Good news! Behind the secrets of aging!
"Intestinal stem cell function declines with age, and dysregulation of these cells is associated with a shortened lifespan. Zhang et al. found that the RNA-editing enzyme adenosine deaminase acting on RNA (ADAR) restrained intestinal stem cell proliferation in fruit flies, and its abundance decreased with aging and after gut injury.
Loss of ADAR in these cells in young flies caused intestinal hyperproliferation and reduced lifespan, whereas ADAR overexpression in aged flies improved gut function and increased lifespan.
Reductions in colonic ADAR2 were associated with aging in humans and with intestinal regeneration in mice, suggesting that ADAR mediated regulation of intestinal stem cells may be conserved."
From the editor's summary and abstract (a very technical abstract):
"Editor’s summary
Intestinal stem cell (ISC) function declines with age, and ISC dysregulation is associated with shortened life span.
Zhang et al. found that the RNA editing enzyme ADAR restrained ISC proliferation in fruit flies, and its abundance and activity decreased with aging and after gut injury.
ISC-specific loss of ADAR in young flies caused intestinal hyperproliferation and reduced life span, whereas ADAR overexpression in aged flies improved gut function and increased life span.
ADAR inhibited proliferative MAPK signaling in ISCs because its RNA editing activity generated a translational repressor of MAPK pathway components. Reductions in colonic ADAR2 and a protein that stabilizes it were associated with aging in humans and with intestinal regeneration in mice, suggesting that ADAR-mediated regulation of ISCs may be conserved. ...
Abstract
Aging impairs intestinal stem cell (ISC) function, disrupting epithelial homeostasis and regenerative repair.
Loss of ISC quiescence promotes intestinal dysfunction and contributes to organismal aging.
Here, we report an epitranscriptomic mechanism through which a decrease in adenosine-to-inosine (A-to-I) RNA editing by the adenosine deaminase ADAR in ISCs during aging disrupts a conserved signaling axis that maintains ISC quiescence.
In Drosophila melanogaster, ISC-specific loss of dADAR triggered hyperproliferation and tissue aging, whereas dADAR overexpression reduced age-related gut dysfunction and extended life span.
Intestinal injury induced a decrease in dADAR, which was necessary for tissue regeneration, and in the zinc finger protein dZn72D, which stabilized dADAR to support intestinal homeostasis during aging. dADAR edited transcripts encoding the RNA binding protein Pumilio (dPUM) to generate an isoform that inhibited translation of two components of the mitogen-activated protein kinase (MAPK), dEGFR and dERK, thereby maintaining ISC quiescence.
The abundance of ADAR2 and of the dZn72D ortholog ZFR decreased in human colonic crypts with aging and in mouse colon after injury, suggesting that attenuation of ADAR activity may play a conserved role in ISC aging and in facilitating colonic regeneration.
Our work identifies a conserved mechanism of epitranscriptomic regulation that safeguards tissues and the decay of ADAR-mediated RNA editing as a form of age-related epigenetic information loss that disrupts ISC homeostasis."
Fig. 1. A-to-I RNA editing in ISCs declines during aging.
Fig. 2. dADAR inhibits ISC proliferation in a cell-autonomous manner.
Fig. 4. dADAR loss drives gut aging and reduces life span in Drosophila.
Fig. 6. dADAR maintains ISC quiescence by inhibiting the MAPK signaling pathway.
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