So let’s do a non-coronavirus post for the weekend. Over the years, I’ve sporadically reported on the (rather contentious) field of aging and its biochemical implications. Many readers will recall the results of the past few years that claim that infusion of young-animal plasma into aged animals seems to have many beneficial effects. Of course, this field is well stocked with controversy. Not everyone believes the results, from what I can see (although, for what it’s worth, there seem to be an increasing number of papers on it). If they’re real, not everyone thinks that they can be readily extrapolated to humans. And even if they can, it doesn’t take very much thought to see a number of ethical implications as well.
There have been a couple of recent papers that will stir things up even more. This preprint from a multinational research team (UCLA and many others) details work on several “methylation clocks” of molecular aging. DNA is methylated (especially on cytosine residues) to a number of transcriptional effects, and the number and distribution of such methyl groups definitely change over the lifespan of most animals. The Horvath lab at UCLA has made a specialty out of this epigenetic research area for some years now, and the changes in DNA methylation with aging seem pretty well established (even if quantifying them is trickier). This new paper draws on a large number of rat samples, with an overall methylation clock detailed, as well as more specific ones for brain, liver, and blood tissue. The addition of an even larger set of human tissue samples provides two more cross-species methylation clocks as well. Previous work from the group has provided similar clocks for mice, which correlate well with known lifespan-extending interventions such as caloric restriction (reviewed here).
This new preprint details the readouts of such clocks after treatment of two-year-old rats (and their various tissues) with a proprietary “plasma preparation” from a company called Nugenics Research (update: corrected spelling of the name). I don’t think that’s going to make publication of this paper in a journal any easier, because that preparation is resolutely not described in any detail at all in the paper, from what I can see. This is no indictment of the paper or its results, but it does make them rather difficult to reproduce, doesn’t it? Two of the paper’s authors are founders and/or owners of Nugenix, and Horvath and another author are consultants for the company (all this, to be sure, is stated in detail).
At any rate, the effects of the plasma preparation on both the methylation signatures and on more traditional readouts of physiological function seem to be pretty dramatic, after two rounds of treatment in elderly rats. By the DNA methylation clock, the ages of the blood, heart, and liver tissue were basically halved (there was much less effect on the hypothalamus, interestingly). Markers of inflammation and oxidative stress went down significantly in the treated animals, and many other blood parameters changed for the better as well (HDL, creatinine, and more). The animals performed better in physical and cognitive tests (grip strength, maze test) with numbers approaching that of the young animals themselves. The authors say that this work “supports the notion that aging can be systemically controlled, at least in part through the circulatory system with plasma as the medium“.
Meanwhile, this paper has also just come out, which looks at whether such effects are due to factors coming in from the young animals or things being removed from the old ones. The authors, from UC-Berkeley and the California Pacific Medical Center, are looking at what they call a “neutral blood exchange”. They replace half the blood volume in mice (both young and old) with isotonic saline plus added albumin protein. The effect of this on the older animals was also significant, with noticeable improvements in wound-healing ability, neurogenesis, and fibrosis/fatty deposits in the liver. The younger mice were not really changed by the treatment. The authors tried several control experiments to make sure that this wasn’t an effect being driven by added albumin protein, and it apparently isn’t. They conclude that removal and substitution of old plasma “is sufficient for most if not all observed positive effects on muscle, brain and liver” in parabiosis-type experiments. It doesn’t exclude the idea of there being beneficial factors in young plasma, but suggests that this is not the driver of many of the results seen. (It would be very interesting to check the DNA methylation status of various tissues before and after this treatment!)
The paper wastes no time in noting that therapeutic plasma exchange (TPE) is already an FDA-approved process (as witness convalescent plasma treatment in the current coronavirus epidemic), and it says that Phase II and III human trials are being planned on the basis of these results. That will be quite interesting to watch, says the 58-year-old dude writing this blog. Overall, I still find such results hard to believe, but at the same time they seem to be showing up from multiple experiments. This second paper especially seems to be a very testable hypothesis indeed. That’s a good thing, because in the end, it’s going to be reproducible human clinical data that decide whether this is real or not – so I’m glad that feasible experiments will allow such data to be collected. Something to watch. . .