An Israeli-led team of scientists recently discovered new clues about the secrets of human aging in the testes of fruit flies.
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The study, led by Haifa University researcher Hila Toledano and published in the journal Nature, helps explain why adult stem cells age and offers hope of reversing the process.
Fruit flies are popular among geneticists because of their rapid life cycle: their genome is simple and they only live about a day. That means the scientists can see the results very quickly after tinkering with their genes.
Adult stem cells are an important reservoir of physical rejuvenation. They multiply to help heal injuries and support tissue health. As people get older, their stem cells dwindle, leaving their bodies less able to perform these tasks.
In recent years, there has been extensive research on the aging-related decline of adult stem cells. Toledano’s new research, conducted at professor Leanne Jones' laboratory at the Salk Institute in La Jolla, California, identifies the arch-villain in this drama – a microRNA molecule called let-7 and furthermore explains its machinations in germline stem cells.
“The discovery may offer a promising route to fight the ageing process in stem cells and allow the elderly body to maintain tissues and heal injuries as adult people do,” said Toledano.
This was not science’s first run-in with let-7. The molecule was already known to be necessary for the differentiation of embryonic stem cells into other types of cells. And in 2008, scientists demonstrated that it causes adult stem cell in the brains of elderly mice to dwindle.
But because neural stem cells are unique, it was not clear if let-7 would have a similar affect in other tissues.
The new research indicates that it does. Adult stem cells – which are found in a variety of bodily tissues where cells have short lifespans, including the heart, gut, blood and semen – are surrounded by groups of various other types of cells, known as niches. Niche cells structurally support and send chemicals to stem cells telling them, among other things, to create new cells.
Toledano’s research found that the increased production of let-7 as people age causes damage to another molecule called Upd, which maintains signaling between stem cells and their niches. The upshot is that stem cells stop working as stem cells.
How does this work?
All microRNAs essentially stop genes from producing proteins. Let-7 stops the production of a protein known as Imp, which plays an important role in stabilizing Upd. When Upd becomes unstable, its ability to maintain the signaling between stem cells and their niches is reduced. As a result, stem cells stop dividing as normal.
Whereas stem cells normally divide into one stem cell and one functional tissue cell, when signaling is impaired, they simply differentiate into a functional tissue cell. Every time this happens, the body loses a stem cell.
“We basically mapped the domino effect of the let-7 molecule,” said Toledano. “There are a few studies of muscle stem cells that point to the molecular mechanisms of the aging-related decline of stem cell function. What’s novel to our work is the finding that this aging-related decline comes from the niche rather than the stem cells themselves.”
One implication of this discovery is that introducing adult stem cells to aged organisms will not work “since the niche doesn’t signal as well as in young organisms,” said Toledano.
Toledano and her team figured out why stem cells become less active by analyzing them in the testes of fruit flies. They also managed to reverse the sequence by increasing the quantity of Imp proteins in the niches of older flies.
Toledano says a similar process probably takes place in humans, although it has yet to be identified. Further research is also needed to determine exactly what causes the increase of let-7 during aging and what other roles the molecule plays.
Professor Amir Orian, a fruit fly expert from the Technion's Rappaport Faculty of Medicine who is collaborating with Toledano, described the new research as “groundbreaking.”
“The problem of stem cell activity in aging is a major concern, and we know little about it,” he said. “Up until Hila's work, the molecular mechanisms involved in adult stem cell aging were mostly unknown. This is a very important discovery that offers us an insight into the role of specific adult stem cells during aging. I predict that the impact of Hila’s finding will be highly relevant beyond this specific system.”