February 16, 2005
STANFORD - Any older person can attest that aging muscles don't heal like young ones. But it turns out that's not the muscle's fault. A study in the Feb. 17 issue of Nature shows that it's old blood that keeps the muscles down.
The study, led by Thomas Rando, MD, PhD, associate professor of neurology and neurological sciences at the Stanford University School of Medicine, built on previous work showing that old muscles have the capacity to repair themselves but fail to do so. Rando and his group studied specialized cells called satellite cells, the muscle stem cells, that dot muscle tissue. These normally lie dormant but come to the rescue in response to damaged muscle-at least they do in young mice and humans.
In older mice the satellite cells hold the same position, but are deaf to the muscle's cry for help. In the Nature study, Rando and his group first attached old mice to their younger lab-mates in a way that caused the two mice to share a blood supply. They then induced muscle damage only in the older mice. Bathed in the presence of younger blood, the old muscles healed normally. In contrast, when old mice were connected to other old mice they healed slowly.
In similar work, the group examined the livers of older mice connected to younger lab-mates. The cells that help liver tissue regenerate are less active in older animals, but again the cells responded more robustly when the livers in older mice were bathed in the younger blood. Clearly, something in the youthful blood revived the regenerative cells in muscle and liver.
'We need to consider the possibility that the niche in which stem cells sit is as important in terms of stem cell aging as the cells themselves,' said Rando, who is also an investigator at the Veterans Affairs Palo Alto Health Care System. It could be the chemical soup surrounding the cells, not the cells themselves, that's at fault in aging.
One clue to what might be going on also comes from previous work. Rando had found that satellite cells in younger muscles begin producing a protein dubbed Delta in response to muscle damage. Older muscles maintained the same pre-injury levels of Delta even after muscle damage. However, in the current study he found that satellite cells in elderly mice joined to younger partners ramped up Delta production to youthful levels after an injury.
The group confirmed their results by putting satellite cells from old and young mice in a lab dish with either old or young blood serum. Old satellite cells in old serum and young satellite cells in young serum both behaved as expected. But when old satellite cells were bathed in young serum they cranked up their production of Delta and began dividing. Likewise, young satellite cells decreased the amount of Delta they produced when in a dish with older serum and divided less frequently.
Rando said that it may be a general phenomenon that a person's inability to repair tissues with age-whether it's muscle, liver, skin or brain-is a matter of the regenerative cell's environment rather than the cells themselves.
Rando said that finding the youth-promoting factors in the blood is no small task. 'It's as big a fishing expedition as you can possibly imagine,' he said. With thousands of proteins, lipids, sugars and other small molecules in the blood serum, deciding where to look first would be tantamount to a roll of the dice. What's more, there's no evidence that the same blood component is responsible for reviving the different types of cells.
'Another approach is to pick factors that are good candidates and see if any of them or some combination recapitulate the effect of the younger blood,' Rando said. His group is now looking for likely targets. He said that for some degenerative diseases such as Alzheimer's or muscular dystrophy, such blood-borne factors may be able to reactivate the regenerative cell's ability to repair tissue that has been damaged.
Postdoctoral scholar Michael Conboy, PhD, and former postdoctoral scholar Irina Conboy, PhD, now an assistant professor of bioengineering at UC-Berkeley, are joint first authors on the paper. Other Stanford researchers who contributed to the work include former postdoctoral scholar Amy Wagers, PhD, now an assistant professor at Harvard, and Iriving Weissman, MD, the Karel and Avice Beekhuis Professor of Cancer Biology.
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