Highlights

Aging brings inevitable decline of function to tissues throughout the body with organs losing their capacity to repair damage and replace dead or dying cells.

Although this is a complex and multi-factorial process, a great deal of attention has focused on the Cdkn2a gene, which encodes two proteins—p16^Ink4a and p19^Arf—that steer cells into an age-dependent state of growth arrest known as senescence. Levels of both factors correlate with aging in a number of tissues, and evidence suggests that their activity is directly induced via the signaling protein called p38 mitogen-activated protein kinase (MAPK).

Dmitry Bulavin and co-workers at the Institute of Molecular and Cellular Biology of A*STAR, Singapore, who are specialists in p38MAPK signaling, have characterized this pathway’s involvement in aging. They engineered mice where one copy of the p38 gene contains changes that prevent it from transmitting signals to downstream binding partners; this mutant (p38^AF/+) acts as a ‘dominant negative’, actively suppressing overall cellular p38MAPK signaling and thereby offering a useful tool for studying this protein’s activity.

Bulavin’s team found that expression levels of p16^Ink4a and p19^Arf climb dramatically in various tissues from older mice, such as pancreatic islets; however, in p38^AF/+ animals, levels of these gene products remained comparable to those seen in younger animals. Likewise, older p38^AF/+ mice showed significantly greater islet cell proliferation than their wild-type counterparts.

The enzyme Wip1 is a known inhibitor of p38MAPK, and accordingly, Bulavin’s team found that Wip1 levels were significantly lower in islets from older mice. In addition, islet cells from mice entirely lacking the Wip1 gene exhibited elevated Cdkn2a expression and reduced proliferation—an effect that appears to be directly dependent on p38MAPK activity, further underscoring the central role of this protein.

“By showing that p38MAPK regulates Cdkn2a expression with aging, we were able to identify an upstream signaling pathway that was completely unknown,” says Bulavin. He notes that although these findings could guide drug development for reducing effects of aging in certain tissues, their impact on diseases with aging-like effects may be limited. “Many of these have different molecular pathways leading to earlier onset of aging, which could be somewhat independent of p38,” he says.

As a next step, Bulavin’s team is exploring how far beyond the pancreas the effects of p38MAPK are felt. “We are looking at life-span in our mice to see whether improvement in organ function is actually translated into longer life,” he says.

The A*STAR-affiliated authors in this highlight are from the Institute of Molecular and Cellular Biology and the Institute of Medical Biology.