Scientists have discovered crucial changes in chromosome structure and gene expression that impact stem cell function as organisms age. Research using fruit flies revealed that these alterations lead to stem cell exhaustion, a state in which stem cells lose their ability to multiply. This study marks the first identification of an independent exhaustion signal and sheds light on how the delicate balance between stem cell exhaustion and proliferation is disrupted during normal aging.
Researchers have uncovered significant changes in chromosome structure and gene expression that influence stem cell function during aging. Their study, conducted using fruit flies and published in iScience on September 9, reveals that these changes result in stem cell exhaustion, a state where stem cells lose their ability to multiply. This groundbreaking discovery provides the first evidence of an independent exhaustion signal and offers new insights into how the balance between stem cell exhaustion and proliferation is disrupted during the aging process.
In healthy organs such as the kidneys or intestines, stem cells respond to damage by multiplying and transforming into the specific cell types needed for repair and regeneration. However, as animals, including humans, age, this regenerative process can become impaired.
Sometimes, stem cells may divide uncontrollably, leading to excessive numbers that can result in cancer. Conversely, they may become depleted and lose their ability to divide, hindering tissue repair—a condition known as stem cell exhaustion.
While the mechanisms of stem cell proliferation are relatively well-understood in humans, the causes of exhaustion remain largely unexplored.
Previously, Sa Kan Yoo and his team at RIKEN BDR discovered how aging can cause intestinal stem cells in fruit flies to become cancerous. Building on this work, the researchers explored whether a mechanism independent of proliferation could also drive stem cell exhaustion.
Using fruit flies as a model, they analyzed the chromatin structure in intestinal stem cells and identified a specific region of chromatin that tends to close during aging. This closure prevents the production of a key regulator encoded in this DNA region. One of the genes affected by this regulator is ced-6, whose expression they evaluated using RNA sequencing.
Their findings revealed that ced-6 expression decreases with age. To investigate its role in stem cell exhaustion, the researchers blocked ced-6 expression, which stopped age-related stem cell proliferation, confirming that this gene helps prevent stem cell exhaustion.
Interestingly, they also found that blocking ced-6 could induce stem cell exhaustion at any age. When intestinal cells were damaged, stem cells typically proliferated, differentiated, and repaired the tissue. However, when ced-6 was blocked in damaged intestinal cells, the stem cells failed to proliferate, leaving the tissue unrepaired.
These findings suggest that the exhaustion triggered by blocking ced-6 or other genes regulated by the same chromatin region is not restricted to advanced age. Instead, it appears to be a general mechanism that helps maintain balance when stem cell proliferation becomes excessive.
“Our study opens the door to significant advancements in aging research,” says Sa Kan Yoo. “By uncovering the mechanisms of stem cell exhaustion in fruit flies, we gain valuable insights into the broader aging process. This research could also provide important clues about how aging affects stem cells in humans. The next step is to investigate whether similar changes occur in human stem cells as they age.”
