Abstract
“Remember this is a proof-of-concept engineering mission, not a science mission. We have to learn how to operate in the vicinity of an asteroid if we are ever going to…deflect a dangerous one.”
Today I highlight an unrelated study—unrelated except insofar as it again focuses on repair of an aspect of aging and has received high-profile media attention. As a year ago, I want to draw attention to the shortcomings of that media attention, but also to the beneficial effects that this attention is already having, and is likely to have in the future, on the public's attitude to the feasibility of repairing the damage of aging as a means of postponing age-related ill-health.
The study in question by the van Deursen lab 3 again used genetically engineered mice. In this case, the aspect of aging being investigated was a different one from the seven categories into which I have traditionally classified the damage of aging: Rather than loss of cells, which is the main thing (stem cells of rapidly renewing tissues, in particular) that telomerase insufficiency causes, it was the accumulation of “death-resistant” cells (often termed senescent cells), which have acquired an aberrant gene expression profile and secretory phenotype, but have also lost the ability to respond to proapoptotic signals from their neighbors. As compared to telomerase insufficiency, death-resistant cells have attracted remarkably little attention over the years, being studied by only a few labs. However, a select few (not least your correspondent) have been aware for over a decade that these cells may be actively toxic, including being procarcinogenic, to neighboring cells, as a result of secreting factors that both stimulate those cells' tendency to divide and degrade the extracellular matrix that helps to contain excessive division. Recently, the possibility has also emerged that some of these secreted factors may have systemic toxicity too, as a result of being released into the circulation.
In the van Deursen study, mice were engineered to accumulate these cells (which overexpress the gene p16) at an accelerated rate as compared to normal mice. Additionally, they were engineered with a drug-inducible “suicide gene” that would kill any p16-overexpressing cells when a drug was given orally to the mice. To cut a long story short, when mice were reared in the absence of the drug, they exhibited a wide range of “accelerated aging” phenotypes and died at half the age of normal mice of the same strain. When the drug was administered and the p16-overexpressing cells thereby ablated halfway through this shortened life span, most of these phenotypes were sharply arrested.
As noted above, the media interest in this study was intense; moreover, I have heard rumors that a company being formed to develop drugs to eliminate p16-overexpressing cells in genetically unmodified animals (and eventually people) received a pledge of several million dollars in seed funding shortly after the paper was published. This is a huge credibility boost to the idea that death-resistant cells are bad for us and that their elimination would be therapeutic, and by extension—not least because of the relatively low profile enjoyed by these cells hitherto—to the general principle that repairing the damage of aging is not monstrously harder than slowing that damage's creation and may even be easier.
However, when one looks at the details, the level of enthusiasm seen in reaction to this publication is even more remarkable than in the case of the DePinho lab paper of a year ago. First, no actual reversal of degeneration was observed in this case, only a marked slowing (though this may have been because the level of degeneration was only examined 5 months after treatment, by which time additional aging might have outweighed bona fide rejuvenating effects). Second, there is as yet no hint of how easy or hard it may be to develop drugs that can stimulate the elimination of these cells, whereas there are already telomerase stimulators (albeit very weak ones) in clinical trials. And third, it is to be presumed (though neither the DePinho lab study nor any other of which I am aware has checked this) that telomerase reactivation would restore the healthy and total longevity of treated mice, whereas in the van Deursen study the main cause of death, a cardiac problem, was not delayed in the treated animals and life span was unaltered.
But you would be completely wrong if you think am I criticizing the reaction to this study and/or disparaging the study's significance. On the contrary: I am delighted both that the study was performed and published in a top journal and that it was so energetically received. The message from those events is clear: Rejuvenation biotechnology is a concept whose time for widespread appreciation has come, such that proof-of concept work in that area can be recognized as having the significance it truly possesses. So what if the road from here to therapies remains long and uncertain? With rewards as great as the wholesale defeat of aging, high-risk work is abundantly justified. And if it reaches the ears of opinion-formers, and hence the public, and hence the public purse-controllers, the impact on the rate of future progress is not uncertain at all.