Nelson J. Chao, MD, MBA

2010-04-27

Dr. Chao indicated no relevant conflicts of interest.

Mayack SR, Shadrach JL, Kim FS, et al. Systemic signals regulate ageing and rejuvenation of blood stem cell niches. Nature. 2010;463:495-500.

Mark Twain famously said, “Age is an issue of mind over matter. If you don’t mind, it doesn’t matter.” True, but then it really does matter. All multicellular organisms age, generally as cellular repair processes slow down. How many of us now notice how much longer it takes to heal from a cut, a torn tendon, a back strain, or a bruised muscle compared to when we were teenagers? Osteoporosis is another example in which bone loss can lead to devastating consequences. And yet other examples are forgetfulness and dementia, as we lose neurons that are not replaced. Aging and the associated pathology are a major and growing challenge, as a significant portion of the population in many of the developed countries is becoming older. Our life span continues to improve, and thus we encounter more frequently what are thought to be the limits of repair possible for a particular organ. The hematopoietic system, which functions remarkably well throughout our lives, does age as well. Hematopoietic stem cells (HSCs) decline in numbers with a shortening of telomeres. Aging is associated with a decline in immune function, marrow dysplasia, and malignancies.

One can think of aging or loss of cells, for example HSCs, in an autonomous and non-autonomous fashion. Autonomous signals would include normal responses to oxidative stress, DNA damage and apoptosis, and expression of senescence genes. However, there is also evidence for non-autonomous signals, especially the important interactions of the HSC with its niche. These niches help regulate HSC function and have an impact on HSC fate and age-related dysfunction. This manuscript by Mayack et al. from Amy Wagers lab at Harvard demonstrates clearly that there are systemic signals that can rejuvenate aged HSCs. Using parabiotic pairs (sharing a common circulation and CD45.1 vs. 45.2, so they can track the animals), they attached a young mouse (2 months old) to an aged partner (>21 months old) and compared these pairs to young-young and old-old animals. As expected, the creation of parabiotic pairs had no impact on HSCs or their function in the young-young or old-old pairs. However, in the young-old pairs, there was a significant recovery of primitive reconstituting HSCs in the older animals, approaching those found in the young ones. The osteoblastic niche, acting through a soluble systemic factor, appeared to be responsible for this remarkable rejuvenation. They demonstrated that the HSC deregulation could be reversed by the systemic circulation of a young mouse or by neutralization (with a monoclonal antibody) of the conserved longevity regulator, insulin-like growth factor-1 (IGF-1) in the marrow microenvironment in the old animals. Therefore, the aged osteoblastic niche relays an aging phenotype to HSCs, and the effects on the niche are modulated by as-yet-undefined factors in the circulation.

While much remains to be worked out, including the systemic factor(s) responsible for this observation, this study opens the possibility that regenerative signals for HSCs and other stem cells could be transmitted through the circulation. However, the effects of any one of these signals may have competing antagonistic effects. For example, IGF-1 in these studies made aging worse in HSCs, while in other studies IGF-1 was shown to maintain the regenerative capacity in muscle cells.

And you thought all of those human growth hormone ads against aging on the back of the airline magazines were a sham!

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