Inhibiting FGF2 in Mice Slows Muscle Stem Cell Decline With Age

The various fibroblast growth factors are known to be involved in stem cell activity, and thus in regeneration and embryonic development. As is usual in these matters the picture is complex and far from fully understood when it comes to what happens to stem cells and their regulation in aging. Nonetheless, inroads are being made into selectively slowing or reversing the decline of stem cell activity with age - which brings with it the progressive failure and frailty of tissues that become inadequately maintained.

This is all very necessary for the field of regenerative medicine, as most of the medical conditions that stem cell science is best placed to tackle are age-related. If therapies are to be based on the use and manipulation of stem cells, then researchers will have to understand how to minimize or remove the deleterious effects that an age-damaged metabolism has on these cells.

The modest advance for today is this: scientists have managed to slow stem cell decline in muscles by inhibiting fibroblast growth factor 2 (FGF2), and in the course of doing so might have shed some more light on the debated question of what happens to stem cells in aging - why exactly it is that their activity declines.

Inadequate cellular rest may explain effects of aging on muscles

Rare muscle stem cells are located inside each skeletal muscle of the body. Also called satellite cells, due to their position on the surface of the muscle fibers they serve and protect, these cells are essential to maintaining the capacity of muscles to regenerate. Satellite cells are able to generate new, differentiated muscle cells while keeping their identity as stem cells, retaining the ability to maintain and repair muscle tissue. Normally in a resting or dormant state, satellite cells respond rapidly to repair injured tissues. The current study finds that aging muscle stem cells lose their ability to maintain a dormant state, so that when called upon to repair injured muscle, they are unable to mount an adequate response. ... Just as it is important for athletes to build recovery time into their training schedules, stem cells also need time to recuperate, but we found that aged stem cells recuperate less often. We were surprised to find that the events prior to muscle regeneration had a major influence on regenerative potential.

In a series of experiments in mice, the authors found that a developmental protein called fibroblast growth factor-2 (FGF2) is elevated in the aging muscle stem cell microenvironment and drives stem cells out of the dormant state. Satellite cells that are forced to replicate lose the ability to maintain their identity as stem cells, reducing the stem cell population.

The authors also found that blocking the age-related increase in FGF signaling both in aged satellite cells or in the cellular microenvironment protected against stem cell loss, maintained stem cell renewal during aging and dramatically improved the ability of aged muscle tissue to repair itself.

This seems like a promising demonstration of what can be achieved as we learn more of the mechanisms that steer stem cell behavior. That said, it is probably the case that any widespread use of therapies to keep stem cells in circulation would have to be matched by an increased vigilance and ability to combat cancer. It is generally thought that declining stem cell activity is an evolved balance between loss of tissue integrity and risk of cancer. More stem cell activity in later life would suggest a raised chance of cancer, if all other things are equal.

Of course we'd like to do far better than "all other things are equal." The proposed future of medicine is one of damage repair at all levels: fixing all the broken proteins, removing all the lingering metabolic waste products, culling senescent cells, and so forth. Sorting out the stem cell issue is just one of many parts to a general rejuvenation biotechnology toolkit.


From online papers, it appears that ACE-inhibitors can block FGF signaling in several tissues. Perhaps there is a therapeutic window for their use as anti-aging agents?

Posted by: Lou Pagnucco at September 26th, 2012 9:19 PM

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