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SAGE KE Bulletin Board

Re: Making Sense of SENS: Criticisms and Suggestions

19 October 2005

Aubrey D.N.J. de Grey

[Ben] I am now wondering how SENS would address the problem of declining mitochondrial replication with age -- or whether you consider this a problem.

Not a problem. Mitochondrial biogenesis rate should remain constant (or if already diminished, should revert to youthful) if all SENS strands are well implemented -- for, how could it not? This is irrespective of whether mtDNA remains present in the mitochondrion.

[Ben] For one thing, the authors suggest that 8OHdG repair by NER may be a backup for OGG1.

Sure, but not an effective one, otherwise we would not see the elevationin 8OHdG levels.

[Ben] For another thing, the tissue being studied is proliferative: liver.

Um, but 8OHdG was reported to be well above controls in various postmitotic tissues too.

[Ben] If everyone unavoidably accumulated toxic metals from the environment with the passage of time, and this resulted in major deterioration of cells & tissues, it should be a priority for SENS. ... Admittedly, these are unquantified postulations, but on the other hand there is not enough evidence to assume that these toxic metals ions are "not abundant enough to matter".

I think there may be enough evidence (though I don't claim to have researched the area as well as I probably should have). The approach I would take is to look at the variation of heavy metal abundance observed in the population: if toxicity is only known when levels are many times higher than average, I think we can leave them out of the SENS calculations for the present.

[Ben] What does SENS do about increasing proteasome dysfunction associated with aging? Do you assume that lysosomes with souped-up enzymes can compensate for proteasome loss?

No - I assume that proteasome function will cease to decline (and to the extent that it has already declined, will recover) if all SENS strands are implemented well (particularly the lysosomal enhancement strand), because proteasomes are not long-lived structures so cannot accumulate damage. New pristine proteasomes are continuously being created and damaged ones destroyed; age-related proteasome dysfunction results from a shift in the kinetics of those processes (and two others, the occurrence of proteasomal damage itself and the proteasomal workload, i.e. damage to proteasome substrates). None of these shifts should occur if SENS as currently stated is implemented well.

[Aubrey] there will be a limit to the rate at which cells can be replaced without compromising tissue function in some tissues

[Ben] How would you determine that limit? For each organ or tissue there may be a choice between organ transplant, stem cells and cell/tissue repair [ie, (2)−(5)]. Organ transplant might be more suitable for heart & kidney, stem cells for skeletal muscle and cell/tissue repair for brain.

Sure, I agree. Determining the cell turnover rate limit for the brain is beyond us at this point, so all we have to wrk with is probabilities, i.e. that a lower rate of replacement is more likely to be possible without impairing function than a higher rate. That's all we need to know to motivate cell repair strategies as complements to cell replacement ones.

[Ben] If cell/tissue repair were efficient enough, you could dispense with stem cells for all tissues.

Um, well, "efficient enough" means "perfect" there, surely? Again, it's just a case of all these things being rather hard and a combination solution (or attempted solution) having a better chance of success at an earlier stage of development, i.e. sooner.

[Ben] By adding more efficient DNA repair to SENS you could dispense with (6) & (7).

Woah - how's that? Perfect repair of premutagenic lesions is impossible; repair of mature mutations is impossible too.

[Ben] Time & money are the needed resources, and if those are not present in sufficient quantity to fulfill SENS tomorrow, they are thus scarce.

No - unless you mean something else than I do by "fulfill". Clearly there is a wealth of detail to be elucidated in actually implementing SENS, the speed of progress on which depends on interim discoveries/setbacks, even if funds were unlimited now and henceforth. I claim that if funds were unlimited, manpower would not demand prioritisation among the seven strands, because different people would be pursuing each.

[Ben] what is in the last column of the following table

Recall I claim no clear answer in the case of mtDNA mutations. Examples for the rest: cell loss causes heart failure when the sinus node has too few cells to maintain a heartbeat; senescent cells (which, I remind other readers, I use in a broad sense better stated as "death-resistant cells", and indeed that's the term I now tend to use) cause immune senescence leading to death from influenza; crosslinks lead to arteriosclerosis/hypertension, which accelerates atherosclerosis and thus heart attacks and strokes; extracellular junk (amyloid) causes congestive heart failure (I use this example because it is better accepted than Abeta's role in Alzheimer's); intracellular junk causes atherosclerosis (foam cells are the start of a plaque).

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