Takayuki Izumo

Background/Objectives: As a result of aging societies, the increasing number of older adults requiring nursing care has become a serious issue and the extension of healthy life expectancy has become an urgent priority. Ergothioneine (EGT) is a sulfur-containing amino acid found in foods such as mushrooms. Low EGT blood concentrations have been reported to be associated with the risk of onset and progression of various diseases. However, the distribution of EGT blood concentrations and their association with dietary habits in the Japanese general population remains unclear. Methods: This cross-sectional study was conducted using data from the third survey of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study, which analyzed 1457 participants (474 men and 983 women) aged ≥ 40 years. Serum EGT concentrations and their association with dietary habits were analyzed. Results: Serum EGT concentrations (1) peaked in the 70s in men and the 60s in women, (2) were higher in women than in men, and (3) showed a significant positive correlation with fish intake and nutrients commonly found in fish. Conclusions: In the present study, we report for the first time an age- and sex-specific serum EGT distribution in a Japanese population and its association with dietary habits, particularly fish intake. These findings help define normal and abnormal EGT levels and suggest new potential sources of EGT.

Background/Objectives: Circadian clocks are endogenous systems that regulate numerous biological, physiological, and behavioral events in living organisms. Aging attenuates the precision and robustness of circadian clocks, leading to prolonged and dampened circadian gene oscillation rhythms and amplitudes. This study investigated the effects of food-derived polyphenols such as ellagic acid and its metabolites (urolithin A, B, and C) on the aging clock at the cellular level using senescent human fibroblast cells, TIG-3 cells. Methods: Lentivirus-infected TIG-3 cells expressing Bmal1-luciferase were used for real-time luciferase monitoring assays. Results: We revealed that urolithins boosted the amplitude of circadian gene oscillations at different potentials; urolithin A (UA) amplified the best. Furthermore, we discovered that UA unstabilizes PER2 protein while stabilizing SIRT1 protein, which provably enhances BMAL1 oscillation. Conclusions: The findings suggest that urolithins, particularly UA, have the potential to modulate the aging clock and may serve as therapeutic nutraceuticals for age-related disorders associated with circadian dysfunction.

Arachidonic acid (ARA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), which are long-chain polyunsaturated fatty acids (LCPUFAs), as well as lutein (L) and zeaxanthin (Z), can potentially improve brain function. However, the effect of a combination of these components (LCPUFAs + LZ) on memory function in healthy older individuals remains unclear. This study aimed to determine if LCPUFAs + LZ-supplemented food could improve memory function. Exploratory and confirmatory trials (Trials 1 and 2, respectively) were conducted in healthy older Japanese individuals with memory complaints. We conducted randomized, double-blind, placebo-controlled, parallel-group trials. Participants were randomly allocated to two groups: placebo or LCPUFAs + LZ. LCPUFAs + LZ participants were provided with supplements containing ARA, DHA, EPA, L, and Z for 24 weeks in Trial 1 and 12 weeks in Trial 2. Memory functions were evaluated using Cognitrax before and after each trial. Combined analyses were performed for subgroups of participants with cognitive decline in Trials 1 and 2. The results showed that supplementation with LCPUFAs + LZ did not significantly affect memory function in healthy, non-demented, older individuals with memory complaints whereas it improved memory function in healthy, non-demented, older individuals with cognitive decline.

Cellular senescence induces inflammation and is now considered one of the causes of organismal aging. Accumulating evidence indicates that age-related deterioration of mitochondrial function leads to an increase in reactive oxygen species (ROS) and DNA damage, which in turn causes cellular senescence. Thus, it is important to maintain mitochondrial function and suppress oxidative stress in order to inhibit the accumulation of senescent cells. Sesamin and its isomer episesamin are types of lignans found in sesame oil, and after being metabolized in the liver, their metabolites have been reported to exhibit antioxidant properties. However, their effects on cellular senescence remain unknown. In this study, the effects of sesamin, episesamin, and their metabolites SC1 and EC1-2 on replicative senescence were evaluated using human diploid lung fibroblasts, and TIG-3 cells. The results showed that sesamin and episesamin treatment had no effect on proliferative capacity compared to the untreated late passage group, whereas SC1 and EC1-2 treatment improved proliferative capacity and mitigated DNA damage of TIG-3 cells. Furthermore, other cellular senescence markers, such as senescence-associated secretory phenotype (SASP), mitochondria-derived ROS, and mitochondrial function (ROS/ATP ratio) were also reduced by SC1 and EC1-2 treatment. These results suggest that SC1 and EC1-2 can maintain proper mitochondrial function and suppress the induction of cellular senescence.

Skeletal muscle fibrosis occurs with aging and has been suggested to impair muscle performance, thereby decreasing quality of life. Recently, muscle stiffness, a surrogate measure of muscle fibrosis, was noninvasively quantified as the shear modulus using ultrasound shear wave elastography (SWE) in humans. We aimed to investigate thigh muscle stiffness in females and males, respectively, across a broad range of ages by using SWE. Eighty-six community-dwelling Japanese people who were aged 30 to 79 years and did not regularly exercise participated in this study. The vastus lateralis (VL) shear modulus was measured at three different knee joint angles: full extension, 90° of flexion, and full flexion. There were no significant main effects of sex or age on the VL shear modulus in full extension or 90° of flexion of the knee. However, the VL shear modulus in knee full flexion was significantly smaller in females than in males and increased with age from 47.9 years. The results suggest that the accelerated increase in VL stiffness that occurs after an individual passes their late 40s may be an important therapeutic target for developing effective treatments and programs that preserve and improve quality of life.

Dietary habits are of considerable interest as a modifiable factor for the maintenance of muscle health, especially sarcopenia. The present study aimed to investigate the association between dietary intake and sarcopenia prevalence in community-dwelling Japanese subjects. This cross-sectional study was conducted using data from the fifth survey of the Research on Osteoarthritis/Osteoporosis against Disability (ROAD) study, and 1345 participants (437 men and 908 women) aged ≥60 years were included in the analysis. Sarcopenia was determined by the definition of the Asian Working Group for Sarcopenia established in 2014, and dietary intake was assessed with the brief-type self-administered diet history questionnaire. Overall, 77 subjects (5.7%) were identified as having sarcopenia, 5.0% of men and 6.1% of women. Multiple logistic regression analysis showed that the odds ratios of sarcopenia for the dietary intake of vitamin E (α-tocopherol, 0.14 (CI 0.04–0.49), β-tocopherol (0.24, CI 0.07–0.78), γ-tocopherol (0.28, CI 0.09–0.87), and fats (fat 0.27, CI 0.08–0.96; monounsaturated fatty acids, 0.22, CI 0.07–0.72, polyunsaturated fatty acids, 0.28, CI 0.09–0.89) at the highest quantile were significantly lower compared with those at the lowest quantile. Therefore, higher dietary intakes of vitamin E and fats would be associated with a lower prevalence of sarcopenia.

Grape seed extract (GSE) is rich in polyphenols composed mainly of proanthocyanidins, which are known to attenuate proinflammatory cytokine production. Repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via toll-like receptor 4 (TLR4) and proinflammatory cytokine pathways, which is a rat irritable bowel syndrome (IBS) model. Thus, we explored the effects of GSE on repeated WAS (1 h for 3 days)-induced visceral allodynia and colonic hyperpermeability in Sprague-Dawley rats. Paracellular permeability, as evaluated by transepithelial electrical resistance and flux of carboxyfluorescein, was analyzed in Caco-2 cell monolayers treated with interleukin-6 (IL-6) and IL-1β. WAS caused visceral allodynia and colonic hyperpermeability, and intragastric administration of GSE (100 mg/kg, once daily for 11 days) inhibited these changes. Furthermore, GSE also suppressed the elevated colonic levels of IL-6, TLR4, and claudin-2 caused by WAS. Paracellular permeability was increased in Caco-2 cell monolayers in the presence of IL-6 and IL-1β, which was inhibited by GSE. Additionally, GSE suppressed the claudin-2 expression elevated by cytokine stimulation. The effects of GSE on visceral changes appear to be evoked by suppressing colonic TLR4-cytokine signaling and maintaining tight junction integrity. GSE may be useful for treating IBS.