Fight Aging!

A great many projects at various stages of development are characterized by their goal of forcing greater stem cell activity in old tissues, but without meaningfully addressing the underlying causes of stem cell decline in later life. This sort of research and development operates at the level of proximate causes, adjusting protein levels to change cell behavior. Among the potential therapies I'd place into this category: telomerase gene therapy; GDF11 upregulation; FGF2 inhibition; NAD+ upregulation; and so on. Muscle stem cells known as satellite cells are one of the better studied stem cell populations in this context, and many of the interventions are focused here. Today's open access research is a representative example, in that the authors describe a portion of the network of genes and proteins that control stem cell behavior, finding that it can be adjusted in order to force greater activity, overriding the normal reaction to an aged and damaged environment.

The loss of stem cell activity with age is thought to be an evolved response to rising levels of DNA damage, inflammation, and immune dysfunction that serves to reduce risk of early death by cancer, at the cost of a certain later decline into frailty. It is a part of the parcel of adjustments that lead our lengthy life spans in comparison to other similarly sized mammals. There has been, and still is, concern that putting cells back to work in this sort of way, without fixing the problems that lead to cancer, will raise cancer risk over the years following intervention. It will be slow and costly to understand whether or not this is the case in humans, but the evidence to date from animal studies show that these and analogous efforts result in far less cancer than might be expected. Perhaps this is due to improvement in immune function in those therapies, such as telomerase gene therapy, for which there is good data on cancer risk in animal models, but a firm answer on mechanisms is yet to arrive.

Possible therapeutic target for slow healing of aged muscles discovered

Skeletal muscles have a tremendous capacity to make new muscles from special muscle stem cells. These "blank" cells are not only good at making muscles but also at generating more of themselves, a process called self-renewal. But their amazing abilities diminish with age, resulting in poorer muscle regeneration from muscle trauma. A research team figured out that a protein called GAS1 is the culprit for this age-related decline.

The protein is found in only a small number of young muscle stem cells, but is present in all aged muscle stem cells, they discovered. Tinkering with muscle stem cells to express GAS1 in the entire young stem cell population resulted in diminished regeneration. By contrast, removing GAS1 from aged muscle stem cells rejuvenated them to a youthful state that supported robust regeneration. They also discovered that GAS1 inhibits another protein, a cell-surface receptor called RET, which they showed to be necessary for muscle stem cell renewal. The more GAS1 protein is present, the more RET's function is reduced. The inhibition of RET by GAS1 could be reversed by the third protein called GDNF, which binds to and activates RET. Indeed, when the researchers injected GDNF directly into the muscles of aged mice, muscle stem cell function and muscle regeneration were restored.

Muscle stem cell renewal suppressed by GAS1 can be reversed by GDNF in mice

Muscle undergoes progressive weakening and regenerative dysfunction with age due in part to the functional decline of skeletal muscle stem cells (MuSCs). MuSCs are heterogeneous, but whether their gene expression changes with age and the implication of such changes are unclear. Here we show that in mice, growth arrest-specific gene 1 (Gas1) is expressed in a small subset of young MuSCs, with its expression progressively increasing in larger fractions of MuSCs later in life. Overexpression of Gas1 in young MuSCs and inactivation of Gas1 in aged MuSCs support that Gas1 reduces the quiescence and self-renewal capacity of MuSCs. GAS1 reduces RET signalling, which is required for MuSC quiescence and self-renewal. Indeed, we show that the RET ligand, glial-cell-line-derived neurotrophic factor can counteract GAS1 by stimulating RET signalling and enhancing MuSC self-renewal and regeneration, thus improving muscle function. We propose that strategies aimed at targeting this pathway can be exploited to improve the regenerative decline of MuSCs.