Nutritional science has primarily studied ‘what and how much to eat.’ On the other hand, even before nutritional sufficiency is achieved, it has long been a human belief that ‘a regular diet is the key to health.’ Every cell in the body has its own clock system, and the mechanism by which the biological clock is controlled by clock genes has been clarified. Furthermore, it has been demonstrated that the body clock can be synchronized by meals, and that the timing of meal intake controls many metabolic rhythms. It has also been shown that irregular eating habits can induce abnormalities of lipid metabolism, leading to obesity and metabolic syndrome. The body clock determined by meal timing can be considered part of an individual's ‘constitution.’ By considering various biological rhythms, including the circadian rhythm, as a ‘rhythmome,’ it becomes possible to obtain a foundational overview for personalized nutrition, termed ‘precision nutrition.’ An understanding of chrononutrition is expected to play a major role in prevention of metabolic syndrome, lifestyle-related diseases, and locomotive syndrome.

Lipid intake and metabolism are involved in the development of lifestyle-related diseases. I have taken a four-pronged approach, focusing mainly on atherosclerosis. (1) I have investigated the regulation of gene expression by lipids and the relationship between the discovery of gene mutations related to lipid metabolism and the pathogenesis of atherosclerosis. (2) In the field of the essentiality of fatty acids and the relationship between their biological behavior and pathological conditions, I have measured the fatty acid compositions of phospholipids in human serum in cross-sectional studies of atherosclerosis and clarified the relationship between these fatty acid compositions and pathological conditions. (3) In relation to trace lipid components in the diet and body and pathophysiology, I am now studying the physiological significance of oxidized cholesterol as a trace component. In particular, I have discovered that oxidized cholesterol inhibits the onset of obesity. (4) I have discovered that probiotic bacteria, a functional ingredient that improves pathological conditions related to lipid metabolism, can be used to ameliorate obesity.

Lipid intake, and its appropriate quantity and quality, are important for the prevention of lifestyle-related diseases caused by obesity. The authors investigated the action of polyunsaturated fatty acids in regulating biological functions and their effects on body metabolism. Since the biological effects of consuming different vegetable oils cannot be explained by fatty acid composition alone, we have also studied the trace constituents of fats and oils. Here, we outline the results of our research on vitamin E. We have shown that tocotrienols, which are abundant in palm oil, maintain insulin secretion during a high-fat diet. Our findings also suggest that tocotrienols may inhibit fibrosis in the early stages of non-alcoholic steatohepatitis (NASH). In addition, the risk of osteoporosis associated with high vitamin E intake was examined from a nutritional perspective under various conditions. These series of studies suggest the need to consider not only fatty acid composition but also the influence of trace constituents of food when offering nutritional guidance on appropriate lipid intake.

Skeletal muscle plays an important role in glucose metabolism, and is associated with several metabolic disorders such as type 2 diabetes mellitus. Excess lipid accumulation in skeletal muscle is known to be involved in insulin resistance in patients with type 2 diabetes, and lipid is thought to play an important role in muscle function. However, lipid analysis of skeletal muscle is very difficult because of the heterogeneity of fast-twitch and slow-twitch fibers, which differ in their lipid metabolism. Using mass spectrometry imaging, I investigated the localization of lipids in skeletal muscle sections at the level of molecular species. This revealed that fast-twitch and slow-twitch fibers differ in their constituent cell membrane phospholipids, and that these phospholipids can change when muscle hypertrophy occurs.

Non-digestible oligosaccharides are defined as “carbohydrates that are hardly digested or absorbed in the human intestinal tract, or are extremely difficult to digest or absorb”. It has been shown that low-molecular-weight non-digestible oligosaccharides are fermented by intestinal microbes in the large intestinal tract and are involved in maintaining and improving health. In order to clarify the bioavailability and physiological modulation functions of non-digestible oligosaccharides, the authors have conducted hydrolysis experiments using rat and human small-intestinal enzymes, animal experiments, and human studies to evaluate their available energy value and maximum permissive dose that would not cause transitory osmotic diarrhea. In addition, using senescence-accelerated mice, we have shown that consecutive feeding with non-digestible oligosaccharides may prolong life span, prevent senile osteoporosis, and enhance the production of intestinal bacteria-derived water-soluble vitamins, including folate, vitamin B₆ and B₁₂, to prevent vitamin deficiency in the host. Furthermore, we have developed an improved method for accurate quantification of non-digestible oligosaccharides using porcine small-intestinal enzymes. Appropriate quantification of non-digestible oligosaccharides in foods is essential for estimation of their health benefits. Moreover, an accurate method for determination of newly developed non-digestible oligosaccharides is imperative for nutrition labeling of prebiotic contents to help consumers chose healthy foods.

Protein malnutrition is largely associated with delay or failure of the healing process in elderly people and hospitalized patients. However, the effect of dietary protein quality on wound healing is largely unknown. This study investigated the effect of dietary protein quality on wound healing and attempted to clarify the regulatory mechanisms responsible in model rats with full-thickness cutaneous wounds. The study findings suggested that low-quality protein diets might have negative effects on wound healing by decreasing collagen deposition in rats.

With the aging of society, brain health issues that arise in the elderly have become a major social issue, attracting attention in relation to both prevention and health promotion in daily life. Recently, epidemiological investigations of Japanese subjects have shown that intake of milk and dairy products reduces the risk of dementia, and preclinical studies have demonstrated that Camembert cheese has a preventive effect against Alzheimer's disease. β-Lactopeptide, with a Trp-Tyr sequence, and its major component β-lactolin, have been newly identified as components of fermented dairy products that improve cognitive function. β-Lactolin reaches the brain after ingestion and activates the dopamine system in the frontal cortex and hippocampus, thereby improving cognitive function. In addition, placebo-controlled clinical trials in healthy subjects have shown that β-lactolin improves cognitive functions such as memory recall and selective attention. Furthermore, in clinical trials using fNIRS, β-lactolin has been shown to increase cerebral blood flow in the dorsolateral prefrontal cortex during working memory tasks. It is known that cerebral blood flow in the prefrontal cortex declines with age, and continuous intake of β-lactolin, which improves cerebral blood flow, is expected to ameliorate age-related cognitive function decline. In addition to diet, continued multifactorial behavior change, including exercise and cognitive training, is important for maintenance of cognitive function. In the future, it is expected that fostering brain health habits that can be continued daily will contribute to solving various social issues.

Urolithins are functional polyphenols produced by human intestinal bacteria metabolizing ellagitannin and ellagic acid, contained in pomegranates and their hydrolysates. We have succeeded in producing urolithin A in one pot from ellagic acid as a starting material by co-culturing urolithin A-producing bacteria and urolithin C-producing bacteria. Based on this technology, in May 2021 we developed a process that can stably ferment and produce urolithin A through co-culture, thus making it possible to establish an industrial-level manufacturing process and commercialize a food material containing 10% urolithin A (Urorich^®). Urolithin A has been reported to have antioxidant and anti-inflammatory effects in addition to mitophagy-promoting effects. We have clarified that urolithin A has functionalities such as suppression of lipid droplet accumulation, suppression of osteoclast differentiation, alteration of human epidermal keratinocytes, and anti-allergic effects on hay fever. Furthermore, we evaluated its vascular endothelial function in humans and clarified the mechanism responsible. Urolithin may contribute to the maintenance and improvement of health as a functional material that meets current needs for human well-being.

Salt reduction is important for prevention of hypertension, but is difficult in practice as it tends to approximate the Dietary Reference Intakes. In a study population of young female subjects, we comparatively evaluated the effects of a control diet with moderate salt reduction, a strictly low-sodium (Na) diet, and a potassium (K)-enriched diet on the urinary Na/K ratio, which is known to be positively correlated with blood pressure. The subjects in the three groups consumed three servings of each test meal per day for two weeks, and urinary Na/K ratios were measured before and after the intervention. The control, low-Na and K-enriched diets provided 3,277 and 1,743, 2,559 and 1,743, and 3,277 and 3,277 mg Na and K, respectively, per day. Otherwise, their energy, protein, fat, and carbohydrate contents were equal. The K-enriched diet intervention resulted in a significant decrease of the urine Na/K ratio (2.8±1.2→1.9±0.6). The low-Na diet also decreased the ratio, but not to a significant degree (3.2±2.0→2.5±1.0). In subjects with a preintervention urinary Na/K ratio of 2 or higher, comparison among the three groups showed that the K-enriched diet had reduced the urinary Na/K ratio to a significantly greater degree than the control diet. These results suggest that a K-enriched diet, as well as a Na-reduced diet, is effective for improving the urinary Na/K ratio, thus likely preventing hypertension.