Polyphenol Supplementation Reverses Age-Related Changes in Microglial Signaling Cascades.

Microglial activity in the aging neuroimmune system is a central player in aging-related dysfunction. Aging alters microglial function via shifts in protein signaling cascades. These shifts can propagate neurodegenerative pathology. Therapeutics require a multifaceted approach to understand and address the stochastic nature of this process. Polyphenols offer one such means of rectifying age-related decline. Our group used mass spectrometry (MS) analysis to explicate the complex nature of these aging microglial pathways. In our first experiment, we compared primary microglia isolated from young and aged rats and identified 197 significantly differentially expressed proteins between these groups. Then, we performed bioinformatic analysis to explore differences in canonical signaling cascades related to microglial homeostasis and function with age. In a second experiment, we investigated changes to these pathways in aged animals after 30-day dietary supplementation with NT-020, which is a blend of polyphenols. We identified 144 differentially expressed proteins between the NT-020 group and the control diet group via MS analysis. Bioinformatic analysis predicted an NT-020 driven reversal in the upregulation of age-related canonical pathways that control inflammation, cellular metabolism, and proteostasis. Our results highlight salient aspects of microglial aging at the level of protein interactions and demonstrate a potential role of polyphenols as therapeutics for age-associated dysfunction.

Effects of nutraceutical intervention on serum proteins in aged rats.

Aging is associated with many pathophysiological changes that could lead to the onset of degenerative disease. Some of the physiological changes that occur with aging include increased inflammation and decreased stem cell proliferation, leading to decreased capacity for tissue regeneration and loss of function. In previous studies, we and others have found nutraceutical intervention to ameliorate some of the deleterious effects associated with aging. In particular, we have previously shown that NT-020, a supplement composed of a proprietary blend of blueberries, green tea, vitamin D3, and carnosine, is able to rescue age-related cognitive deficits, impaired neurogenesis, and inflammation in rats. We have also previously demonstrated that stem cells cultured with old serum showed decreased proliferation; however, when stem cells were cultured in serum from old rats given a diet supplemented with NT-020, proliferation did not differ from that of cells cultured with serum from young rats. While it is clear that NT-020 is exerting a therapeutic, anti-aging effect, the mechanisms of action were yet to be fully elucidated.To that end, in the present study, we conducted a bioinformatics experiment to examine the rat proteome of serum from young and old control rats and young and old rats given a diet supplemented with NT-020. Serum from old rats showed an increase in some inflammatory and pro-aging factors while serum from old rats given a diet supplemented with NT-020 showed an increase in some anti-aging factors, most notably proteins associated with the complement system and autophagy. A number of immune functions that increase with age were shown to be downregulated with NT-020 treatment.

Astaxanthin supplementation modulates cognitive function and synaptic plasticity in young and aged mice.

The incidence of neurodegenerative disorders and cognitive impairment is increasing. Rising prevalence of age-related medical conditions is associated with a dramatic economic burden; therefore, developing strategies to manage these health concerns is of great public health interest. Nutritionally based interventions have shown promise in treatment of these age-associated conditions. Astaxanthin is a carotenoid with reputed neuroprotective properties in the context of disease and injury, while emerging evidence suggests that astaxanthin may also have additional biological activities relating to neurogenesis and synaptic plasticity. Here, we investigate the potential for astaxanthin to modulate cognitive function and neural plasticity in young and aged mice. We show that feeding astaxanthin to aged mice for 1 month improves performance on several hippocampal-dependent cognitive tasks and increases long-term potentiation. However, we did not observe an alteration in neurogenesis, nor did we observe a change in microglial-associated IBA1 immunostaining. This demonstrates the potential for astaxanthin to modulate neural plasticity and cognitive function in aging.

NT-020 treatment reduces inflammation and augments Nrf-2 and Wnt signaling in aged rats.

BACKGROUND: Aging is associated with a decline in stem cell proliferation that is thought to be a result of dysregulated signaling in the neurogenic niche. This results in a diminished and less efficient pool of progenitors. The Wnt pathway plays a key role in the proliferation and differentiation of progenitor cells. Recent publications suggest that the age-related decline in the function of Wnt is a contributor to age-dependent decline in neural progenitors. Similarly, the aged neurogenic niche is characterized by higher levels of inflammatory cytokines. This increased inflammation contributes to the declining function of neural progenitor cells. NT-020, a proprietary blend of polyphenols, has been shown to increase proliferation of neural progenitors and improve cognitive function in aged rats. PURPOSE AND METHODS: In this study, we examined the neurogenic niche in the subgranular zone of the dentate gyrus (SGZ) and the subventricular zone (SVZ) of young and aged rats to determine if dietary supplementation with NT-020 could regulate inflammation and oxidative stress response pathways in neurons, astrocytes, and microglia. Further, we examined NT-020's ability to modulate Wnt signaling in the aged neurogenic niche. To accomplish this, we utilized gene PCR arrays and immunohistochemistry. RESULTS: We observed an increase in nuclear localization of immunopositive labeling of ß-catenin, HO-1, and Nrf2 in all subsets of cell types in both young and aged rats in the SGZ and SVZ following NT-020 treatment. NeuN-positive cells showed a basal increase in nuclear ß-catenin in the aged rats, which was not observed in doublecortin (DCX)-labeled cells, microglia, or astrocytes. Reverse transcription polymerase chain reaction (RT-PCR) analysis of isolated hippocampal tissue revealed that a significant percent of genes involved with inflammation are affected by treatment with NT-020. In addition, several genes that regulate Wnt activity were affected by supplementation. CONCLUSIONS: The results suggest that NT-020 activates oxidative stress response pathways and supports pro-neurogenic gene expression in the hippocampus. This may represent the mechanism by which the NT-020 formula enhances performance in learning and memory tasks in aged mice.

Characteristics of rural hospital services for people with dementia: findings from the Hospital Dementia Services Project.

OBJECTIVE: To obtain information about aged care services in rural New South Wales public hospitals, and to describe key operational aspects of their service delivery models. DESIGN: A mixed methods design was used to combine data collected from: (i) a survey of public hospitals and (ii) qualitative site visits in a sample of eleven rural sites. SETTING: Rural public hospitals in NSW, Australia. PARTICIPANTS: Qualitative data were collected from multidisciplinary clinicians, managers and community service providers who participated in site visits in 2010 and from surveys of NSW public hospitals in 2009/10 about aged care and dementia services. RESULTS: Survey and site visit findings demonstrated that rural hospitals have fewer secure beds for managing patients with disturbed behaviour due to dementia and delirium and fewer speciality aged care staff than metropolitan hospitals. Site visit participants also described how secure environments can aid care for people with dementia even in the absence of clinical specialists. CONCLUSION: The care of people with dementia in rural hospitals is constrained by access to specialist aged care staff and the physical environment of the hospital. Clinicians are adept at maximising resources to manage diagnosis and transitions for people with dementia. Further understanding of how key operational aspects of clinical leadership and environmental modifications impact on a range of patient outcomes would be valuable.

Spirulina promotes stem cell genesis and protects against LPS induced declines in neural stem cell proliferation.

Adult stem cells are present in many tissues including, skin, muscle, adipose, bone marrow, and in the brain. Neuroinflammation has been shown to be a potent negative regulator of stem cell and progenitor cell proliferation in the neurogenic regions of the brain. Recently we demonstrated that decreasing a key neuroinflammatory cytokine IL-1beta in the hippocampus of aged rats reversed the age-related cognitive decline and increased neurogenesis in the age rats. We also have found that nutraceuticals have the potential to reduce neuroinflammation, and decrease oxidative stress. The objectives of this study were to determine if spirulina could protect the proliferative potential of hippocampal neural progenitor cells from an acute systemic inflammatory insult of lipopolysaccharide (LPS). To this end, young rats were fed for 30 days a control diet or a diet supplemented with 0.1% spirulina. On day 28 the rats were given a single i.p. injection of LPS (1 mg/kg). The following day the rats were injected with BrdU (50 mg/kg b.i.d. i.p.) and were sacrificed 24 hours after the first injection of BrdU. Quantification of the BrdU positive cells in the subgranular zone of the dentate gyrus demonstrated a decrease in proliferation of the stem/progenitor cells in the hippocampus as a result of the LPS insult. Furthermore, the diet supplemented with spirulina was able to negate the LPS induced decrease in stem/progenitor cell proliferation. In a second set of studies we examined the effects of spirulina either alone or in combination with a proprietary formulation (NT-020) of blueberry, green tea, vitamin D3 and carnosine on the function of bone marrow and CD34+ cells in vitro. Spirulina had small effects on its own and more than additive effects in combination with NT-020 to promote mitochondrial respiration and/or proliferation of these cells in culture. When examined on neural stem cells in culture spirulina increased proliferation at baseline and protected against the negative influence of TNFalpha to reduce neural stem cell proliferation. These results support the hypothesis that a diet enriched with spirulina and other nutraceuticals may help protect the stem/progenitor cells from insults.

New steroidal antiinflammatory antedrugs: Methyl 3,20-dioxo-9 alpha-fluoro-11 beta,17 alpha,21-trihydroxy-1,4-pregnadiene-16 alpha-carboxylate and its 21-O-acyl derivatives.

In a continuing effort to increase local to systemic activity ratios of potent steroidal antiinflammatory antedrugs, a series of 21-O-acyl derivatives of methyl 3,20-dioxo-9 alpha-fluoro-11 beta,17 alpha,21-trihydroxy-1,4-pregnadiene-16 alpha-carboxylate, FP16CM, were synthesized. These derivatives were evaluated for antiinflammatory activity and their adverse effects in an acute and semi-chronic croton oil-induced ear edema bioassay. Following a single topical application in the croton oil-induced ear edema bioassay, treatment with all the compounds resulted in dose-dependent inhibition of edema. From these dose-response profiles, the following ID(50) values (nmol/ear resulting in a 50% reduction of edema) were calculated: prednisolone (Pred); 454, FP16CM; 255, 21-acetate (FP16CM-acetyl); 402, 21-propionate (FP16CM-propionyl); 474, 21-valerate (FP16CM-valeryl); 446 and 21-pivalate (FP16CM-pivalyl); 219 nmol. In a 5-day semi-chronic study at the equipotent doses, the novel steroidal antedrugs did not significantly alter body weight gain, thymus weights or plasma corticosterone levels unlike the parent compound Pred. The compounds were assessed for high-affinity glucocorticoid receptor binding and glucocorticoid-mediated inhibition of nitric oxide (NO) generation in an in vitro RAW 264.7 macrophage cell culture system. Binding affinities for cytosolic glucocorticoid receptors were Pred; 85, FP16CM-acetyl; 86, FP16CM-propionyl; 169, FP16CM-valeryl; 149, FP16CM-pivalyl; 126 nM, respectively. Concomitant potencies for inhibition of NO generation by macrophages stimulated with lipopolysaccharide were Pred; 159, FP16CM-acetyl; 377, FP16CM-propionyl; 405, FP16CM-valeryl; 344, FP16CM-pivalyl; 311 nM, respectively. Collectively, results of these investigations suggest that esterification of 21-OH with various anhydrides did not improve receptor binding, inhibition of NO generation and ear edema inhibition, however, serum corticosterone level and local over systemic activities (L/S) were markedly improved.