Creating Induced Pluripotent Cells From Old Cells Removes At Least Some of the Markers of Age

A cell is basically a (very complicated) self-modifying program, encoded in proteins. The same basic outline of human cellular machinery can encompasses everything from germline cells - that seem to be essentially immortal - through to the embryonic stem cells that give rise to all other lineages in the body during early development, through to the hundreds of types of specialized, differentiated cell that run the day to day operations of a living organism.

At some point in the process of creating a new individual, old cells with comparatively heavy damage loads work together to create young cells with comparatively light damage loads (the developing embryo). So there is rejuvenation hidden in there somewhere - possibly occurring in very early embryonic development, prior to the point at which a lot of tissue structure exists to be disrupted by what has to happen.

As the research community is learning to reprogram cells to look and act more like embryonic stem cells or germline cells, producing what are known as induced pluripotent stem cells (or iPS cells), we might not be terribly surprised to see what looks like rejuvenation. Some markers of age in reprogrammed cells and their offspring are removed or diminished in comparison to the cells prior to this reprogramming - though scientists are far from any sort of complete measure of all of the effects, and there are numerous different ways in which cells can be reprogrammed to become more like stem cells. Back in 2010, one group of researchers demonstrated the removal of accumulated mitochondrial damage: take skin cells, obtain induced pluripotent cells from them, then differentiate those iPS cells back into skin cells, and find that the new skin cells lack the mitochondrial damage of the old ones.

This sort of research is encouraging when it comes to the prospects for cell therapies that depend on taking cells from the patient, growing large numbers of them, and then infusing them back into the body. The returning cells are likely going to be of a better quality than those removed.

Here is a more recent example of some specific markers of age being removed from a cell lineage via the use of induced pluripotency. The researchers focused on blood-generating stem cells, reprogramming them into iPs cells, and then deriving a new lineage of these stem cells that was placed into laboratory animals to assess their function. The find that young blood-generating stem cells and old cells that go through this process are fairly similar, which suggests that it is epigenetic changes that cause observed differences between old and young blood in the wild, and that those changes are somehow smoothed out by the reprogramming process:

An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state

Aging of hematopoietic stem cells (HSCs) leads to several functional changes, including alterations affecting self-renewal and differentiation. While it is well established that many of the age-induced changes are intrinsic to HSCs, less is known about the stability of this state.

Here, we entertained the hypothesis that HSC aging is driven by the acquisition of permanent genetic mutations. To examine this issue at a functional level in vivo, we applied induced pluripotent stem (iPS) cell reprogramming of aged hematopoietic progenitors and allowed the resulting aged-derived iPS cells to reform [an HSC lineage]. Next, we functionally characterized iPS-derived HSCs in primary chimeras and following the transplantation of 're-differentiated' HSCs into new hosts; the gold standard to assess HSC function.

Our data demonstrate remarkably similar functional properties of iPS-derived and endogenous blastocyst-derived HSCs, despite the extensive chronological and proliferative age of the former. Our results therefore favor a model in which an underlying, but reversible, epigenetic component is a hallmark of HSC aging rather than being driven by an increased DNA mutation burden.


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