SAGE KE Bulletin Board

Re: Making Sense of SENS: Criticisms and Suggestions

12 October 2005

Ben Best

Reply to Aubrey

For reference purposes, I repeat my numbering and rewording of your seven molecular repair strategies: (1) Cell loss can be repaired (reversed) just by suitable exercise in the case of muscle, but for other tissues it needs various growth factors to stimulate cell division, or in some cases it needs stem cells. (2) Senescent cells can be removed by activating the immune system against them. Or they can be destroyed by gene therapy to introduce "suicide genes" that only kill senescent cells. (3) Protein cross-linking can largely be reversed by drugs that break the links. But for some of the links we may need to develop enzymatic methods. (4) Extracellular garbage can be eliminated by vaccination that gets immune cells to "eat" the garbage. (5) For intracellular junk we need to introduce new enzymes, possibly enzymes from soil bacteria, that can degrade the junk that our own natural enzymes cannot degrade. (6) For mitochondrial mutations the plan is not to repair them but to prevent harm from the mutations by putting suitably modified copies of the mitochondrial genes into the nucleus by gene therapy. The mitochondrial DNA experiences so much mutation damage because most free radicals are generated in the mitochondria. If mitochondrial DNA can be moved into the nucleus it will be better protected from free radicals, and there will be better DNA repair when damage occurs. All mitochondrial proteins would then be imported into the mitochondria. (7) For cancer (the most lethal consequence of mutations) the strategy is to use gene therapy to delete the genes for telomerase and to eliminate telomerase-independent mechanisms of turning normal cells into "immortal" cancer cells. To compensate for the loss of telomerase in stem cells we would introduce new stem cells every decade or so.

I see no meaningful distinction between "obviation strategy" and "preemption strategy", in contrast to seeing a great distinction between repair versus obviation/preemption strategies. In the context of your model of engineering versus gerontonology, the engineer repairs the roof whereas the gerontologist obviates/preempts wind damage by planting big trees around the house. SENS strategies (1)−(5) are repair, but (6) moving mtDNA to the nucleus and (7) deleting telomerase genes to prevent cancer are obviation/preemption.

I concede your point about infection and increased vulnerability due to immunosenescence. However, if you insist that cancer is somehow "aging" rather than simply "age-related disease", then I see no grounds for excluding (8) Alzheimer's Disease and an "obviation strategy" of ensuring that everyone has the e2 apolipoprotein E allele [NEUROBIOLOGY OF AGING; Raber,J; 25(5):641-650 (2004)]. By some accounts Alzheimer's Disease causes nearly as many deaths as cancer. An anti-aging program that did not eliminate Alzheimer's Disease would be about as valuable as an anti-aging program that did not eliminate cancer. If you argue that strategies (1)−(6) should be sufficient to eliminate Alzheimer's Disease, you must also establish why (1)−(6) could not eliminate cancer. Aberrant telomerase could only lead to cancer in the context of other cellular damage. The cellular damage and the aberrant telomerase could be repaired or replaced (or the cells or tissues could be replaced).

I also think that your list should include (9) removal of accumulated toxic metals from tissues. This would "obviate" much free-radical damage, much like strategy (6). But it is also comparable to (3)−(5) because accumulation of excess toxic metal ions in tissues as one ages is not fundamentally different than protein cross-links, extracellular garbage and the kind of intracellular junk that can be removed by better lysosomal enzymes. In fact, the Hamilton, paper I cited -- [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Hamilton,ML; 98(18):10469-10474 (2001)] -- suggested that elevated iron content in tissues is the source of potentiated oxidative stress in old mice.

Also concerning Hamilton,, you said they "measured the steady-state 8OHdG, not its rate of formation." I quote from the last paragraph of the paper: "we estimate that the de novo formation of oxo9dG in brain tissue of a young mouse would be ~27,000 oxo8dG lesions in a 24-h period, compared with 96,000 oxo8dG lesions in a 24-h period for a brain cell from an old mouse."

I agree that gene therapy could be a delivery method for (2), (4), (5), (6) and (7), but I disagree that organ transplantation is a delivery method for any of them. How could an organ transplant be a delivery method for a molecular repair technology? Organ transplant would make certain molecular repairs unnecessary, such as (1), (3), (4) and (5), but that does not count as a "delivery method". Organ transplantation would be strategy (10).

Strategy (6) shows a clear concern about oxidative damage from mitochondria, but SENS says nothing about repairing the oxidative damage that has already occurred. Better lysosomes could play a role in replacing defective proteosomes to assist in replacing oxidized proteins, but what about nDNA in neurons that has already been damaged by oxidation, hydrolysis, radiation, etc. -- including nDNA that produces nDNA repair enzymes? Organ transplantation or stem cells to replace all neurons are not options. SENS would have to include means of repairing nDNA if it is to achieve its goal of lifespans in the hundreds or even thousands of years. Make that strategy (11).

Concerning DNA damage, I gave the references that led me to believe that mtDNA damage and nDNA damage repair defects are central to aging -- not the reference or arguments you gave and argued against. Concerning nDNA you argued against a simple nDNA damage cause of aging. What I said concerning nDNA was:

Nuclear DNA damage due to mutagens more readily leads to cancer, but defective nDNA repair more readily leads to aging. It may be that mutagens damage both nDNA as well as cellular defenses against nDNA damage, but that when nDNA repair is defective cells can respond by inducing cellular senescence or apoptosis -- preventing cancer, but accelerating aging.

I cited "accelerated aging diseases" and I stressed a multifactorial aging, with mtDNA also being prominent.

Your point about deletions being the most frequent mtDNA mutation was not relevant to what I said either. I was not defending a vicious cycle theory wherein mtDNA damage/mutation caused by free-radicals leads to mitochondria that produce higher levels of free-radicals. I acknowledge your expertise in this area, but I do believe that the superoxide/ATP production ratio increases with aging [EXPERIMENTAL BIOLOGY AND MEDICINE; Wei,Y; 227(9):671-682 (2002)]. My thought had been that although lysosomes may normally eliminate mitochondria producing the most superoxide, engorged dysfunctional lysosomes eventually become incapable of removing those mitochondria. I also considered that damaged mitochondria might be leading to cell loss through apoptosis. If "it is the wild-type mitochondria that are generating most of the superoxide", as you say, then lysosomal enhancement seems less "vital". And if lysosomes are not selecting mitochondria with mtDNA deletions for removal, better lysosomal enzymes are an inadequate solution.

Which brings me back to the central issue of my initial posting: the use of mechanisms of aging to prioritize the strategies in your program. I was seeking to rate each item by achievability and impact on aging damage. If mtDNA and nDNA damage-repair defects are the mechanisms resulting in the most aging damage, then removal of protein cross-links would be less important. Migration of mtDNA to the nucleus might be important, but astronomically costly (difficult) to achieve. I was believing that lysosomal enhancement was of high importance in removing deleterious mitochondria, but our discussion has made me less certain.

With scarce resources (including time) and lives at stake, I think it is very important to prioritize. I would do this by taking the damages/strategies, ranking their relative impact on aging, ranking the achievability of repair and then combining the two factors to arrive at priorities. For example, I would have said [ although I am now less sure about (5)]:

Impact: (5) > (6) > (7) > (1) > (3) > (4) > (2)

Achievability: (1) > (3) > (4) > (2) > (5) > (7) > (6)

Priority: (5) > (1) > (7) > (3) > (4) > (2) > (6)

I would like to hear your rankings and justifications, your priorities and justifications priorities in particular.

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