老化細胞のメカニズム
Hello everyone, SCIEN-SPOT is a podcast that shines a spotlight on the latest scientific
technology from Japan. Your host is REN from SCIEN-TALK. Today I'm going to talk about the
discovery regarding the mechanism of aging cells. This research was announced by a collaborative
group from the Kyoto University, University of Tokyo, and RIKEN.
First, what exactly is cellular senescence? It's a phenomenon where our body's cells,
when exported to various stresses such as oncogene activation, DNA damage, or replication stress,
irreversibly stop dividing. Originally, this cellular senescence serves a crucial
protective function. By preventing damaged cells from proliferating, it helps suppress cancer.
However, it has also been found to be deeply involved in many age-related diseases,
including lifestyle-related disease and neurodegenerative conditions.
Furthermore, a very characteristic feature of senescent cells is something called SASP,
which stands for Senescence Associated Secretory Phenotype.
SASP is a general term for the phenomenon where senescent cells secrete various bioactive
substances that can cause inflammation or even promote senescence in surrounding normal cells.
You can think of it like a single rotten apple in a barrel,
which simply by being there starts to spoil the healthy apples around it.
While previous studies using cultured cells suggested that SASP could affect surrounding
老化細胞の連鎖反応
cells, the process mechanism of how a tiny number of senescent cells in our bodies
contribute to widespread aging throughout the entire organism has remained a significant mystery
until now. It has been challenging to accurately identify and track these senescent cells within
the living body. Research group developed a grand-blanking new mouse model that allows them
to directly observe and track senescent cells within the living body. Specifically, they created
genetically modified mice that could artificially and constitutively activate two key signaling
pathways, the ERK pathway and the p-sided MAPK pathway, which are known to be involved
in cellular senescence by administrating a specific drug called doxycycline, and these
pathways are activated thereby inducing cellular senescence in vivo. What they found surprisingly
was that when they directly induced senescence in cells using doxycycline, not only did these
cells become senescent, but even the healthy cells surrounding them also started to age,
as if caught in a chain reaction. This is a clear evidence that senescence propagates,
meaning secondary cellular senescence occurs. To observe this propagation in more detail,
the research team developed a unique two-color labeling system. Primarily, senescent cells were
labeled with red fluorescence, and secondary senescent cells were labeled with green fluorescence.
細胞老化のメカニズム
This allowed them to accurately visualize and analyze how cellular senescence
spreads and affects cells within the living body at a single cell level.
Another crucial finding from this model was the manner of cellular senescence varied significantly
depending on the tissue type, the factors that induce it. For instance, the cellular senescence
response was very different in various cell types such as liver, large intestine,
and mouse embryonic fibroblasts. Even more surprisingly, within the same type of cell,
like liver cells, the senescence state was not uniform, but was suggested to consist of
multiple cell populations with diverse gene expression patterns. This suggests that just
like fire spreads differently in a wooden house compared to reinforced concrete, building cellular
senescence is not a uniform process, but rather exhibits diverse characteristics. The liver has
a precise structure called zonation, which consists of three functionally distinct regions.
They found that inducing cellular senescence, especially through ERK pathway activation,
disrupted this intricate zonal structure of the liver, potentially leading to a decline
in liver function. This is an important insight, confirming that the changes at the cellular level
can impact the function of an entire organ and are closely related to individual aging.
So how does this secondary cellular senescence, this chain reaction with surrounding cells age,
老化細胞のメカニズム
actually occurs at the molecular level? The research group found a crucial clue to this
secret conversation. By thoroughly analyzing the comprehensive gene expression data of secondary
senescent cells, they discovered that an information transmission pathway called IL-1
signaling plays a vital role in inducing secondary senescent cells.
Further investigation revealed that the primary source of this IL-1 signal,
particularly in the liver, is a type of immune cell called macrophages. Macrophages are known
as eating cells because they could lure foreign invaders and cellular devils from the body,
but they also secrete an inflammatory cytokine called IL-1 beta, which acts as a communication
substance between cells. In this research, they demonstrated that when they used a drug to
selectively deplete macrophages throughout the body, or a drug to inhibit the receptor that
received IL-1 beta, the expression of the marker for secondary cellular senescence was suppressed.
This strongly suggests that IL-1 beta secreted by macrophages acts like a signal
interacting surrounding cells to get old, thereby triggering the chain reaction of aging.
It's as if at a fire scene, the firefighter who should be leading the extinguishing efforts
was actually giving the command to start a fire, a truly astounding discovery.
This research represents a groundbreaking achievement as it is the first time that the
老化細胞の影響
behavior of primary and secondary senescent cells in the living body and their impact on
the surrounding cells has been clarified with single-cell resolution. The new mass model
developed in this study is expected to significantly accelerate future aging research,
and in turn, contribute a fundamental basis for the development of completely
new treatment strategies for various age-related diseases.
I think most people don't want to age, and I certainly don't either. That's why I'm
really looking forward to advancement in research like the ones we discussed today,
as I believe they'll give us a much clearer picture. While there are many reported cases
in aging research, human studies are still very much in their early stages,
so if there are any updates, I want to cover them on this podcast again.
That's all for today's SciencePod. This podcast is broadcast daily on weekday morning
in both Japanese and English. I hope today's discovery has changed how you view your
thoughts, and I'd love for you to listen to the podcast and post
your notes and thoughts with the hashtag SciencePod. See you next time!
