SENS: A Reply to Ben Best
Cryonics, 2nd Quarter 2011
By Aubrey de Grey
This article is a response to: Ben Best – Deficiencies in the SENS Approach to Rejuvenation
SENS, my proposal for combating aging with regenerative medicine, was first formulated in 2000 and first published in 2002 . In 2005 and 2006, the first scientific critiques of SENS [2,3] appeared that were worthy of the name – in other words, that focused squarely on the scientific details of SENS rather than speaking in generalities. Both featured many profound flaws, as outlined in my replies [4,5], but I was under no illusion that this meant that SENS will definitely work. Accordingly, it has been a source of disappointment to me that the subsequent five years have not seen better-informed and better-founded critiques, even though an undercurrent of intuitive pessimism about SENS undoubtedly survives. I am therefore gratified that Cryonics Institute CEO Ben Best has published a careful analysis of what he sees as deficiencies in SENS, in the previous issue of CRYONICS .
Ben’s first criticism is a terminological one, and to a large extent I accept it. Specifically, he disputes the legitimacy of describing the SENS approaches to combating mutations, whether mitochondrial or nuclear, as “damage repair.” In the case of mitochondrial mutations I think it is just about reasonable to claim that the SENS approach is indeed damage repair: the approach is to render such mutations harmless by inserting suitably modified copies of the relevant genes into the nuclear DNA, and the goal is to restore function to mitochondria that have lost the ability to metabolise oxygen because of mutations . In other words, this intervention will indeed repair dysfunctional mitochondria, in the sense of restoring their function. However, I concede that its main impact will be pre-emption of dysfunction more than repair, since the genes will mostly be inserted into cells whose mitochondria are not yet mutated. Similarly, the approach that SENS highlights for combating the effects of nuclear mutations consists of repairing and/or pre-empting those effects, rather than repairing the mutations themselves. In this case the intervention entails eliminating cells that have become “death-resistant” (typically as a result of nuclear DNA damage), replacing cells that have died (again typically as a result of nuclear DNA damage) and have not been automatically replaced by division of other cells, and most importantly eliminating the genes that allow rare cells which mutate into a “quiescence-resistant” state to divide indefinitely as tumours . This last item is clearly mostly a case of pre-emption rather than bona fide repair: it is repair only to the extent that cells which are already cancerous or pre-cancerous can be eliminated by the apoptosis that results from further cell division following the therapy.
Therefore, my only objection to this criticism is Ben’s characterisation of it as “a procrustean attempt to force two strategies into a model purporting to only be concerned with damage and repair.” It is not the model itself that purports to revolve around damage and repair, but merely the sound-bite description of that model. I know that both Ben and our readers appreciate that painfully approximate terminology is a sad necessity in the quest to communicate our message to those whose attention has not yet been gripped by the understanding that the defeat of aging is humanity’s most important mission. Accordingly I am pleased that Ben took the trouble to stress that this criticism of SENS is minor.
In the remainder of what follows, therefore, I shall address the more substantive issues that Ben raises, and explain why I feel that they do not stand up to detailed scrutiny.
First of all, Ben focuses on nuclear DNA damage that does not fall under the three categories addressed by aspects of SENS (see above). I will hereafter refer to such damage as “non-specific.” Before continuing, I should mention another terminological issue – one which does not lead to any dispute between Ben and myself, but which may confuse readers. Ben very reasonably uses the term “DNA damage” in the way that it is customarily used by those who work on DNA repair; however, it is important to clarify, which Ben indirectly does but only later on in his article, that this usage is unfortunately at variance with the way in which I use the term “damage” when describing SENS. Specifically, “damage” in the DNA repair literature refers to molecular changes that the cell possesses machinery to repair, such as double-strand breaks, whereas in SENS, “damage” denotes precisely the changes that the cell cannot repair, such as mutations. Accordingly, in what follows I shall studiously avoid using the term “damage” at all, and instead refer to “mutations” (which should be understood to include epimutations, explained below) and “lesions” (a term also commonly used in the DNA repair literature to refer to damage that is amenable to repair). Thus, a lesion is what happens to DNA as a result of free radical attack and such like, and a mutation is what happens to DNA when the cell’s machinery fails to repair a lesion correctly but instead “repairs” it wrongly.
OK, so to Ben’s concern. In a nutshell, he appeals to the “coincidence” that various syndromes which exhibit many facets of normal age-related ill-health at an abnormally early age are caused by congenital defects in DNA repair. I have two responses to this. First, Ben is implying that because breaking some process accelerates lots of aspects of aging, therefore an intervention that does not improve that process would fail to deliver postponement of aging. This is only true if the proposed means to postpone aging leaves untouched key pathways in the mechanism by which imperfections in the process in question mediate accelerated aging. For example, if the various progerias caused by defects in DNA repair and maintenance occur because the resulting lesions and/or mutations cause premature accumulation of death-resistant cells, and/or premature loss of vital cells (most notably stem cells), and/or premature emergence of cancer, the claim that SENS will work is not challenged, because SENS addresses those things. I am not aware of evidence against this scenario – and, indeed, Ben highlights evidence that these are indeed mechanisms underlying the progerias. Second, Ben notes that the double strand break repair mechanism normally defective in progerias is homologous recombination, even though the mechanism agreed to be the main source of mutations is non-homologous end-joining. There is a clear disconnect there.
Ben goes on to acknowledge that SENS incorporates elimination of death-resistant cells and replacement of lost cells, but then he makes the erroneous claim that such approaches cannot be applied to non-dividing cells such as neurons. In organs such as the heart, it is critical that new cells should integrate properly and form the appropriate junctions with existing cells, but the burgeoning field of heart repair using stem cells is founded on the belief that that is by no means a fanciful goal. Ben correctly highlights the brain as the organ in which this replacement-associated integration is the most critical, but I believe he is wrong in his belief that the replacement – slow replacement, to be sure, but replacement nonetheless – of lost neurons necessitates a loss of personal identity, memory, etc. Rather, my view is that the distributed, holographic structure of memory, combined with the fact that recalling a memory automatically reinforces it, allows for the retention of all memories and other aspects of personality that are significant enough to care about, even if all neurons were progressively replaced over a very long life.
Ben then cites evidence not relating to progerias that he claims also demonstrates a key role of non-specific mutations. However, here he confuses lesions with mutations. He notes that lesions are more abundant in old rats than young, and that this is probably due to lower activity of repair machinery, which in turn probably results from lower energy availability. He infers, and I see no reason to disagree, that this drives an age-related acceleration of the accumulation of mutations. But what he fails to show is that the absolute abundance of mutations, even taking into account this acceleration, rises to anywhere near the level that would be needed in order for non-specific mutations to contribute to ill-health. Moreover, he overlooks the essential point that this acceleration applies with equal force to mutations of the three categories that SENS obviates. As I have noted in print in the past, it may be precisely the risk of ill-health posed by those mutations (specifically those causing quiescence-resistance, i.e. cancer) that has driven evolution to make our natural DNA repair and maintenance machinery as effective as it is .
Finally, Ben notes that even though there may be evolutionary arguments (see above) to be optimistic that non-specific mutations are of no importance in aging, it would be much better if we had definitive data on the question. Here I agree wholeheartedly – and I have put my (or, to be more precise, SENS Foundation’s) money where my mouth is. Jan Vijg’s group has demonstrated, in many papers over the past decade or more, that nuclear mutation load accumulates during development in every mouse tissue but during adulthood only in a few, and not at all in the cerebral cortex . If mutations do not accumulate, then their accumulation definitively cannot contribute to aging. It therefore remains only to examine whether types of irreparable DNA damage not assayed in Vijg’s studies may accumulate. There are such types: in particular, there are epimutations, i.e. random and unregulated changes not to the DNA sequence but to the “decorations” that determine which genes a given cell transcribes (forming RNA and thence proteins) and which it does not. While the evolutionary logic I have provided applies equally to epimutations as to mutations, no direct evidence of the form available for mutations has been forthcoming.
Therefore, in recognition that the evolutionary arguments noted above do not give adequate peace of mind for this critical purpose, SENS Foundation has for the past two years been funding a project in Vijg’s lab to explore exactly this. The most challenging aspect of the project, at its outset, was development of the necessary technique for determining the epigenetic state of single cells, starting from pre-existing techniques that needed to pool 1000 or more cells. I am delighted to report that this has now been achieved (as will be described in a forthcoming publication), so we are now on the verge of answering this question. Of course, if epimutations are indeed found to accumulate in the cortex during adulthood, it will remain to determine whether the extent of that accumulation is sufficient to contribute to aging – but if they do not, we can truly rest easy in the knowledge that the three SENS strands targeted at the cellular consequences of mutations (and epimutations), once successful, will allow us to neglect such mutations in the course of our attempt to postpone age-related ill-health, at least until we have lived a very great deal longer than anyone lives at present.
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- Vijg, J., Dollé, M.E., 2002. Large genome rearrangements as a primary cause of aging. Mech. Ageing Dev. 123, 907-915.
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