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SAGE KE Bulletin Board

Re: Making Sense of SENS: Criticisms and Suggestions

12 October 2005

Aubrey D.N.J. de Grey

Hello Ben - many thanks for these further points.

I think the key thing that distinguishes obviation from pre-emption is that an obviating intervention in a process interferes later in the chain of events comprising that process. In the case of mtDNA damage, for example, changing the genes encoding certain Complex I subunits to emulate birds is quite likely to be able to lower superoxide production considerably (and we are probably quite close to discovering which of those subunits, and which sequence changes, are most promising to try). That would be pre-emption because it would alter the chain of events (going from respiration to ROS production to mtDNA damage to whatever downstream pathologies mtDNA damage may cause) at an early point, ROS production. Allotopic expression is an obviation strategy because it intervenes late -- it lets the mtDNA mutations accumulate but it stops them from having pathogenic downstream effects. I group obviation in the same bracket as repair, rather than with pre- emption, because the obviation strategies that interest me share with repair, but not with pre-emption, the property that they are much less likely to have side- effects, because the chemistry of metabolism is not being interfered with. Taking your example of apoE, I think gene targeting to turn apoE4 into apoE3 or even apoE2 is a great idea, and you may recall it was actually mentioned at SENS2 in questions to Matthew Porteous, whose zinc finger helicase technology may well be able to perform it. But, since we don't yet know why apoE genotype affects susceptibility to AD, we may find that this does not in fact help people already in the early (let alone late) stages of AD -- for example, the principal effect could be in youth. So it might not be an obviation strategy after all.

Your proposed strands 8-11 of SENS are interesting for a variety of reasons. AD is certainly not overlooked in the existing seven-strand SENS, but rather it is described in terms of some of those seven -- extracellular and intracellular junk and loss of cells, mainly. Toxic metals come in two major classes: ones originally performing useful metabolic roles that have become sequestered in excessive quantities (most especially iron in the lysosome which probably derives mainly from mitochondrial cytochromes) and heavy metals with no metabolic role that are introduced in the diet and accumulate in various places (particularly adipocytes). The presumption of SENS is that the former will be reutilised or excreted as in youth once lysosomal and other functions are restored, and that the latter are not abundant enough to matter within a normal or modestly extended lifespan. I think of organ transplantation as a delivery method because the transplanted organ will (presumably!) be more youthful than the one that it has replaced, so the consequence in terms of the biological age of (that part of) the individual is repair of accumulated damage, just as if the rejuvenation had been performed one molecule at a time. Finally, I entirely agree that nuclear DNA damage over and above that leading to cancer must eventually be eliminated -- but, as with heavy metals, not within a currently normal lifetime, and SENS is a first-things-first strategy on account of the escape velocity concept. In the case of the brain, I think it is very plausible that we can ramp up stem cell-mediated replacement of neurons to a rate (still a very slow rate by the standards of most tissues) that matches the rate of neuronal cell death needed to keep nuclear DNA damage to a tolerable level. This will be much harder than any of the initial SENS strands, to be sure - but we have time.

Thank you for the correction re Hamilton et al. Regarding the role of lysosomal rejuvenation in combating excessive ROS production (and excessive proton leak, i.e. energy consumption not leading to ATP synthesis), however, no -- my view is that lysosomal degradation is preferentially targeted at mitochondria with damaged membranes, and mutant mitochondria damage their membranes less fast so survive and clonally expand. You're quite right that better lysosomal enzymes are not a solution for the accumulation of mtDNA mutations -- that is why I include allotopic expression as a key SENS strand.

I'm not convinced that prioritising the SENS strands is important in terms of impact, because (a) there is not really a scarcity of the relevant resources, since different scientists will be working on each one whatever the funding levels, and (b) apart from mtDNA mutations it is reasonably clear that all the SENS categories are the dominant category for at least one major age-related cause of death or disability, i.e. my observation about the need to include cancer as "part of aging" applies to all the others too. (It quite probably applies to mtDNA mutations -- just that the evidence isn't so conclusive there yet.)

In terms of achievability my ranking would be exactly the same as yours except that I place number 7, cancer, as even more difficult than mitochondrial mutations.

Because of what I say about impact, my priority ordering is simply the inverse of my achievability ordering -- i.e., we need the most effort on the hardest parts.


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