Replication Stress Explains Some of Blood Stem Cell Aging

The stem cells responsible for generating blood, hematopoietic stem cells, are of considerable importance because they are the origination point for new immune cells. Much of the ongoing investigation into mechanisms that cause the age-related decline of the immune system focus on the thymus, where T cells develop, and on structural deficiencies in the immune system's operation that lead to memory T cells crowding out the naive T cells needed to destroy pathogens. There is a great deal in those two areas that might be done to restore the old immune system to former strength: rejuvenate the thymus to boost the pace at which immune cells come to readiness after creation, or selectively destroy excess memory T cells to prompt the generation of fresh replacement naive T cells.

Here, however, is another line of thinking and another contribution to the reduced influx of new immune cells. It is based on a form of damage to hematopoietic stem cells, though as for many of these things it is unclear at this point as where the observed changes stand in the hierarchy of damage and reactions to damage. Most stem cell populations have evolved to decline in function with age, most likely because this reduces the risk of cancer: the longer human life span in comparison to other primates is somewhat linked with this balance between failing tissue maintenance and lowered cancer risk. Different populations of stem cells may have achieved this decline in wildly divergent ways, however, and so a whole range of entirely different mechanisms are probably involved. Investigations of muscle stem cells strongly suggest that these mechanisms are largely reactions to damage and can be reversed by suitable signals or epigenetic changes - or in theory by repairing the damage, such as via SENS rejuvenation therapies. Again, however, this isn't necessarily the case for every stem cell population in the body. Biology is enormously complex, and finding similarities should be the more surprising outcome, not finding differences.

Key to Aging Immune System Is Discovered

Blood and immune cells are short-lived, and unlike most tissues, must be constantly replenished. The cells that must keep producing them throughout a lifetime are called "hematopoietic stem cells." Through cycles of cell division these stem cells preserve their own numbers and generate the daughter cells that give rise to replacement blood and immune cells. But the hematopoietic stem cells falter with age, because they lose the ability to replicate their DNA accurately and efficiently during cell division.

In old blood-forming stem cells, the researchers found a scarcity of specific protein components needed to form a molecular machine called the mini-chromosome maintenance helicase, which unwinds double-stranded DNA so that the cell's genetic material can be duplicated and allocated to daughter cells later in cell division. In their study the stem cells were stressed by the loss of activity of this machine and as a result were at heightened risk for DNA damage and death when forced to divide.

The researchers discovered that even after the stress associated with DNA replication, surviving, non-dividing, resting, old stem cells retained molecular tags on DNA-wrapping histone proteins, a feature often associated with DNA damage. However, the researchers determined that these old survivors could repair induced DNA damage as efficiently as young stem cells. "Old stem cells are not just sitting there with damaged DNA ready to develop cancer, as it has long been postulated. Everybody talks about healthier aging. The decline of stem-cell function is a big part of age-related problems. Achieving longer lives relies in part on achieving a better understanding of why stem cells are not able to maintain optimal functioning."

Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells

Haematopoietic stem cells (HSCs) self-renew for life, thereby making them one of the few blood cells that truly age. Paradoxically, although HSCs numerically expand with age, their functional activity declines over time, resulting in degraded blood production and impaired engraftment following transplantation. While many drivers of HSC ageing have been proposed, the reason why HSC function degrades with age remains unknown.

Here we show that cycling old HSCs in mice have heightened levels of replication stress associated with cell cycle defects and chromosome gaps or breaks, which are due to decreased expression of mini-chromosome maintenance (MCM) helicase components and altered dynamics of DNA replication forks. Nonetheless, old HSCs survive replication unless confronted with a strong replication challenge, such as transplantation. Our results identify replication stress as a potent driver of functional decline in old HSCs, and highlight the MCM DNA helicase as a potential molecular target for rejuvenation therapies.


As my layman's brain understands this: If proteins in blood stem cells get damaged they just get broken down and replaced. But if the protein machinery involved in the translation of DNA into proteins occurs then this is a spanner in the works as this essential protein cannot now be replaced.

But why don't the still healthy blood stem cells multiply to fill the gap left by these damaged cells?

Posted by: Jim at August 1st, 2014 10:58 PM

@Jim: Probably because this will turn out to be the results of a reaction to changes in the signaling environment that take place as tissues age, and thus it affects all of these stem cells.

Posted by: Reason at August 2nd, 2014 8:51 AM

So I'm guessing it is just a cell lose issue in some ways (you don't have to reply to this speculation by the way, I realize that this is currently unknown). Your body matures and a certain number of blood stem cells are created. Over time this population gets reduced by the damage to the DNA replication proteins. When young, the blood stems cells divide to produce more blood stem cells and replenish their stock, but when older, the aged body environment suppresses this replenishment. But the original stem cells can still make non stem daughter cells so that people don't run out of red blood cells etc.

Posted by: Jim at August 2nd, 2014 8:52 PM

Is this pointing out to a similar "path" as the GDF11, that can rejuvenate some aging aspects?

Posted by: alc at August 4th, 2014 8:25 AM

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