The new year reminds us that we have aged another 365 days—as have some of our stem cells. And new research links defective stem cells to shortened lifespan and aging-related pathology in a mouse model of premature aging (progeria). In the study, published online January 3 in Nature Communications, Johnny Huard and Laura Niedernhofer of the University of Pittsburgh School of Medicine, Pennsylvania, and colleagues show they can slow aging in progeroid mice by transplanting muscle-derived stem cells from young, normal mice. The improvements came despite minimal donor cell engraftment, suggesting that secreted molecules mediate the therapeutic effect. Though the findings heighten the potential for using adult stem cells to delay aging or treat age-related disorders, considerable work remains to move stem cell strategies toward clinical use, experts caution.

Prior research correlated aging with reduced numbers and function of stem cells, but did not determine whether “old” stem cells are a cause or consequence of the degenerative process. In the current study, first author Mitra Lavasani of the Huard lab, and colleagues, addressed the causality issue using mice that mimic a human progeroid syndrome. The mice lack the DNA repair enzyme ERCC1 and survive on average just 21 days, whereas normal mice live more than two years. Niedernhofer and colleagues have extensively studied ERCC1-deficient mice (see Gregg et al., 2011, and Dollé et al., 2006) and the human disorder they model (Niedernhofer et al., 2006), and here she and Huard explored whether defective stem cells contribute to the premature aging.

The researchers focused on the musculoskeletal system, isolating stem/progenitor cells from mouse skeletal muscle with a method developed by Huard’s lab (Gharaibeh et al., 2008). The procedure uses collagen-coated flasks to separate highly differentiated “sticky” cells from less differentiated “floating” fractions enriched for stem cells. The team isolated muscle-derived stem/progenitor cells (MDSPCs) from aged (two-year-old) wild-type mice and ERCC1 mutant mice, and found that these cells divide slowly and do not differentiate as well as MDSPCs from young (three-week-old) normal mice. In addition, old wild-type and ERCC1 mutant mice did not regenerate muscle as robustly as did young wild-type mice in response to toxin-induced injury. These experiments suggest that stem cells from old and progeroid mice are similarly defective.

If loss of stem cell function causes premature aging, the authors reasoned, then young wild-type stem cells should relieve the damage. This was true, to some extent. When the researchers injected 17-day-old ERCC1 knockout mice intraperitoneally with young wild-type MDSPCs, the mutant mice lived 60 to 70 days—three times longer than usual, but still a far cry from the two-year lifespan of a normal mouse. Injections of old wild-type or ERCC1-deficient MDSPCs, or of young wild-type fibroblasts, did not extend lifespan.

To explore the mechanism behind the rescue, Lavasani and colleagues tracked donor cell whereabouts. They injected ERCC1-deficient mice with young, wild-type MDSPCs expressing a β-galactosidase reporter, then stained various host tissues with the galactose derivative X-gal to identify donor cells one to nine weeks later. Hydrolysis of X-gal yields a blue color that turned up in the liver, kidney, pancreas, and spleen—but not in skeletal muscle or brain, despite signs of youth in these tissues. Weak muscles and poor vascularization of the brain hamper ERCC1-deficient mice relative to controls. However, after the infusion of musculoskeletal stem/progenitor cells from young, normal mice, ERCC1-/- animals had bigger calf muscle myofibers, and their cortical vasculature grew back to wild-type levels. The number of engrafted cells was “not a lot, considering the drastic effects we saw in the ERCC1 mice,” Huard said in an interview with ARF.

Given the scant engraftment in areas showing improvement histologically, the researchers wondered if young, wild-type MDSPCs confer their benefits through secreted molecules. They tested this possibility by exposing ERCC1-deficient MDSPCs to conditioned media from young, wild-type MDSPCs. “In a matter of days, those progeroid cells that were defective started to act like young cells,” Huard said. They proliferated and differentiated into muscle cells better than did ERCC1-/- cells grown in plain media.

Taken together, the data “provide evidence that loss of stem cell function directly contributes to short lifespan and aging-related pathology,” Huard said. “We can somehow delay aging (in progeroid mice) by injecting stem cells from young, wild-type animals, and we think the effect is mediated by release of cytokine growth factors that stimulate angiogenesis,” he added.

Curt Freed of the University of Colorado School of Medicine, Aurora, offered another explanation for the benefits conferred by muscle-derived stem cell transplantation. “It is also possible that the animals’ own immune systems are reacting to the foreign cells to promote changes in lifespan,” Freed wrote in an e-mail to ARF.

Moreover, Freed noted, “because the transplants have added only 30 days to these animals’ short lives, the results are interesting but are hardly a turnaround in this devastating disease model.” Lavasani called the effect “dramatic,” but acknowledged it occurred in an acute progeria model and is “not translatable to natural aging in humans.”

The authors also injected young, wild-type MDSPCs into a less acute model of progeria—ERCC1 hypomorphic mutants that live about seven months. They did not test if the stem cells increased lifespan, but found that 75 percent of aging-related symptoms were delayed in treated mice compared to siblings that got a placebo. “Since the symptoms are typical of human aging (e.g., hunched back due to osteoporosis, unstable gait due to neurodegeneration, muscle wasting, low activity), this result is exciting and potentially more translatable,” Niedernhofer noted in an e-mail to ARF. The authors would like to see if muscle-derived stem cells from young, wild-type mice can also extend the lifespan of normal old mice.

A recent parabiosis study also suggests that blood-borne factors can regulate brain aging (ARF related news story on Villeda et al., 2011). If the “magical” secreted factors could someday be identified and purified, maybe “we don’t need the stem cells (to rescue aging defects),” Huard speculated. One of those factors might be brain-derived neurotrophic factor (BDNF), which mediates neural stem cell restoration of synapses and cognition in AD transgenic mice (see ARF related news story on Blurton-Jones et al., 2009).

A paper in the January 4 Cell Metabolism lends further support to the idea that waning stem cells contribute to premature aging in mice. Researchers led by Anu Suomalainen of the University of Helsinki, Finland, analyzed mutant mice that rack up mitochondrial DNA mutations due to defective DNA polymerase γ (Polg) exonuclease activity. Mitochondrial dysfunction has been linked to accelerated aging and Alzheimer’s disease (see ARF Live Discussion; ARF related news story). The new study reports that mitochondrial DNA mutagenesis causes early dysfunction in somatic stem cells, driving premature aging.—Esther Landhuis


  1. The data presented by Huard and colleagues are complementary to the report by Villeda et al. in that they’re studying the effects of young cells in progeria, while Wyss-Coray's team studied effects of young blood plasma in healthy aging.

    I am not sure how these cell transplants could affect brain vasculature via soluble factors in regions shielded by the blood-brain barrier (such as the cortex). Measurements of vascular density in brain are notoriously difficult and need really to be done by stereology. Also, some functional readout correlating with more vessels would be informative.

    Potential therapeutic application would depend on having the ability to obtain young histocompatible cells (or the equivalent such as isogenic induced pluripotent stem cells) and show that they’d ameliorate the outcomes of aging or age-related neurodegeneration.


    . The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011 Sep 1;477(7362):90-4. PubMed.

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News Citations

  1. Paper Alert: Do Blood-Borne Factors Control Brain Aging?
  2. Support Cast: Neural Stem Cell BDNF Prompts Memory in AD Mice
  3. Poor Proofreading May Shorten Your Lifespan

Webinar Citations

  1. A "Mitochondrial Cascade Hypothesis" for Sporadic Alzheimer's Disease

Paper Citations

  1. . Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease. DNA Repair (Amst). 2011 Jul 15;10(7):781-91. PubMed.
  2. . Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. Mutat Res. 2006 Apr 11;596(1-2):22-35. PubMed.
  3. . A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature. 2006 Dec 21;444(7122):1038-43. PubMed.
  4. . Isolation of a slowly adhering cell fraction containing stem cells from murine skeletal muscle by the preplate technique. Nat Protoc. 2008;3(9):1501-9. PubMed.
  5. . The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011 Sep 1;477(7362):90-4. PubMed.
  6. . Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13594-9. PubMed.

External Citations

  1. progeria

Further Reading


  1. . The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011 Sep 1;477(7362):90-4. PubMed.

Primary Papers

  1. . Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in polg mutator mice. Cell Metab. 2012 Jan 4;15(1):100-9. PubMed.
  2. . Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. Nat Commun. 2012;3:608. PubMed.