February 16, 2005
Young Mice Blood Turns On Regenerative Ability Of Old Mice Muscle

Young blood makes old cells act younger.

STANFORD, Calif. - 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.

Of course another possibility is that something in the aged blood is suppressing stem cells and repair mechanisms. Does their work rule out that possibility? I don't see that it does. But I haven't read the original paper.

It would be interesting to know how the effect of the young versus old blood scaled as they were blended in different ratios. For example, does one quarter young blood mixed with three quarters old blood have a quarter the effect of pure young blood or more or less than a quarter of the effect?

There is a potential bright side to this report: If blood could be made young again then possibly cells thoroughout the body in many tissue types would act young again.

"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.

However, there is a less optimistic interpretation to this result: The body may have evolved to produce stem cell growth suppressor compounds as the body ages in order to suppress cell divisions that could produce cancer cells. So blood that causes old stem cells to grow and repair tissue more vigorously might increase the risk of cancer. My guess is young blood would do that to older people.

The young blood effect was confirmed using cells grown in culture.

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.

This is an important report. But I repeat my caution above: If the presence or absence of some compound(s) in the blood is reducing the repair ability of a variety of tissue types (and it seems likely other tissue types will also be found to be affected by young versus old blood) then there is a decent chance that this reduction in repair ability was selected for to achieve some benefit, most likely a reduction in cancer risk.

Having stated the caution the ability to turn up repair capabilities could still be therapeutically useful for people who have dire needs for repair of some organ or tissue type. For example, turning up repair temporarily after major surgery or an accident could be worth the increased risk of cancer in some cases.

Suppose that changes in levels (either increases in suppressor molecules or decreases in cell growth stimulating molecules) of one or more compounds in the blood as we age happens in order to reduce the risk of cancer. Well, this is problematic for hopes to derive maximal benefits from replacing aged stem cell reservoirs with youthful stem cells. The old stem cells could be replaced with younger cells. There'd be immediate gains from lowered risk of cancer and relative improvements in the vigor and health of adult stem cells. So that is still worth doing. Yet the young replacement stem cells would still be restrained by levels of compounds in the aged blood. Here's the problem: If some but not all stem cell reservoirs have their stem cells replaced with younger stem cells it might not be safe to change the blood to make it more like young blood. It might be necessary to rejuvenate all stem cell reservoirs before the blood can safely be made more like young blood.

Here is an analogy: Imagine you have a car. It is old and it has 4 bad axles that will fall off if the car is driven too fast as well as a steering column that will fall apart at high speeds. Suppose you know how to replace the 4 axles but not the steering column. Well, if you replace only the 4 axles you still can't safely drive your car at high speeds. But with humans this problem is even tougher because there are many stem cell reservoirs located near every muscle and organ that would need to be rejuvenated before they could all have their level of stimulation by the blood safely raised to youthful levels.

Once really effective anti-cancer treatments (even treatments that kill all precancerous cells) are developed then most (all?) safety worries from making blood young again would go away. Any cancers that popped up in response to having youthful and growth-stimulating blood could quickly be slain or they could be slain even before the blood was rejuvenated. So great cancer-slaying treatments would make rejuvenation treatments easier to implement.

Share |      Randall Parker, 2005 February 16 09:34 PM  Aging Reversal

Robert Silvetz said at February 16, 2005 10:56 PM:

Two words: Shed receptors. If I had to go off and look for compounds that were suppressing cell-side reproduction I would look for shed receptors being too high relative to more youthful animals. The extra buffering from the excess shed receptors keeps the needed signaling at bay.

Michael Vassar said at February 17, 2005 9:33 AM:

Most probably, a mere dilution of the stem-cell repressors would not lead to dramatic changes in regeneration. Assuming that aging-related change accumulates at an accelerating rate, the result of mixing a young and an old mouse should produce two mice which are effectively closer to the old mouse if the suppressors are being diluted and closer to the young mouse if stem cells are being shared.

Kelly Parks said at February 17, 2005 9:58 AM:

Worrying about increased cancer risk is a legitimate concern but I don't think a suppression of stem cells late in life could really be selected for very effectively, since this occurs after your "breeder" years are over. Once you've already passed on your genes, evolution really can't do much to you.

On the other hand you could make the argument, I suppose, that one of the reasons humans developed such (comparitively) long life spans is that groups with long-lived elders were able to benefit from their wisdom and thus were more likely to survive and that this mechanism might help select for longevity in people past breeding age (since the group they were helping would include their descendants).

"You know, it's funny, Smithers. I tried every tincture and poultice and
tonic and patent medicine there is, and all I really needed was the blood
of a young boy."
--C. Montgomery Burns

Randall Parker said at February 17, 2005 9:58 AM:


Keep in mind that one of the experiments was the sharing of old and young mouse blood by connecting their vascular systems. So that would have diluted repressor molecules in the old mouse assuming that repressor molecules are the mechanism by which old tissues become less able to repair themselves.


But if receptors are too high in concentration that would not be fixed by exposure to young blood. The receptors would be on the stem cells. Or are you saying that shed receptors would be in the blood circulating and basically sopping up molecules that would otherwise be stimulating repair mechanisms?

Randall Parker said at February 17, 2005 10:02 AM:


Yes, I certainly believe that life beyond menopause was actively selected for as the human brain came to store more skills that parents and grandparents could use to help progeny and as the length of time for child development became longer and the need for child care became greater.

Robert Silvetz said at February 17, 2005 10:37 AM:

The interesting thing of shed receptors is that the system is a chaotic response surface. Small changes in either signalling molecules or shed receptor concentrations produce non-linear changes, so perturbing the system with young blood might be all that's needed. Hope that helps shed some light. I expect that manipulation of the shed receptor domains in the proximate future will open up new avenues to treat disease.

fub said at February 17, 2005 12:33 PM:

On a more literary note, it would appear that the late William Empson, poet, critic and mathematician, was on the right track in his villanelle many years ago:

Missing Dates
William Empson

Slowly the poison the whole blood stream fills.
It is not the effort nor the failure tires.
The waste remains, the waste remains and kills.

It is not your system or clear sight that mills
Down small to the consequence a life requires;
Slowly the poison the whole blood stream fills.

They bled an old dog dry yet the exchange rills
Of young dog blood gave but a month's desires;
The waste remains, the waste remains and kills.

It is the Chinese tombs and the slag hills
Usurp the soil, and not the soil retires.
Slowly the poison the whole blood stream fills.

Not to have fire is to be a skin that shrills.
The complete fire is death. From partial fires
The waste remains, the waste remains and kills.

It is the poems you have lost, the ills
From missing dates, at which the heart expires.
Slowly the poison the whole blood stream fills.
The waste remains, the waste remains and kills.

jmgordon said at February 17, 2005 5:40 PM:

This is exciting research. However, I have to wonder if some of the effects might be explained by already known effects. For example, I wonder if some of the improved muscle healing could simply be exposure to higher androgen levels coming from the younger mouse. I point to the fact that many professional bodybuilders are capable of phenomenal muscle recovery rates well past middle-age through the use of anabolic steroids (essentially massive testosterone replacement/augmentation). Does anybody know mice testosterone levels for the ages of the mice used in the study? I've no time right now to dig through the endocrinology literature.

Jeff Gordon

Bob said at October 30, 2005 6:04 PM:

Isn't there a phrase in the Bible that goes something like" "The life is in the blood." ?

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