Research | Laboratory for Nutritional Biology

The traditional Japanese phrase "Hara Hachi Bu", which emphasizes the idea that overeating is harmful, has been recognized. In many model organisms, restricting dietary intake has been shown to extend healthspan, and the elucidation of the underlying mechanisms has progressed. As a result, it is now understood that amino acids supplied from ingested proteins play a key role in many of the effects of dietary restriction. However, the comprehensive understanding of how amino acids are sensed within the body and what impact their depletion has on various cells composing the body remains unclear. Additionally, many questions remain unanswered regarding when and under what conditions amino acid levels and metabolic states change, as well as how the extension of healthspan through amino acid restriction occurs.

The essential amino acid, methionine, has been reported to be closely linked to lifespan, and it has been found that restricting methionine intake from the diet can extend lifespan. In our laboratory, we are using Drosophila to explore the mechanisms through which amino acids, including methionine, influence organismal lifespan and to clarify the effective range of these mechanisms. In this context, it has been discovered that the lifespan extension through methionine restriction is limited to the early stages of life and diminishes with aging (Kosakamoto, Obata et al., Nat Commun, 2023). Restricting methionine only during the early adulthood (the first 4 weeks of the 8–10 week lifespan of Drosophila) results in extended lifespan even when subsequently fed a normal diet. This indicates that the effects of dietary restriction depend on age. Numerous questions persist, such as why nutrient responses change with aging, how irreversible effects occur, and whether these findings apply to humans and mammals. Since amino acids other than methionine are also found to be associated with lifespan, we are analyzing their effects as well. Furthermore, it has been revealed that the intake of other nutrients affects methionine metabolism, and we are gradually unraveling the complex nutritional response mechanisms.

Molecules (nutrients) that we intake daily through our diet are said to exceed 10,000 types, presenting a formidable challenge in ensuring their proper intake. However, it is believed that organisms possess mechanisms to specifically sense and adapt to each nutrient. For example, when a particular nutrient is deficient, its consumption and breakdown are suppressed, with an increase in biosynthesis if possible. Additionally, there is speculation that behavior (preference) may change to stimulate appetite and absorption of that nutrient. However, mechanisms for specific sensing of a diverse range of nutrients and their adaptive responses to deficiencies or excesses remain unknown.

In our laboratory, we have previously elucidated adaptive mechanisms occurring when Drosophila larvae are subjected to a relatively mild protein-restricted diet during development. As a result, even under protein conditions with minimal negative impacts on growth, we observed a drastic reduction in translation and enhancement of feeding behavior, among other effects on energy and amino acid consumption. The mechanism revealed the significance of the non-essential amino acid "tyrosine," which has long been believed unnecessary to be obtained from the diet (Kosakamoto et al., Nat Metab, 2022). Tyrosine deficiency was found to control a transcription factor ATF4 in adipose tissue, triggering the adaptive response to a low-protein diet. Furthermore, we have discovered that tyrosine metabolism breakdown is strongly regulated in response to protein intake (Kosakamoto et al., Development, 2024). This tyrosine catabolism is activated through a transcription factor FoxO, which is shown to occur in epithelial, rather than adipose, tissues. The mechanisms governing the sensing and adaptation to a single nutrient vary across different organs, revealing an intricate and complex network. Our research extends beyond amino acids to include vitamins and minerals, and we are uncovering the existence of specific mechanisms for each nutrient.

Nutritional and environmental stress during the developmental and early life stages are suggested to be memorized in organisms, potentially influencing the physiological state and aging process of adults. This hypothesis, known as DOHaD (Developmental Origins of Health and Disease), proposes the existence of mechanisms (nutritional programming) that "program" the physiological functions of adults and the risk of lifestyle diseases based on the environment during early life stages. However, DOHaD research is time-consuming due to the significant time gap between cause and consequence. Drosophila melanogaster, with its short life cycle, is suitable for analyzing how the healthspan is affected by the developmental environment.

Previously, it was found that feeding Drosophila low concentrations of oxidants during development (larval stage) led to changes in metabolism and immunity, resulting in an extended lifespan (Obata et al., Nat Commun, 2018, Yamauchi et al., iScience, 2020). Analyzing the cause of this lifespan extension revealed an irreversible change in the composition of gut bacteria, particularly emphasizing the importance of the lifelong removal of Acetobacter genus bacteria. Recently, it was discovered that the peptidoglycan constituting the cell wall of Acetobacter genus bacteria shortens the healthspan of individuals through immune activation (Onuma et al., PLoS Genet, 2023). On the other hand, it was found that this bacterium enhances resistance to oral infection and oxidative stress, suggesting a lifestyle that promotes a "thick and short" life for Drosophila. Gut bacteria occupy a significant portion of our body and influence our health, but many aspects of their mechanism remain unknown. In our laboratory, we are working to elucidate the impact of immune activation by gut bacteria and the metabolites they produce on the host. Additionally, we are studying the functions of gut bacteria under various nutritional conditions.

Furthermore, it has been discovered that organismal lifespan can alter due to nutritional restriction during the early life stages. Given the uncertainty about how changes in protein levels not only affect growth but also influence subsequent healthspan, we are conducting analyses using Drosophila and higher animals to understand this mechanism better.

Vector-borne diseases such as dengue fever and severe fever with thrombocytopenia syndrome (SFTS) are infectious diseases in which pathogens are transmitted by arthropods such as mosquitoes and ticks and pose a significant global threat to both humans and animals. Because blood-feeding behavior contributes to the pathogen transmission cycle between the vector and the vertebrate host, it is critical to elucidate the entire process and underlying mechanisms of blood-feeding and subsequent blood metabolism in order to develop effective vector control strategies.

Mosquitoes attracted to hosts do not necessarily initiate blood-feeding immediately. They assess the taste of blood before deciding whether it is suitable for feeding. Thus, our aim is to understand how mosquitoes perceive the taste of blood and initiate blood-feeding (positive control) and how they sense fullness and stop blood-feeding (negative control). Blood-feeding represents an ultimate form of feeding, resulting in a state of nutrient excess by ingesting a large amount of nutrients at once. We are investigating how mosquitoes digest, absorb, and metabolize such a large amount of nutrients efficiently for utilization.

Adenosine triphosphate (ATP) derived from host blood has long been recognized as a crucial factor in positive control. However, the mechanism by which mosquitoes sense ATP has remained a mystery. Therefore, by focusing on mosquito taste perception, we are working to elucidate the molecules and neurons involved in ATP perception. The mechanisms that negatively regulate blood/ATP perception during blood feeding, i.e., the mechanism that stop feeding, are largely unknown. Revealing the neural basis of behaviors that act in the negative direction, in addition to the previously known positive mechanisms, is expected to provide important insights for manipulating mosquito behavior, such as inducing pseudo-blood-feeding cessation. In mosquito research, we leverage the use of Drosophila melanogaster, the same dipteran insect as mosquitoes, to deepen our comparative physiological understanding of blood-feeding behavior and the metabolism of abundant nutrients.