There’s been a good amount of coverage of this paper, which is certainly worth a read. It concerns the “Yamanaka factors”, four proteins whose expression seems to be key for induced pluripotent stem cells and many other cellular programs besides. This latest work shows that cyclic expression of these in adult (indeed, elderly) rodents seems to ameliorate many signs of aging.
The Yamanaka recipe is expression of Oct4, Sox2, Klf4 and c-Myc, so it’s also referred to as OSKM. These are all pretty heavy-hitting proteins, and despite a great deal of work their functions are far from being completely understood. But the connection between aging and stem cell characteristics became clear when the various functions of the OSKM treatment began to be worked out, and many of them matched up with epigenetic processes known to be deficient in aging cells. A number of studies have shown that cells from older animals and those with accelerated-aging phenotypes can apparently be rejuvenated in vitro by the sort of treatment that you would also use to turn adult cells lines back into stem cells.
Some experiments along these lines have also been tried in whole animals, but this seems to be the most comprehensive so far. The authors used a mutant mouse strain with a defective Lmna gene, which animals are known to suffer from premature aging and other disorders (likewise humans with mutations in the homologous gene). They crossed these with another mouse strain that had been engineered with an inducible gene cassette for OSKM expression, producing prematurely aged mice who could have extra OSKM proteins expressed on exposure to doxycycline.
That’s a good way to do it. The tricky part about all these cellular-reprogramming ideas and stem cells in general is that you’re walking just this side of inducing uncontrolled cellular growth, better known as cancer. Early experiments in animals with induced stem cells, in fact, led to notably higher rates of several different tumors, which is one rather large reason why the human stem cell hype of the last ten or fifteen years has been slow to deliver miracle cures. If you just walk into an animal’s genome and put the pedal down on OSKM expression, you are highly likely to get results that you didn’t want. c-Myc, to pick the prime example, has been known for many years as a protein whose overexpression/overactivity is a hallmark of many tumor types, and there have been many attempts (so far without success) to inhibit its actions as a means of cancer therapy. So the idea of actually upregulating it, and the other three, has to be approached with caution.
You also don’t want to blast cells all over the body back into becoming pluripotent stem cells, because who knows what that’s going to lead to. The idea with the doxycycline-driven expression system is to try to reset many of those epigenetic markers, without losing cellular identity or inducing tumor formation, and there’s no real way to know a priori how many times that button has to be pushed (or how many times is too many). A similar inducible OSKM technique had already been shown to lead to cancer in mice, so none of this is idle speculation. And indeed, in this present work if they tried continuously inducing OSKM in these hybrid mice by just putting doxycycline in their drinking water, they only lasted a few days before succumbing to multiple organ failure, probably through just that sort of changing-back-into-stem-cell mechanism just mentioned.
Just inducing expression for shorter periods on a cyclic schedule, though, seemed to work. It’s still a close race, because the mice showed progressive weight loss, which is not normal for rodents and is considered a bad sign. But these animals also showed a significant lifespan increase compared to their untreated cohort – half of them were still alive at an age when all the untreated ones were dead. (Giving doxycycline to the fast-aging mice without the OSKM expression genes did nothing for them, in case you were wondering – a good control to have run). Examination of their various organs and tissues showed unmistakable signs of the treatment, with the OSKM-cycled mice looking far more like wild type than their premature aging phenotype should have allowed. This went all the way from gross pathology, through histopathology examination, and down to specific cellular markers. No signs of tumor formation were seen.
Another marker of aging in tissues and organ systems is a decreased ability to deal with injury and stress. This paper looked also at stressing the pancreas with streptozotocin (STZ), a well-known way to kill off beta-cells and induce insulin insufficiency. Young mice are better able to recover from low-dose STZ exposure than older ones, and OSKM expression, as above, seems to restore the animals’ ability to deal with the loss of beta-cells. Similarly, injury of muscle cells with snake venom cardiotoxin also was tolerated far better in the OSKM-cycled mice, suggesting that repair and regeneration pathways were significantly enhanced.
So when you put all this together, it appears that there’s real promise here that many of the important defects of aging are, in fact, reversible. It’s going to be tricky to realize these effects without stepping over the line into tissue problems and tumorigenesis, as mentioned above, but the important thing about this paper is that it shows that there is a window there that can be targeted. Cycling aged human cells with OSKM expression seemed to lead to similar effects on markers of aging as were seen in the mice cells, so there’s no reason, so far, to think that this is impossible in humans.
Of course, actually doing this in humans will not be easy at all. We’re not quite ready to modify our germ lines to include the OSKM expression cassette in the human genome, nor would we wish to wait several decades while these first modified humans aged to the point that we could see whether putting doxycycline into their drinks would improve them. If we’re going to make people undergo pulsed OSKM expression, we’re going to have to go about it another way, and every possibility comes with its own dangers and unknown factors. It may well be that we’ll have to sneak up on the downstream effects from another direction entirely; it’s too early to say. But at the moment, it looks like this is a goal that’s well worth trying for, and could actually be possible – eventually – to reach.