Transgenic growth hormone mice (TGM) are a recognized model of accelerated aging with characteristics including chronic oxidative stress, reduced longevity, mitochondrial dysfunction, insulin resistance, muscle wasting, and elevated inflammatory processes. Growth hormone/IGF-1 activate the Target of Rapamycin known to promote aging. TGM particularly express severe cognitive decline. We previously reported that a multi-ingredient dietary supplement (MDS) designed to offset five mechanisms associated with aging extended longevity, ameliorated cognitive deterioration and significantly reduced age-related physical deterioration in both normal mice and TGM. Here we report that TGM lose more than 50% of cells in midbrain regions, including the cerebellum and olfactory bulb. This is comparable to severe Alzheimer’s disease and likely explains their striking agerelated cognitive impairment. We also demonstrate that the MDS completely abrogates this severe brain cell loss, reverses cognitive decline and augments sensory and motor function in aged mice. Additionally, histological examination of retinal structure revealed markers consistent with higher numbers of photoreceptor cells in aging and supplemented mice. We know of no other treatment with such efficacy, highlighting the potential for prevention or amelioration of human neuropathologies that are similarly associated with oxidative stress, inflammation and cellular dysfunction. Environ. Mol. Mutagen. 57:382–404, 2016.
A dietary supplement containing ingredients commonly found in health food stores appears to prevent the decline in brain structure and function typically seen in Alzheimer’s disease, the results of an animal study indicate. Dietary Supplement May Prevent Cognitive Decline In a mouse model of accelerated aging and severe cognitive decline, a combination of vitamins and minerals, as well as nutraceuticals, such as beta carotene, bioflavonoids, cod liver oil, flax seed, garlic, and green tea extract, not only maintained brain cell numbers and mass and cognitive function but also appeared to prevent deterioration of sight and smell. Mechanisms of degenration , which include oxidative stress, inflammation, and mitochondrial dysfunction, “happen in a multitude of species as they get older” and are not “something that is specifically a human phenomenon that has been attempted to be recreated in a mouse model.
Effects of treatment with a multi-ingredient dietary supplement designed to ameliorate key mechanisms of aging showed treatment was associated with reduced anxiety-like behaviors, augmented discrimination of environmental context, improved motor balance, and improved visual and olfactory acuity. This was correlated with positive morphological changes and higher neuronal populations in the cerebellum and olfactory bulb, increased overall brain cell numbers and improved brain function. Intact olfaction is strongly indicative of suppression of neuronal degeneration. Retinal atrophy (associated with AMD) was also diminished in supplemented mice. Given that MDS treatment has been shown to signifi-cantly reduce oxidative damage, boost mitochondrial function [Lemon et al 2008a,b; Aksenov et al., 2010; Aksenov et al., 2013] and alleviate symptoms of inflammation [Lemon et al., 2005], suggests that neuronal protection and sensory function are likely attributed to diminishing oxidative/inflammatory stress and improved energy balance. The extent of functional benefits attained by our MDS here and in earlier studies [Lemon et al., 2003, 2005, 2008a,b; Aksenov et al., 2010, 2013; Long et al., 2012; Hutton et al., 2015’ strongly suggests that aging animals retain the capacity to support youthful phenotypes and that powerful impacts can be achieved through multi-ingredient dietary supplementation that addresses the multifactorial nature of aging organisms.
Table 1. Formulation of a Dietary Supplement Designed to Reduce Oxidative Stress and Inflammation, Maintain Membrane and Mitochondrial Integrity, and Enhance Insulin Sensitivity Supplement Dosage Vitamin B1b 0.72 mg/day Vitamin B3b 0.72 mg/day Vitamin B6b 0.72 mg/day Vitamin B12b 0.72 mcg/day Vitamin Cb 3.6 mg/day Vitamin Db 2.5 IU/day Vitamin Eb 1.44 IU/day Acetyl L-carnitinec 14.4 mg/day Alpha-lipoic acide 0.72 mg/day ASAd 2.5 mg/day Beta caroteneb 50.0 IU/day Bioflavinoidsh 4.32 mg/day Chromium picolinatei 1.44 mcg/day Cod liver oilb 5.04 IU/day CoEnzyme Q10h 0.44 mg/day DHEAg 0.15 mg/day Flax seed oilh 21.6 mg/day Folic acidb 0.01 mg/day Garlicb 21.6 mcg/day Gingerh 7.2 mg/day Gingko bilobah 1.44 mg/day Ginseng (Canadian)h 8.64 mg/day Green tea extractsf 7.2 mg/day L-Glutathionea 0.36 mg/day Magnesiumb 0.72 mg/day Melatoning 0.01 mg/day N-Acetyl cysteinee 7.2 mg/day Potassiumb 0.36 mg/day Rutinh 0.72 mg/day Seleniumh 1.08 mcg/day Zinc (chelated)b 0.14 mg/day
Vitamin brands are as follows: a ¼ Cell Life; b ¼ Jamieson vitamins; c ¼ Jarrow Formulas; d ¼ Lifebrand; e ¼ Natural Factors; f ¼ Naka; g ¼ Promatrix; h ¼ Swiss vitamins; i ¼ Vitamin Power Inc
That is typically because our cells are working in such a complex way that we have many mechanisms that are occurring simultaneously, and when something’s going wrong, it’s usually knocking everything out of balance. When the level of one particular component is increased in the cells, “you tend to also knock everything out of whack.
Previous research by the team showed that the supplement extended longevity and reduced cognitive and age-related physical deterioration in both normal mice and transgenic growth hormone mice (TGM). TGM are characterized by accelerated aging accompanied by severe cognitive decline, as well long-term oxidative stress, insulin resistance, and other traits.
For the current study, the team mated heterozygous TGM and normal mice to create equal numbers of TGM and normal mice with a similar genetic background. The mice were then randomly assigned at weaning either to receive a liquid form of the supplement every day, with the doses of the ingredients adjusted to correspond to the amounts recommended for humans, or to be left untreated.
The mice then underwent a series of somatosensory tests to determine the severity of age-related losses in motor coordination and overall mobility. Their brains were examined for histologic changes, and the degree of apoptosis and changes in cell counts were assessed. Single-photon emission computed tomography and positron-emission tomography scanning was also performed.
The team found that compared with normal mice, untreated TGM displayed brain cell losses, deterioration of sensory function, and reductions in cerebral metabolic rate and blood perfusion that were equivalent to those seen in patients with Alzheimer’s disease.
Specifically, the mice had greater than a 50% loss at a cellular level, a 36% reduction in brain mass, and at least twofold reductions in brain metabolism and blood flow at 12 months. Furthermore, in the untreated TGM, motor and cognitive functions were severely compromised.
Although the supplement did not have significant effects on brain cell numbers, brain weight, or brain metabolism or perfusion in normal mice, it had striking effects in TGM.
With the supplement, brain mass and brain cell density were maintained at levels seen in young mice. Brain metabolic activity was comparable to that in control mice, with no significant difference between the groups. Moreover, the supplement was associated with a twofold increase in brain perfusion in TGM.
The results also showed that the supplement restored cognitive function in TGM and led to significant improvements in motor coordination. It also appeared to reduce anxiety, allowing TGM to explore “unsafe/novel” environments.
The team found that the supplement appeared to offset deterioration of visual acuity in TGM. It was associated with increases in the thickness of the retinal outer nuclear layer and outer segment of 26% and 29%, respectively, in TGM compared with untreated mice.
TGM that received the supplement also showed improvements in olfactory sensitivity and greater numbers of mitral cells in the olfactory bulb in comparison with untreated mice. Inasmuch as olfactory loss is associated with an increased risk of developing severe neurodegenerative conditions, the researchers say these findings suggest that the supplement may be offsetting neurodegeneration throughout the brain.
Above from Medscape:
total brain volume losses were lower in individuals with higher baseline vitamin B12 levels, whereas the opposite was true of those with increased homocysteine levels. Vitamin B12 and tHcy [total homocysteine] might be independent predictors of markers of brain aging in elderly individuals without dementia. Venous blood samples were collected at baseline, from which circulating levels of vitamin B12, red blood cell folate, and sulfur amino acids were determined. These were correlated with changes in brain tissue volumes and total white matter hyperintensity (WMH) over 6 years
Between baseline and the 6-year follow-up, the mean total brain tissue (TBT) volume decreased from 74.3% to 71.6% of the total cranial volume (P < .001), whereas the mean WMH volume increased from 0.0004% to 0.0007% (P < .001).
Multiadjusted linear mixed model analysis revealed that increased baseline levels of vitamin B12 and holotranscobalamin (the biologically active fraction of B12) were associated with a decreased rate of TBT volume loss, at respective beta values of 0.048 (P < .001) and 0.040 (P = .002) for each standard deviation increase. Furthermore, the researchers found that each standard deviation increase in total homocysteine levels was linked to more rapid rates of TBT volume loss, at a beta value of -0.035 (P = .02). Increases in total homocysteine levels were also associated with increases in the progression of WMH in individuals with a systolic blood pressure >140 mmHg, at 0.000019 per standard deviation increase (P = .047).
Results In the multi-adjusted linear mixed models, among 501 participants (300 women [59.9%]; mean [SD] age, 70.9 [9.1] years), higher baseline vitamin B12 and holotranscobalamin levels were associated with a decreased rate of total brain volume loss during the study period: for each increase of 1 SD, β (SE) was 0.048 (0.013) for vitamin B12 (P < .001) and 0.040 (0.013) for holotranscobalamin (P = .002). Increased total homocysteine levels were associated with faster rates of total brain volume loss in the whole sample (β [SE] per 1-SD increase, –0.035 [0.015]; P = .02) and with the progression of white matter hyperintensity among participants with systolic blood pressure greater than 140 mm Hg (β [SE] per 1-SD increase, 0.000019 [0.00001]; P = .047). No longitudinal associations were found for red blood cell folate and other sulfur amino acids.
Conclusions and Relevance This study suggests that both vitamin B12 and total homocysteine concentrations may be related to accelerated aging of the brain. Randomized clinical trials are needed to determine the importance of vitamin B12 supplementation on slowing brain aging in older adults.
Methods and Findings
Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B6 and B12 in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and vitamin B6 (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans.
A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63–0.90] in the active treatment group and 1.08% [0.94–1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category.
Conclusions and Significance
The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer’s disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer’s disease, trials are needed to see if the same treatment will delay the development of Alzheimer’s disease.
the single-center, randomized VITACOG study, in which 271 individuals older than 70 years who had mild cognitive impairment received supplementation with high-dose folic acid and vitamins B6 and B12. They lost less brain compared to people who had normal homocysteine and normal vitamin levels, meaning that those with high levels of homocysteine or with clinical or biochemical vitamin deficiency can benefit from supplementation.
Presented here at the Alzheimer’s Association International Conference (AAIC) 2012, results from an open-label extension (OLE) trial of a medical nutrition product (Souvenaid, Nutricia/Danone) showed that memory performance continued to improve in drug-naïve patients with mild AD for up to 48 weeks.
Efficacy of Souvenaid in Mild Alzheimer’s Disease: Results from a Randomized, Controlled Trial
Abstract: Souvenaid aims to improve synapse formation and function. An earlier study in patients with Alzheimer’s disease (AD) showed that Souvenaid increased memory performance after 12 weeks in drug-naïve patients with mild AD. The Souvenir II study was a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial to confirm and extend previous findings in drug-naïve patients with mild AD. Patients were randomized 1:1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. The primary outcome was the memory function domain Z-score of the Neuropsychological Test Battery (NTB) over 24 weeks. Electroencephalography (EEG) measures served as secondary outcomes as marker for synaptic connectivity. Assessments were done at baseline, 12, and 24 weeks. The NTB memory domain Z-score was significantly increased in the active versus the control group over the 24-week intervention period (p=0.023; Cohen’s d=0.21; 95% confidence interval [-0.06]–[0.49]). A trend for an effect was observed on the NTB total composite z- score (p=0·053). EEG measures of functional connectivity in the delta band were significantly different between study groups during 24 weeks in favor of the active group. Compliance was very high (96.6% [control] and 97.1% [active]). No difference between study groups in the occurrence of (serious) adverse events. This study demonstrates that Souvenaid is well tolerated and improves memory performance in drug-naïve patients with mild AD. EEG outcomes suggest that Souvenaid has an effect on brain functional connectivity, supporting the underlying hypothesis of changed synaptic activity.
To investigate the effect of a medical food on cognitive function in people with mild Alzheimer’s disease (AD).
A total of 225 drug-naïve AD patients participated in this randomized, double-blind controlled trial. Patients were randomized to active product, Souvenaid, or a control drink, taken once-daily for 12 weeks. Primary outcome measures were the delayed verbal recall task of the Wechsler Memory Scale–revised, and the 13-item modified Alzheimer’s Disease Assessment Scale–cognitive subscale at week 12.
At 12 weeks, significant improvement in the delayed verbal recall task was noted in the active group compared with control (P = .021). Modified Alzheimer’s Disease Assessment Scale–cognitive subscale and other outcome scores (e.g., Clinician Interview Based Impression of Change plus Caregiver Input, 12-item Neuropsychiatric Inventory, Alzheimer’s disease Co-operative Study–Activities of Daily Living, Quality of Life in Alzheimer’s Disease) were unchanged. The control group neither deteriorated nor improved. Compliance was excellent (95%) and the product was well tolerated.
Supplementation with a medical food including phosphatide precursors and cofactors for 12 weeks improved memory (delayed verbal recall) in mild AD patients. This proof-of-concept study justifies further clinical trials.
Synapse loss, he said, is an early event in the AD process. By providing the nutritional precursors and cofactors for synapse formation, researchers hope to support the formation and function of synapses.
The once-a-day drink contains a patented nutrient combination with the following ingredients:
- Eicospentaenoic acid, 300 mg
- Docosahexaenoic acid, 1200 mg
- Phospholipids 106 mg
- Choline, 400 mg
- Uridine monophosphate, 625 mg
- Vitamin E (alpha-tocopherol equivalents), 40 mg
- Selenium, 60 µg
- Vitamin B12, 3 µg
- Vitamin B6, 1 mg
- Folic acid, 400 µg
The current findings also showed there was a statistically significant beneficial effect on memory in favor of Souvenaid at 6 months. Of the 238 patients who completed this trial, 198 participants entered the OLE study. Of these participants, 181 completed it. The results revealed that at 48 weeks, the product was well tolerated with no serious adverse events. In addition, the compliance rate was more than 90% The OLE results also revealed that memory performance as measured by the neuropsychological test battery (NTB) continued to improve significantly in study participants who received Souvenaid for the full 48 weeks (P = .025). In addition, in the group that received placebo for the first 24 weeks, there was a significant improvement in NTB memory scores during the OLE following conversion to the active treatment (P = .009).