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International Collaborative Research Program focusing on Aging
by Yasuo Yanagi
Assoc Prof. Duke-NUS Medical School, Singapore National Eye Centre, Singapore Eye Research Institute


The future of our health system depends on having a critical mass of researchers with the international knowledge necessary to meet current challenges. Singapore National Eye Centre (SNEC) and Singapore Eye Research Institute (SERI) have tremendous strengths, including the relative strength of our strong research base. To further strengthen our basic science research, we are working together with professional peers from other Asian countries. In the coming years, international collaboration will be increasingly important for SNEC and SERI.

Our international collaboration - with the University of Tokyo

We will build further on the international experience and structures that have been built up over recent years. Strategic International Collaborative Research Program (SICORP) in the aging research area, an A*STAR-A*MED Joint call, is one of such collaborations. This joint call was based on the Memorandum of Cooperation dated March 16th, 2016, where the Japan Agency for Medical Research and Development (AMED) and the Agency for Science, Technology, and Research (A*STAR), Singapore, expressed the wish to strengthen R&D cooperation between scientists in Japan and Singapore in the field of biomedical and scientific research. Research collaborations within the field of "Biological and Molecular Determinants of Human Aging" is the area the AMED-A*STAR is planning to strengthen. For that purpose, the joint call was launched to take the AMED-A*STAR engagement to a deeper level and to world-class scientific results through the development and use of new and innovative technologies, which can address the challenges facing the international community in the area of health research in both Japan and Singapore. For this year's first grant call, "Aging" was selected as the specific research area. Fortunately, our collaboration between SNEC/SERI and the University of Tokyo was awarded with this grant. This is a unique multidisciplinary research program integrating clinician-scientists, and basic scientists from SNEC/SERI and cardiologists, immunologists and clinician scientists from the University of Tokyo.

Key research areas of our program

Our collaboration started in 2014. Through this collaboration, we had strengthened our research in terms of quality, credibility, and impact. Since one of the authors (YY) moved to Singapore, we have developed an international collaboration to address our common healthcare problems, especially focusing on ocular diseases including age-related macular degeneration (AMD) and heart disease. AMD is a chronic, progressive disease with two end stages, exudative AMD and geographic atrophy (GA). Exudative AMD is characterized by choroidal neovascularization (CNV), which leads to leakage of fluid, lipids, and blood in the retina and is more common than GA in Asian countries. Exudative AMD is an important cause of irreversible vision loss, and with an aging population, the size of the affected patient population is increasing. Worldwide, it is estimated that 288 million persons will be affected by AMD by 2040, with 113 million persons in Asia. Interestingly, results from our collaboration indicate that sympathetic activity contribute to CNV via the recruitment of macrophages to the eye, suggesting the involvement of systemic immune response in the pathogenesis of the neovascularization of the choroid, corroborating clinical studies which demonstrated upregulated C-reactive protein and plasma antibody, altered gene expression in peripheral WBCs and altered metabolomics profiles in plasma of patients with AMD. Together with the fact that the markers for pan-macrophage and alternatively activated macrophages are expressed in human AMD (Yanagi Y, unpublished results), we hypothesize the function of macrophages/monocytes from AMD patients are different from those from control subjects. However, the involvement of inflammation in the pathogenesis of AMD is still unclear. Regarding heart failure model, as preliminary results, we found that the cardiac function of aged mice decreases and that it recovers after transplantation of bone marrow from juvenile mice, and that the cardiac function of juvenile mice decreases after transplantation of bone marrow from aged mice.

Thus, our work will be mainly focused on revealing that the basic pathology of lifestyle-related diseases which arises from the intercellular interactions among inflammatory cells, mainly the parenchymal cells and macrophages in each organ and tissue. This can be achieved only by bringing together the knowledge and experience of vascular biology and immunology in different research fields, i.e., ocular and cardiac diseases. Of note, results from us and others suggest homeostasis is maintained by a system in which multiple organs are coordinated against various external stressors, and the transformation and breakdown of this system are the cause of abnormalities in multiple organs, among which the innate immune system, primarily as myeloid cells including macrophages, and the cranial nerve system were thought to play the role of an important network mechanism.

Therefore, we hypothesize that either aging, as the tangible age-related changes in the bone marrow and spleen themselves, or stressors on various organs cause epigenetic changes, which can also be called "aging memory," in the innate immune system via the brain and nervous system, which may then possibly bring about the onset of peripheral organ diseases. Our study will focus on and analyze epigenetic changes due to the aging of innate immune system cells in a newly identified inter-organ network. We will continue our analysis while focusing on the facts that aging and disease arise from epigenetic changes in macrophages and that these changes can be a mechanism of disease onset. Specifically, the purposes of our collaboration include:

  1. Characterizing the similarities and differences between age-related and disease-related epigenetic changes of myeloid cells using ocular and cardiovascular disease models in mice
  2. Investigating the effects of age-related epigenetic change of myeloid cells on the vulnerability to the development of ocular and cardiovascular diseases using mouse models.
    ... And beyond

This is the first research proposed to identify and characterize the role of "aging memory" of macrophages/monocytes and epigenetic changes with age-related ocular and cardiovascular diseases. When this study is complete, our group will be able to provide novel pathways which will produce information to better understand the pathogenesis of these age-related diseases and information extracted in this study will lead to the development of novel therapeutic agents that target these pathways.

Both SNEC/SERI and the University of Tokyo already had strengths. But we believe science is international and only with effective international collaboration, would we have access to breakthrough scientific knowledge generated by researchers in other countries. Otherwise, the quality of the scientific knowledge generated locally would decline. Through our international collaboration, we will further bolster the relationship between vascular and ocular biologists in Singapore and experts in immunology in Japan and our collaboration. The proposed collaboration should build on and reinforce ongoing research activities in each group and significantly add value to them. Addressing aging problems is an important goal of health systems worldwide and has become increasingly important as a means for finding solutions in communities where the occurrence and severity of health problems are greatest. Singapore and Japan are no exceptions. The goal of our collaboration is to build an integrated part of local, regional, and national strategies to meet the needs of disadvantaged communities by addressing issues of aging.

Ultimately, our collaboration may disclose how chronic inflammation contributes to the pathology of age-related diseases and the roles of myeloid cell aging memory on ocular and cardiac diseases. The results of these experiments will make a major contribution to a better understanding of the pathology of age-related diseases and will contribute important knowledge for the development of therapies. Furthermore, this study may help in explaining certain aspects of a series of phenomena, including age-related systemic and local changes in the eyes and heart, cellular aging, and apoptosis, thus contributing to the discovery of the general principles of aging in addition to identifying the underlying pathology of age-related diseases.

We believe that outcomes that will be brought about by this collaboration will be one more step to improve our understanding of aging diseases. In an age where innovation is an essential part of keeping ahead of the competition, international collaboration will give a competitive edge, and will make Singapore and Japan a world leader for current and future generations.

About the Author

Assoc Prof Yasuo Yanagi
Clinician Scientist, Retina
Singapore National Eye Centre and Singapore Eye Research Institute
Duke-NUS Medical School

Associate Professor Yanagi received his M.D. from the University of Tokyo in 1995. Subsequently, he completed his research and clinical fellowship training at the International Medical Center of Japan and the University of Tokyo. He obtained his Ph.D. from the University of Tokyo in 2001. He specializes in retinal disorders and served as the director of both the Macula clinic and the Retina clinic of the Tokyo University Hospital until 2015. He is currently a senior clinician scientist managing medical retinal conditions at the Singapore National Eye Centre. He is also an Associate professor with Duke-NUS Graduate School of Medicine.

Assoc Prof Yanagi has research interest in retinal diseases, including age related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV), two very important blinding conditions in Singapore. He has engaged in primate work developing animal models for AMD and looked at novel new strategies for delivering drugs for the condition under the retina. He is currently collaborating with national and international investigators to study the pathology of AMD and PCV. He also conducted a number of international clinical trials for these 2 conditions. His other research interests include retinovascular conditions including retinal vein occlusion and diabetic retinopathy.

He is the author >100 peer-reviewed international papers, including top biomedical journals such as Nature Materials and Journal of Biology and Chemistry. He received, among others, Young Investigator Award from Japanese Ophthalmological Society (2008), Rohto Award (2010), APAO Nakajima Award (2011), JRVS Tano Young Investigator Award (2011) and JOS Councilors Nominated Award (2014).

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