Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence has shown that mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, and induce the expression of antioxidant genes and genes involved in mitochondrial quality/quantity control. Mild physiological stress, such as caloric restriction and exercise, elicits beneficial effects through a process known as “mitohormesis”. Exercise induces NOX4 expression in the heart, which activates Nrf2 and increases endurance capacity. Mice transiently depleted of SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated antioxidant gene expression and PGC1α-mediated mitochondrial biogenesis. ATF4 activation may induce a transcriptional program that enhances NADPH synthesis in the mitochondria and might cooperate with the Nrf2 antioxidant system. In response to severe oxidative stress, Nrf2 induces Klf9 expression, which represses mtROS-eliminating enzymes to enhance cell death. Nrf2 is inactivated in certain pathological conditions, such as diabetes, but Keap1 down-regulation or mtROS elimination rescues Nrf2 expression and improves the pathology. These reports aid us in understanding the roles of Nrf2 in pathophysiological alterations involving mtROS.

To confirm the usefulness of noninvasive measurements of skin carotenoids to indicate vegetable intake and to elucidate relationships between skin carotenoid levels and biomarkers of circulatory diseases and metabolic syndrome, we conducted a cross-sectional study on a resident-based health checkup (n = 811; 58% women; 49.5 ± 15.1 years). Skin and serum carotenoid levels were measured via reflectance spectroscopy and high-performance liquid chromatography, respectively. Vegetable intake was estimated using a dietary questionnaire. Levels of 9 biomarkers (body mass index [BMI], brachial-ankle pulse wave velocity [baPWV], systolic and diastolic blood pressure [SBP and DBP], homeostasis model assessment as an index of insulin resistance [HOMA-IR], blood insulin, fasting blood glucose [FBG], triglycerides [TGs], and high-density lipoprotein cholesterol [HDL-C]) were determined. Skin carotenoid levels were significantly positively correlated with serum total carotenoids and vegetable intake (r = 0.678 and 0.210, respectively). In women, higher skin carotenoid levels were significantly associated with lower BMI, SBP, DBP, HOMA-IR, blood insulin, and TGs levels and higher HDL-C levels. In men, it was also significantly correlated with BMI and blood insulin levels. In conclusion, dermal carotenoid level may indicate vegetable intake, and the higher level of dermal carotenoids are associated with a lower risk of circulatory diseases and metabolic syndrome.

The influx of intestinal bacteria-derived lipopolysaccharide (LPS) into the blood has attracted attention as a cause of diseases. The aim of this study is investigating the associations between the influx of LPS, dietary factors, gut microbiota, and health status in the general adult population. Food/nutrient intake, gut microbiota, health status and plasma LPS-binding protein (LBP; LPS exposure indicator) were measured in 896 residents (58.1% female, mean age 54.7 years) of the rural Iwaki district of Japan, and each correlation was analyzed. As the results, plasma LBP concentration correlated with physical (right/left arms’ muscle mass [β = −0.02, −0.03]), renal (plasma renin activity [β = 0.27], urine albumin creatinine ratio [β = 0.50]), adrenal cortical (cortisol [β = 0.14]), and thyroid function (free thyroxine [β = 0.05]), iron metabolism (serum iron [β = −0.14]), and markers of lifestyle-related diseases (all Qs < 0.20). Plasma LBP concentration were mainly negatively correlated with vegetables/their nutrients intake (all βs ≤ −0.004, Qs < 0.20). Plasma LBP concentration was positively correlated with the proportion of Prevotella (β = 0.32), Megamonas (β = 0.56), and Streptococcus (β = 0.65); and negatively correlated with Roseburia (β = −0.57) (all Qs < 0.20). Dietary factors correlated with plasma LBP concentration correlated with positively (all βs ≥ 0.07) or negatively (all βs ≤ −0.07) the proportion of these bacteria (all Qs < 0.20). Our results suggested that plasma LBP concentration in the Japanese general adult population was associated with various health issues, and that dietary habit was associated with plasma LBP concentration in relation to the intestinal bacteria.

Sulforaphane (SFN) is a potent activator of the transcriptional factor, Nuclear Factor Erythroid 2 (NF-E2)-Related factor 2 (NRF2). SFN and its precursor, glucoraphanin (sulforaphane glucosinolate, SGS), have been shown to ameliorate cognitive function in clinical trials and in vivo studies. However, the effects of SGS on age-related cognitive decline in Senescence-Accelerated Mouse Prone 8 (SAMP8) is unknown. In this study, we determined the preventive potential of SGS on age-related cognitive decline. One-month old SAMP8 mice or control SAM resistance 1 (SAMR1) mice were fed an ad libitum diet with or without SGS-containing broccoli sprout powder (0.3% w/w SGS in diet) until 13 months of age. SGS significantly improved long-term memory in SAMP8 at 12 months of age. Interestingly, SGS increased hippocampal mRNA and protein levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α) and mitochondrial transcription factor A (TFAM), which are master regulators of mitochondrial biogenesis, both in SAMR1 and SAMP8 at 13 months of age. Furthermore, mRNAs for nuclear respiratory factor-1 (NRF-1) and mitochondrial DNA-encoded respiratory complex enzymes, but not mitochondrial DNA itself, were increased by SGS in SAMP8 mice. These results suggest that SGS prevents age-related cognitive decline by maintaining mitochondrial function in senescence-accelerated mice.

Pulse wave velocity (PWV), an indicator of vascular stiffness, increases with age and is increasingly recognized as an independent risk factor for cardiovascular disease (CVD). Although many mechanical and chemical factors underlie the stiffness of the elastic artery, genetic risk factors related to age-dependent increases in PWV in apparently healthy people are largely unknown. The transcription factor nuclear factor E2 (NF-E2)-related factor 2 (Nrf2), which is activated by unidirectional vascular pulsatile shear stress or oxidative stress, regulates vascular redox homeostasis. Previous reports have shown that a SNP in the NRF2 gene regulatory region (−617C>A; hereafter called SNP−617) affects NRF2 gene expression such that the minor A allele confers lower gene expression compared to the C allele, and it is associated with various diseases, including CVD. We aimed to investigate whether SNP−617 affects vascular stiffness with aging in apparently healthy people. Analyzing wide-ranging data obtained from a public health survey performed in Japan, we evaluated whether SNP−617 affected brachial-ankle PWV (baPWV) in never-smoking healthy subjects (n = 642). We also evaluated the effects of SNP−617 on other cardiovascular and blood test measurements. We have shown that not only AA carriers (n = 55) but also CA carriers (n = 247) show arterial stiffness compared to CC carriers (n = 340). Furthermore, SNP−617 also affected blood pressure indexes such as systolic blood pressure and mean arterial pressure but not the ankle brachial pressure index, an indicator of atherosclerosis. Multivariate analysis showed that SNP−617 accelerates the incremental ratio of baPWV with age. This study is the first to show that SNP−617 affects the age-dependent increase in vascular stiffness. Our results indicate that low NRF2 activity induces premature vascular aging and could be targeted for the prevention of cardiovascular diseases associated with aging.

Consumption of fruits and vegetables rich in carotenoids has been widely reported to prevent cardiovascular diseases. However, the relationship between serum carotenoid concentrations and visceral fat area (VFA), which is considered a better predictor of cardiovascular diseases than the body-mass index (BMI) and waist circumference, remains unclear. Therefore, we examined the relationship in healthy individuals in their 20s or older, stratified by sex and age, to compare the relationship between serum carotenoid concentrations and VFA and BMI. The study was conducted on 805 people, the residents in Hirosaki city, Aomori prefecture, who underwent a health checkup. An inverse relationship between serum carotenoid concentrations and VFA and BMI was observed only in women. In addition, the results were independent of the intake of dietary fiber, which is mainly supplied from vegetables as well as carotenoids. This suggests that consumption of a diet rich in carotenoids (especially lutein and beta-carotene) is associated with lower VFA, which is a good predictor of cardiovascular disease, especially in women. This study is the first to comprehensively evaluate the association between serum carotenoid levels and VFA in healthy individuals.