Fight Aging!

The commentary linked below takes a look at some recent work on the topic of cellular reprogramming and the rejuvenation it appears to cause inside cells. In the grand scheme of things, it really hasn't been that long since researchers first discovered how to reprogram somatic cells into induced pluripotent stem cells. These artificially altered cell populations have the same characteristics as embryonic stem cells, able to generate any type of cell in the body given the right stimulus and environment. Reprogramming is so easy to carry out that it swept through the research community with great rapidity, and the improvements and further experimentation started almost immediately. Along the way, numerous researchers have found that reprogramming old cells in this fashion appears to revert a number of characteristic signs of cellular aging. Damaged mitochondria are removed, some epigenetic markers are altered in the direction of youthfulness, and so forth.

It is understood that cells are, in principle, capable of rejuvenation. Something must happen to repair the damage and epigenetic changes of aging in between that point at which aged germ cells get together and the point at which a young embryo is growing. Parents are old. Babies are young. A range of intriguing research on early embryonic development suggests the existence of a program of cleansing and repair that operates when the embryo is still only a handful of cells. It is not unreasonable to think that cellular reprogramming as it currently exists is triggering some fraction of those developmental rejuvenation mechanisms as something of a side-effect. The interesting question is whether or not there are useful near future medical applications that might result from a greater understanding and control of cellular rejuvenation of this nature.

The most obvious application is that any sort of cell therapy using the patients own cells is probably going to be improved if the cells are more rather than less youthful. Since reprogramming has this effect, and researchers are working towards using induced pluripotent stem cells in therapies, this will probably happen by default at the outset, and then be improved via degrees of optimization as the field of regenerative medicine progresses. On the other hand, safely inducing some form of rejuvenation-like repair or alteration of cell state in site in the body and brain sounds like a much more challenging proposition. It isn't at all clear that such an approach is even possible or plausible; a greater understanding is needed when it comes to exactly how rejuvenation is being achieved in reprogrammed cells. For example, it may well be the case that some of what appears to be rejuvenation is in fact a selection effect. Reprogramming typically has a low rate of success when you look at the number of cells in a sample that are converted, and perhaps those are all less damaged examples. But see what you think of this commentary and its references:

Stem cells for all ages, yet hostage to aging

Researchers showed that aging transcriptional changes in fibroblasts were reversed in induced pluripotent stem cells (iPSCs) derived from donors across the lifespan. Subsequently, when iPSCs were induced to form neurons by direct induction (iNS), the aging transcriptional signature was also absent. In contrast, when aging fibroblasts were directly programmed to iNS by a similar protocol, they maintained an aging transcriptional signature. Remarkably, much of this signature was not the original signature of the fibroblasts but a new age-associated signature more closely allied to neural related gene action. Thus, fibroblast-derived iNS retained an "aging state" on direct cell programming, but not a hard wired, age-related transcriptional signature. The potential for fibroblast rejuvenation extends to 'senescent cells': from the same 74 years old individual, iPSCs were derived from either primary fibroblasts or replicatively senescent fibroblasts after serial in vitro passaging: both differentiated into normal embryonic lineages. Surprisingly, given the huge attention to regulatory mechanisms underlying iPSC generation, there has not been extensive comparison of iPSCs by donor age.

How do pre-existing problems such as DNA damage relate to these processes? Mutations accumulate in aging skin as in all other mammalian tissues. Primary fibroblasts from breast skin of donors aged 20-70 showed exponential increases in double-strand DNA breaks against a linear doubling of chromosome structural abnormalities, 10% to 20% across the adult lifespan. Are their corrective mechanisms as part of the reprogramming process, and if so, how do these work? Alternatively, reprogramming may select against damaged cells within a mixed cell population, which might be estimated by the efficiency of reprogramming. Future studies may define a threshold level of DNA damage that is permissive for iPSC generation. It has been proposed that iPSC generation with extensive cell proliferation would "dilute any accumulated molecular damage" which could not occur during iNS generation under conditions that limited cell proliferation. While replicative processes may weed out protein damage, it is not clear how these would remove DNA damage. As well as selecting against damage to nuclear DNA, selection is also likely for mitochondrial function. Other groups have shown remarkable mitochondrial rejuvenation in iPSCs generated from aging donors.

These findings have broad ramifications for the field of regenerative medicine. Whatever the mechanisms at play, the loss of aging signatures in iPSCs is good news for autologous iPSC directed-cell therapies where the aging population will be the major target for personalized regenerative medicine. However, while iPSCs and their direct derivatives may be rejuvenated, the host's aging environment is problematic. For example, grafts of embryonic neurons into older Parkinson patients show donor cells acquire features of diseased host neurons. Inflammation related to Alzheimer disease, and to basic aging itself, can also attenuate grafted stem cell function. Thus, prospects for rejuvenation by iPSC may still remain hostage to the aged host.