Abstract:

For preventing age-related decline and extending healthy life expectancy, preemptive medicine interfering the initial processes of aging and age-related diseases would be effective. To develop such medical approach, the processes priming aging and age-related diseases should be clarified. Our laboratory is tackling to unravel previously unidentified mechanisms of aging and tissue homeostasis using small fish models and state-of-the-art technologies.

Recently, by zebrafish imaging analyses, we discovered a newly emerged precancerous cell with the RasG12V mutation in healthy epithelia are sensed and then eliminated by neighboring normal cells in an immune cell-independent manner. However, additional mutation of tumor suppressor gene or inflammation prevents the elimination of precancerous cells and then survived precancerous cells secrete inflammatory molecules that convert neighboring normal cells into either senescent or proliferative cells, generating a heterogeneous primary tumor. Thus, we revealed the novel mechanisms controlling the initial step of tumorigenesis (Nature Commun 2019; 2022). On the other hand, we are also tackling to clarify the fundamental mechanisms of systemic aging using an ultra-short-lived killifish Nothobranchius furzeri (N. furzeri) as a model. We successfully set up a large-scale breeding facility for N. furzeri and establish rapid reverse genetics methods for creating knockout and knock-in reporter N. furzeri (Sci Rep 2022). Utilizing these methods, we have identified several new factors that control systemic aging (under revision). In this talk, I would like to introduce these challenges and recent results.

References:

1. Haraoka et al., Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis.” Nature Commun. 2022, 13(1), 1417. doi: 10.1038/s41467-022-29061-6.

2. Oginuma et al., Rapid reverse genetics systems for Nothobranchius furzeri, a suitable model organism to study vertebrate aging. Sci Rep. 2022, 12(1), 11628. doi: 10.1038/s41598-022-15972-3.

3. Akieda et al., Cell competition corrects noisy Wnt morphogen gradients to achieve robust patterning in the zebrafish embryo. Nature Commun. 2019, 10(1), 4710. doi: 10.1038/s41467-019-12609-4.