What if Senolytics Fail? By Aschwin de Wolf
T
here is a school of thought within the life extension movement that favors prioritizing the promotion of cryonics over anti-aging efforts. There are a number of arguments for this. A technical argument has been put forward in Thomas Donaldson’s seminal article “Why Cryonics Will Probably Help You More Than Anti-aging.” The most rigorous test to determine whether an anti-aging therapy works entails giving it to a group of people and determining whether these people live longer (without any detrimental side-effects). The timescales entailed do not permit rapid progress in a field. Aiming for outright rejuvenation might be a better strategy because it allows for more short-term objective metrics to be used. Some of these metrics are common sense (athletic performance, skin appearance, cognitive tests etc.), others are more controversial (biochemical “biomarkers” of aging). Wherever one comes down in this debate, it cannot be denied that cryobiological research can be pursued in a more precise, time-efficient manner. For example, if you want to determine whether a vitrification solution resists freezing when it is cooled to cryogenic temperatures, you need no more than a day to perform the experiment and document the results. This vitrification solution can then be introduced to an organ to determine whether the organ can be vitrified and recovered without ice formation. This is not just conjecture. Since the mid-20th century a small number of dedicated cryobiologists have solved the problem of designing cryoprotectants that do not freeze at realistic coolingand-warming rates. Major progress has been made in mitigating toxicity and chilling injury of those cryoprotectants as well. It is important to keep this in mind when cryonics advocates are taken to task for not making as much progress as the people in the anti-aging field. Another advantage of the field of cryobiology is that most of its findings are observed in all popular mammalian animal models. Phenomena such as cryoprotectant toxicity and cryoprotectantinduced brain shrinking are observed in both small- and large animal models. In aging research, however, the important role of evolution and genetics makes translating results from small animal models to humans a lot trickier. After all, an evolutionary perspective on aging needs to explain different lifespans in different animals and species (and even within). An intervention 26
that prolongs the life in a small animal may only have minor health benefits in humans (like caloric restriction). On a conceptual level the major figures in the life extension advocacy field cannot even agree on what aging is (put Aubrey de Grey, Michael Rose, and Joshua Mitteldorf in one room and see the sparks fly!) and the field is not immune to succumbing to one fad after another (while believing that this time it is for real). Part of this problem is related to the lack of objective, short-term measures to determine the effectiveness of an antiaging treatment in humans. If it would be possible to assess the effectiveness of an anti-aging therapy in a quick and unambiguous manner, one theory of aging might be more easily favored over another. Recent developments in the field of biomarkers of aging and “aging clocks” have given hope to those who believe that it now will be easier and time-efficient to determine the effectiveness of an anti-aging intervention. As of writing, there are several different biomarkers of aging and there is no consensus if these measures capture all the important aspects of aging. In fact, whether one clock is favored over another is itself reflective of one’s perspective on what aging is, which brings us back to the fundamental disagreements over aging that continue to divide biogerontologists. One thing that these biomarkers of aging will not be able to tell is whether an intervention is effective and safe in the long run. Or whether the maximum human life span would be altered by a specific intervention. It cannot be emphasized enough that, as of writing, there is not one single anti-aging biotechnology that has been demonstrated to produce extension of the maximum human lifespan, let alone unambiguous evidence of rejuvenation. This should have a sobering effect on dispassionate observers of the field but it is no exaggeration to claim that many movers and shakers in the field are not dispassionate and actually prone to embracing the next big thing, which often generates (predictable) cycles of great enthusiasm and disillusion. The current big thing in the anti-aging field is the identification and validation of senolytics. Since the clearing of senescent cells is one of the pillars of the SENS program, the success of this approach will have important consequences for the “aging as damage accumulation” school of aging. Billions are flowing into this field in the anticipation of successful biomedical applications. So far, the results in small animal models look modestly
Cryonics / 1st Quarter 2021
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