Comparison of the effects of resveratrol and caloric restriction on learning and memory in juvenile C57BL/6J mice

Document Type : Original Article


1 Central Laboratory, Xuanwu Hospital, Capital Medical University, Key Laboratory for Neurodegenerative Disease of Ministry of Education, Beijing Geriatric Medical Research Center, No. 45 Changchun Street, Xicheng District, Beijing 100053, China

2 Department of Neurology, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China

3 Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China


Objective(s): Both caloric restriction (CR) and resveratrol (RSV) have been shown to improve learning and memory, but their potential effects in juvenile animals were unknown. Here, we evaluated the effects of RSV and CR on learning and memory function in juvenile mice and investigated potential molecular mechanisms.
Methods: Six-week-old C57BL/6J mice were assigned to one of three different dietary groups: normal control (stock diet) (n=12), CR diet (30% caloric reduction diet) (n=12), and RSV diet (stock diet supplemented with 18.6 mg/kg RSV) (n=12), for 6 months. Body weight and blood glucose were measured every 4 weeks. Serum cholesterol and serum triglyceride levels were examined using biochemical methods. Serum insulin and insulin-like growth factor 1 (IGF-1) levels were evaluated using enzyme linked immunosorbant assay (ELISA), and protein expression of silent mating type information regulation 2 homology 1 (SIRT1), p53, p16, peroxisome proliferator-activated receptor γ (PPARγ), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), phosphorylated-cAMP response element-binding protein (p-CREB), and IGF-1 were examined with immunohistochemistry.
Results:Although long-term CR diet did not alter physiological conditions in juvenile mice relative to control, RSV supplementation slightly elevated blood glucose, serum triglyceride, and serum insulin levels. Both CR and RSV improved learning and memory function, although the effect of CR was significantly greater. Both CR and RSV downregulated p53 and upregulated IGF-1 in hippocampal CA1 region of mice.
Conclusion:We demonstrate that CR and RSV may improve learning and memory by downregulating p53 and upregulating IGF-1 in hippocampal CA1 region of juvenile mice.


1. Brem AK, Ran K, Pascual-Leone A. Learning and memory. Handb Clin Neurol 2013; 116:693-737.
2. Gillette-Guyonnet S, Vellas B. Caloric restriction and brain function. Curr Opin Clin Nutr Metab Care 2008; 11:686-692.
3. Dong W, Wang R, Ma LN, Xu BL, Zhang JS, Zhao ZW, et al. Autophagy involving age-related cognitive behavior and hippocampus injury is modulated by different caloric intake in mice. Int J Clin Exp Med. 2015;8:11843-11853.
4. Kuhla A, Lange S, Holzmann C, Maass F, Petersen J, Vollmar B, et al. Lifelong caloric restriction increases working memory in mice. PLoS One 2013; 8:e68778.
5. Geng YQ, Guan JT, Xu MY, Xu XH, Fu YC . Behavioral study of calorie-restricted rats from early old age. Conf Proc IEEE Eng Med Biol Soc 2007; 2007:2393-2395.
6. Carrizzo A, Forte M, Damato A, Trimarco V, Salzano F, Bartolo M, et al. Antioxidant effects of resveratrol in cardiovascular, cerebral and metabolic diseases. Food Chem 2013; 61:215-226.
7. Carter LG, D'Orazio JA, Pearson KJ. Resveratrol and cancer: focus on in vivo evidence. Endocrin Relat Cancer 2014; 21:R209-25.
8. Zhao YN, Li WF, Li F, Zhang Z, Dai YD, Xu AL, et al. Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway. Biochem Biophys Res Commun 2013; 435:597-602.
9. Gupta R, Gupta LK, Mediratta PK, Bhattacharya SK. Effect of resveratrol on scopolamine-induced cognitive impairment in mice. Pharmacol Rep 2012; 64:438-444.
10. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG,et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003; 425:191-196.
11. Paraiso AF, Mendes KL, Santos SH. Brain activation of SIRT1: role in neuropathology. Mol Neurobiol 2013; 48:681-689.
12. O'Neill C, Kiely AP, Coakley MF, Manning S, Long-Smith CM. Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease. Biochem SocTtrans 2012; 40:721-727.
13. Ma L, Zhao Z, Wang R,  Zhang J, Dong W, Xu B, et al. Caloric restriction can improve learning ability in C57/BL mice via regulation of the insulin-PI3K/Akt signaling pathway. Neurological Sciences: 2014; 35:1381-1386.
14. Alberdi G, Rodriguez VM, Miranda J, Macarulla MT, Arias N, Andrés Lacueva C, et al. Changes in white adipose tissue metabolism induced by resveratrol in rats. Nutr Metab 2011; 8:29.
15. Tome-Carneiro J, Larrosa M, Gonzalez-Sarrias A, Tomás-Barberán FA, Almagro García-Conesa MT, Espín JC. Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr Pharm Des 2013; 19:6064-6093.
16. Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984; 11:47-60.
17. Silan C. The effects of chronic resveratrol treatment on vascular responsiveness of streptozotocin-induced diabetic rats. Biol Pharm Bull 2008; 31:897-902.
18. Palsamy P, Subramanian S. Ameliorative poten-tial of resveratrol on proinflammatory cytokines, hyperglycemia mediated oxidative stress, and pancreatic beta-cell dysfunction in streptozotocin-nicotinamide-induced diabetic rats. J Cell Physiol 2010; 224:423-432.
19. Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 2012; 489:318-321.
20. Adams MM, Shi L, Linville MC,  Forbes ME, Long  AB, Bennett C,  et al. Caloric restriction and age affect synaptic proteins in hippocampal CA3 and spatial learning ability. Exp Neurol 2008; 211:141-149.
21. Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature 2000; 408:255-262.
22. Tucci P. Caloric restriction: is mammalian life extension linked to p53? Aging 2012; 4:525-534.
23. Marcel V, Dichtel-Danjoy ML, Sagne C, Hafsi H, Ma D, Ortiz-Cuaran S.  Biological functions of p53 isoforms through evolution: lessons from animal and cellular models. Cell Death Differ 2011; 18:1815-1824.
24. Medrano S, Scrable H. Maintaining appearances--the role of p53 in adult neurogenesis. Biochem Biophys Res Commun 2005; 331:828-833.
25. Xu BL, Wang R, Meng XH, Zhao ZW, Wang HJ, Ma LN, et al. Effects of analog P165 of amyloid precursor protein 5-mer peptide on learning, memory and brain insulin receptors in the rat model of cognitive decline. Neurol Sci 2014; 35:1821-1826
26. Diegues JC, Pauli JR, Luciano E, de Almeida Leme JA, de Moura LP, Dalia RA, et al. Spatial memory in sedentary and trained diabetic rats: molecular mechanisms. Hippocampus 2014; 24:703-711.
27. Landi F, Capoluongo E, Russo A, Onder G, Cesari M, Lulli P, et al. Free insulin-like growth factor-I and cognitive function in older persons living in community. Growth Hormone IGF Res 2007; 17:58-66.
28. Harada N, Zhao J, Kurihara H, Nakagata N, Okajima K.. Resveratrol improves cognitive function in mice by increasing production of insulin-like growth factor-I in the hippocampus. J Nutr Biochem 2011; 22:1150-1159.