Prabhupada: There is a Indian proverb that “Disease and unwanted guest, if you don’t give food, they will go away.” If some guest has come whom you do not want, don’t give him food. Then he will go away. Similarly, disease, if you fast, it will go away.
Influences of Calorie Intake on Aging
Richard Weindruch Ph.D., University of California-Los Angeles: It has been known for 65 years that caloric restriction (CR), if properly executed without malnutrition, will greatly extend the maximum life span of mice and rats and decrease the incidence of cancer and other late-life diseases (for a review of CR, see Weindruch and Walford, 1988). Although regarded more as a curiosity for much of that time, interest in CR-induced phenomena grew substantially with increased research on aging processes since the 1970s and continues to this day.
Most of the CR studies carried out in my laboratory have been in mice from long-lived strains that develop cancer (lymphoma, hepatoma) late in life. Mice on CR eat up to 50% fewer calories than controls while consuming the same amounts of proteins, vitamins and minerals. In one of our studies, CR increased the average life span from 32 months to 45 months, and increased by 34% the maximum (last decile) life span from 40 months to 53 months. Overall tumor incidence was 38% in the CR group vs. 78% in the control group. In addition to living longer, we found that mice on CR stay “younger longer” than controls as judged by such age-sensitive biologic parameters as immune responses, eye lens proteins, liver enzyme activities, learning and behavior.
Two main questions now face this field of research and serve to focus the efforts of this laboratory. These are: 1) What are the mechanisms underlying the retardation of aging and disease processes by CR in rodents?, and 2) Does CR also act to retard aging and diseases in nonhuman and human primates?
Our present work in rodents involves testing the possibility that CR acts by reducing oxidative stress in postmitotic tissues. In 1998, a collaboration began with Dr. Tomas Prolla using oligonucleotide microarrays to conduct the first gene expression profiling studies in gerontology. Data from these studies strengthen the idea that CR may slow aging by reducing free radical damage to tissues. Whether this mechanism is operative in opposing late-life cancers is worthy of expanded exploration.
My laboratory is also exploring the efficacy of CR initiated in middle age (or later) to retard aging processes in nonhuman primates. These studies are being done in collaboration with Drs. Kemnitz, Schoeller and others who are exploring age-sensitive parameters in adult monkeys subjected to CR of 30%. The feasibility of human studies is under active consideration.
Representative Publications
Colman, R.J., Beasley, T.M., Allison, D.B., & Weindruch, R. (2008). Attenuation of sarcopenia by dietary restriction in rhesus monkeys. Journals of Gerontology Series A- Biological Sciences and Medical Sciences, 63(6), 556-559.
Hagopian, K., Ramsey, J.J., & Weindruch, R. (2008). Enzymes of glycerol and glyceraldehyde metabolism in mouse liver: effects of caloric restriction and age on activities. Bioscience Reports, 28(2), 107-11.
Fowler, C.G., Chiasson, K.B., Hart, D.B., Beasley, T.M., Kemnitz, J., & Weindruch, R. (2008). Tympanometry in rhesus monkeys: effects of aging and caloric restriction. Int. J. Audiol., 47(4), 209-14.
Barger, J.L., Kayo, T., Vann, J.M., Arias, E.B., Wang, J., Hacker, T.A., Wang, Y., Raederstorff, D., Morrow, J.D., Leeuwenburgh, C., Allison, D.B., Saupe, K.W., Cartee, G.D., Weindruch, R., & Prolla, T.A. (2008). A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE, 3(6), e2264.
Li, H., Costantini, C., Scrable, H., Weindruch, R., & Puglielli, L. (2008). Egr-1 and Hipk2 are required for the TrkA to p75NTR switch that occurs downstream of IGF1-R. Neurobiology of Aging, 2008 April 2. [Epub ahead of print].
Fu, V.X., Dobosy, J.R., Desotelle, J.A., Almassi, N., Ewald, J.A., Srinivasan, R., Berres, M., Svaren, J., Weindruch, R., & Jarrard, D.F. (2008). Aging and cancer-related loss of insulin-like growth factor 2 imprinting in the mouse and human prostate. Cancer Research, 68(16), 6797-680.
Dobosy, J.R., Fu, V.X., Desotelle, J.A., Srinivasan, R., Kenowski, M.L., Almassi, N., Weindruch, R., Svaren, J., & Jarrard, D.F. (2008). A methyl-deficient diet modifies histone methylation and alters Igf2 and H19 repression in the prostate. Prostate, 68(11), 1187-119.
Barger, J.L., Kayo, T., Pugh, T.D., Prolla, T.A., & Weindruch, R. (2008). Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart. Experimental Gerontology, 43(9), 859-86.
Anderson, R.M., Barger, J.L., Edwards, M.G., Braun, K.H., O’Connor, C.E., Prolla, T.A., & Weindruch, R. (2008). Dynamic regulation of PGC-1alpha localization and turnover implicates mitochondrial adaptation in longevity and the stress response. Aging Cell, 7, 10.
Someya, S., Yamasoba, T., Kujoth, G.C., Pugh, T.D., Weindruch, R., Tanokura, M., & Prolla, T.A. (2008). The role of mtDNA mutations in the pathogenesis of age-related hearing loss in mice carrying a mutator DNA polymerase gamma. Neurobiology of Aging, 29(7), 1080-109.
Park, S.K., Page, G.P., Kim, K., Allison, D.B., Meydani, M., Weindruch, R., & Prolla, T.A. (2008). Alpha- and gamma-tocopherol prevent age-related transcriptional alterations in the heart and brain of mice. Journal of Nutrition, 138(6), 1010-101.
Raman, A., Ramsey, J.J., Kemnitz, J.W., Baum, S.T., Newton, W., Coleman, R.J., Weindruch, R., Beasley, M.T., & Schoeller, D.A. (2007). Influences of calorie restriction and age on energy expenditure in the rhesus monkeys. Am. J. Physiol., 292, E101-6.
Fowler, C.G., Chaisson, K.B., Brown Hart, D., Kemnitz J., & Weindruch, R. (2007). Tympanometric findings in rhesus monkeys: Effects of aging and caloric restriction. International Journal of Audiology, 47(4), 209-214.
Raman, A., Baum, S.T., Colman, R.J., Kemnitz, J.W., Weindruch, R., & Schoeller, D.A. (2007). Metabolizable energy intake during long-term calorie restriction in rhesus monkeys. Exp. Gerontol., 42(10), 988-94.
Edwards, M.G., Anderson, R.M., Yuan, M., Kendziorski, C., Weindruch, R., & Prolla, T.A. (2007). Gene expression profiling of aging reveals activation of a p53-mediated transcriptional program. BMC Genomics, 8, 80.
Anderson, R.M., & Weindruch, R. (2007). Metabolic reprogramming in calorie restriction. In C.V. Mobbs, K. Yen, P.R. Hof., & A.G. Karger (Eds.), Mechanisms of calorie restriction in aging and disease (Interdisciplinary Topics in Gerontology) (Vol. 35, pp. 18-38). Switzerland.
Anderson, R.M., & Weindruch, R. (2006). Calorie Restriction: Progress during mid-2005 to mid-2006. Exp. Gerontology, 41, 1247-9.
Blanc, S., Colman, R., Kemnitz, J., Weindruch, R., Baum, S., Ramsey, J., & Schoeller, D. (2005). Assessment of nutritional status in rhesus monkeys: comparison of dual-energy X-ray absorptiometry and stable isotope dilution. J. Med. Primatol., 34(3), 130-8.
Raman, A., Colman, R.J., Cheng, Y., Kemnitz, J.W., Baum, S.T., Weindruch, R., & Schoeller, D.A. (2005). Reference body composition in adult rhesus monkeys: glucoregulatory and anthropometric indices. J. Gerontol. A. Biol. Sci. Med. Sci., 60(12), 1518-24.
Costantini, C., Weindruch, R., Della Valle, G., & Puglielli, L. (2005). A TrkA to p75NTR molecular switch activates amyloid beta-peptide generation during aging. Biochem. J., 391, 59-67.
Bruns, C.M., Baum, S.T., Colman, R.J., Eisner, J.R., Kemnitz, J.W., Weindruch, R., & Abbott, D.H. (2004). Insulin resistance and impaired insulin secretion in prenatally androgenized male rhesus monkeys. J. Clin. Endocrinol. Metab., 89(12), 6218-23.
Gonzalez, A.A., Kumar, R., Mulligan, J.D., Davis, A.J., Weindruch, R., & Saupe, K.W. (2004). Metabolic adaptations to fasting and chronic caloric restriction in heart, muscle, and liver do not include changes in AMPK activity. Am. J. Physiol. Endocrinol. Metab., 287(5), E1032-7.
Blanc, S., Schoeller, D., Kemnitz, J., Weindruch, R., Colman, R., Newton, W., Wink, K., Baum, S., & Ramsey, J. (2003). Energy expenditure of rhesus monkeys subjected to 11 years of dietary restriction. J. Clin. Endocrinol. Metab., 88, 16-23.
Atwood, C.S., Barzilai, N., Bowen, R.L., Brown-Borg, H.M., Jarrard, D.F., Fu, V.X., Heilbronn, L.K., Ingram, D.K., Ravussin, E., Schwartz, R.S., & Weindruch, R. (2003). Pennington scientific symposium on mechanisms and retardation of aging. Experimental Gerontology, 38(10), 1217-1226.
Lee, C.K., Allison, D.B., Brand, J., Weindruch, R., & Prolla, T.A. (2002). Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc. Natl. Acad. Sci. USA, 99, 14988-14993.
Kayo, T., Allison, D.B., Weindruch, R., & Prolla, T.A. (2001). Influences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys. Proc. Natl. Acad. Sci. USA, 98, 5093-5098.
Weindruch, R., Keenan, K.P., Fernandes, G., Feuers, R.J., Floyd, R.A., Halter, J.B., Ramsey, J.J., Richardson, A.G., & Spindler, S.R. (2001). Caloric restriction mimetics: Metabolic interventions. J. Gerontol. Biol. Sci., 56A, 20-33.
Lopez, M.E., Van Zeeland, N.L., Dahl, R.D., Weindruch, R., & Aiken, J.M. (2000). Cellular phenotypes of age-associated skeletal muscle mitochondrial abnormalities in rhesus monkeys. Mutation Research, 452, 123-138.
Ramsey, J.J., Colman, R.J., Binkley, N.C., Christensen, J.D., Gresl, T.A., Kemnitz, J.W., & Weindruch, R. (2000). Dietary restriction and aging in rhesus monkeys: The University of Wisconsin Study. Exp. Gerontol., 35, 1131-1149.
Hall, D.M., Oberley, T.D., Moseley, P.M., Oberley, L.W., Weindruch, R., & Kregel, K.C. (2000). Caloric restriction improves thermotolerance and reduces hyperthermia-induced cellular damage in old rats. FASEB J., 14, 78-86.
Zainal, T.A., Oberley, T.D., Allison, D.B., Szweda, L.I., & Weindruch, R. (2000). Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle. FASEB J., 14, 1825-1836.
Lee, C.K., Weindruch, R., & Prolla, T.A. (2000). Gene expression profile of the aging brain in mice. Nat. Genet., 25, 294-297.
Ramsey, J.J., Harper, M.E., & Weindruch, R. (2000). Restriction of energy intake, energy expenditure, and aging. Free Radic. Biol. Med., 29, 946-968.
Pugh, T.D., Oberley, T.D., & Weindruch, R. (1999). Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice. Cancer Res., 59, 1642-1648.
Lee, C.K., Klopp, R.G., Weindruch, R., & Prolla, T.A. (1999). Gene expression profile of aging and its retardation by caloric restriction. Science, 285, 1390-1393.
Ripple, M.O., Henry, W.F., Schwarze, S.R., Wilding, G., & Weindruch, R. (1999). Effect of antioxidants on androgen-induced AP-1 and NF-kappa B DNA-binding activity in prostate carcinoma cells. J. Natl. Cancer Inst., 91, 1227-1232.
Weindruch, R., & Sohal, R.S. (1997). Caloric intake and aging. New Engl. J. Med., 337, 986-994.
Weindruch, R. (1996). Caloric restriction and aging. Scientific American, 1, 46- 52.
Sohal, R.S., & Weindruch, R. (1996). Oxidative stress, caloric restriction, and aging. Science, 273, 59-63.
Weindruch, R., & Walford, R.L. (1988). The retardation of aging and disease by dietary restriction. Springfield IL: C.C. Thomas.
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