Nelson J. Chao, MD, MBA
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.
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
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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