Cited by 243Vitamin C and Antioxidants ResearchAlzheimer's disease research and treatmentsAntioxidant Activity and Oxidative Stress

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Vitamin C, Aging and Alzheimer’s Disease

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Monacelli, Fiammetta, Acquarone, Erica, Giannotti, Chiara, Borghi, Roberta, Nencioni, Alessio·2017·Nutrients

DOI 10.3390/nu9070670PMC PMC5537785

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Abstract

Accumulating evidence in mice models of accelerated senescence indicates a rescuing role of ascorbic acid in premature aging. Supplementation of ascorbic acid appeared to halt cell growth, oxidative stress, telomere attrition, disorganization of chromatin, and excessive secretion of inflammatory factors, and extend lifespan. Interestingly, ascorbic acid (AA) was also found to positively modulate inflamm-aging and immunosenescence, two hallmarks of biological aging. Moreover, ascorbic acid has been shown to epigenetically regulate genome integrity and stability, indicating a key role of targeted nutrition in healthy aging. Growing in vivo evidence supports the role of ascorbic acid in ameliorating factors linked to Alzheimer’s disease (AD) pathogenesis, although evidence in humans yielded equivocal results. The neuroprotective role of ascorbic acid not only relies on the general free radical trapping, but also on the suppression of pro-inflammatory genes, mitigating neuroinflammation, on the chelation of iron, copper, and zinc, and on the suppression of amyloid-beta peptide (Aβ) fibrillogenesis. Epidemiological evidence linking diet, one of the most important modifiable lifestyle factors, and risk of Alzheimer's disease is rapidly increasing. Thus, dietary interventions, as a way to epigenetically modulate the human genome, may play a role in the prevention of AD. The present review is aimed at providing an up to date overview of the main biological mechanisms that are associated with ascorbic acid supplementation/bioavailability in the process of aging and Alzheimer’s disease. In addition, we will address new fields of research and future directions.

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BackgroundMethod
Role of Ascorbate and Protein Thiols in the Release of Nitric oxide from S-Nitroso-Albumin and S-Nitroso-Glutathione in Human Plasma
Scorza, G., Pietraforte, D., & Minetti, M. (1997) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(96)00378-4 · Cited by 131 · cited 1×
“AA also favored the restoration of NO metabolism from S-nitrosothiols in plasma [127], reducing nitrite (NO2) to NO, which may preserve NO in tissues or plasma.”
Background
Combating inflammaging through a Mediterranean whole diet approach: The NU-AGE project's conceptual framework and design
Santoro, A., Pini, E., Scurti, M., Palmas, M. G., Berendsen, A. A. M., Brzozowska, A., Pietruszka, B., Szczecińska, A., Cano, N., Meunier, N., et al. (2013) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2013.12.001 · Cited by 129
High-dose of vitamin C supplementation reduces amyloid plaque burden and ameliorates pathological changes in the brain of 5XFAD mice
Kook, S.-Y., Lee, K.-M., Kim, Y., Cha, M.-Y., Kang, S., Baik, S., Lee, H., Park, R., & Mook‐Jung, I. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.26 · Cited by 129 · cited 1×
“The higher supplementation of AA in KO-Tg mice resulted in the amelioration of BBB disruption and mitochondrial alteration, with substantial reduction of amyloid plaque burden [114].”
Background
Copper, β-amyloid, and Alzheimer's disease: Tapping a sensitive connection
Bush, A. I., Masters, C. L., & Tanzi, R. E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2135061100 · Cited by 128
Amyloid β−Cu2+Complexes in both Monomeric and Fibrillar Forms Do Not Generate H2O2Catalytically but Quench Hydroxyl Radicals
Nadal, R. C., Rigby, S. E. J., & Viles, J. H. (2008) · Biochemistry · doi:10.1021/bi8011093 · Cited by 119 · cited 1×
“of Fenton-Haber Weiss reactions of ascorbate and Cu2+, rapidly quenching harmful radicals [112].”
Background
Vitamin C restores healthy aging in a mouse model for Werner syndrome
Massip, L., Garand, C., Paquet, É. R., Cogger, V. C., O'Reilly, J. N., Tworek, L., Hatherell, A., Taylor, C. G., Thorin, É., Zahradka, P. C., et al. (2009) · The FASEB Journal · doi:10.1096/fj.09-137133 · Cited by 114 · cited 1×
“It is noteworthy that in healthy mice, the beneficial effects of AA on health and lifespan were not significant and the supplementation significantly reduced the oxidative damage only in Wrn∆hel/∆hel mouse liver [30,34].”
Background
Dementia and Alzheimer's Disease in Community-Dwelling Elders Taking Vitamin C and/or Vitamin E
Fillenbaum, G. G., Kuchibhatla, M. N., Hanlon, J. T., Artz, M. B., Pieper, C. F., Schmader, K. E., Dysken, M. W., & Gray, S. L. (2005) · Annals of Pharmacotherapy · doi:10.1345/aph.1g280 · Cited by 113 · cited 1×
“In a population study of North Carolina, 616 elders aged over 75 years and long-term supplement users of AA did not show any neuroprotection against developing AD [142].”
Background
Metal chelation, radical scavenging and inhibition of Aβ42 fibrillation by food constituents in relation to Alzheimer’s disease
Chan, S., Kantham, S., Rao, V. M., Palanivelu, M. K., Pham, H. L., Shaw, P. N., McGeary, R. P., & Ross, B. P. (2015) · Food Chemistry · doi:10.1016/j.foodchem.2015.11.118 · Cited by 113 · cited 1×
“In addition, a recent report evaluated the in vitro effects of different food constituents on brain metal chelation, oxidative stress, and fibrillogenesis [89].”
Background
Increased Protein and Lipid Oxidative Damage in Mitochondria Isolated from Lymphocytes from Patients with Alzheimer's Disease: Insights into the Role of Oxidative Stress in Alzheimer's Disease and Initial Investigations into a Potential Biomarker for this Dementing Disorder
Sultana, R., Mecocci, P., Mangialasche, F., Cecchetti, R., Baglioni, M., & Butterfield, D. A. (2011) · Journal of Alzheimer's Disease · doi:10.3233/jad-2011-101425 · Cited by 111 · cited 1×
“Oxidative stress interacts with multiple features associated with AD pathogenesis, such as APP processing, mitochondrial dysfunction, and metal accumulation [80].”
Background
Noninvasive quantification of ascorbate and glutathione concentration in the elderly human brain
Emir, U. E., Raatz, S. K., McPherson, S. E., Hodges, J. S., Torkelson, C. J., Tawfik, P. N., White, T. J. H., & Terpstra, M. (2011) · NMR in Biomedicine · doi:10.1002/nbm.1646 · Cited by 111 · cited 2×
“With testing by neuroimaging, recent research has demonstrated that it is possible to detect brain levels of AA by using a MEGA-PRESS mediated spectra (MEGA-PRESS, MEGA-point-resolved spectroscopy) [144].”
BackgroundMethod
Cupric–amyloid β peptide complex stimulates oxidation of ascorbate and generation of hydroxyl radical
Dikalov, S., Vitek, M. P., & Mason, R. P. (2003) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2003.11.004 · Cited by 110
Vitamin C Restores Behavioral Deficits and Amyloid-β Oligomerization without Affecting Plaque Formation in a Mouse Model of Alzheimer's Disease
Murakami, K., Murata, N., Ozawa, Y., Kinoshita, N., Irie, K., Shirasawa, T., & Shimizu, T. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101971 · Cited by 108 · cited 1×
“[91], in APP transgenic mice, showed that AA administration attenuated oligomerization, but not the total amyloid plaque volume.”
Background
Antioxidants attenuate hyperglycaemia‐mediated brain endothelial cell dysfunction and blood–brain barrier hyperpermeability
Allen, C., & Bayraktutan, U. (2009) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2008.00987.x · Cited by 105 · cited 1×
“Moreover, an in vitro study provided evidence that AA reversed hyperglycemia-mediated BBB disruption [130].”
Background
Vitamin C reduces spatial learning deficits in middle-aged and very old APP/PSEN1 transgenic and wild-type mice
Harrison, F. E., Hosseini, A. H., McDonald, M. P., & May, J. M. (2009) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2009.06.006 · Cited by 103 · cited 1×
“A previous study in APP/PSEN 1 transgenic mice showed that parenteral administration of AA possessed nootropic properties, without altering the AD-like features of plaque deposition, oxidative stress and acetylcholinesterase activity [85].”
Background
Antioxidants reveal an inverted U‐shaped dose‐response relationship between reactive oxygen species levels and the rate of aging in Caenorhabditis elegans
Desjardins, D., Cacho‐Valadez, B., Liu, J., Wang, Y., Yee, C. S., Bernard, K., Khaki, A., Breton, L., & Hekimi, S. (2016) · Aging Cell · doi:10.1111/acel.12528 · Cited by 101 · cited 1×
“In particular, in a Caenorhabdilis elegans model, [48] AA displayed an inverted U-shaped dose–response relationship between ROS levels and lifespan; both high and low levels of ROS were detrimental for longevity.”
Background
“Inflamm‐aging” influences immune cell survival factors in human bone marrow
Pangrazzi, L., Meryk, A., Naismith, E., Kozieł, R., Lair, J., Krismer, M., Trieb, K., & Grubeck‐Loebenstein, B. (2016) · European Journal of Immunology · doi:10.1002/eji.201646570 · Cited by 100 · cited 1×
“This study is of key relevance in assessing the protective role for AA in immunosenescence [35].”
Ascorbic Acid and the Brain: Rationale for the Use against Cognitive Decline
Harrison, F. E., Bowman, G. L., & Polidori, M. C. (2014) · Nutrients · doi:10.3390/nu6041752 · Cited by 99 · cited 6×
“The lack of accuracy in study designs and methodologies may also affect the reliability of the findings [57].”
BackgroundInfluential
Brain inflammation and oxidative stress in a transgenic mouse model of Alzheimer-like brain amyloidosis.
Yao, Y., Chinnici, C. M., Tang, H., Trojanowski, J. Q., Lee, V. M. ‐., & Praticò, D. (2004) · Journal of Neuroinflammation · doi:10.1186/1742-2094-1-21 · Cited by 91
Maillard Degradation Pathways of Vitamin C
Smuda, M., & Glomb, M. A. (2013) · Angewandte Chemie International Edition · doi:10.1002/anie.201300399 · Cited by 87 · cited 1×
“In addition, it has been recently documented that 75% of ascorbic acid degradation is due to Maillard degradation pathways (amide-AGEs) [146].”
Background
The Association of Antioxidants and Cognition in the Nurses' Health Study
Devore, E. E., Kang, J. H., Stampfer, M. J., & Grodstein, F. (2012) · American Journal of Epidemiology · doi:10.1093/aje/kws202 · Cited by 86 · cited 1×
“Another large population study has shown a protective role for AA in vascular dementia and cognitively-intact subjects, but no protective role of AA was shown for Alzheimer’s disease [139].”
Background
The Haptoglobin 2-2 Phenotype Affects Serum Markers of Iron Status in Healthy Males
Langlois, M. R., Martin, M., Boelaert, J. R., Beaumont, C., Taes, Y., Buyzere, M. D., Bernard, D. R., Neels, H. M., & Delanghe, J. (2000) · Clinical Chemistry · doi:10.1093/clinchem/46.10.1619 · Cited by 85
Vitamin C Transporters, Recycling and the Bystander Effect in the Nervous System: SVCT2 versus Gluts
Nualart, F. (2014) · Journal of Stem Cell Research & Therapy · doi:10.4172/2157-7633.1000209 · Cited by 85 · cited 4×
“This bystander effect is responsible for AA recycling activity between neurons and astrocytes and plays a role in the fine balance between pro-oxidative and anti-oxidative status [53].”
BackgroundInfluential
Reaction Rates and Mechanism of the Ascorbic Acid Oxidation by Molecular Oxygen Facilitated by Cu(II)-Containing Amyloid-β Complexes and Aggregates
Jiang, D., Li, X., Liu, L., Yagnik, G. B., & Zhou, F. (2010) · The Journal of Physical Chemistry B · doi:10.1021/jp9095375 · Cited by 83 · cited 2×
“Moreover, reaction rates and mechanisms of AA oxidation resulted in greater biological relevance in the presence of Cu(II)-containing Aβ oligomers and fibrils, given the close proximity of ROS to cell membranes [104].”
Background
A parallel randomized trial on the effect of a healthful diet on inflammageing and its consequences in European elderly people: Design of the NU-AGE dietary intervention study
Berendsen, A., Santoro, A., Pini, E., Cevenini, E., Ostan, R., Pietruszka, B., Rolf, K., Cano, N., Caille, A., Lyon-Belgy, N., et al. (2013) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2013.10.002 · Cited by 82
A Review of the Major Vascular Risk Factors Related to Alzheimer's Disease
Polidori, M. C., Pientka, L., & Mecocci, P. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120871 · Cited by 80 · cited 1×
“The efficacy of AA against BBB breakdown due to cortical compression was reported [90].”
Background
Vitamin C alleviates aging defects in a stem cell model for Werner syndrome
Li, Y., Zhang, W., Chang, L., Han, Y., Sun, L., Gong, X., Tang, H., Liu, Z., Deng, H., Ye, Y., et al. (2016) · Protein & Cell · doi:10.1007/s13238-016-0278-1 · Cited by 79 · cited 1×
“The positive effects of AA on premature cellular events was confirmed by treatment with AA on Werner’s syndrome protein (WRN-deficient) human mesenchymal stem cells (MSCs) [33].”
Background
The Possible Role of Antioxidant Vitamin C in Alzheimer’s Disease Treatment and Prevention
Heo, J., Lee, H., & Lee, K. (2013) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317512473193 · Cited by 79 · cited 2×
“Therefore, several in vitro and in vivo studies underpin the therapeutic role of AA in AD, bolstering oxidative defense [99].”
Background
Ascorbic Acid and Rates of Cognitive Decline in Alzheimer's Disease
Bowman, G. L., Dodge, H. H., Frei, B. B., Calabrese, C., Oken, B., Kaye, J. A., & Quinn, J. F. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-0923 · Cited by 78
Similarity of the yellow chromophores isolated from human cataracts with those from ascorbic acid-modified calf lens proteins: evidence for ascorbic acid glycation during cataract formation
Cheng, R., Lin, B., Lee, K., & ORTWERTH, B. J. (2001) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(01)00051-5 · Cited by 78 · cited 1×
“Evidence from a mouse model that selectively over-expressed the AA transporter SVCT2 in the eye [107] implicated AA in age-related damage to crystalline proteins in the lens.”
Background
Age-related decline of sodium-dependent ascorbic acid transport in isolated rat hepatocytes
Michels, A. J., Joisher, N., & Hagen, T. M. (2003) · Archives of Biochemistry and Biophysics · doi:10.1016/s0003-9861(02)00678-1 · Cited by 77 · cited 1×
“AA enters the cells through the sodium-dependent vitamin C transporters SVCT1 and SVCT2, a process favored by the electrochemical sodium gradient: due to its high capacity and low affinity, SVCT1 assures the intestinal and renal absorption and reabsorption [14].”
Background
Ascorbate‐induced differentiation of embryonic cortical precursors into neurons and astrocytes
Lee, J., Chang, M., Park, C., Kim, H., Kim, J., Son, H., Lee, Y., & Lee, S. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10647 · Cited by 77 · cited 1×
“[55] further demonstrated that AA (at a 200 millimolar concentration) was effective in differentiating neuronal and astrocytes precursors, promoting synaptic maturation.”
Background
Effect of ascorbic acid on release of acetylcholine from synaptic vesicles prepared from different species of animals and release of noradrenaline from synaptic vesicles of rat brain
Kuo, C., Hata, F., Yoshida, H., Yamatodani, A., & Wada, H. (1979) · Life Sciences · doi:10.1016/0024-3205(79)90341-2 · Cited by 77 · cited 1×
“Further, AA was reported to decrease acetylcholinesterase activity in mice [101] and to positively restore presynaptic acetylcholine release [102].”
Background
Endogenous ROS levels are increased in replicative senescence in human bone marrow mesenchymal stromal cells
Jeong, S., & Cho, G. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.03.136 · Cited by 75 · cited 1×
“Moreover, differentiation into adipocytes and osteocytes was significantly increased [38].”
Background
Comparative Brain Cholinesterase-Inhibiting Activity of Glycyrrhiza glabra , Myristica fragrans , Ascorbic Acid, and Metrifonate in Mice
Dhingra, D., Parle, M., & Kulkarni, S. K. (2006) · Journal of Medicinal Food · doi:10.1089/jmf.2006.9.281 · Cited by 75 · cited 1×
“Further, AA was reported to decrease acetylcholinesterase activity in mice [101] and to positively restore presynaptic acetylcholine release [102].”
Background
Lowered plasma vitamin C, but not vitamin E, concentrations in dementia patients.
Charlton, K. E., Rabinowitz, T. L., Geffen, L., & Dhansay, M. A. (2004) · PubMed · Cited by 74
Consumption of High-Dose Vitamin C (1250 Mg per Day) Enhances Functional and Structural Properties of Serum Lipoprotein to Improve Anti-Oxidant, Anti-Atherosclerotic, and Anti-Aging Effects via Regulation of Anti-Inflammatory MicroRNA
Kim, S.-M., Lim, S.-M., Yoo, J.-A., Woo, M.-J., & Cho, K.-H. (2015) · Food & Function · doi:10.1039/c5fo00738k · Cited by 69 · cited 2×
“Therefore, the supplementation with AA could exert protective effects against atherosclerosis and related systemic inflammation by reducing the oxidized LDL and macrophage phagocytosis, with reduced conversion to foam cells [42].”
Background
Vitamin C Transporter Gene Polymorphisms, Dietary Vitamin C and Serum Ascorbic Acid
Cahill, L. E., & El‐Sohemy, A. (2009) · Lifestyle Genomics · doi:10.1159/000314597 · Cited by 68 · cited 1×
“Moreover, both AA transporter genotypes modify the strength of the correlation between dietary AA and serum levels [24].”
Background
Dual Role of Vitamin C on the Neuroinflammation Mediated Neurodegeneration and Memory Impairments in Colchicine Induced Rat Model of Alzheimer Disease
Sil, S., Ghosh, T., Gupta, P., Ghosh, R., Kabir, S. N., & Roy, A. (2016) · Journal of Molecular Neuroscience · doi:10.1007/s12031-016-0817-5 · Cited by 68 · cited 1×
“In particular, a colchicine-induced oxidative stress/neuroinflammation AD rat model [84] showed that administration of AA was effective in preventive memory impairment, and reducing inflammatory markers (TNF alpha, IL 1 beta), ROS, and nitrite levels in the hippocampus of AD rats.”
Background
Ascorbic acid protects SH-SY5Y neuroblastoma cells from apoptosis and death induced by β-amyloid
Huang, J., & May, J. M. (2006) · Brain Research · doi:10.1016/j.brainres.2006.04.047 · Cited by 67 · cited 2×
“Additionally, AA was shown to protect SH-SY5Y neuroblastoma cells from apoptosis mediated by Aβ [86], decreasing the rate of endogenous amyloid generation.”
Background
Ascorbic acid, cognitive function, and Alzheimer's disease: A current review and future direction
Bowman, G. L. (2012) · BioFactors · doi:10.1002/biof.1002 · Cited by 66
Vitamin C consumption is associated with less progression in carotid intima media thickness in elderly men: A 3-year intervention study
Ellingsen, I., Seljeflot, I., Arnesen, H., & Tonstad, S. (2008) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2008.01.006 · Cited by 66 · cited 1×
“Endothelial dysfunction is associated with arterial stiffness which, in turn, is a strong predictor for cognitive decline [124].”
Background
Twenty years of metallo-neurobiology: where to now?
Bush, A. I., & Curtain, C. C. (2007) · European Biophysics Journal · doi:10.1007/s00249-007-0228-1 · Cited by 62 · cited 1×
“Metals can affect the morphology of Aβ, accelerating fibrillation and cytotoxicity of Aβ [71].”
Background
Ascorbate prevents cell death from prolonged exposure to glutamate in an in vitro model of human dopaminergic neurons
Ballaz, S., Moráles, I., Rodrı́guez, M., & Obeso, J. A. (2013) · Journal of Neuroscience Research · doi:10.1002/jnr.23276 · Cited by 62 · cited 1×
“Interestingly, it is also presumed that AA moderates the oxidative stress mediated by glutamate, protecting from excitotoxicity in the brain [56,88].”
Background
Ascorbic Acid Prevents Blood–Brain Barrier Disruption and Sensory Deficit Caused by Sustained Compression of Primary Somatosensory Cortex
Lin, J.-L., Huang, Y., Shen, Y.-C., Huang, H.-C., & Liu, P.-H. (2010) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2009.277 · Cited by 60
Intra-arterial vitamin C prevents endothelial dysfunction caused by ischemia-reperfusion
Pleiner, J., Schaller, G., Mittermayer, F., Marsik, C. L., MacAllister, R. J., Kapiotis, S., Ziegler, S., Ferlitsch, A., & Wolzt, M. (2007) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2007.06.011 · Cited by 58 · cited 1×
“A model of ischemic-reperfusion [126] and BBB breakdown with reduced NO bioavailability may be considered a prototypical model to understand the pleiotropic roles of AA on endothelial function.”
Background
Antioxidants in Alzheimer's disease-vitamin C delivery to a demanding brain
Quinn, J. F., Suh, J. H., Moore, M. M., Kaye, J. A., & Frei, B. B. (2003) · Journal of Alzheimer s Disease · doi:10.3233/jad-2003-5406 · Cited by 57 · cited 1×
“The study of Quinn [141] showed that the mean CSF-to-plasma AA ratio was significantly lower in AD compared with controls.”
Result
Capturing a Reactive State of Amyloid Aggregates
Parthasarathy, S., Yoo, B., McElheny, D., Tay, W. M., & Ishii, Y. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.511345 · Cited by 55 · cited 1×
“Further evidence indicated a pro-oxidative role for AA in the interaction of the redox-active copper ions with misfolded amyloid β and AD pathogenesis, with particular relevance to catalytic sites for Cu+ present in full-length Aβ instead of in any particular Aβ conformation [82].”
Background
Ascorbate stimulates endothelial nitric oxide synthase enzyme activity by rapid modulation of its phosphorylation status
Ladurner, A., Schmitt, C. A., Schachner, D., Atanasov, A. G., Werner, E. R., Dirsch, V. M., & Heiss, E. H. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.03.022 · Cited by 54 · cited 1×
“Low levels of BH4 compromise eNOS function by promoting the transfer of electrons to oxygen molecules instead of L-arginine: in turn, eNOS produces a superoxide anion instead of generating NO [19].”
Background
Alzheimer’s disease and endothelial dysfunction
Bomboi, G., Castello, L., Cosentino, F., Giubilei, F., Orzi, F., & Volpe, M. (2009) · Neurological Sciences · doi:10.1007/s10072-009-0151-6 · Cited by 54 · cited 1×
“Again, oxidative stress is considered a key relevant mediator, confirming the pathogenetic link between AD and vascular disease [116].”
Background
Dehydroascorbic Acid Promotes Cell Death in Neurons Under Oxidative Stress: a Protective Role for Astrocytes
García-Krauss, A., Ferrada, L., Astuya, A., Salazar, K., Cisternas, P., Martínez, F., Ramírez, E., & Nualart, F. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9497-3 · Cited by 53 · cited 1×
“In turn, the direct contact of activated glial cells with neurons may generate immune mediators (nitric oxide, ROS, pro-inflammatory cytokines, and chemokines) that are neurotoxins, spreading inflammation in the central nervous system [78,79].”
Background
Reprint of: A parallel randomized trial on the effect of a healthful diet on inflammageing and its consequences in European elderly people: Design of the NU-AGE dietary intervention study
Berendsen, A. A. M., Santoro, A., Pini, E., Cevenini, E., Ostan, R., Pietruszka, B., Rolf, K., Cano, N., Caillé, A., Lyon-Belgy, N., et al. (2014) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2014.03.001 · Cited by 48
Antioxidants and endothelial nitric oxide synthesis
Heller, R., Werner‐Felmayer, G., & Werner, E. R. (2005) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-005-0009-7 · Cited by 48 · cited 1×
“AA is also implicated in the endothelial integrity associated with NO bioavailability [17].”
Background
Reduced Risk of Alzheimer Disease in Users of Antioxidant Vitamin Supplements: The Cache County Study
Zandi, P. P. (2004) · Archives of Neurology · doi:10.1001/archneur.61.1.82 · Cited by 47
Neuroprotection by vitamin C against ethanol -induced neuroinflammation associated neurodegeneration in developing rat brain
Ahmad, A., Shah, S. A., Badshah, H., Kim, M. J., Ali, T., Yoon, G. H., Kim, T. H., Abid, N. B., Rehman, S. U., Khan, S. H., et al. (2016) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527315666151110130139 · Cited by 46 · cited 2×
“In addition, a rat model of ethanol-induced oxidative stress showed that AA was effective in counteracting ethanol-induced oxidative stress, neuroinflammation, and apoptotic neuronal loss with beneficial effects against ethanol damage to brain development [87].”
Background
Ascorbic Acid Reduces the Adverse Effects of Delayed Administration of Tissue Plasminogen Activator in a Rat Stroke Model
Allahtavakoli, M., Amin, F., Esmaeeli-Nadimi, A., Shamsizadeh, A., Kazemi-arababadi, M., & Kennedy, D. D. (2015) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.12413 · Cited by 45 · cited 1×
“In a model of stroke with substantial BBB disruption, AA significantly reduced BBB permeability [128].”
Background
Pro-oxidant diet enhances β/γ secretase-mediated APP processing in APP/PS1 transgenic mice
Choudhry, F., Howlett, D. R., Richardson, J. C., Francis, P. T., & Williams, R. J. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.07.008 · Cited by 43
Molecular Targeting Regulation of Proliferation and Differentiation of the Bone Marrow-Derived Mesenchymal Stem Cells or Mesenchymal Stromal Cells
Chen, B., Wang, X., Chen, L.-W., & Luo, Z.-J. (2012) · Current Drug Targets · doi:10.2174/138945012799499749 · Cited by 40 · cited 2×
“In the metabolic profile, inflammatory status was improved and, at a molecular level, the normalization of the phosphorylation of AKT kinase, transcriptional levels of NF-kappa B, protein kinase delta (PKC delta), peroxisome proliferator-activated receptor alpha (PPAR-alpha) and hypoxia-inducible factor-1 alpha (HIF1-…”
Background
High Dietary Intake of Vitamin C Suppresses Age-Related Thymic Atrophy and Contributes to the Maintenance of Immune Cells in Vitamin C-Deficient Senescence Marker Protein-30 Knockout Mice
Uchio, R., Hirose, Y., Murosaki, S., Yamamoto, Y., & Ishigami, A. (2015) · British Journal of Nutrition · doi:10.1017/s0007114514003857 · Cited by 39 · cited 1×
“Further, AA was found to modulate immune cell surveillance in SMP30 knockout mice [40].”
Background
Suppression of Amyloid β A11 Antibody Immunoreactivity by Vitamin C
Cheng, F., Cappai, R., Ciccotosto, G. D., Svensson, G., Multhaup, G., Fransson, L., & Mani, K. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.243345 · Cited by 39 · cited 2×
“In the absence of AA, the temporary interaction between the Aβ domain and small NO-catalyzed release of anhydromannose (anMan)-containing oligosaccharides is prevented, with the increased induction of neurotoxic fibrillogenesis [103].”
Background
Vitamin C modulates the metabolic and cytokine profiles, alleviates hepatic endoplasmic reticulum stress, and increases the life span of Gulo−/− mice
Aumailley, L., Warren, A., Garand, C., Dubois, M. J., Paquet, É. R., Couteur, D. G. L., Marette, A., Cogger, V. C., & Lebel, M. (2016) · Aging · doi:10.18632/aging.100902 · Cited by 38 · cited 1×
“In addition, in the same in vivo model, AA supplementation was shown to improve T cell-mediated acute response after liver injury, suggesting a modulation of the immune system [31].”
Background
Beta-amyloid deposition in the brains of rats chronically infused with thiorphan or lipopolysaccharide: the role of ascorbic acid in the vehicle
Hauss‐Wegrzyniak, B., & Wenk, G. L. (2002) · Neuroscience Letters · doi:10.1016/s0304-3940(02)00087-3 · Cited by 37 · cited 1×
“A previous study demonstrated that chronic administration of AA in the brain chronically infused with lipopolysaccharide and tiorphan was associated with increased deposition of Aβ amyloid plaques and increased Aβ neuronal immunoreactivity [92].”
Background
The Antioxidant N-Acetylcysteine Prevents the Mitochondrial Fragmentation Induced by Soluble Amyloid-F Peptide Oligomers
SanMartín, C. D., Adasme, T., Hidalgo, C., & Paula-Lima, A. C. (2012) · Neurodegenerative Diseases · doi:10.1159/000334901 · Cited by 37 · cited 1×
“Brain accumulation of Aβ1-42 oligomers results in increased neuronal vulnerability to oxidative stress [64,65] neuroinflammation with impairment of synaptic plasticity [66], and neuronal death.”
Background
Nutrigenomics at the Interface of Aging, Lifespan, and Cancer Prevention
Riscuta, G. (2016) · The Journal of Nutrition · doi:10.3945/jn.116.235119 · Cited by 37 · cited 1×
“It is able to modulate telomeres activity, bioenergetics, DNA repair and oxidative stress, indicating a nutrigenomic role in the process of aging as well [49].”
Background
Ascorbic acid prevents increased endothelial permeability caused by oxidized low density lipoprotein
May, J. M., & Qu, Z. (2010) · Free Radical Research · doi:10.3109/10715762.2010.508496 · Cited by 35 · cited 1×
“An oxidized endothelium is known to increase BBB permeability [117] and the AA-associated protective mechanism on lipid metabolism was found to improve BBB endothelial disruption.”
Background
Sustained choroid plexus function in human elderly and Alzheimer’s disease patients
Spector, R., & Johanson, C. E. (2013) · Fluids and Barriers of the CNS · doi:10.1186/2045-8118-10-28 · Cited by 35
Ascorbic acid is a dose-dependent inhibitor of adipocyte differentiation, probably by reducing cAMP pool
Rahman, F., Frouh, F. A., Bordignon, B., Fraterno, M., Landrier, J., Peiretti, F., & Fontés, M. (2014) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2014.00029 · Cited by 34 · cited 1×
“Since aging is associated with sarcopenia and defects in body weight, the current observations suggest that AA-mediated stem cell effects could play a role in the aging process [36,37].”
Background
Vitamin C levels in blood are influenced by polymorphisms in glutathione S-transferases
Horská, A., Mišľanová, C., Bonassi, S., Ceppi, M., Volkovová, K., & Dušinská, M. (2010) · European Journal of Nutrition · doi:10.1007/s00394-010-0147-2 · Cited by 33
L-Ascorbate Attenuates the Endotoxin-Induced Production of Inflammatory Mediators by Inhibiting MAPK Activation and NF-κB Translocation in Cortical Neurons/Glia Cocultures
Huang, Y.-N., Lai, C.-C., Chiu, C.-T., Lin, J.-J., & Wang, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097276 · Cited by 32 · cited 1×
“In line with these data, AA was also observed to suppress the lipopolysaccharide (LPS)-stimulated production of inflammatory mediators in neuron/glia co-cultures by inhibiting the MAPK and NF-κB signaling pathways [113].”
Background
Bridging the Pathophysiology of Alzheimer's Disease with Vascular Pathology: The Feed-Back, the Feed-Forward, and Oxidative Stress
Polidori, M. C., & Pientka, L. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-111034 · Cited by 32
Nitric oxide mediates tightening of the endothelial barrier by ascorbic acid
May, J. M., & Qu, Z. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.12.046 · Cited by 31
Expression profile of Caenorhabditis elegans mutant for the Werner syndrome gene ortholog reveals the impact of vitamin C on development to increase life span
Dallaire, A., Proulx, S., Simard, M. J., & Lebel, M. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-940 · Cited by 28 · cited 1×
“Conversely, in the wild-type worms, AA only influenced the biological process of proteolysis [32].”
Background
Ascorbate improves metabolic abnormalities in Wrn mutant mice but not the free radical scavenger catechin
Lebel, M., Massip, L., Garand, C., & Thorin, É. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05189.x · Cited by 27 · cited 1×
“It is noteworthy that in healthy mice, the beneficial effects of AA on health and lifespan were not significant and the supplementation significantly reduced the oxidative damage only in Wrn∆hel/∆hel mouse liver [30,34].”
Background
Antioxidants and Dementia Risk: Consideration through a Cerebrovascular Perspective
Lam, V., Hackett, M. J., & Takechi, R. (2016) · Nutrients · doi:10.3390/nu8120828 · Cited by 26
Dehydroascorbic Acid Attenuates Ischemic Brain Edema and Neurotoxicity in Cerebral Ischemia: Anin vivoStudy
Song, J., Park, J., Kim, J. H., Choi, J. Y., Kim, J. Y., Lee, K. M., & Lee, J. E. (2015) · Experimental Neurobiology · doi:10.5607/en.2015.24.1.41 · Cited by 25 · cited 1×
“Similarly, in a mouse model of cerebral ischemia, AA ameliorated BBB dysfunction by reversing tight junction claudin-5 and attenuated edema and neuronal loss [129].”
Background
A preliminary study on the effects of star fruit consumption on antioxidant and lipid status in elderly Thai individuals
Leelarungrayub, J., Yankai, A., Pinkaew, D., Puntumetakul, R., Laskin, J., & Bloomer, R. J. (2016) · Clinical Interventions in Aging · doi:10.2147/cia.s110718 · Cited by 25
Mechanisms Involved in the Modulation of Astroglial Resistance to Oxidative Stress Induced by Activated Microglia: Antioxidative Systems, Peroxide Elimination, Radical Generation, Lipid Peroxidation
Röhl, C., Armbrust, E., Herbst, E., Jess, A., Gülden, M., Maser, E., Rimbach, G. H., & Boesch, C. (2009) · Neurotoxicity Research · doi:10.1007/s12640-009-9108-z · Cited by 24 · cited 1×
“It is well documented that AA is a first-line antioxidant defense to neutralize ROS reactivity, promoting the regeneration of endogenous antioxidants (GSH, catalase, vitamin E) [98].”
Background
Consumption of star fruit juice on pro-inflammatory markers and walking distance in the community dwelling elderly
Leelarungrayub, J., Laskin, J., Bloomer, R. J., & Pinkaew, D. (2015) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2015.12.001 · Cited by 24 · cited 1×
“The associated AA antioxidant capacity also mediated anti-inflammatory effects by the reduction of pro-inflammatory cytokine secretion, especially TNF-alpha and interleukin-23 (IL-23) excluding interleukin-2 (IL-2) [51,52].”
Background
Nanocapsulated Ascorbic Acid in Combating Cerebral Ischemia Reperfusion- Induced Oxidative Injury in Rat Brain
Sarkar, S., Mukherjee, A. K., Swarnakar, S., & Das, N. (2016) · Current Alzheimer Research · doi:10.2174/1567205013666160625082839 · Cited by 23 · cited 1×
“[87] recently reported that high-dose supplementation of AA reduced amyloidosis in AD mice (5XFAD) via the reduction of BBB disruption and mitochondrial alteration [96].”
Background
Ascorbic acid drives the differentiation of mesoderm‐derived embryonic stem cells. Involvement of p38 MAPK/CREB and SVCT2 transporter
Rahman, F., Bordignon, B., Culerrier, R. M., Peiretti, F., Spicuglia, S., Djabali, M., Landrier, J., & Fontés, M. (2016) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201600506 · Cited by 21 · cited 1×
“Since aging is associated with sarcopenia and defects in body weight, the current observations suggest that AA-mediated stem cell effects could play a role in the aging process [36,37].”
Background
Association of increased carotid intima–media thickness and lower plasma levels of vitamin C and vitamin E in old age subjects: implications for Alzheimer’s disease
Polidori, M. C., Ruggiero, C., Croce, M. F., Raichi, T., Mangialasche, F., Cecchetti, R., Pelini, L., Paolacci, L., Ercolani, S., & Mecocci, P. (2015) · Journal of Neural Transmission · doi:10.1007/s00702-014-1357-1 · Cited by 19 · cited 1×
“Recently, a pathophysiological role of the vascular component in the pathogenesis of AD has been demonstrated [115].”
Background
Cytoplasmic superoxide radical
Murakami, K., & Shimizu, T. (2012) · Communicative & Integrative Biology · doi:10.4161/cib.19548 · Cited by 19
New criteria for supplementation of selected micronutrients in the era of nutrigenetics and nutrigenomics
Schwartz, B. (2014) · International Journal of Food Sciences and Nutrition · doi:10.3109/09637486.2014.898258 · Cited by 16
Impact of vitamin C on the cardiometabolic and inflammatory profiles of mice lacking a functional Werner syndrome protein helicase
Aumailley, L., Dubois, M. J., Garand, C., Marette, A., & Lebel, M. (2015) · Experimental Gerontology · doi:10.1016/j.exger.2015.10.012 · Cited by 16 · cited 1×
“This study suggested that AA could be a potential cardiometabolic biomarker in patients with WS [39].”
Background
Survival Rate in Patients Affected by Dementia Followed by Memory Clinics (UVA) in Italy
Ientile, L., Pasquale, R. D., Monacelli, F., Odetti, P. R., Traverso, N., Cammarata, S., Tabaton, M., & Dijk, B. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130002 · Cited by 16 · cited 1×
“The increasing burden of this life-threatening condition [60] and the lack of disease-modifying drugs have guided the research towards preventive strategies, targeting AD modifiable risk factors [12].”
BackgroundSelf-citation
Pentosidine determination in CSF: a potential biomarker of Alzheimer’s disease?
Monacelli, F., Borghi, R., Pacini, D., Serrati, C., Traverso, N., & Odetti, P. R. (2013) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2012-0829 · Cited by 14 · cited 1×
“In addition, lower concentrations of the fluorescent AGE pentosidine were observed in the CSF of AD patients, compared to healthy subjects, in support of a role for altered AGE metabolism in AD pathogenesis [73].”
BackgroundSelf-citation
Ascorbic acid prevents protein oxidation in livers of senescence marker protein-30/gluconolactonase knockout mice
Sato, Y., Amano, A., Kishimoto, Y., Takahashi, K., Handa, S., Maruyama, N., & Ishigami, A. (2013) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/ggi.12162 · Cited by 9 · cited 1×
“In line with these data, Sato and colleagues suggested that AA plays an important role in preventing protein oxidation in the liver of SM30/gluconolactonase knockout mice, with potential implications in overall health and aging [41].”
Result
[Vitamin C promotes in vitro proliferation of bone marrow mesenchymal stem cells derived from aging mice].
Zheng, C., Sui, B., Hu, C., & Jin, Y. J. (2015) · PubMed · Cited by 7

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Diet and Inflammation in Cognitive Ageing and Alzheimer’s Disease
McGrattan, A., McGuinness, B., McKinley, M. C., Kee, F., Passmore, P., Woodside, J. V., & McEvoy, C. T. (2019) · Current Nutrition Reports · doi:10.1007/s13668-019-0271-4 · Cited by 414
Neuroinflammation in Alzheimer’s Disease
Onyango, I. G., Jauregui, G. V., Čarná, M., Bennett, J. P., & Stokin, G. B. (2021) · Biomedicines · doi:10.3390/biomedicines9050524 · Cited by 330
Preventive and Therapeutic Strategies in Alzheimer's Disease: Focus on Oxidative Stress, Redox Metals, and Ferroptosis
Plascencia‐Villa, G., & Perry, G. L. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8134 · Cited by 188
“Ascorbic acid supplementation showed neuroprotective properties, reducing free radicals and neuroinflammation, also iron chelation and Ab reduction (118).”
Background
Dietary habits, lifestyle factors and neurodegenerative diseases
Popa‐Wagner, A., Dumbrava, D., Dumitrascu, D., Căpitănescu, B., Petcu, E. B., Surugiu, R., & Fang, W.-H. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.266045 · Cited by 190
Promoting Successful Cognitive Aging: A Ten-Year Update
Krivanek, T. J., Gale, S. A., McFeeley, B. M., Nicastri, C. M., & Daffner, K. R. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201462 · Cited by 189
“fatty acids [173, 174], antioxidant vitamins [175],”

See all 243

Authors: Monacelli, F., Acquarone, E., Giannotti, C., Borghi, R., & Nencioni, A.
Affiliations: University of Genoa (IT)
Corresponding author: Monacelli, Fiammetta
ORCID: Monacelli, Fiammetta
Acquarone, Erica
Giannotti, Chiara
Nencioni, Alessio
Venue: Nutrients
Publisher: MDPI AG
Published: 2017-06-27
Volume: 9
Issue: 7
Pages: 670
ISSN: 2072-6643 (ISSN-L)
DOI: 10.3390/nu9070670
PMC: PMC5537785
OpenAlex: W2724874603
Cited by: 243
References: 148
Citations by year: 2026: 9 · 2025: 29 · 2024: 37 · 2023: 31 · 2022: 38 · 2021: 34 · 2020: 27 · 2019: 22 · 2018: 14 · 2017: 2
FWCI: 1.83
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Nutrients (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
Topics: Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
Keywords: vitamin C, aging, Alzheimer's disease, accelerated senescence, inflammaging, immunosenescence, telomere shortening, oxidative stress, epigenetic regulation, neuroinflammation, dietary supplementation, lifespan extension, healthy aging
MeSH terms: Aging, Alzheimer Disease, Animals, Ascorbic Acid, Brain, Disease Models, Animal, Humans, Vascular Diseases, Randomized Controlled Trials as Topic, Oxidative Stress, Nutrigenomics, Epigenomics, Plaque, Amyloid, Observational Studies as Topic

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