A Perspective on Stem Cell Aging and Rejuvenation

This open access paper from some of the researchers involved in parabiosis research, aiming for at least partial restoration of youthful stem cell activity and tissue maintenance in old individuals, is a reminder that there is a lot of politics and happenstance in research, as in every other human endeavor:

It has been 10 years since the paradigm-shifting observations that in heterochronic parabiosis, the young systemic milieu rapidly and broadly rejuvenates organ stem cells in muscle, brain/hippocampus and liver, while the old systemic milieu rapidly and broadly ages myogenesis, liver regeneration and neurogenesis, with the responsible biochemical pathways being re-set to their young or old states. Before this work, the prevalent theories of tissue decline in aging focused on cumulative cell intrinsic changes as culprits: telomere attrition, DNA damage, oxidative damage, mitochondrial dysfunction, etc.). While all of the above continue to be true for differentiated cells, it is important to realize that organ stem cells age "extrinsically", and maintain a relative "youth" that could be due to the state of quiescence, which is default for most if not all postnatal stem cells. As such, stem cell regenerative capacity persists throughout life, but sadly, the biochemical cues regulating organ stem cells change with age in ways that preclude productive regenerative responses, causing the abandonment of tissue maintenance and repair in the old.

If all this has been known for 10 years, why is there still no therapeutics? One reason is that instead of reporting broad rejuvenation of aging in three germ layer derivatives, muscle, liver, and brain by the systemic milieu, the impact of the study published in 2005 became narrower. The review and editorial process forced the removal of the neurogenesis data from the original manuscript. Originally, some neurogenesis data were included in the manuscript but, while the findings were solid, it would require months to years to address the reviewer's comments, and the brain data were removed from the 2005 paper as an editorial compromise. The phenomenon and its magnitude were replicated, expanded and elegantly described in a 2011 paper, but if the friendly neighbor of the original lab had not been interested in this project after learning of our findings, this important result could have been lost or remained on a "back-burner" indefinitely. While it is certainly better late than never and even if the data are more elaborated than in the original manuscript, one can argue that the scientific community could already have been working on the extrapolation of these results and translating them into therapeutics against neuro-degeneration for 10 years.

Another reason for the slow pace in developing therapies to broadly combat age-related tissue degenerative pathologies is that defined strategies, which are "beyond parabiosis", for the rejuvenation of multiple old organs have been very difficult to publish in high impact journals; only the magic of "heterochronic parabiosis" seems to keep the editors' and reviewers' attention. As the result, in the current dynamically raging scientific waters, significant work that is directly relevant to attenuation or even reversal of human tissue aging (e.g., molecules that work in mice and are FDA approved or in clinical trials for human applications) can sadly get washed over, particularly, when relevant publications from lower impact journals are not always noticed or cited.

Link: http://www.impactaging.com/papers/v7/n10/full/100819.html


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