Science: Senescent cells help repair damaged tissue

Scientists re-evaluate the role
of "zombie" cells that anti-aging drugs are trying to eliminate.
According to a new study from the University of California, San Francisco, not all senescent cells are harmful "zombies" that should be eliminated to prevent age-related diseases
.
The study found that some senescent cells are embedded in young, healthy tissue, promoting normal repair
of damage.

Scientists have now seen these cells play a role in lung tissue, as well as in other organs such as the small intestine, colon and skin that act as a barrier for the body
.
When they killed these cells with a drug called senolytics, the damage to lung tissue healed more slowly
.

Tien Peng, MD, associate professor of pulmonary, intensive care, allergy and sleep medicine and senior author of the study, said: "Senescent cells can take a special position as 'sentinels,' monitoring tissue damage and responding
by stimulating nearby stem cell growth and initiating repair.
" The study was published in the October 13, 2022 issue of
the journal Science.

Senescent cells can both damage and heal

Peng said scientists were understandable at first that senescent cells were purely
harmful.
As people age, the accumulation of senescent cells has the characteristics of senescent, failing cells, including the inability to produce new cells
.
Instead of dying like normal senescent cells, they continue to live, spewing out a cocktail of inflammatory compounds that form a senescence-associated secretory phenotype (SASP).

These factors are linked
to Alzheimer's, arthritis, and other age-related diseases, including cancer.
People have coined the catchy name "zombie cells"
for them.

Using senolytics to target and kill "zombie cells," researchers have made the exciting discovery that clearing senescent cells from animals can stop or reduce age-related diseases and extend the animal's lifespan
.
Since then, research activities have flourished in research labs and pharmaceutical companies, focusing on discovering and refining more powerful versions
of these drugs.

But killing senescent cells is dangerous, and on the one hand, current research shows that senescent cells also have the ability to
promote normal healing by activating stem cell repair.
Professor Peng said: "Our study suggests that senolytics may adversely affect normal repair, but they also have the potential to target diseases
in which senescent cells drive pathological stem cell behavior.
"

Illuminates senescent cells

A major challenge in studying senescent cells is that senescent biomarkers, such as the gene p16, are often very scarce, making it very difficult
to detect cells.
In early experiments, researchers extracted cells called fibroblasts into a petri dish, allowed them to grow and produce enough cells to conduct the experiment, and then applied chemicals to pressure those cells to induce them to age
.
But in living organisms, cells interact with surrounding tissues, strongly influencing the cell's gene activity
.
This means that the properties of cells grown independently in a glass dish may be very different
from those of cells grown in their natural environment.

To create a more powerful tool for their research, postdoctoral scholar Nabora Reyes de Barboza, PhD, and his colleagues refined a commonly used technique for fusing related genes — in this case, the overactive p16 gene in senescent cells — with green fluorescent protein (GFP) as a marker that can show the location of
cells under ultraviolet light.
By increasing the number and stability of green fluorescent protein in these senescent cells, the fluorescence signal was greatly amplified, ultimately enabling researchers to see senescent cells
in their natural habitat in living tissue.

"Zombies" stimulate stem cells soon after birth

Using this highly sensitive tool, the researchers found that senescent cells are present in young and healthy tissues to a greater extent than previously thought, and actually begin to appear
soon after birth.
The scientists also discovered specific growth factors
secreted by senescent cells that stimulate stem cell growth and repair tissue.
Associated with senescence and tissue damage, cells of the immune system such as macrophages and monocytes can activate senescent cells, suggesting that inflammation seen in aged or damaged tissues is a key modifier of
senescent cell activity and regeneration.

In a study of lung tissue, Peng's team observed green, glowing senescent cells next to stem cells on the basement membrane, which acts as a barrier against foreign cells and harmful chemicals from entering the body and also allows oxygen to diffuse from the air in the lungs to the underlying tissues
.
Damage can occur at this dynamic interface
.
The team found senescent cells in similar locations in other barrier organs such as the small intestine, colon, and skin, and the results confirmed that lung stem cells could not repair the barrier surface
properly if senescent cells were killed with senolytics.
Dr.
Leanne Jones, director of the Stuart Lindsay Professor of Experimental Pathology at the University of California, San Francisco's Bakar Institute on Aging, said Peng's research is indeed significant in the field of aging research, where the goal is to help individuals live longer, healthier
lives.

"These studies suggest that senolytics research should focus on identifying and pinpointing harmful senescent cells while retaining beneficial cells
when there are only the earliest signs of disease," she said.
The findings underscore the need to develop better drugs and small molecules that will target specific subpopulations
of senescent cells associated with disease rather than regeneration.
”