Ending aging by undoing aging: piecemeal, but in a good way
Aubrey D.N.J. de Grey
SENS Research Foundation, Mountain View, USA
Readers of Aging Matters want to stay young, but can we? The information provided in this publication, as in other high-quality fora on the topic, helps one to make the best selection among what dietary or pharmacological options are currently available, but without disguising the fact that the best outcome we can currently hope for is only a modest postponement of age-related physical and mental decline. That’s why I hope you, like your editor (as demonstrated by his invitation to me to write this piece), are also acutely interested in the ongoing research efforts to develop interventions that can do better.
For about a century, at least a few people have understood that the diseases and disabilities of old age cannot realistically be alleviated – not much, anyway – by the kind of medicine that works against infections, nor even by putative genetic manipulations that might be available to address congenital conditions. That is where the field of biogerontology came from, and it remains its raison d’etre, even though most biogerontologists (at least until recently) have focused on descriptive and mechanistic studies to elucidate the nature of aging rather than to manipulate it. There are two main reasons why it is so: First, age-related ill-health is a side effect of essential metabolic processes that progressively damage the body, meaning that any therapy targeting the pathological consequences of that damage will necessarily become less and less effective as the damage further accumulates; and second, the pathologies of old age are hugely many and varied (and they interact with each other), so tackling them one by one is simply impractical.
So, what alternatives have biogerontologists explored? Most translational biogerontology work (of which there has, of course, been tragically little in total) has been predicated on the assumption that aging is a somewhat unitary process, such that relatively simple (and, maybe, simply implementable) genetic “knob-twiddling” can emulate the differences in rate of aging seen between quite closely-related species, slowing down our own. This approach has not yet led to any benefit in the clinic, but it is too soon to say that it never will. Even if we decided that it is very unlikely to, that still wouldn’t justify giving up the search for the most effective knobs (and, indeed, accelerating it via increased funding), given that even a very low perceived probability of success must be multiplied by the indisputably vast humanitarian and economic benefit in order to determine whether the investment is justified.
However, unless we were conversely to decide that that quest is extremely likely to bear fruit quite soon, we would also be unjustified in restricting our efforts to that line of research. That is what led me, 15 years ago or so, to seek alternatives that might also have merit. The strategy that I came up with, since known as SENS (“strategies for engineered negligible senescence”), can best be described as intermediate between the above approach and the “one disease at a time” geriatric medicine option. Like knob-twiddling, it is preventative, in the sense of being designed mainly for use by people who are not yet sick. But like geriatrics, it is a treatment that restores a more youthful body composition and thus function than the recipient had prior to treatment, rather than just slowing down their decline. In a nutshell, SENS is about repairing the accumulating damage that leads to age-related ill-health, thus breaking the link between metabolism (which creates that damage) and pathology (which results from the damage).
Some biogerontologists have expressed doubts about the feasibility of SENS. Historically, this was partly because much of the underlying proof-of-concept work on which SENS is based had been done by non-biogerontologists, for reasons other than the postponement of aging, and was thus unknown to those of my colleagues who had not found the time to read my papers (and especially the experimental work I cited in them) in detail. That problem has largely been corrected over time, not least via the conference series that I and SENS Research Foundation have organized since 2003. However, there remains a degree of pessimism in some quarters concerning the overall feasibility of SENS, even if the feasibility of its individual components is provisionally accepted. This is above all because, like geriatric medicine, SENS is a multi-component approach, in which many different types of damage are proposed to be tackled individually. If that’s a fatal flaw in geriatric medicine, why not also in SENS?
I fully acknowledge that this question needs a solid answer if SENS is to be deemed feasible. It comes in three parts.
First, SENS has a coherent structure. It classifies the many different types of damage into just seven categories (such as loss of cells via cell death not balanced by cell division and differentiation, or accumulation of molecular “garbage” consisting of metabolic byproducts that the body has no mechanism to destroy or excrete), and asserts that within each category there is a generic therapy (such as stem cell transplantation, or introduction of new catabolic enzymes found elsewhere in nature) that can reasonably be expected to work for all examples of damage within that category. By “generic” I mean that even though the therapy will certainly differ in detail (just what stem cells, or what enzymes) from one type of damage to another, the essence of the method will not. This means that the inherent complexity of SENS is far lower than for geriatric medicine; developing a new therapy for a new type of damage will be much more straightforward if it can be done by just modifying the details of something that has already been developed.
Second, SENS is mainly designed to target damage that is not yet abundant enough to have become pathogenic. This can be stated in another way: the damage is not participating in metabolism at the time it is targeted. Why is this so important? Because the most fundamental obstacle to the efficacy of any combination therapy is the multiplicity of interactions of its components with each other, and the most fundamental obstacle to the efficacy of any therapy is the side effects arising from the good things that its target is doing at the same time as doing bad things, such as the fact that statins reduce cholesterol (a vital molecule) as well as reducing oxysterols (the actual problem), or that reducing free radical levels (as dietary antioxidants are designed to do) diminishes their signaling function as well as their toxicity. In the case of SENS, the targets are not doing anything while they are at sub-pathogenic levels, so these challenges are hugely reduced.
Third, it is becoming progressively less plausible that the SENS classification is incomplete. Even though the past decade has certainly seen the discovery of important new types of damage in aging, every one of them is unequivocally an example of a SENS category. While this is of course only a circumstantial argument, and SENS Research Foundation is indeed funding work to identify other damage, it is becoming hard to deny that this seven-point classification is standing the test of time.
Putting all this together, I believe that there is now a decisive case for pursuing the “knob-twiddling” and SENS approaches in tandem if we are seeking to save the most lives and alleviate the most suffering in the long term. The above considerations certainly do not add up to the conclusion that SENS is easy, and I think it is highly likely that we will identify and implement the best possible knob-twiddling options well before we implement SENS. However, if we objectively evaluate the risk that those best options will only deliver a modest postponement of aging, especially for those who are already in middle age when they are developed (which is not the case for “rejuvenation” options such as SENS), and if we further evaluate the difficulty of developing each of the SENS components and (via the above arguments) what this says for the likely timeframe for making the whole of SENS work, it is in my view inescapeable that we must pursue both alternatives as aggressively as possible.