The 15th symposium

Speech

Special　Lecture1

“Functions of senescent cells and the SASP in the cancer microenvironment”
Akiko Takahashi
Chief, Division of Cellular Senescence, Cancer Institute of Japanese Foundation for Cancer Research
Project Leader, Cancer Cell Communication Project, NEXT-Ganken Program

Cellular senescence is induced by various stresses in vivo and acts as an important tumor mechanism to stop proliferation of damaged cells. However, the senescence-associated secretory phenotype (SASP) increases the secretion of inflammatory proteins and extracellular vesicles such as exosomes in senescent cells. The SASP is known to cause chronic inflammation and contribute to the development of age-related diseases such as cancer, arteriosclerosis, and pulmonary fibrosis. We previously reported that activation of nucleic acid sensors (the cGAS-STING pathway) by genomic DNA fragments in the cytoplasm (Takahashi et al., Nature Commun., 2018) and epigenomic alterations during cellular senescence (Takahashi et al., Mol. Cell, 2012; Miyata et al., PNAS, 2021) are key to induce the SASP. Recently, we found that the SASP factor secreted from senescent cells promotes the survival of oncogenic mutated cells by inhibiting cell competition, which is a mechanism eliminating oncogenic cells from normal epithelial layers in the early stage of cancer development (Igarashi et al., Nature Commun., 2022). Senolytics drugs, that selectively induce cell death in senescent cells, recovered the efficiency of cell competition, suggesting that senolytic drugs are promising strategy to suppress age-related diseases. In this talk, I will present the latest findings on the functions of senescent cells and the SASP in the cancer microenvironment.

Special　Lecture2

“The Phenomenon of Stem Cell Aging according to Methylation Estimates of Age After Hematopoietic Stem Cell Transplantation”
Makoto Onizuka
Associate Professor, Department of Hematology & Oncology, Tokai University

Over the past few years, research has indicated that clonal hematopoiesis of indeterminate potential (CHIP) is actively involved in systemic aging. Therefore, the mechanism of hematopoietic cell aging needs to be elucidated in light of human aging. There are two major obstacles to the analysis of mechanism by which human hematopoietic cells age. First, mice are commonly used in hematopoietic research, but their lifespan differs considerably from that of humans, hampering elucidation of the aging of human hematopoietic cells in animal models. Second, there is no objective method by which to measure cellular age. Given this, we focused on hematopoietic stem cell transplantation, which has become the standard treatment for hematological disorders. Allogeneic hematopoietic stem cell transplantation between donors and recipients of different ages is the only human model that allows an analysis of how transplanted donor cells age in a patient. In 2013, we used the Horvath method to objectively measure cellular age after allogeneic transplantation. This method is based on the identification of 353 methylation sites that closely correlate with chronological age according to a comprehensive analysis of CpG island methylation (Genome Biol. 2013). Analysis of these 353 methylation sites allowed us to objectively measure cellular age for the first time, something that had not been possible before, and we analyzed how donor cells age in patients after cord blood transplantation. Results revealed that transplanted cord blood cells age about twice as fast as the elapsed time (chronological age). The details of the findings obtained from cord blood transplant donors are presented based on a mouse model of hematopoietic stem cell aging that we have created.