Abstract
Mammalian aging is associated with reduced tissue regeneration and loss of physiological integrity. With age, stem cells diminish in their ability to regenerate adult tissues, likely contributing to age‐related morbidity. Thus, we replaced aged hematopoietic stem cells (HSCs) with young‐donor HSCs using a novel mobilization‐enabled hematopoietic stem cell transplantation (HSCT) technology as an alternative to the highly toxic conditioning regimens used in conventional HSCT. Using this approach, we are the first to report an increase in median lifespan (12%) and a decrease in overall mortality hazard (HR: 0.42, CI: 0.273–0.638) in aged mice following transplantation of young‐donor HSCs. The increase in longevity was accompanied by reductions of frailty measures and increases in food intake and body weight of aged recipients. Young‐donor HSCs not only preserved youthful function within the aged bone marrow stroma, but also at least partially ameliorated dysfunctional hematopoietic phenotypes of aged recipients. This compelling evidence that mammalian health and lifespan can be extended through stem cell therapy adds a new category to the very limited list of successful anti‐aging/life‐extending interventions. Our findings have implications for further development of stem cell therapies for increasing health and lifespan.
Highlights
To reduce the adverse effects of cytotoxic conditioning agents, we developed a mobilization-based conditioning procedure, eliminating the need for irradiation, followed by transplantation of donor hematopoietic stem cells (HSCs)
The average daily food intake of recipients of young-donor HSCs improved significantly, peaking at 3.45 ± 0.15 grams per day (Figure 3c). Given that these food intake measurements were obtained on a per-cage basis, the differences in survival of HSC-recipient versus control mice brings up potential cage effects that might influence eating behaviors, especially at later ages
Young (2-month-old) and aged (19-month-old) recipients of a single mobilization-based hematopoietic stem cell transplantation (HSCT) cycle were assessed for GFP+ young-donor HSCs contribution in the peripheral blood
Summary
Stem cells are critical to tissue regeneration and homeostasis during aging and disease (Signer & Morrison, 2013). The average daily food intake of recipients of young-donor HSCs improved significantly, peaking at 3.45 ± 0.15 grams per day (Figure 3c) Given that these food intake measurements were obtained on a per-cage basis, the differences in survival of HSC-recipient versus control mice brings up potential cage effects that might influence eating behaviors, especially at later ages. Young (2-month-old) and aged (19-month-old) recipients (all female) of a single mobilization-based HSCT cycle were assessed for GFP+ young-donor HSCs contribution in the peripheral blood (see Figure S4 for gating strategy and representative flow plots). Four months post-HSCT, donor chimerism was 15.0 ± 0.4% and 21.5 ± 0.9% of lineage-negative bone marrow cell contribution within young and aged recipients (6- and 23-monthold at the time of analysis), respectively (Figure 4f; see Fig. S5 for gating strategy and representative flow plots).
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