Updated 31 March 2005

Forum Discussion: Caloric Restriction: Eat Less, Live Longer!

Mark Mattson

We invite you to participate in this Forum Discussion with Matt Mattson (National Institute on Aging). This discussion will not be hosted via our live discussion software. Forum discussions invite written exchanges between our participants and the discussion leader to allow for a slower format. Send comments, and replies at your leisure! We invite all of you to send questions to Tom Fagan (tfagan@alzforum.org). We will post comments on the site as we receive them.

See comment by Giulio Pasinetti—Posted 27 January 2005
See comment by William Grant—Posted 3 February 2005
See comment by Richard Bowen and Craig Atwood—Posted 31 March 2005
See comment by Richard Bowen—Posted 31 March 2005
See comment by Todd E. Morgan and Caleb E. Finch—Posted 31 March 2005

Converging lines of evidence from studies of human populations, patients, and animal models suggest that a diet low in calories and saturated fats can protect the brain against neurodegenerative disorders. Although much more research is required, data from several epidemiological studies suggest that individuals with low calorie intake are at reduced risk of Alzheimer disease (AD) and Parkinson disease (PD). Dietary restriction is also a proven means of reducing one's risk of stroke, inasmuch as overeating is a major risk factor for this trauma.

When mice or rats are maintained long-term (months) on caloric restriction or intermittent fasting diets, neurons in their hippocampus, substantia nigra, and striatum are more resistant to neurotoxins in models relevant to AD, PD, and Huntington disease (HD), respectively. Rodents maintained on dietary restriction regimens prior to experimental stroke exhibit reduced brain damage and improved functional outcome compared to control animals fed ad libitum. Caloric restriction has also been shown to reduce amyloid-β peptide accumulation in the brain in APP mutant mice. In addition, intermittent fasting suppresses the neurodegenerative process, delays the onset of motor dysfunction, and extends survival in huntingtin mutant mice.

While in many cases caloric restriction and intermittent fasting are beneficial when followed in a prophylactic manner, such diets may be ineffective or detrimental in some cases. For example, intermittent fasting is not beneficial and, in fact, accelerates disease progression in Cu/Zn-SOD mutant mice, a model of amyotrophic lateral sclerosis (ALS). It is also important to consider that dietary restriction may not be useful in the treatment of patients with neurodegenerative disorders, and in some cases may be detrimental. Indeed, AD, PD, HD, and ALS patients typically have difficulty maintaining body weight as the disease progresses. On the other hand, stroke patients might benefit from dietary restriction, which is known to reduce blood pressure and improve glucose and lipid metabolism (risk factors for stroke).

In addition to the amount of food consumed, the quality and quantity of fats in the diet appear to influence the development of neurodegenerative disorders. This is well-established in the case of stroke—adverse effects of dietary saturated fats and cholesterol on cerebral blood vessels increase the risk. Recent findings also suggest that diets high in saturated fats and cholesterol may increase the risk of AD, possibly by increasing the production of amyloid-β peptide. On the other hand, omega-3 fatty acids such as docosohexanoic acid (DHA), which are present at high levels in fish, may protect against AD.

The cellular and molecular changes that may be responsible for the effects of different diets on the nervous system are beginning to be revealed. Caloric restriction and intermittent fasting may reduce oxidative stress and induce beneficial cellular stress resistance responses. For example, intermittent fasting induces the expression of brain-derived neurotrophic factor (BDNF) and heat shock protein 70 in neurons in several brain regions of rats and mice. Caloric restriction in rhesus monkeys upregulates basal ganglia expression of BDNF and glial cell line-derived neurotrophic factor, which is associated with increased resistance of dopaminergic neurons in a model of PD. Interestingly, at least some of the beneficial effects of dietary restriction on the periphery (increased insulin sensitivity and reduced blood pressure, for example) may be mediated by neurotransmitter and neurotrophic factor signaling pathways in the brain.

Discussion Points

1. One major concern in extrapolating data from animal models to humans is that the control animals in nearly all published studies are overfed and obese. While data from the animal studies therefore suggest that dietary restriction will benefit the nervous systems of obese humans, they do not address if, and to what extent, dietary restriction will benefit normal weight humans.

2. Presumably, there are levels of calorie intake and meal frequency that are optimal for health of the nervous system during aging. At the present time, insufficient information is available to make specific recommendations. What kinds of studies are required to generate data that can be used to make recommendations?

3. Are there genetic factors that determine if, and to what extent, dietary factors affect one's risk for specific neurodegenerative disorders?

4. What kinds of epidemiological and dietary intervention studies in humans are needed to establish the effects of calorie intake, meal frequency, and dietary fat intake on disease risk?

5. What are the cellular and molecular mechanisms by which diet affects the vulnerability of the nervous system to disease?

6. How, and to what extent, are the effects of diet on peripheral systems such as the cardiovascular and glucose-regulating systems mediated by signaling pathways in the brain?

7. Can dietary supplements and drugs be developed that suppress appetite, mimic the beneficial effects of dietary restriction, or counteract the adverse effects of overeating and high fat diets on the nervous system?

References (a few selected relevant articles)

Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N Jr, Ashe KH, Frautschy SA, Cole GM. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron. 2004 Sep 2;43(5):633-45. Abstract

Maswood N, Young J, Tilmont E, Zhang Z, Gash DM, Gerhardt GA, Grondin R, Roth GS, Mattison J, Lane MA, Carson RE, Cohen RM, Mouton PR, Quigley C, Mattson MP, Ingram DK. Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease. Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18171-6. Epub 2004 Dec 16. Abstract

Mattson MP, Maudsley S, Martin B. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 2004 Oct;27(10):589-94. Abstract

Mattson MP. Gene-diet interactions in brain aging and neurodegenerative disorders. Ann Intern Med. 2003 Sep 2;139(5 Pt 2):441-4. Review. Abstract

Mayeux R. Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003;26:81-104. Epub 2003 Jan 24. Review. Abstract

Reiss AB, Siller KA, Rahman MM, Chan ES, Ghiso J, de Leon MJ. Cholesterol in neurologic disorders of the elderly: stroke and Alzheimer's disease. Neurobiol Aging. 2004 Sep;25(8):977-89. Review. Abstract

Comment by Giulio Pasinetti—Posted 27 January 2005

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" α-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

Comment by William Grant—Posted 3 February 2005

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

Comment by Richard Bowen and Craig Atwood—Posted 31 March 2005

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).

Comment by Richard Bowen—Posted 31 March 2005

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.

Comment by Todd E. Morgan and Caleb E. Finch—Posted 31 March 2005

The benefits of caloric restriction (CR) to normal brain aging have been a long-standing interest in our lab. In a rat model we showed that CR attenuates age-associated activation of astrocytes and microglia, which have implications on oxidative stress (Morgan et al., 1997; 1999). More recently, in collaboration with David Morgan (no relation to T.E. Morgan), we showed that CR attenuates amyloid deposition and glial activation in two unique transgenic mouse models of AD-related amyloidosis (Patel et al., 2005; NOTE: This paper was accepted on September 20, 2004 and initially scheduled for publication in 2004 by Neurobiology of Aging, as shown on the proofs). We examined the brains from mice possessing either mutated amyloid β precursor protein (APPswe/ind) alone (Mucke et al., 2000) or mutated APPswe and presenilin 1M146L (APP+PS1)(Holcomb et al., 1998). Both transgenics develop senile plaques by six months of age. As little as six weeks of CR substantially decreased the accumulation of Aß deposits. However, CR did not decrease APP levels. Of course, turnover of APP, Aβ, and other products must be determined before excluding effects of CR on processing, deposition and/or degradation. The likely involvement of astrocytes is predicted since CR attenuated astrocytic activation in this model. In particular, CR regulates astrocyte-derived apolipoproteins E & J (Morgan et al., 1999); both apoE and apoJ have a profound effect on Aβ deposition (DeMattos et al., 2004). Evidence for additional pathways was reported in Wang et al. (2005) which showed that a reduction in carbohydrate intake in Tg2576 mice influenced both Aβ processing (increase in α-secretase) and degradation (increase in insulin-degrading enzyme).

Our CR regime consists of the reduction in total calories (40%) from all energy sources (carbohydrates, proteins and fats) while maintaining micronutrients. Therefore, the effects of CR do not depend on restriction of a particular energy source. Thus, the benefit of reducing only carbohydrates (as in the Wang study) is mainly attributable to the general reduction in total calorie intake. A key question is raised by these studies: will CR slow the progression of Aβ deposition once deposits are already present? We have unpublished data suggesting that it will. At the 9th International Conference on Alzheimer's Disease and Related Disorders meeting in Philadelphia (July 2004), we showed data that Aβ deposition is reduced even if CR is initiated after Aβ deposits are already present. For this study we varied the age at CR initiation and found that the CR mice always had fewer plaques. However, we do not know whether CR affects established plaques. In this study we also determined that a 20% reduction in calories was sufficient (not published). Since CR affects a myriad of physiological pathways (e.g., lowers glucose, lowers insulin, increases glucocorticoids) (Patel et al., 2002), it will be critical to determine if the beneficial affects we see in our transgenic models require more than one of these pathways. On-going experiments to manipulate single pathways should answer this question. Regardless of the mechanism the penultimate question remains: What is the ideal body mass index required to minimize age- and disease-related neurodegenerative events?

References:
DeMattos R. B., Cirrito J. R., Parsadanian M., May P. C., O'Dell M. A., Taylor J. W., Harmony J. A., Aronow B. J., Bales K. R., Paul S. M. and Holtzman D. M. (2004) ApoE and Clusterin Cooperatively Suppress Abeta Levels and Deposition. Evidence that ApoE Regulates Extracellular Abeta Metabolism In Vivo. Neuron 41: 193-202. Abstract

Holcomb, L., Gordon, M.N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., Sanders, S., Zehr, C., O'Campo, K., Hardy, J., Prada, C.M., Eckman, C., Younkin, S., Hsiao, K. and Duff, K., (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes, Nat Med, 4: 97-100. Abstract

Patel, N.V. and Finch, C.E. (2002) The glucocorticoid paradox of caloric restriction in slowing brain aging, Neurobiol Aging, 23: 707-17. Abstract

Patel, N.V., M. N. Gordon, K. E. Connor, R. A. Good, R. W. Engelman, J. Mason, D. G. Morgan, T. E. Morgan, C. E. Finch (2005) "Caloric Restriction Attenuates Aß-deposition in Alzheimer Transgenic Models." Neurobiol Aging 26/7: 995-1000. Abstract

Morgan, T. E., I. Rozovsky, S. K. Goldsmith, D. J. Stone, T. Yoshida and C. E. Finch (1997) Increased transcription of the astrocyte gene GFAP during middle-age is attenuated by food restriction: implications for the role of oxidative stress. Free Radic Biol Med 23: 524-8. Abstract

Morgan, T. E., Z. Xie, S. Goldsmith, T. Yoshida, A. S. Lanzrein, D. Stone, I. Rozovsky, G. Perry, M. A. Smith and C. E. Finch (1999) The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction. Neuroscience 89: 687-99. Abstract

Mucke, L., Masliah, E., Yu, G.Q., Mallory, M., Rockenstein, E.M., Tatsuno, G., Hu, K., Kholodenko, D., Johnson-Wood, K. and McConlogue, L. (2000) High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation, J Neurosci, 20: 4050-8. Abstract

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. Abstract