Graduate School of Agricultural and Life Sciences, The University of Tokyo

Extending Healthy Lifespan by Regulating Insulin-like Bioactivity

In Japan, which has entered a super-aging society, the importance of research aimed at extending healthy lifespans is increasing. Target diseases in this field include lifestyle-related disorders such as cardiovascular disease and diabetes, as well as malignant tumors and neurological diseases. Our research focuses on two hormones—insulin and insulin-like growth factors (IGFs)—and explores how proper regulation of their physiological activity (“insulin-like bioactivity”) can help diagnose and prevent these diseases, ultimately contributing to healthier longevity.
So far, our studies have revealed that:
１）Insulin-like bioactivity is regulated by nutritional factors such as amino acids.
２）Nutritional factors, particularly amino acids, can act directly as signals—metabolically regulated amino acid signals—that induce insulin-like bioactivity.
３）Dysregulation of insulin-like bioactivity or amino acid signaling contributes to the onset of many of the diseases mentioned above.
We aim to elucidatethe mechanism by which insulin-like biological activity is regulated at the molecular level and diagnose the onset of many of these diseases at a pre-symptomatic stage by utilizing AI and mathematical analysis. We are striving for tailor-made preemptive medicine from the perspective of "co-creation of medicine and food," which integrates nutrition with medicine. We are also involved in developing high-quality food resources, such as marbled pork and foie gras (white liver), by regulating metabolically regulated amino acid signals.

Elucidating the Molecular Mechanisms Regulating Insulin-like Bioactivity

Recently, we discovered that dietary protein restriction leads not only to growth retardation but also to a wide range of metabolic changes across multiple tissues, including fatty liver, intramuscular fat deposition, thickening of subcutaneous fat, increased visceral fat, enhanced insulin sensitivity, and reduced gluconeogenic activity. Detailed analysis of these phenomena revealed that amino acids—the building blocks of protein—regulate distinct phenotypes in a tissue-specific manner through different mechanisms.
It is also known that excessive promotion or suppression of the biological activity of insulin and IGF (insulin-like activity) can induce diseases like cancer and diabetes. We are working to elucidate the molecular mechanisms that regulate insulin-like biological activity, and we have isolated numerous proteins involved in insulin resistance and carcinogenesis, clarifying their functions. Looking ahead to the global environmental issues that have recently gained attention, we will explain new trends such as models for adapting to environmental changes, in addition to classical resource management.
Based on this perspective, our laboratory promotes the following research themes:
1. To elucidate the molecular mechanisms underlying excessive activation or suppression of insulin-like signaling, focusing on proteins that interact with signaling molecules.
2. To clarify the nature of “metabolically regulated amino acid signals”, in which amino acids themselves directly transmit signals to regulate metabolism.

Developing Technologies for the Diagnosis, Prevention, and Treatment of Lifestyle-related disorders

As noted above, dietary protein restriction induces diverse metabolic changes across multiple tissues. We have also demonstrated that the balance of circulating amino acids regulates distinct phenotypes in a tissue-specific manner, and that disturbances in this balance are key contributors to the onset of many lifestyle-related disorders. Because of this, measuring and improving the circulating amino acid profile has broad applications. It can be used for pre-symptomatic diagnosis of lifestyle diseases, personalized preemptive medicine through diet, frailty prevention, sports nutrition, and the development of high-quality food products like marbled pork and foie gras.
In addition, using animal and cellular models of cancer and diabetes, we've clarified the molecular mechanisms that regulate insulin-like biological activity. We've also isolated several new proteins critical for controlling signal pathway activity and have successfully isolated compounds that regulate their function.
Since both diets that improve the blood amino acid profile and compounds that control insulin-like biological activity show great promise for treating and preventing many diseases, we actively seek collaborative research with scientists and industry partners both within and outside the university.