Table 2.
Vitamin C and aging.
| Species | Intervention | Measurement | Outcome | Reference | |
|---|---|---|---|---|---|
| In vivo studies | |||||
| APP/PSEN1 and B6C3F1/J mice (6–10 months). | VitC in diet (1 g/kg) and high or low dose VitE (750/400 IU/kg). | Functional assessment, amyloid, F4-neuroprostanes and MDA. | Supplementation with VitC and low VitE decreased markers of oxidative stress in transgenic mice (p < 0.05). Improvement of MWM performance was seen in low VitE group (0.05 > p < 0.001). | [127] | |
| Swiss mice (3 and 7 months). | IP injection of 60 and 120 mg/kg VitC for three or eight consecutive days. | Elevated plus maze, passive avoidance test. | Treatment improved performance in young animals (p < 0.05) and reversed performance deficits in old animals (p < 0.05). | [111] | |
| Dunkin Hartley guinea pig (3–9 months and 36–42 months). | Diet containing 325 mg VitC/kg or 100 mg VitC/kg. | VitC, MDA, glutathione, 8-oxodG and SOD in brain. SVCT2 mRNA expression in brain. | Deficiency did not cause significant changes in oxidative stress markers but aging per se showed a significant effect (p < 0.05). No detectable effect on SVCT mRNA expression in deficient. | [116] | |
| AβPP mice (6–12 months). | 1333 mg/kg/day VitC in drinking water. | IHC for anti-Aβ, Western blot, Aβ-ELISA, OxyBlot, glutathione, functional assessment by MVM and elevated plus maze. | VitC prevented some behavioral abnormalities in AβPP mice (0.05 > p < 0.02), down-regulated amyloid (p < 0.05), significant difference of Aβ42/Aβ40 ratio (p < 0.02) and increased in synaptophysin (p < 0.05). Phosphorylated tau was decreased (p < 0.05). | [129] | |
| Female ovariectomized Wistar rats (80 days). | VitE (40 mg/kg) and VitC (100 mg/kg) IP once daily for 30 days. | MWM, open field test. | Vitamin C + E treatment prevented deficits in reference memory in MWM (0.01 > p < 0.05). | [114] | |
| Swiss mice (3 months). | VitC (60 mg/kg) IP injection of for three consecutive days. | Elevated plus maze and passive avoidance. | VitC injection reversed amnesia induced by scopolamine (0.4 mg/kg) and diazepam (1 mg/kg) (p < 0.05). | [111] | |
| B6C3F1/J mice (12 weeks). | VitC (125 mg/kg) IP. | Behavioral testing, MDA and Asc content in cortex, AChE activity, brain glutathione. | VitC treatment reversed some of the memory deficits induced by scopolamine (1 mg/kg IP) (0.05 > p < 0.001) and increased medial forebrain AChE acticity (p < 0.001). | [130] | |
| CD1 mice (16 months). | Oxiracetam (62.5/125/250 mg/kg), VitC (50/100/200 mg/kg), VitC (125 mg/kg) + oxiracetam (100 mg/kg) IP for three consecutive days. | Light-dark aversion test. | VitC alone or in combination with oxiracetam significantly reduced scopolamine-induced (0.25 mg/kg IP, day 4) amnesia (p < 0.01). | [136] | |
| Dunkin Hartley guinea pigs (3–9 and 8–14 months). | Diet with 325 mg/kg VitC. | VitC in brain and CSF. | Concentrations of VitC significantly increased in CSF with age (p < 0.05). Elevated Asc oxidation ratio in young compared to old animals (p < 0.05). | [115] | |
| Dunkin Hartley guinea pigs (3–9 and 36–42 months). | Diet with 325 mg VitC/kg or 100 mg VitC/kg. | VitC in CSF and 8-oxodG, MDA, glutathione and SOD in brain. | No effect was observed besides on VitC concentration in brain and CSF in deficient animals. | [116] | |
| Design and Subjects | Intervention | Measurements | Outcome | Reference | |
| Clinical Studies | |||||
| Cohort studies | 12 AD or dementia patients (71 ± 11 years) and healthy controls (35 ± 5 years). | Blood samples of VitC and DHA. | Dementia and AD patients had significantly lower Asc and DHA levels (p < 0.001). | [137] | |
| Patients (n = 134) (AD, vascular dementia or Parkinson’s) and 58 matching controls. | Plasma content of: α-carotene, β-carotene, lycopene, VitA, VitC, VitE and TAC. | VitC was significantly lower in AD (p < 0.001), vascular dementia (p < 0.001) and Parkinson’s disease with dementia (p < 0.01). | [117] | ||
| Prospective cohort study: 633 participants age ≥65 years. | Direct inspection of ingested supplements (two weeks of base-line). Participants were followed for a mean of 4.3 years. | None of the VitE or VitC users developed AD despite a predicted incidence of 3.9 and 3.2, respectively (p = 0.04). | [132] | ||
| Nurses’ Health study: 14,968 women age 70–79 in 1995–2000. | Semi-quantitative questionnaire on lifestyle, supplemental use and medical history biennially from 1980. | TICS, 10-word list, immediate and delayed recall, verbal fluency, digit span backwards test. | Long-term VitC + E supplementation was associated with better cognitive function (p = 0.03) and a trend toward better performance (p = 0.04) | [118] | |
| The Honolulu-Asia Aging Study: 3385 men age 71–93 years. | Questionnaires on vitamin supplementation in 1982/1988. | Assessment of cognitive performance by CASI in 1991–1993. | VitC and/or VitE supplementation decreased the incidence of vascular (OR: 0.12) and mixed/other type dementia (OR: 0.31) and was associated with a higher cognitive performance (OR: 1.25). | [119] | |
| The Rotterdam Prospective Study: 5395 participants age ≥55 years in 1990–1993 | Interview of dietary intake of VitC, VitE, β-carotene, supplements, educational level, etc. | Clinical examination and MMSE, GMS, CAMDEX in 1993–1994 and 1997–1999. | High dietary intake of VitC and VitE may lower the risk of Alzheimer’s disease. RR = +0.82/standard deviation increase in VitC intake. | [16] | |
| Prospective cohort study: 32 patients with mild to moderate AD age 71 ± 7 years. | Physical examination. | ADAS-cog, MMSE, CDR and geriatric depression. CSF and blood samples at baseline. | CSF/Plasma VitC content predicted cognitive decline partially due to a compromised blood brain barrier integrity. | [15] | |
| Nurses’ Health Study: 16,010 women age ≥70 years in 1995–2000. | Food-questionnaire in 1980 and expanded version in 1984, 1986, and every four years thereafter. FRAP assessment. | TICS scores and ten word list, global composite scores, East Boston Memory test on three occations. | No significant association between FRAP scores and cognitive function, when adjusted for confounders. | [138] | |
| Adult Changes in Thought Prospective Study: 2969 participants age ≥65 years. | Self-reported VitC, VitE or multivitamin supplement. Participants were followed for a mean of 5.5 years. | Health and lifestyle parameters (e.g., BMI, smoking and alcohol consumption) CASI score every second year. | Neither VitC, VitE nor multivitamin use was associated with a decreased incidence of AD or dementia. | [133] | |
| Prospective cohort study: 137 elderly age 66–90 years. | Nutritional data collected in 1980 and 1986. | Cognitive evaluation in Logical Memory, Abstraction and Visual Reproduction trials in 1986. | Plasma concentrations of VitC were positively correlated with Rey-Osterrieth Copy test performance and Visual Reproduction (p < 0.05). | [139] | |
| Prospective cohort study: 921 elderly age ≥65 years. | A one week food diary or interviews to quantify consumer habits. Participants were followed for 20 years. | Medical examination including Hodkinson Abbreviated Mental test. | Participants with the lowest dietary/plasma VitC status had the poorest cognitive function (OR: 1.6). | [3] | |
| Clinical trials | Randomized open-label clinical trial: 23 AD patients receiving cholinergic treatment. | 400 IU VitE and 1000 mg VitC per day or no vitamin treatment. CSF samples at baseline, one month and twelve months. | Clinical and neuropsychological assessment. | Significant increases in VitC content in CSF and decreases in autoxidation (p < 0.05). No neuropsychological differences. | [140] |
Abbreviations: VitC, vitamin C; VitE, vitamin E; DHA, dehydroascorbic acid; Asc, ascorbate; VitA, vitamin A; AchE, Acethylcholine esterase; TAC, total antioxidant capacity; SOD, superoxide dismutase; MDA, malondialdehyde; SVCT, sodium-dependent vitamin C transporter; Aβ, beta-amyloid; AD, Alzheimer’s disease; CSF, cerebrospinal fluid; BMI, body mass index; ELISA, enzyme-linked immunosorbent assay; IP, intra-peritoneal; IHC, immunohistochemistry; FRAP, ferric reducing antioxidant capacity; MMSE, Mini Mental State Examination; CAMDEX, Cambridge Mental Disorders of the Elderly Examination; ADAS-cog, Alzheimer’s Disease Assessment Scale; TICS, Telephone Interview of Cognitive Status; CASI, Cognitive Abilities Screening Instrument; GMS, Geriatric Mental State; CDR, Clinical Dementia Rating; RR, relative risk; OR, odds ratio; SD, standard deviation.