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Red light, green light: Simultaneous stop and go signals on stem cells' genes may enable fast activation, provide "aging clock"

red light green lightVirtually all cells in a person's body have the same genes. But in each different type of cell - fat, nerve, muscle, liver, etc. - only the genes involved in that particular cell type's business are in a state of being reader-friendly to the hulking molecular machines that, studiously following  genes' instructions, manufacture the proteins that shape a cell's structure and do most of its work.

Prominent among the various mechanisms dictating the on/off status of each of a cell's 20,000-odd genes is set of chemical "chalk marks" scrawled on histones, the protein husks that coat DNA in every animal or plant cell. Think of those marks on histones as red or green traffic signals that remain stably red or green. (Otherwise our brain cells could turn into fat cells, and then where would we be?) Over a cell's lifetime, though, some of these traffic lights do gradually change colors. They can change pretty fast and prolifically when a stem cell is changing its status (for instance, when a stem cell is differentiating into a mature cell).

In a just-published study in Cell Reports, a team led by Stanford neuromuscular maven and longevity researcher Tom Rando, MD, PhD, identified characteristic differences in "histone signatures" between stem cells from the muscles of young versus old mice, and between quiescent and activated stem cells in mice's muscles.

Rando's group found that large numbers of the genes that muscle-resident stem cells would need in order to develop into mature muscle cells harbor both "stop" and "go" signals simultaneously. Rando suggests that this ambivalent markup might poise stem cells for rapid maturation in response to an environment cue such as, say, an injury to the muscle.

Curiously, in these muscle-resident stem cells that lots of genes muscle cells don't ever need to use but other kinds of cells do are also marked by both "on" and "off" signals. That was a total surprise, Rando told me in an interview for my news release about the discovery:

We figured all the muscle genes would be either poised for activity — marked with both ‘on’ and ‘off’ signals — or ‘on,’ and that all the other genes would be turned off. But [these muscle-resident stem cells] seem ready to become all kinds of cells. It’s a mystery.

He wondered out loud whether "muscle" stem cells might, under the right conditions, be capable of turning into quite different kinds of tissue.

The team also found characteristic differences between histone signatures among stem cells of young versus old mice. Rando, the director of the Stanford-based Glenn Laboratories for the Biology of Aging, thinks these differences may prove useful as an objective yardstick of a cell's age. That's important, because we're only as young as the cells we're made of.

Might it ever be possible to reverse the aging process at the level of the cell, leading to a wrinkle-free, supple-kneed late adulthood? If we can figure out why old stem cells have different genes locked in the "on" or "off" states than young stem cells of the same type do - and then find ways to reverse those states - maybe.

Previously: Visible symptoms: Muscular-dystrophy mouse model's muscles glow like fireflies as they break down, Can we reset the aging clock, one cell at a time? and Aging research comes of age
Photo by MoToMo

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