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Supplementation of PO + AC for 12-month improved cognitive function in healthy Japanese elderly, presumably by lowering serum triglyceride, blood glucose and N-(epsilon)-carboxymethyl-lysine.

Long-term intake of encapsulated perilla seed oil + immature ponkan powder enhances serum BDNF and antioxidant potential, and may improve age-related cognitive decline in healthy elderly Japanese by increasing red blood cell ω-3 fatty acid levels.

Learning and memory impairment may result from age-related decline in synaptic plasticity-related proteins in the hippocampus. Therefore, exploration of functional foods capable of ameliorating memory and cognition decline is an interesting endeavor in neuroscience research. We report the effects of Anredera cordifolia (AC) extract on learning and memory deficits in a senescence-accelerated mouse-prone 8 (SAMP8) mouse model, which demonstrate age-related memory deficits and related pathological changes in the brain. After 8 weeks of oral administration of AC extract, the mice were trained in the Novel Object Recognition (NOR) task, and after 7 more weeks, in the Morris Water Maze (MWM) task. Following the completion of behavioral testing, the blood biochemistry parameters, the hippocampal levels of brain-derived neurotropic factor (BDNF), PSD95, and NR2A, and the p-cAMP-response element binding (p-CREB)/CREB ratio were measured. The AC-treated group spent more time exploring the novel objects in the NOR task, and showed faster acquisition and better retention in the MWM task than the negative control (CN) group. In addition, AC enhanced the levels of the aforementioned neuronal plasticity-related proteins, and did not affect the blood biochemistry parameters. Therefore, our data suggest that the AC extract may improve learning and memory without causing any noticeable side effects in the body.

Prospective cardiovascular adjustment occurs before starting voluntary exercise, increasing heart rate and arterial pressure followed by muscle vasodilation; however, the precise mechanisms and significance for this vasodilation remain unknown. We found that during the countdown before starting exercise cerebral blood flow velocity increased, followed by increases in heart rate and arterial pressure, which suppressed MSNA through baroreflex, resulting in thigh muscle vasodilation to increase oxygen consumption rate, which might make it easier to start exercise.

Motivated behaviors, characterized by goal-directed and persistent movements, are indispensable for living. However, how cerebro-cardiovascular adjustment occurs during such behaviors remains unknown. By focusing on food-seeking behavior in a food-deprived condition using free-moving mice, we found that this condition enhanced the linkage between cerebral activation and suppression of baroreflex control of heart rate through central vasopressin V1a receptors, making it easier to start motivated behaviors by enhancing pressor response.

Bone embrittlement with aging, namely osteoporosis, is characterized by low bone mass and deterioration of bone tissue, and can lead to increased risk of fracture. The development of functional foods that can prevent geriatric diseases is in progress. Our focus was on brown rice because of its properties. An interventional study using of ultra-high hydrostatic pressurized brown rice (UHHPBR) for human has not yet been conducted. In this study, we investigated whether long-term dietary intake of UHHPBR prevents aging-related decline of bone mineral density in elderly Japanese individuals. Elderly participants (n=40; mean 73.1 y) in Iinan-cho, Shimane, Japan, were randomly divided into two groups. The UHHPBR-intake group (n=20) consumed 100 g of UHHPBR and 100 g of white rice (WR) per day for 12 mo, while the WR-intake group (n=20) consumed 200 g of WR per day. Pre- and 12-mo post-intervention, bone mineral density was evaluated by quantitative ultrasound. After 12 mo of intervention, the UHHPBR group's bone mineral density was significantly higher than the WR group's bone mineral density. Moreover, chronic intake of UHHPBR had no adverse side effects on participants. Long-term oral UHHPBR intake may have beneficial effects on bone mineral density decline and may attenuate osteoporosis in the elderly.

Salivary immunoglobulin A (IgA) plays a critical role in mucosal immunity. Chronic exposure to moderate heat induces heat acclimation, which modifies salivary functions. However, the changes in salivary IgA secretion in heat-acclimated rats are unclear. In this study, we investigated salivary IgA secretion and the expression of polymeric Ig receptor (pIgR), a key mediator of mucosal IgA secretion, in the submandibular glands (SMGs) of heat-acclimated rats. Following maintenance at an ambient temperature (Ta) of 24 &plusmn, 0.1 &deg, C for 10 days, male Wistar rats were subjected to Ta of 32 &plusmn, 0.2 &deg, C for 5 days (HE group) for heat acclimation or maintained at Ta of 24 &plusmn, 0.1&deg, C (CN group). The rats were then anesthetized, pilocarpine (0.5 mg/kg) was intraperitoneally injected, and saliva was collected. Afterward, the SMGs and plasma were sampled. The salivary IgA concentration and IgA flow rate were significantly higher in the HE group than in the CN group. Similarly, SMG pIgR expression was significantly higher in HE rats. The levels of plasma cytokines, including interleukin (IL)-5, IL-6, and interferon- were significantly greater in HE rats than in CN rats. Heat acclimation may enhance oral immunity through salivary IgA secretion and pIgR upregulation in the SMGs.

Theobromine is a caffeine derivative and the primary methylxanthine in Theobroma cacao. We have shown previously that theobromine inhibits the Akt‐mammalian target of rapamycin (mTOR) signal in vitro. In this study, we investigated whether orally administered theobromine could inhibit mTOR activity in rats. mTOR is phosphorylated by Akt. Thus, the level of phosphorylated mTOR was used as an index of mTOR activity. Male Wistar rats were divided into two groups. The control group (CN) was fed a normal diet, while the theobromine group (TB) was fed a diet supplemented with 0.05% theobromine for 40 days. We measured body‐weights and tissue weights, food and water intake, blood count, concentrations of theobromine in the plasma, liver and brain, and the levels of phosphorylated mTOR in the liver and brain. Orally administered theobromine did not affect the body‐weights and tissue weights, food and water intake, and blood count as determined by comparison with levels in rats that were fed standard chow. Theobromine was detected in the plasma, liver and brain obtained from TB rats, but was not detected in tissues obtained from CN rats. The phosphorylated mTOR levels in the liver and brain were significantly lower in TB rats than in CN rats. The results suggest that oral theobromine inhibits mTOR signalling in vivo.

Previous research has shown that habitual chocolate intake is related to cognitive performance and that frequent chocolate consumption is significantly associated with improved memory. However, little is known about the effects of the subchronic consumption of dark chocolate (DC) on cognitive function and neurotrophins. Eighteen healthy young subjects (both sexes, 20&ndash, 31 years old) were randomly divided into two groups: a DC intake group (n = 10) and a cacao-free white chocolate (WC) intake group (n = 8). The subjects then consumed chocolate daily for 30 days. Blood samples were taken to measure plasma levels of theobromine (a methylxanthine most often present in DC), nerve growth factor (NGF), and brain-derived neurotrophic factor, and to analyze hemodynamic parameters. Cognitive function was assessed using a modified Stroop color word test and digital cancellation test. Prefrontal cerebral blood flow was measured during the tests. DC consumption increased the NGF and theobromine levels in plasma, enhancing cognitive function performance in both tests. Interestingly, the DC-mediated enhancement of cognitive function was observed three weeks after the end of chocolate intake. WC consumption did not affect NGF and theobromine levels or cognitive performance. These results suggest that DC consumption has beneficial effects on human health by enhancing cognitive function.

Theobromine (TB) is a primary methylxanthine found in cacao beans. cAMP-response element-binding protein (CREB) is a transcription factor, which is involved in different brain processes that bring about cellular changes in response to discrete sets of instructions, including the induction of brain-derived neurotropic factor (BDNF). Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been strongly implicated in the memory formation of different species as a key regulator of gene expression. Here we investigated whether TB acts on the CaMKII/CREB/BDNF pathway in a way that might improve the cognitive and learning function in rats. Male Wistar rats (5 weeks old) were divided into two groups. For 73 days, the control rats (CN rats) were fed a normal diet, while the TB-fed rats (TB rats) received the same food, but with a 0.05% TB supplement. To assess the effects of TB on cognitive and learning ability in rats: The radial arm maze task, novel object recognition test, and Y-maze test were used. Then, the brain was removed and the medial prefrontal cortex (mPFC) was isolated for Western Blot, real-time PCR and enzyme-linked immunosorbent assay. Phosphorylated CaMKII (p-CaMKII), phosphorylated CREB (p-CREB), and BDNF level in the mPFC were measured. In all the behavior tests, working memory seemed to be improved by TB ingestion. In addition, p-CaMKII and p-CREB levels were significantly elevated in the mPFC of TB rats in comparison to those of CN rats. We also found that cortical BDNF protein and mRNA levels in TB rats were significantly greater than those in CN rats. These results suggest that orally supplemented TB upregulates the CaMKII/CREB/BDNF pathway in the mPFC, which may then improve working memory in rats.

In Japan, the incidence of heat illness in older people has rapidly increased during midsummer in the last decade, and we suggested that whey-protein+carbohydrate supplementation during aerobic training would increased plasma volume (PV) to enhance thermoregulatory adaptation in older men ( J Appl Physiol 107: 725-733, 2009); however, >60% of people age 65 and older suffer from hypertension, and the symptoms may be worsened by hypervolemia. To examine this, we randomly divided 21 older men (∼69 yr) with ∼160 mmHg for systolic and ∼90 mmHg for diastolic blood pressure at rest into two groups: Glc ( n = 11) consuming glucose alone (25 g) and Pro-Glc ( n = 10) consuming whey protein (10 g) + glucose (15 g), immediately after cycling exercise at 60–75% of peak aerobic capacity (V̇o2 peak) for 60 min/day, 3 days/wk, for 8 wk. Before and after training, we measured PV (dye dilution), baroreflex sensitivity (BRS) of heart rate (Valsalva maneuver), and carotid arterial compliance (CAC) from carotid arterial diameter (ultrasound imaging) responses to pulsatile arterial pressure change (photoplethysmography) at rest. Additionally, we measured esophageal temperature (Tes) and forearm skin blood flow (plethysmography) during exercise at 60% pretraining V̇o2 peak for 20 min in a warm environment. We found that the forearm skin vascular conductance response to increased Tes was enhanced in Pro-Glc with increased PV, but this was not found in Glc; however, despite the increased PV, arterial blood pressures rather decreased with increased CAC and BRS in Pro-Glc. Thus, the prescription was applicable to older men with hypertension to prevent heat illness during exercise.

A reduction in exercise efficiency with aging limits daily living activities. We examined whether 5-aminolevulinic acid (ALA) with sodium ferrous citrate (SFC) increased exercise efficiency and voluntary achievement of interval walking training (IWT) in older women. Ten women [65 ± 3(SD) yr] who had performed IWT for >12 mo and were currently performing IWT participated in this study. The study was conducted in a placebo-controlled, double-blind crossover design. All subjects underwent two trials for 7 days each in which they performed IWT with ALA+SFC (100 and 115 mg/day, respectively) or placebo supplement intake (CNT), intermittently with a 2-wk washout period. Before and after each trial, subjects underwent a graded cycling test at 27.0°C atmospheric temperature and 50% relative humidity, and oxygen consumption rate, carbon dioxide production rate, and lactate concentration in plasma were measured. Furthermore, for the first 6 days of each trial, exercise intensity for IWT was measured by accelerometry. We found that, in the ALA+SFC trial, oxygen consumption rate and carbon dioxide production rate during graded cycling decreased by 12% ( P < 0.001) and 11% ( P = 0.001) at every workload, respectively, accompanied by a 16% reduction in lactate concentration in plasma ( P < 0.001), although all remained unchanged in the CNT trial ( P > 0.2). All of the reductions were significantly greater in the ALA+SFC than the CNT trial ( P < 0.05). Furthermore, the training days, impulse, and time at fast walking were 42% ( P = 0.028), 102% ( P = 0.027), and 69% ( P = 0.039) higher during the ALA+SFC than the CNT intake period, respectively. Thus ALA+SFC supplementation augmented exercise efficiency and thereby improved IWT achievement in older women.

No long-term exercise training regimen with high adherence and effectiveness in middle-aged and older people is broadly available in the field. We assessed the adherence to, and effects of, our long-term training program comprising an interval walking training (IWT) and an information technology network system and the factors affecting adherence. Middle-aged and older men and women [ n = 696, aged 65 ± 7(SD) yr] underwent IWT. The subjects were instructed to repeat five or more sets of fast and slow walking for 3 min each at ≥70 and 40% peak aerobic capacity for walking (V̇o2peak), respectively, per day ≥4 days/wk for 22 mo. Adherence was assessed as training days accomplished relative to the target of 4 days/wk over 22 mo. The effects on the V̇o2peak and lifestyle-related disease score were evaluated every 6 mo. The independent factors affecting adherence were assessed by multiple-regression analysis after adjustment for baseline physical characteristics and other possible covariates, including vasopressin V1a receptor polymorphisms. The adherence over 22 mo averaged 70% and was highly correlated with a 13% reduction in the lifestyle-related disease score ( R2 = 0.94, P = 0.006) and with a 12% increase in V̇o2peak ( R2 = 0.94, P = 0.006). The major determinant of higher adherence was lower baseline body mass index (BMI) ( P < 0.0001) and male sex ( P < 0.0001). For men, in addition to BMI, nonsmokers ( P = 0.031) and V1a receptor polymorphisms ( P = 0.033) were independent determinants of higher adherence. Thus the long-term IWT program is an effective regimen. Moreover, baseline BMI and sex for all subjects, and smoking and V1a receptor polymorphisms for men, were associated with adherence.

There is no long-term exercise training regimen with high adherence and effectiveness for middle-aged and older people that is broadly available in the field. To solve this problem, we developed an exercise training regimen comprised of interval walking training (IWT) and an IT network system that only requires minimal staff support. We found that adherence to the 22-month IWT program was relatively higher than other previously reported long-term exercise programs requiring more personnel support and that the program was accompanied by greater improvements in lifestyle-related disease risk factors and physical fitness in middle-aged and older people. Moreover, when congenital and acquired factors affecting adherence were assessed, we found that baseline body mass index and gender for all subjects, as well as smoking and vasopressin V1a receptor polymorphisms for men, were independent determinants of adherence to the IWT program. To elucidate the mechanism underlying the effect of V1a receptor polymorphisms on adherence to an exercise program, we assessed whether voluntary locomotion was impaired in mice genetically deficient in V1a receptors (V1a KO). We found that voluntary locomotion in wild-type mice was more probable after cerebral activation, while in V1a KO mice the probability was markedly reduced with no suppression of baroreflex control of heart rate during cerebral activation. Moreover, the findings in V1a KO mice were confirmed after local infusion of a V1a receptor antagonist into the nucleus tractus solitarii of the wild-type mice. Thus, central V1a receptors play an important role in facilitating voluntary exercise and thereby contribute to adherence to the IWT program.

Saliva-a water-based fluid containing electrolytes, immunoglobulins, and enzymes-has many functions, including the protection and hydration of mucosal structures within the oral cavity and the initiation of digestion. Aquaporins (AQPs) are proteins that act as water channels through membranes. We have previously reported upregulation of the expression levels of AQP 1 and 5 in the submandibular glands (SMGs) in heat-acclimated rats. In this study, we investigated pilocarpine-induced saliva secretion and AQP expression in rats after voluntary exercise. Male, 10-week-old Wistar rats were initially maintained at an ambient temperature of 24 °C for 10 days and were then kept for 40 days in cages either with a running wheel (exercise rats, n = 6) or with a locked wheel [control rats (CN), n = 6]. After the training period, the rats were anesthetized and pilocarpine, an M3 muscarinic receptor agonist, was intraperitoneally injected (0.5 mg·kg-1) to stimulate saliva secretion. Saliva was collected, and the SMGs were sampled and subjected to western blot, RT-PCR, and immunohistochemical analyses. Pilocarpine induced a greater amount of saliva in the exercised rats than in the CN. Expression levels of AQP1 mRNA and protein were significantly higher in SMGs of exercised rats than in those of the CN, but the expression of AQP5 was not affected by voluntary exercise. Voluntary exercise increased the expression of vascular endothelial growth factor (VEGF) and cluster of differentiation 31 (CD31), a marker for endothelial cells, in the SMGs. Voluntary exercise promoted pilocarpine-induced saliva secretion, probably via an increase in the expression level of AQP1 due to VEGF-induced CD31-positive angiogenesis in the SMG.

We previously reported that cerebral activation suppressed baroreflex control of heart rate (HR) at the onset of voluntary locomotion. In the present study, we examined whether vasopressin V1a receptors in the brain were involved in these responses by using free-moving V1a receptor knockout (KO, n = 8), wild-type mice locally infused with a V1a receptor antagonist into the nucleus tractus solitarii (BLK, n = 8) and control mice (CNT, n = 8). Baroreflex sensitivity (HR/MAP) was determined from HR response (HR) to a spontaneous change in mean arterial pressure (MAP) every 4 s during the total resting period, which was ∼8.7 h, of the 12 h measuring period in the three groups. HR/MAP was determined during the periods when the cross-correlation function (R(t)) between HR and MAP was significant (P 0.05). Moreover, the probability that mice started to move after an increase in /δ was 24 ± 4% in KO and 24 ± 6% in BLK, markedly lower than 61 ± 5% in CNT (both P < 0.001), with no suppression of the baroreflex control of HR. Thus, central V1a receptors might play an important role in suppressing baroreflex control of HR during cerebral activation at the onset of voluntary locomotion.

Exercise training protects against age- and lifestyle-related diseases. We recently reported that middle-aged and older Japanese men carrying the TT genotype of the single nucleotide rs1042615 polymorphism in the vasopressin V1a receptor had significantly higher body mass index and diastolic blood pressure than those who did not. However, these higher values decreased to levels comparable to those of men carrying other genotypes following 5 months of interval walking training (IWT), suggesting that they might have been physically inactive before starting IWT. Therefore, we postulated that TT men would have lower adherence to long-term exercise programs. To assess this, middle-aged and older men underwent IWT for 29 months. We found that adherence to the exercise program was markedly decreased in TT men compared with men of other genotypes during the training period.