rations, consuming a mere 1,600 calories per day and keeping his weight at 130 pounds. Walford didn't beat the odds; he succumbed to Lou Gehrig's disease last year at the age of 71.

View all comments by Richard Bowen