Researchers at the Stanford University School of Medicine have pinpointed why normal aging is accompanied by a diminished ability to regain strength and mobility after muscle injury: Over time, stem cells within muscle tissues dedicated to repairing damage become less able to generate new muscle fibers and struggle to self-renew.
"In the past, it's been thought that muscle stem cells themselves don't change with age, and that any loss of function is primarily due to external factors in the cells' environment," said Helen Blau, PhD, the Donald and Delia B. Baxter Foundation Professor. "However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age. In fact, two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles."
Blau and her colleagues also identified for the first time a process by which the older muscle stem cell populations can be rejuvenated to function like younger cells. "Our findings identify a defect inherent to old muscle stem cells," she said. "Most exciting is that we also discovered a way to overcome the defect. As a result, we have a new therapeutic target that could one day be used to help elderly human patients repair muscle damage."
Blau, a professor of microbiology and immunology and director of Stanford's Baxter Laboratory for Stem Cell Biology, is the senior author of a paper describing the research, which will be published online Feb. 16 in Nature Medicine. Postdoctoral scholar Benjamin Cosgrove, PhD, and former postdoctoral scholar Penney Gilbert, PhD, now an assistant professor at the University of Toronto, are the lead authors.
The researchers found that many muscle stem cells isolated from mice that were 2 years old, equivalent to about 80 years of human life, exhibited elevated levels of activity in a biological cascade called the p38 MAP kinase pathway. This pathway impedes the proliferation of the stem cells and encourages them to instead become non-stem, muscle progenitor cells. As a result, although many of the old stem cells divide in a dish, the resulting colonies are very small and do not contain many stem cells.
Using a drug to block this p38 MAP kinase pathway in old stem cells (while also growing them on a specialized matrix called hydrogel) allowed them to divide rapidly in the laboratory and make a large number of potent new stem cells that can robustly repair muscle damage, Blau said.
"Aging is a stochastic but cumulative process," Cosgrove said. "We've now shown that muscle stem cells progressively lose their stem cell function during aging. This treatment does not turn the clock back on dysfunctional stem cells in the aged population. Rather, it stimulates stem cells from old muscle tissues that are still functional to begin dividing and self-renew."
The researchers found that, when transplanted back into the animal, the treated stem cells migrate to their natural niches and provide a long-lasting stem cell reserve to contribute to repeated demands for muscle repair.
"In mice, we can take cells from an old animal, treat them for seven days - during which time their numbers expand dramatically, as much as 60-fold - and then return them to injured muscles in old animals to facilitate their repair," Blau said.