Opinion: Younger Is Better

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.

Opinion: Younger Is Better

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