July 24, 2007
Gene Expression Shows Stem Cell Aging In Mice

Your stem cells grow old.

Stuart Chambers, Margaret Goodell, and their colleagues investigated the molecular mechanisms underlying aging of stem cells by looking at the gene expression profiles of aging hematopoietic stem cells (HSCs), the precursors of blood cells. They found that genes involved in the inflammatory and stress response became more active with age, while genes important for regulating gene expression and genomic integrity became less active. These results lend strong support to the notion that HSCs succumb to the wear and tear of aging, just like other cells, and shed light on the mechanisms of aging.

To study HSCs’ regenerative capacity over time, Chambers et al. isolated HSCs from young (aged 2 months) and old (aged 21 months) mice and then transplanted either young or old cells into mice whose bone marrow cells had been destroyed by radiation. The young and old HSCs gave rise to new marrow cells at roughly the same pace 4 weeks after transplantation. But at 8 and 16 weeks after transplantation, the old HSCs’ contributions had dropped considerably, suggesting that aging HSCs lose their repopulating capacity. Yet, because HSCs increased in number, overall blood production from HSCs remained stable.

This is good news. Our stem cells grow old. Youthful stem cells perform better than older stem cells in the same sorts of organisms. The development of techniques to create youthful stem cells will yield cells that make great rejuvenation therapies. Youthful stem cells probably will not create as much inflammation in the body.

The finding that genes involved in the inflammatory response are expressed more (called up-regulation) as HSCs age fits with evidence linking inflammation and aging in the kidney, brain, and arteries. It may also help explain why HSCs lose function. One of the up-regulated genes, P-selectin, encodes a cell surface adhesion molecule. Because transplanted HSCs depend on cell adhesion to colonize bone marrow properly, the researchers explain, inappropriate up-regulation of genes encoding P-selectin may interfere with this process.

This result illustrates why Aubrey de Grey calls for development of youthful stem cell therapies to replace aged reservoirs of stem cells in our bodies with younger stem cells. Our aging stem cells gradually malfunction in more and more ways. We'd feel and function at a much higher level if we had younger stem cells that could repair lots of aged tissues all over the body.

The full Plos Biology article is available online. About 3000 genes undergo changes in their levels of expression as a result of aging.

Age-related defects in stem cells can limit proper tissue maintenance and hence contribute to a shortened lifespan. Using highly purified hematopoietic stem cells from mice aged 2 to 21 mo, we demonstrate a deficit in function yet an increase in stem cell number with advancing age. Expression analysis of more than 14,000 genes identified 1,500 that were age-induced and 1,600 that were age-repressed. Genes associated with the stress response, inflammation, and protein aggregation dominated the up-regulated expression profile, while the down-regulated profile was marked by genes involved in the preservation of genomic integrity and chromatin remodeling. Many chromosomal regions showed coordinate loss of transcriptional regulation; an overall increase in transcriptional activity with age and inappropriate expression of genes normally regulated by epigenetic mechanisms was also observed. Hematopoietic stem cells from early-aging mice expressing a mutant p53 allele reveal that aging of stem cells can be uncoupled from aging at an organismal level. These studies show that hematopoietic stem cells are not protected from aging. Instead, loss of epigenetic regulation at the chromatin level may drive both functional attenuation of cells, as well as other manifestations of aging, including the increased propensity for neoplastic transformation.

I am very curious to know which genes or regulatory regions in chromosomes accumulate the most damage with age. If the number of key damaged areas is not too great then gene therapies could some day go in and repair those locations in the genome which accumulate damage.

Share |      Randall Parker, 2007 July 24 12:06 AM  Aging Mechanisms


Comments
Kurt9 said at July 24, 2007 10:28 AM:

This research suggests that aging is an epigenetic phenomenon.

Randall Parker said at July 24, 2007 8:20 PM:

Kurt9,

Maybe. Why does the expression of so many genes change? Maybe because a small number of them become damaged and create effects that cause so many others to change their levels of expression.

We really need to know what sets off changes in levels of expression of a few thousand genes. My guess is that they are up and down regulated in big groups. What are the initiating stimuli for these changes?

It could be genetic damage in mitochondria causes production of messed up enzymes that cause greater amounts of ROS generation and that ROS generation causes the genes to shift their expression. Aubrey de Grey could be right. Or maybe the main mutated genes are in the nucleus. I do not know.

Scientists should be able to narrow the field by tracing back to the earlier stages of change to look for the genes whose expression change first. Maybe they all change and do slowly. But maybe a few lead the way.

Kralizec said at July 26, 2007 4:23 PM:

I wonder about the characterization of all the changes in gene expression as being related to aging. The changes occur over time, and the mice age over time, but the mice probably also live in little cages and eat standard mouse chow ad libitum over time. I'd like to know what the changes, and relative lack thereof, in gene expression would be, in a sample of mice for which real care had been given to matters of environment, diet, and exercise.

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