Alk Inhibitors to Slow Aging

A number of receptor tyrosine kinases are implicated in areas of metabolism known to influence the pace of aging in short-lived laboratory species. Researchers here investigate Alk, a receptor tyrosine kinase previously understudied in this context. It isn't clear that this will do any better as a basis for human therapies. In general this class of efforts to manipulate metabolism produces diminishing returns as species life span increases. Short-lived worms, flies, and mice exhibit a life span that can vary widely in response to environmental circumstances and changes in metabolism. We long-lived humans do not.

Inhibition of signalling through several receptor tyrosine kinases (RTKs), including the insulin-like growth factor receptor and its orthologues, extends healthy lifespan in organisms from diverse evolutionary taxa. This raises the possibility that other RTKs, including those already well studied for their roles in cancer and developmental biology, could be promising targets for extending healthy lifespan. Here, we focus on anaplastic lymphoma kinase (Alk), an RTK with established roles in nervous system development and in multiple cancers, but whose effects on aging remain unclear.

We find that several means of reducing Alk signalling, including mutation of its ligand jelly belly (jeb), RNAi knock-down of Alk, or expression of dominant-negative Alk in adult neurons, can extend healthy lifespan in female, but not male, Drosophila. Moreover, reduced Alk signalling preserves neuromuscular function with age, promotes resistance to starvation and xenobiotic stress, and improves night sleep consolidation. We find further that inhibition of Alk signalling in adult neurons modulates the expression of several insulin-like peptides, providing a potential mechanistic link between neuronal Alk signalling and organism-wide insulin-like signalling. Finally, we show that TAE-684, a small molecule inhibitor of Alk, can extend healthy lifespan in Drosophila, suggesting that the repurposing of Alk inhibitors may be a promising direction for strategies to promote healthy aging.

Link: https://doi.org/10.1111/acel.13137

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