Cutting edge Seminar
Speaker: Yoshikazu Johmura (Division of Cancer and Senescence Biology, Cancer Research Institute, Kanazawa University)
Title: Development of advanced healthy life extension approaches through an integrated understanding of cellular senescence
※This seminar can also be attended through ZOOM. Please check the URL on “HIGO Cutting-Edge Seminar” at Moodle.
https://md.kumamoto-u.ac.jp/course/view.php?id=114380
Abstract:
Cells in mammals, including humans, undergo cellular senescence induced by intrinsic and extrinsic stress. This state is characterized by an irreversible cell cycle arrest mediated by the increased expression of cell cycle inhibitors like p16Ink4a, and the active secretion of physiologically active factors such as cytokines, a phenomenon known as the senescence-associated secretory phenotype (SASP). These senescent cells have been known to accumulate in the body with aging and contribute to various age-related diseases, including cancer. Moreover, genetic
engineering and pharmacological approaches have shown that the removal of senescent cells can improve age-related changes and diseases, thereby extending healthy lifespan. Consequently, senescent cells are considered to have negative impacts on the organism.
On the other hand, recent analyses of senescent cells in various models have reported that senescent cells are not only increased with aging but are also induced during embryonic development, skin wound healing, and acute tissue injury. While senescent cells that increase with aging accumulate in the body, those induced during development and acute tissue injury are thought to be rapidly cleared from the body by immune cells such as macrophages. The molecular mechanisms behind these differences in the dynamics of senescent cells remain largely unknown. This presentation will outline the results of analyses regarding the dynamics, origins, and functions of senescent cells in acute liver injury using a mouse model that allows for single-cell level visualization and removal of p16-positive cells.
Furthermore, our latest single-cell gene expression analysis revealed that senescent cells include non-proliferative cell types that are difficult to regenerate, such as neurons and cardiomyocytes. This finding indicates that the removal of senescent cells is not a perfect technique that invariably brings great benefits for
extending healthy lifespan, and that the long-term effects and side effects of removing senescent cells from non-proliferative cell types need to be considered. Thus, as a new approach alternative to the removal of senescent cells, we will also introduce the latest findings on “senescent cell reprogramming,” which involves the transient expression of Yamanaka factors specifically in senescent cells to rejuvenate them into normal cells.
References
1. LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits Li D, *Johmura Y, … *Nakanishi M. Nature Aging 2023, 3(8), 1001-1019.
2. Wang TW, Johmura Y*, Suzuki N, Omori S, Migita T, Yamaguchi K, Hatakeyama S, Yamazaki S, Shimizu E, Imoto S, Furukawa Y, Yoshimura A, Nakanishi M*. Blocking PD-L1 boosts senescence surveillance and improves aging phenotypes. Nature 2022, 611(7935), 358-364.
3. Reyes NS, Krasilnikov M, Allen NC, Lee JY, Hyams B, Zhou M, Ravishankar S, Cassandras M, Wang C, Khan I, Matatia P, Johmura Y, Molofsky A, Matthay M, Nakanishi M, Sheppard D, Campisi J, Peng T*. Sentinel p16INK4a+ cells in the
basement membrane form a reparative niche in the lung. Science. 2022, 14;378(6616):192-201.
4. *Johmura Y, Yamanaka T, Omori S, Wang TW, Sugiura Y, Matsumoto M, Suzuki N, Kumamoto S, Yamaguchi K, Hatakeyama S, Takami T, Yamaguchi R, Shimizu E, Ikeda K, Okahashi N, Mikawa R, Suematsu M, Arita M, Sugimoto M, Nakayama KI, Furukawa Y, Imoto S, *Nakanishi M. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science. 2021, 371(6526), 265–270.
5. Omori S, Wang TW, *Johmura Y, Kanai T, Nakano Y, Kido T, Susaki EA, Nakajima T, Shichino S, Ueha S, Ozawa M, Yokote K, Kumamoto S, Nishiyama A, Sakamoto T, Yamaguchi K, Hatakeyama S, Shimizu E, Katayama K, Yamada Y, Yamazaki S, Iwasaki K, Miyoshi C, Funato H, Yanagisawa M, Ueno H, Imoto S, Furukawa Y, Yoshida N, Matsushima K, Ueda HR, Miyajima A, *Nakanishi M. Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16 high Cells In Vivo. Cell Metabolism. 2020, 32(5), 814–828.
