Caloric restriction: beneficial effects on brain aging and Alzheimer’s disease

Mammalian Genome

Volumn 27, Issue 7-8, 2016, Pages 300-319

  Van Cauwenberghe, Caroline ^a   Vandendriessche, Charysse ^a   Libert, Claude ^a   Vandenbroucke, Roosmarijn E ^a  

^a GHENT UNIVERSITY   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

RAPAMYCIN; RESVERATROL; STILBENE DERIVATIVE;

AGING; ALZHEIMER DISEASE; BIOCHEMICAL ANALYSIS; BRAIN AGING; CALORIC RESTRICTION; CLINICAL TRIAL (TOPIC); DEGENERATIVE DISEASE; EPIGENETICS; HUMAN; LIFESPAN; LIFESTYLE MODIFICATION; NONHUMAN; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; BIOMIMETICS; BRAIN; DIET THERAPY; DRUG EFFECTS; ENERGY METABOLISM; GENETICS; METABOLISM; PATHOLOGY; PATHOPHYSIOLOGY;

AGING; ALZHEIMER DISEASE; BIOMIMETICS; BRAIN; CALORIC RESTRICTION; ENERGY METABOLISM; HUMANS; SIROLIMUS; STILBENES;

EID: 84973137402     PISSN: 09388990     EISSN: 14321777     Source Type: Journal    
DOI: 10.1007/s00335-016-9647-6     Document Type: Review

References (203)

1. Adams MM, Shi L, Linville MC, Forbes ME, Long AB, Bennett C, Newton IG, Carter CS, Sonntag WE, Riddle DR, Brunso-Bechtold JK (2008) Caloric restriction and age affect synaptic proteins in hippocampal CA3 and spatial learning ability. Exp Neurol 211(1):141–149
2. Albert V, Hall MN (2015) mTOR signaling in cellular and organismal energetics. Curr Opin Cell Biol 33:55–66
3. Anisimov VN, Bartke A (2013) The key role of growth hormone-insulin-IGF-1 signaling in aging and cancer. Crit Rev Oncol Hematol 87:201–223
4. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Rosenfeld SV, Blagosklonny MV (2011) Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 10:4230–4236
5. Armentero MT, Levandis G, Bramanti P, Nappi G, Blandini F (2008) Dietary restriction does not prevent nigrostriatal degeneration in the 6-hydroxydopamine model of Parkinson’s disease. Exp Neurol 212:548–551
6. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA (2008) A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 3:e2264
7. Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78:547–581
8. Bekinschtein P, Oomen CA, Saksida LM, Bussey TJ (2011) Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable? Semin Cell Dev Biol 22:536–542
9. Bellaver B, Souza DG, Souza DO, Quincozes-Santos A (2014) Resveratrol increases antioxidant defenses and decreases proinflammatory cytokines in hippocampal astrocyte cultures from newborn, adult and aged Wistar rats. Toxicol In Vitro 28:479–484
10. Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WH, Nixon RA (2008) Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J Neurosci 28:6926–6937
11. Bordone L, Cohen D, Robinson A, Motta MC, van Veen E, Czopik A, Steele AD, Crowe H, Marmor S, Luo J, Gu W, Guarente L (2007) SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6:759–767
12. Brachmann CB, Sherman JM, Devine SE, Cameron EE, Pillus L, Boeke JD (1995) The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev 9:2888–2902
13. Brownlow ML, Joly-Amado A, Azam S, Elza M, Selenica ML, Pappas C, Small B, Engelman R, Gordon MN, Morgan D (2014) Partial rescue of memory deficits induced by calorie restriction in a mouse model of tau deposition. Behav Brain Res 271:79–88
14. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S (2010) Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem 285:13107–13120
15. Caccamo A, Magri A, Medina DX, Wisely EV, Lopez-Aranda MF, Silva AJ, Oddo S (2013) mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies. Aging Cell 12:370–380
16. Calvert S, Tacutu R, Sharifi S, Teixeira R, Ghosh P, de Magalhaes JP (2016) A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans. Aging Cell 15:256–266
17. Canto C, Auwerx J (2011) Calorie restriction: is AMPK a key sensor and effector? Physiology (Bethesda) 26:214–224
18. Cava E, Fontana L (2013) Will calorie restriction work in humans? Aging (Albany NY) 5:507–514
19. Chan MF, Liang G, Jones PA (2000) Relationship between transcription and DNA methylation. Curr Top Microbiol Immunol 249:75–86
20. Chen C, Liu Y, Liu Y, Zheng P (2009a) mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2:75
21. Chen Y, Zhou K, Wang R, Liu Y, Kwak YD, Ma T, Thompson RC, Zhao Y, Smith L, Gasparini L, Luo Z, Xu H, Liao FF (2009b) Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci USA 106:3907–3912
22. Chin D, Huebbe P, Pallauf K, Rimbach G (2013) Neuroprotective properties of curcumin in Alzheimer’s disease–merits and limitations. Curr Med Chem 20:3955–3985
23. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305:390–392
24. Colman RJ, Beasley TM, Allison DB, Weindruch R (2008) Attenuation of sarcopenia by dietary restriction in rhesus monkeys. J Gerontol A Biol Sci Med Sci 63:556–559
25. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325:201–204
26. Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM (2014) Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun 5:3557
27. Craft S, Cholerton B, Baker LD (2013) Insulin and Alzheimer’s disease: untangling the web. J Alzheimers Dis 33(Suppl 1):S263–S275
28. Cuervo AM (2008) Autophagy and aging: keeping that old broom working. Trends Genet 24:604–612
29. da Luz PL, Tanaka L, Brum PC, Dourado PM, Favarato D, Krieger JE, Laurindo FR (2012) Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats. Atherosclerosis 224:136–142
30. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370:737–749
31. Dhahbi JM, Mote PL, Fahy GM, Spindler SR (2005) Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genom 23:343–350
32. Duan W, Mattson MP (1999) Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease. J Neurosci Res 57:195–206
33. Duan W, Lee J, Guo Z, Mattson MP (2001) Dietary restriction stimulates BDNF production in the brain and thereby protects neurons against excitotoxic injury. J Mol Neurosci 16:1–12
34. Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP (2003) Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci USA 100:2911–2916
35. Elshorbagy AK, Valdivia-Garcia M, Mattocks DA, Plummer JD, Orentreich DS, Orentreich N, Refsum H, Perrone CE (2013) Effect of taurine and N-acetylcysteine on methionine restriction-mediated adiposity resistance. Metabolism 62:509–517
36. Feng X, Liang N, Zhu D, Gao Q, Peng L, Dong H, Yue Q, Liu H, Bao L, Zhang J, Hao J, Gao Y, Yu X, Sun J (2013) Resveratrol inhibits beta-amyloid-induced neuronal apoptosis through regulation of SIRT1-ROCK1 signaling pathway. PLoS One 8:e59888
37. Finkel T (2015) The metabolic regulation of aging. Nat Med 21:1416–1423
38. Flynn JM, O’Leary MN, Zambataro CA, Academia EC, Presley MP, Garrett BJ, Zykovich A, Mooney SD, Strong R, Rosen CJ, Kapahi P, Nelson MD, Kennedy BK, Melov S (2013) Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell 12:851–862
39. Fok WC, Chen Y, Bokov A, Zhang Y, Salmon AB, Diaz V, Javors M, Wood WH 3rd, Zhang Y, Becker KG, Perez VI, Richardson A (2014) Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome. PLoS One 9:e83988
40. Fontana L, Partridge L, Longo VD (2010) Extending healthy life span–from yeast to humans. Science 328:321–326
41. Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ (2007) Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem 102:1095–1104
42. Gillette-Guyonnet S, Secher M, Vellas B (2013) Nutrition and neurodegeneration: epidemiological evidence and challenges for future research. Br J Clin Pharmacol 75:738–755
43. Goldberg EL, Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub JL, Smithey MJ, Limesand KH, Sempowski GD, Brooks HL, Nikolich-Zugich J (2015) Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell 14:130–138
44. Gorlé N, Van Cauwenberghe C, Libert C, Vandenbroucke RE (2016) The effect of aging on brain barriers and the consequences for Alzheimer's disease development. Mamm Genome. doi:10.1007/s00335-016-9637-8
45. Goto S, Takahashi R, Radak Z, Sharma R (2007) Beneficial biochemical outcomes of late-onset dietary restriction in rodents. Ann N Y Acad Sci 1100:431–441
46. Greer EL, Dowlatshahi D, Banko MR, Villen J, Hoang K, Blanchard D, Gygi SP, Brunet A (2007) An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 17:1646–1656
47. Guarente L, Picard F (2005) Calorie restriction–the SIR2 connection. Cell 120:473–482
48. Haigis MC, Guarente LP (2006) Mammalian sirtuins–emerging roles in physiology, aging, and calorie restriction. Genes Dev 20:2913–2921
49. Halagappa VK, Guo Z, Pearson M, Matsuoka Y, Cutler RG, Laferla FM, Mattson MP (2007) Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 26:212–220
50. Halloran J, Hussong SA, Burbank R, Podlutskaya N, Fischer KE, Sloane LB, Austad SN, Strong R, Richardson A, Hart MJ, Galvan V (2012) Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience 223:102–113
51. Hamadeh MJ, Rodriguez MC, Kaczor JJ, Tarnopolsky MA (2005) Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse. Muscle Nerve 31:214–220
52. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392–395
53. Heitman J, Movva NR, Hall MN (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253:905–909
54. Hine C, Mitchell JR (2015) Calorie restriction and methionine restriction in control of endogenous hydrogen sulfide production by the transsulfuration pathway. Exp Gerontol 68:26–32
55. Hine C, Harputlugil E, Zhang Y, Ruckenstuhl C, Lee BC, Brace L, Longchamp A, Trevino-Villarreal JH, Mejia P, Ozaki CK, Wang R, Gladyshev VN, Madeo F, Mair WB, Mitchell JR (2015) Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160:132–144
56. Holloszy JO, Fontana L (2007) Caloric restriction in humans. Exp Gerontol 42:709–712
57. Horie NC, Serrao VT, Simon SS, Polo Gascon MR, Xavier Dos Santos A, Zambone MA, Bigio de Freitas MM, Cunha-Neto E, Marques EL, Halpern A, Edna de Melo M, Mancini MC, Cercato C (2016) Cognitive effects of intentional weight loss in elderly obese individuals with mild cognitive impairment. J Clin Endocrinol Metab 101:1104–1112
58. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196
59. Hsu CC, Wahlqvist ML, Lee MS, Tsai HN (2011) Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis 24:485–493
60. Hu J, Lin T, Gao Y, Xu J, Jiang C, Wang G, Bu G, Xu H, Chen H, Zhang YW (2015) The resveratrol trimer miyabenol C inhibits beta-secretase activity and beta-amyloid generation. PLoS One 10:e0115973
61. Huang TC, Lu KT, Wo YY, Wu YJ, Yang YL (2011) Resveratrol protects rats from Abeta-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation. PLoS One 6:e29102
62. Hulbert AJ (2005) On the importance of fatty acid composition of membranes for aging. J Theor Biol 234:277–288
63. Imfeld P, Bodmer M, Jick SS, Meier CR (2012) Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case-control study. J Am Geriatr Soc 60:916–921
64. Ingram DK, Weindruch R, Spangler EL, Freeman JR, Walford RL (1987) Dietary restriction benefits learning and motor performance of aged mice. J Gerontol 42:78–81
65. Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA, Roth GS, deCabo R (2006) Calorie restriction mimetics: an emerging research field. Aging Cell 5:97–108
66. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590
67. Jiang M, Wang J, Fu J, Du L, Jeong H, West T, Xiang L, Peng Q, Hou Z, Cai H, Seredenina T, Arbez N, Zhu S, Sommers K, Qian J, Zhang J, Mori S, Yang XW, Tamashiro KL, Aja S, Moran TH, Luthi-Carter R, Martin B, Maudsley S, Mattson MP, Cichewicz RH, Ross CA, Holtzman DM, Krainc D, Duan W (2012) Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med 18:153–158
68. Johnson SC, Rabinovitch PS, Kaeberlein M (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493:338–345
69. Joseph JA, Fisher DR, Cheng V, Rimando AM, Shukitt-Hale B (2008) Cellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of aging. J Agric Food Chem 56:10544–10551
70. Juhasz G, Erdi B, Sass M, Neufeld TP (2007) Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev 21:3061–3066
71. Kadonaga JT (1998) Eukaryotic transcription: an interlaced network of transcription factors and chromatin-modifying machines. Cell 92:307–313
72. Kanaya T, Kyo S, Takakura M, Ito H, Namiki M, Inoue M (1998) hTERT is a critical determinant of telomerase activity in renal-cell carcinoma. Int J Cancer 78:539–543
73. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S (2004) Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14:885–890
74. Karuppagounder SS, Pinto JT, Xu H, Chen HL, Beal MF, Gibson GE (2009) Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer’s disease. Neurochem Int 54:111–118
75. Kaur M, Sharma S, Kaur G (2008) Age-related impairments in neuronal plasticity markers and astrocytic GFAP and their reversal by late-onset short term dietary restriction. Biogerontology 9:441–454
76. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461–464
77. Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26:3169–3179
78. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–946
79. Ladiwala AR, Lin JC, Bale SS, Marcelino-Cruz AM, Bhattacharya M, Dordick JS, Tessier PM (2010) Resveratrol selectively remodels soluble oligomers and fibrils of amyloid Abeta into off-pathway conformers. J Biol Chem 285:24228–24237
80. Lafay-Chebassier C, Perault-Pochat MC, Page G, Rioux Bilan A, Damjanac M, Pain S, Houeto JL, Gil R, Hugon J (2006) The immunosuppressant rapamycin exacerbates neurotoxicity of Abeta peptide. J Neurosci Res 84:1323–1334
81. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109–1122
82. Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG, Kouzarides T (2002) Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 21:2383–2396
83. Law BK (2005) Rapamycin: an anti-cancer immunosuppressant? Crit Rev Oncol Hematol 56:47–60
84. Lee J, Duan W, Long JM, Ingram DK, Mattson MP (2000) Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats. J Mol Neurosci 15:99–108
85. Lee J, Duan W, Mattson MP (2002) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375
86. Lee CC, Kuo YM, Huang CC, Hsu KS (2009) Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation. Neurobiol Aging 30:377–387
87. Leibiger IB, Berggren PO (2006) Sirt1: a metabolic master switch that modulates lifespan. Nat Med 12:34–36 discussion 36
88. Li E, Beard C, Jaenisch R (1993) Role for DNA methylation in genomic imprinting. Nature 366:362–365
89. Li Y, Liu L, Tollefsbol TO (2010) Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. FASEB J 24:1442–1453
90. Li Y, Daniel M, Tollefsbol TO (2011) Epigenetic regulation of caloric restriction in aging. BMC Med 9:98
91. Li XM, Zhou MT, Wang XM, Ji MH, Zhou ZQ, Yang JJ (2014) Resveratrol pretreatment attenuates the isoflurane-induced cognitive impairment through its anti-inflammation and -apoptosis actions in aged mice. J Mol Neurosci 52:286–293
92. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM (2001) The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21:8370–8377
93. Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289:2126–2128
94. Lin AL, Zheng W, Halloran JJ, Burbank RR, Hussong SA, Hart MJ, Javors M, Shih YY, Muir E, Solano Fonseca R, Strong R, Richardson AG, Lechleiter JD, Fox PT, Galvan V (2013) Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s disease. J Cereb Blood Flow Metab 33:1412–1421
95. Lipinski MM, Zheng B, Lu T, Yan Z, Py BF, Ng A, Xavier RJ, Li C, Yankner BA, Scherzer CR, Yuan J (2010) Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc Natl Acad Sci USA 107:14164–14169
96. Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, Cascajo MV, Allard J, Ingram DK, Navas P, de Cabo R (2006) Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA 103:1768–1773
97. Lord J, Cruchaga C (2014) The epigenetic landscape of Alzheimer’s disease. Nat Neurosci 17:1138–1140
98. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107:137–148
99. Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, Hudspeth B, Chen C, Zhao Y, Vinters HV, Frautschy SA, Cole GM (2009) Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci 29:9078–9089
100. Mair W, Morantte I, Rodrigues AP, Manning G, Montminy M, Shaw RJ, Dillin A (2011) Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470:404–408
101. Majumder S, Richardson A, Strong R, Oddo S (2011) Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One 6:e25416
102. Marambaud P, Zhao H, Davies P (2005) Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem 280:37377–37382
103. Marino G, Pietrocola F, Madeo F, Kroemer G (2014) Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers. Autophagy 10:1879–1882
104. Martin B, Mattson MP, Maudsley S (2006) Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing Res Rev 5:332–353
105. Martin CK, Anton SD, Han H, York-Crowe E, Redman LM, Ravussin E, Williamson DA (2007) Examination of cognitive function during six months of calorie restriction: results of a randomized controlled trial. Rejuvenation Res 10:179–190
106. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4:2192
107. Martins R, Lithgow GJ, Link W (2016) Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell 15:196–207
108. Marwarha G, Dasari B, Prabhakara JP, Schommer J, Ghribi O (2010) beta-Amyloid regulates leptin expression and tau phosphorylation through the mTORC1 signaling pathway. J Neurochem 115:373–384
109. Masoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev 126:913–922
110. 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 (2004) Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson’s disease. Proc Natl Acad Sci USA 101:18171–18176
111. Mattson MP (2002) Brain evolution and lifespan regulation: conservation of signal transduction pathways that regulate energy metabolism. Mech Ageing Dev 123:947–953
112. Mattson MP (2012) Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab 16:706–722
113. Mattson MP (2015) Lifelong brain health is a lifelong challenge: from evolutionary principles to empirical evidence. Ageing Res Rev 20:37–45
114. Mattson MP, Duan W, Guo Z (2003) Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms. J Neurochem 84:417–431
115. McCay CM, Crowell MF, Maynard LA (1989) The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition 5:155–171 discussion 172
116. Means LW, Higgins JL, Fernandez TJ (1993) Mid-life onset of dietary restriction extends life and prolongs cognitive functioning. Physiol Behav 54:503–508
117. Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, Weinberg RA (1997) hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90:785–795
118. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 66:191–201
119. Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R (2014) Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13:468–477
120. Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147:728–741
121. Mladenovic Djordjevic A, Perovic M, Tesic V, Tanic N, Rakic L, Ruzdijic S, Kanazir S (2010) Long-term dietary restriction modulates the level of presynaptic proteins in the cortex and hippocampus of the aging rat. Neurochem Int 56:250–255
122. Mouton PR, Chachich ME, Quigley C, Spangler E, Ingram DK (2009) Caloric restriction attenuates amyloid deposition in middle-aged dtg APP/PS1 mice. Neurosci Lett 464:184–187
123. Munoz-Najar U, Sedivy JM (2011) Epigenetic control of aging. Antioxid Redox Signal 14:241–259
124. Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424:277–283
125. Murphy T, Dias GP, Thuret S (2014) Effects of diet on brain plasticity in animal and human studies: mind the gap. Neural Plast 2014:563160
126. Neff F, Flores-Dominguez D, Ryan DP, Horsch M, Schroder S, Adler T, Afonso LC, Aguilar-Pimentel JA, Becker L, Garrett L, Hans W, Hettich MM, Holtmeier R, Holter SM, Moreth K, Prehn C, Puk O, Racz I, Rathkolb B, Rozman J, Naton B, Ordemann R, Adamski J, Beckers J, Bekeredjian R, Busch DH, Ehninger G, Graw J, Hofler H, Klingenspor M, Klopstock T, Ollert M, Stypmann J, Wolf E, Wurst W, Zimmer A, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Ehninger D (2013) Rapamycin extends murine lifespan but has limited effects on aging. J Clin Invest 123:3272–3291
127. Nikolai S, Pallauf K, Huebbe P, Rimbach G (2015) Energy restriction and potential energy restriction mimetics. Nutr Res Rev 28:100–120
128. Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cani O, Clementi E, Carruba MO, Valerio A (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310:314–317
129. Omodei D, Fontana L (2011) Calorie restriction and prevention of age-associated chronic disease. FEBS Lett 585:1537–1542
130. Pamplona R, Barja G, Portero-Otin M (2002) Membrane fatty acid unsaturation, protection against oxidative stress, and maximum life span: a homeoviscous-longevity adaptation? Ann N Y Acad Sci 959:475–490
131. Pani G (2015) Neuroprotective effects of dietary restriction: evidence and mechanisms. Semin Cell Dev Biol 40:106–114
132. Park SK, Prolla TA (2005) Lessons learned from gene expression profile studies of aging and caloric restriction. Ageing Res Rev 4:55–65
133. Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, Ke H, Rehmann H, Taussig R, Brown AL, Kim MK, Beaven MA, Burgin AB, Manganiello V, Chung JH (2012) Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148:421–433
134. Pasinetti GM, Eberstein JA (2008) Metabolic syndrome and the role of dietary lifestyles in Alzheimer’s disease. J Neurochem 106:1503–1514
135. Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, Morgan DG, Morgan TE, Finch CE (2005) Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol Aging 26:995–1000
136. Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K (2011) Clinical trials of resveratrol. Ann N Y Acad Sci 1215:161–169
137. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157–168
138. Peric A, Annaert W (2015) Early etiology of Alzheimer’s disease: tipping the balance toward autophagy or endosomal dysfunction? Acta Neuropathol 129:363–381
139. Perrone CE, Malloy VL, Orentreich DS, Orentreich N (2013) Metabolic adaptations to methionine restriction that benefit health and lifespan in rodents. Exp Gerontol 48:654–660
140. Porquet D, Casadesus G, Bayod S, Vicente A, Canudas AM, Vilaplana J, Pelegri C, Sanfeliu C, Camins A, Pallas M, del Valle J (2013) Dietary resveratrol prevents Alzheimer’s markers and increases life span in SAMP8. Age (Dordr) 35:1851–1865
141. Porquet D, Grinan-Ferre C, Ferrer I, Camins A, Sanfeliu C, Del Valle J, Pallas M (2014) Neuroprotective role of trans-resveratrol in a murine model of familial Alzheimer’s disease. J Alzheimers Dis 42:1209–1220
142. Prolla TA (2002) DNA microarray analysis of the aging brain. Chem Senses 27:299–306
143. Pugh TD, Oberley TD, 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
144. Pyo JO, Yoo SM, Ahn HH, Nah J, Hong SH, Kam TI, Jung S, Jung YK (2013) Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun 4:2300
145. Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, Roberts SB, Group CS (2015) A 2-Year Randomized Controlled Trial of Human Caloric Restriction: feasibility and Effects on Predictors of Health Span and Longevity. J Gerontol A Biol Sci Med Sci 70:1097–1104
146. Redman LM, Ravussin E (2011) Caloric restriction in humans: impact on physiological, psychological, and behavioral outcomes. Antioxid Redox Signal 14:275–287
147. Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361:1545–1564
148. Ribaric S (2012) Diet and aging. Oxid Med Cell Longev 2012:741468
149. Richardson A, Galvan V, Lin AL, Oddo S (2015) How longevity research can lead to therapies for Alzheimer’s disease: the rapamycin story. Exp Gerontol 68:51–58
150. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434:113–118
151. Rogina B, Helfand SL (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci USA 101:15998–16003
152. Rothman SM, Griffioen KJ, Wan R, Mattson MP (2012) Brain-derived neurotrophic factor as a regulator of systemic and brain energy metabolism and cardiovascular health. Ann N Y Acad Sci 1264:49–63
153. Sanchez-Roman I, Barja G (2013) Regulation of longevity and oxidative stress by nutritional interventions: role of methionine restriction. Exp Gerontol 48:1030–1042
154. Santos J, Leitao-Correia F, Sousa MJ, Leao C (2015) Ammonium is a key determinant on the dietary restriction of yeast chronological aging in culture medium. Oncotarget 6:6511–6523
155. Savaskan E, Olivieri G, Meier F, Seifritz E, Wirz-Justice A, Muller-Spahn F (2003) Red wine ingredient resveratrol protects from beta-amyloid neurotoxicity. Gerontology 49:380–383
156. Schafer MJ, Alldred MJ, Lee SH, Calhoun ME, Petkova E, Mathews PM, Ginsberg SD (2015) Reduction of beta-amyloid and gamma-secretase by calorie restriction in female Tg2576 mice. Neurobiol Aging 36:1293–1302
157. Schulingkamp RJ, Pagano TC, Hung D, Raffa RB (2000) Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev 24:855–872
158. Selkoe DJ (2011) Alzheimer’s disease. Cold Spring Harb Perspect Biol. doi:10.1101/cshperspect.a004457
159. Sharma S, Singh R, Kaur M, Kaur G (2010) Late-onset dietary restriction compensates for age-related increase in oxidative stress and alterations of HSP 70 and synapsin 1 protein levels in male Wistar rats. Biogerontology 11:197–209
160. Shen LR, Parnell LD, Ordovas JM, Lai CQ (2013) Curcumin and aging. BioFactors 39:133–140
161. Shytle RD, Tan J, Bickford PC, Rezai-Zadeh K, Hou L, Zeng J, Sanberg PR, Sanberg CD, Alberte RS, Fink RC, Roschek B Jr (2012) Optimized turmeric extract reduces beta-Amyloid and phosphorylated Tau protein burden in Alzheimer’s transgenic mice. Curr Alzheimer Res 9:500–506
162. Siman R, Cocca R, Dong Y (2015) The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy. PLoS ONE 10:e0142340
163. Simonsen A, Cumming RC, Brech A, Isakson P, Schubert DR, Finley KD (2008) Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy 4:176–184
164. Smith DL Jr, Elam CF Jr, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB (2010a) Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci 65:468–474
165. Smith PJ, Blumenthal JA, Babyak MA, Craighead L, Welsh-Bohmer KA, Browndyke JN, Strauman TA, Sherwood A (2010b) Effects of the dietary approaches to stop hypertension diet, exercise, and caloric restriction on neurocognition in overweight adults with high blood pressure. Hypertension 55:1331–1338
166. Sohal RS, Forster MJ (2014) Caloric restriction and the aging process: a critique. Free Radic Biol Med 73:366–382
167. Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273:59–63
168. Sohal RS, Ku HH, Agarwal S, Forster MJ, Lal H (1994) Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse. Mech Ageing Dev 74:121–133
169. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One 5:e9979
170. Sridhar GR, Lakshmi G, Nagamani G (2015) Emerging links between type 2 diabetes and Alzheimer’s disease. World J Diabetes 6:744–751
171. Srivastava S, Haigis MC (2011) Role of sirtuins and calorie restriction in neuroprotection: implications in Alzheimer’s and Parkinson’s diseases. Curr Pharm Des 17:3418–3433
172. Stenesen D, Suh JM, Seo J, Yu K, Lee KS, Kim JS, Min KJ, Graff JM (2013) Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies. Cell Metab 17:101–112
173. Stewart J, Mitchell J, Kalant N (1989) The effects of life-long food restriction on spatial memory in young and aged Fischer 344 rats measured in the eight-arm radial and the Morris water mazes. Neurobiol Aging 10:669–675
174. Strong R, Miller RA, Astle CM, Baur JA, de Cabo R, Fernandez E, Guo W, Javors M, Kirkland JL, Nelson JF, Sinclair DA, Teter B, Williams D, Zaveri N, Nadon NL, Harrison DE (2013) Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 68:6–16
175. Subramanian L, Youssef S, Bhattacharya S, Kenealey J, Polans AS, van Ginkel PR (2010) Resveratrol: challenges in translation to the clinic–a critical discussion. Clin Cancer Res 16:5942–5948
176. Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292:107–110
177. Theendakara V, Patent A, Peters Libeu CA, Philpot B, Flores S, Descamps O, Poksay KS, Zhang Q, Cailing G, Hart M, John V, Rao RV, Bredesen DE (2013) Neuroprotective Sirtuin ratio reversed by ApoE4. Proc Natl Acad Sci USA 110:18303–18308
178. Toth ML, Sigmond T, Borsos E, Barna J, Erdelyi P, Takacs-Vellai K, Orosz L, Kovacs AL, Csikos G, Sass M, Vellai T (2008) Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 4:330–338
179. Tung BT, Rodriguez-Bies E, Ballesteros-Simarro M, Motilva V, Navas P, Lopez-Lluch G (2014) Modulation of endogenous antioxidant activity by resveratrol and exercise in mouse liver is age dependent. J Gerontol A Biol Sci Med Sci 69:398–409
180. Tung BT, Rodriguez-Bies E, Thanh HN, Le-Thi-Thu H, Navas P, Sanchez VM, Lopez-Lluch G (2015) Organ and tissue-dependent effect of resveratrol and exercise on antioxidant defenses of old mice. Aging Clin Exp Res 27:775–783
181. Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, Brewer JB, Rissman RA, Raman R, Aisen PS, Alzheimer’s Disease Cooperative S (2015) A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 85:1383–1391
182. van der Heide LP, Ramakers GM, Smidt MP (2006) Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol 79:205–221
183. Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107:149–159
184. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F (2003) Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426:620
185. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122:253–270
186. Vivar C, Potter MC, van Praag H (2013) All about running: synaptic plasticity, growth factors and adult hippocampal neurogenesis. Curr Top Behav Neurosci 15:189–210
187. Wakeling LA, Ions LJ, Ford D (2009) Could Sirt1-mediated epigenetic effects contribute to the longevity response to dietary restriction and be mimicked by other dietary interventions? Age (Dordr) 31:327–341
188. Wang J, Ho L, Qin W, Rocher AB, Seror I, Humala N, Maniar K, Dolios G, Wang R, Hof PR, Pasinetti GM (2005) Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer’s disease. FASEB J 19:659–661
189. Wang Y, Oh SW, Deplancke B, Luo J, Walhout AJ, Tissenbaum HA (2006) C. elegans 14-3-3 proteins regulate life span and interact with SIR-2.1 and DAF-16/FOXO. Mech Ageing Dev 127:741–747
190. Wang DT, He J, Wu M, Li SM, Gao Q, Zeng QP (2015) Artemisinin mimics calorie restriction to trigger mitochondrial biogenesis and compromise telomere shortening in mice. PeerJ 3:e822
191. Weiss EP, Fontana L (2011) Caloric restriction: powerful protection for the aging heart and vasculature. Am J Physiol Heart Circ Physiol 301:H1205–H1219
192. Wilkinson JE, Burmeister L, Brooks SV, Chan CC, Friedline S, Harrison DE, Hejtmancik JF, Nadon N, Strong R, Wood LK, Woodward MA, Miller RA (2012) Rapamycin slows aging in mice. Aging Cell 11:675–682
193. Willcox BJ, Willcox DC (2014) Caloric restriction, caloric restriction mimetics, and healthy aging in Okinawa: controversies and clinical implications. Curr Opin Clin Nutr Metab Care 17:51–58
194. Witte AV, Fobker M, Gellner R, Knecht S, Floel A (2009) Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci USA 106:1255–1260
195. Witte AV, Kerti L, Margulies DS, Floel A (2014) Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci 34:7862–7870
196. Wood SH, van Dam S, Craig T, Tacutu R, O’Toole A, Merry BJ, de Magalhaes JP (2015) Transcriptome analysis in calorie-restricted rats implicates epigenetic and post-translational mechanisms in neuroprotection and aging. Genome Biol 16:285
197. Wu P, Shen Q, Dong S, Xu Z, Tsien JZ, Hu Y (2008) Calorie restriction ameliorates neurodegenerative phenotypes in forebrain-specific presenilin-1 and presenilin-2 double knockout mice. Neurobiol Aging 29:1502–1511
198. Wu JJ, Liu J, Chen EB, Wang JJ, Cao L, Narayan N, Fergusson MM, Rovira II, Allen M, Springer DA, Lago CU, Zhang S, DuBois W, Ward T, deCabo R, Gavrilova O, Mock B, Finkel T (2013) Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep 4:913–920
199. Zhang S, Salemi J, Hou H, Zhu Y, Mori T, Giunta B, Obregon D, Tan J (2010) Rapamycin promotes beta-amyloid production via ADAM-10 inhibition. Biochem Biophys Res Commun 398:337–341
200. Zhang Y, Bokov A, Gelfond J, Soto V, Ikeno Y, Hubbard G, Diaz V, Sloane L, Maslin K, Treaster S, Rendon S, van Remmen H, Ward W, Javors M, Richardson A, Austad SN, Fischer K (2014) Rapamycin extends life and health in C57BL/6 mice. J Gerontol A Biol Sci Med Sci 69:119–130
201. Zhao HF, Li N, Wang Q, Cheng XJ, Li XM, Liu TT (2015a) Resveratrol decreases the insoluble Abeta1-42 level in hippocampus and protects the integrity of the blood-brain barrier in AD rats. Neuroscience 310:641–649
202. Zhao J, Zhai B, Gygi SP, Goldberg AL (2015b) mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proc Natl Acad Sci USA 112:15790–15797
203. Zhao Z, Sui Y, Gao W, Cai B, Fan D (2015c) Effects of diet on adenosine monophosphate-activated protein kinase activity and disease progression in an amyotrophic lateral sclerosis model. J Int Med Res 43:67–79