Sabotaging a Mechanism of Decline in Age-Related Stem Cell Activity

Stem cells are responsible for maintaining surrounding tissue function via generation of daughter cells to make up losses. Stem cell activity declines with age, and research of the past twenty years suggests that a sizable fraction of this decline is a reaction to rising levels of cell and tissue damage, rather than being due to intrinsic damage to the stem cells themselves. Thus researchers are searching for the signals that influence stem cell activity, with the intent of interfering in order to boost stem cell activity in old tissues. This seems a worse strategy than repairing the underlying damage that causes stem cell decline, but it is nonetheless a popular field of research, and there is plenty of evidence for it to be possible to produce some degree of benefits via this approach.

Researchers have discovered how regenerative capacity of intestinal epithelium declines when we age. Targeting of an enzyme that inhibits stem cell maintaining signaling rejuvenates the regenerative potential of an aged intestine. This finding may open ways to alleviate age-related gastrointestinal problems, reduce side-effects of cancer treatments, and reduce healthcare costs in the ageing society by promoting recovery.

The age-induced reduction in tissue renewal makes dosing of many common drugs challenging. Targeting of an inhibitor called Notum may provide a new way to increase the therapeutic window and to promote recovery in societies with the aging population. Researchers believe that in addition to direct targeting of Notum, lifestyle factors such as diet may also provide means to reduce Notum, and thus improve tissue renewal and repair.

Using organoid culture methods, researchers understood that poor function of tissue repairing stem cells in old intestine was due to aberrant signals from the neighboring cells, known as Paneth cells. "Modern techniques allowed us to examine tissue maintenance at a single cell level, and revealed which cell types contribute to the decline in tissue function. We were surprised to find that even young stem cells lost their capacity to renew tissue when placed next to old neighbors."

Normally intestinal epithelium is renewed by stem cells that rely on activity of Wnt-signaling pathway. Surrounding cells produce molecules that activate this pathway. The study shows that during ageing, Paneth cells begin to express a secreted Wnt-inhibitor called Notum. Notum enzymatically inactivates Wnt-ligands in the stem cell niche, decreasing regenerative potential of intestinal stem cells. However, pharmacologic inhibition of Notum rejuvenated stem cell activity and promoted the recovery of old animals after treatment with a commonly used chemotherapeutic drug with severe side-effects in the gut.



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