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Opinion: Younger Is Better

Stem cells collected from younger donors are more effective for transplantation and regenerative medicine than those from older individuals.

By | August 31, 2012

image: Opinion: Younger Is Better Colorized scanning electron micrograph of a human embryonic stem cell (gold) growing on a layer of supporting cells (fibroblasts) Wellcome Images, Annie Cavanagh

Talk of stem cells as medical therapies have become almost commonplace these days.  Millions have now collected and stored their stem cells in biobanks for potential future use, and tens of thousands of patients have received stem cell transplants or infusions for the treatment of cancer or various experimental regenerative medicine therapies.  It is estimated that the likelihood of a member of your family needing a stem cell transplant for cancer by age 70, using their own cells or someone else’s, is 1 in 217.  And the odds of use in regenerative medicine may be even greater.

But often overlooked are the common factors that may impair the utility of these stem cells.  Two such factors are stem cell age and donor health. Most therapeutic stem cells are derived from relatives or unrelated donors, and it is often difficult to find suitably matched donors. As a result, the selection criteria for those that do match are very low: as long as the donor is free of select infectious diseases, little thought is given to the age of the stem cells or health of the stem cell donor. But increasingly, evidence is accumulating that both of these factors can significantly impact the therapeutic potential of stem cells.

Looking at stem cell use in hematopoietic transplantation, my colleagues and I demonstrated that children transplanted with newborn stem cells derived from cord blood had significantly longer telomeres in cells isolated from their blood than comparable children transplanted with adult stem cells. Because they carry longer telomeres, recipients of young stem cell transplants would be less likely to undergo premature cellular aging than those receiving older cells, which would be particularly important in pediatric patients who might live for decades after transplantation.

For research in the arena of regenerative medicine, many are looking at mesenchymal stem cells (MSC).  Numerous studies have indicated that MSCs isolated from older donors, as well as from patients with chronic disease conditions, are neither as prevalent (in terms of the number of cells in the sample) nor as potent as those isolated from younger, healthier donors. MSCs collected from older or disease-afflicted donors seem less able to differentiate into different cell types needed for tissue engineering, have a reduced capacity to proliferate and expand to numbers of cells that would allow for multiple treatments, and are more prone to dying during culture and use. Thus it is not surprising that there is anecdotal evidence that MSC donor age and chronic disease status negatively impacts clinical utility and successful clinical outcomes.

Cord tissue-derived MSCs (one of the youngest stem cell sources available) show great potential for a variety of regenerative medicine applications. A particularly striking quality is their proliferative capacity, with one study showing that the cord tissue MSCs can be expanded over 300-fold in culture, 30 percent more than adult MSCs harvested from young adults. These cells are also receptive to genetic manipulation, indicating that they may be particularly well-suited to applications involving gene therapy. The cells have also shown differentiation capability to cells outside the mesenchymal lineage, such as myocytes (muscle cells) and neurons, both in vitro and in in vivo animal experiments, while adult MSCs appear to lose the ability to differentiate as they get older.

Such evidence that MSC quality declines with donor age warrants concern when using adult MSCs for cell based therapies. The ability of older stem cells to respond to injury and disease may be compromised during aging and could contribute to inferior tissue repair. In addition to longer doubling times, aged MSCs exhibit increased apoptosis and decreased osteoblast generation and differentiation.  A possible explanation of these observations is the accumulation of endogenous DNA damage, which is known to occur in a variety of cell types and would be expected to limit the utility of aged stem cells.

A recent example of the importance of stem cell age comes from a study by Jinui Shen of University of Texas at Arlington and colleagues, which found that aging female mice transplanted with MSCs from young donors had prolonged life span (by 15 to 20 percent). In contrast, MSCs isolated from the older donor animals failed to prolong life span at all, showing significantly less capability to differentiate into bone, fat, neural, and muscular cells as compared to MSCs from younger animals.

So it seems cells, like the rest of our bodies, suffer from the ravages of time: stem cells collected from younger, healthier people are proving to be more successful therapeutics than cells taken from older or less healthy donors.  This seems to be holding true for multiple types of stem cells, making a strong case for the preservation of newborn stem cells from the umbilical cord and cord blood for potential future use, and for the consideration of donor age when transplanting adult cells.

David T Harris is a professor in the Department of Immunobiology at the University of Arizona in Tucson.

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Comments

Avatar of: corrigible

corrigible

Posts: 42

September 3, 2012

Isn't it interesting that, from the moment of conception, a clock begins to tick, so to speak.
Not only does the number of telomeres have a limit but, also, the unprevented and uncorrected number of "errors" accumulate in compromising the initial DNA program. And, while nurture might make some difference in these processes, nature has the greater "say" in it.
If the intitial DNA program (at conception) is seriously "flawed," accumulated physiological dysfunction and increase propensity to die in the short term are accelerated.
For some individuals the initial program is better and the accumulation of errors is slower.
Smoking, excess sugar, excess salt... speed the accumulation.
At seventy eight,
I feel GREAT;
But the end appears nearer
If I look in a mirror
( : > )

Avatar of: Shi V. Liu

Shi V. Liu

Posts: 1457

September 3, 2012

Of course! Please search for my views on this topic by Googlling "Shi V. Liu and aging".

Avatar of: Guest

Anonymous

September 3, 2012

Went to your site. Impressive. Assuming the study or studies indicating stem cells from a younger human provide more telomeres, and fewer mutations (or "errors") in DNA "program" at conception, that would seem to suggest that transfusions and stem cell transfers from mature hosts might need to be eliminated altogether -- provided, that is, we can get enough mesenchemal cells from younger hosts.
Can't you just imagine how much flack might ensue if all stem cells were obtained from babies and/or embryos.
Soon we may be hearing of sellers of stem cells from infants as a veritable fountain of youth. If those infant-source stem cells set off a new set of cells in a body, with more telomeres, then infant-cource stem cells might be sold as the next best thing known to water from the fountain of youth.
Not meaning to knock the idea, and not meaning to hawk it, but if cells from an aged host are transferred to a child, and that raises the number of mutated, or mutating, cells in that child, that certainly is something to be avoided (provided results of studies suggesting same turn out to be replicable.
If current stem cells tend to be obtained from volunteer donors, maybe parents can be persuaded to sell stem cells from their young children.
Before I would support such a "market," I would want to be very, very sure the results of the cited study are replicated in many samplings.
I expect you will concur.

Avatar of: corrigible

corrigible

Posts: 42

September 3, 2012

Checked your web site. Impressive. In view of your background, I believe you will concur that there are some additional factors in need of mention. First, if it is true that the older a donor of stem cells is, the fewer telomeres of cells engendered by them, and the greater the number of accumulated, and accumulating, mutations (or "errors") those cells set to reproducing in the graft host, then the converse is implied, i.e., that the younger the donor the more telomeres in cells resulting, and the fewer accumulated mutations (or "errors")accumulating.
Such a prospect, assuming it is authentic and the results of the subject study are
robustly supported by further work, then the result might be a rush to obtain mesenchemal cells exclusively from young children or from embryos.

Children and fetuses, below the age of consent, might be "volunteered" by their parents,for a price.
One implication of the result, if supported by more studies, might be that a "market" would develop (and probably quite quickly and voluminously) of "buyers" who just want some younger stem cells inserted into themselves, as the nearest thing to getting water from the fountain of youth.

Now please understand that I am neither intending to denegrate, nor fascilitate, a "market" in stem cells from children or embryos.

All I am saying is that -- PROVIDED -- further studies robustly replicate and reinforce the implications cited here, this is going to become an enormous area of
controversy over what is ethical.

If we have atheletes in the world today who are ready, willing and able to have their bodies doped, for the short term goal of winning sporting contests (even where the doping may tend to reduce the quality of the remainder of the athelete's life, or foreshorten it) it staggers the imagination to conceive of how many individuals with the means to pay for it might desire to have youthful stem cells inserted into their bodies, to provide at least some of their bodies' cells reproducing with optimal telomere numbers and minimal mutation numbers.

But there is another wrinkle to consider in this matter, as well. If a human individual wanted infant stem cells inserted in his or her body, he/she surely would want to know the genetic history of the infant or embryo donor. This is because some infant donors' mesenchymal cells might harbor some draw back other than just the age factor.
To be sure to get the fountain of youth injections "right," the new host would most likely want to know the DNA history of the particular infant. Thus if an infant had the best of both to offer -- an excellent genetic heritage and and the excellence of youthful stem cells to offer, the parents of such a child (and hopefully the child, as well) might be a fortune waiting around to be made.
As for me, I think it could be a healthy situation if handled responsibly. But, as always, there are charlatans clamoring for a new gimmick to profit from.
Further studies are most definitely indicated, in hopes their results will robustly replicate the findings of the subject one, or ones.
My guess is that if they do, the reverberations of this will be loud and long and boisterous.
Would you say "of course" to that, also?

Avatar of: corrigible

corrigible

Posts: 42

September 3, 2012

Sorry, this was my post. I edited it somewhat, and it showed as submitted by guest (my misspellings, grammatical errors and all (: > )
Went to Liu's site as requested. Impressive.
Assuming the study or studies indicating stem cells from a younger human provide more telomeres, and fewer mutations (or "errors") in DNA "program" at conception, that would seem to suggest that transfusions and stem cell transfers from mature hosts might need to be eliminated altogether -- provided, that is, we can get enough mesenchymal cells from younger hosts.

Can't you just imagine how much flack might ensue if all stem cells were obtained from babies and/or embryos.

Soon we may be hearing of sellers of stem cells from infants as a veritable fountain of youth. If those infant-source stem cells set off a new set of cells in a body, with more telomeres, then infant-cource stem cells might be sold as the next best thing known to water from the fountain of youth.

Not meaning to knock the idea, and not meaning to hawk it, but if cells from an aged host are transferred to a child, and that raises the number of mutated, or mutating, cells in that child, that certainly is something to be avoided (provided results of studies suggesting same turn out to be replicable.

If current stem cells tend to be obtained from volunteer donors, maybe parents can be persuaded to sell stem cells from their young children.

Before I would support such a "market," I would want to be very, very sure the results of the cited study are replicated in many samplings.

I expect you will concur.

Avatar of: John A Polagruto

John A Polagruto

Posts: 1457

September 4, 2012

Isn't epigenetic programming important as well? Having not worked with stem cells, I am unfamiliar with their culturing, but I gather that it is NOT common to demethylate the DNA in order to strip off all of the epigenetic tags that accumulate from day one, conception.

(Tiwns evidence suggests that older twins are far more different epigenetically than younger twins.)

Thus, if stems cells from a donor are introduced into a recipient (not the same patient), then the recipient receives all of the epigenetic programming from the donor. (E.g., Do smokers who donate stems cells donate their smoke-related epigenetic tags as well???).

Avatar of: Syafiqah Kamarudin

Syafiqah Kamarudin

Posts: 1457

September 23, 2012

first, i wanna say what a great article this is, it really intrigues me to think which lead me to wonder this second: when the stem cells taken from the newborns are kept in a bank for a considerable long period of time, won't they be aging and affected by time too?

Avatar of: Gune

Gune

Posts: 4

October 11, 2012

The developmental plasticity that is their in the cord blood cells is certainly more than mesenchymal stem cells and cells derived from other areas in older people. It should be noted, that the cord blood cells is easy to be isolated aseptically and kept for longer periods of time than other types of stem cells.

There is a drawback though the cells that are kept in the bak should be monitored and checked for teloere shrtening on a daily basis so as to prove its worth as stem cells with immence potential. The above comment is indeed valid.

Also it shoud be kept in mind that the essence of regenerative medicine is to help mankind to develop an effective means to survive and not to be thrown in the dungeons of dispair. 

For the sake reserach in bright and young areas of regenartive mediine, researchers should be ideally made aware of the pitfalls and high risks associated with the same.

 

My suggestion would be to excercise caution and imposition of informed decision from the FDA, who should appoint a highly motivated group of individuals or laboratories, who should be the torchbearers of acceptiblity of thiese types of exciting research going on in the world

In the real life scenario these types of research should be more tected in animal models before using it in human patients. So caution is the key, not exuberance.

Avatar of: Gune

Gune

Posts: 4

October 11, 2012

The developmental plasticity that is their in the cord blood cells is certainly more than mesenchymal stem cells and cells derived from other areas in older people. It should be noted, that the cord blood cells is easy to be isolated aseptically and kept for longer periods of time than other types of stem cells.

There is a drawback though the cells that are kept in the bak should be monitored and checked for teloere shrtening on a daily basis so as to prove its worth as stem cells with immence potential. The above comment is indeed valid.

Also it shoud be kept in mind that the essence of regenerative medicine is to help mankind to develop an effective means to survive and not to be thrown in the dungeons of dispair. 

For the sake reserach in bright and young areas of regenartive mediine, researchers should be ideally made aware of the pitfalls and high risks associated with the same.

 

My suggestion would be to excercise caution and imposition of informed decision from the FDA, who should appoint a highly motivated group of individuals or laboratories, who should be the torchbearers of acceptiblity of thiese types of exciting research going on in the world

In the real life scenario these types of research should be more tected in animal models before using it in human patients. So caution is the key, not exuberance.

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