Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


SAGE KE Bulletin Board

Re: Making Sense of SENS: Criticisms and Suggestions

17 October 2005

Ben Best

Reply to Aubrey

I will adopt your means of identifying the source of statements.

[Aubrey] I prefer PubMed to Google when seeking help on obscure biomedical terms.

I was suggesting that for communication with a broad range of specialists as well as with a general audience, it might be best to avoid obscure words not found in standard medical dictionaries.

[Aubrey]AE isn't "changing mtDNA to nDNA" -- it's making modified copies of the mtDNA and placing them in the nucleus. So the bona fide mtDNA still exists, mutations in it accumulate, but the proteins it encodes are not depleted as a result because they're also being expressed from the new nuclear genes.

I had mistakenly believed that you would eliminate the mtDNA protein genes from mitochondria. I am now wondering how SENS would address the problem of declining mitochondrial replication with age -- or whether you consider this a problem.

[Aubrey]The relevance of 8OHdG to either aging or cancer is challenged, incidentally, by the lack of phenotype of mice with a homozygous deletion of the gene encoding the enzyme that repairs it...Klungland A et al., Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci USA 96(23):13300-13305. Abstract says: "OGG1-deficient mice ... show no marked pathological changes". Main text says: "Null animals remained viable and apparently healthy into adulthood (oldest mice are 18 months) with no overt phenotype; systematic histopathological examination of two such animals sacrificed at 8 and 11 months of age did not reveal any abnormalities".

Thanks for the reference -- [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Klungland,A; 96(23):13300-13305 (1999)] -- but I draw different conclusions. For one thing, the authors suggest that 8OHdG repair by NER may be a backup for OGG1. For another thing, the tissue being studied is proliferative: liver. I repeat a paragraph from my initial posting:

"A comparison of the heart mitochondria in rats (4-year lifespan) and pigeons (35-year lifespan) showed that pigeon mitochondria leak fewer free-radicals than rat mitochondria, despite the fact that both animals have similar metabolic rate and cardiac output. Pigeon heart mitochondria (Complexes I & III) showed a 4.6% free radical leak compared to a 16% free radical leak in rat heart mitochondria [MECHANISMS OF AGING AND DEVELOPMENT; Herrero,A; 98(2):95-111 (1997)]. A comparison of 7 non-primate mammals (mouse, hamster, rat, guinea-pig, rabbit, pig and cow) showed that the rate of mitochondrial superoxide and hydrogen peroxide production in heart & kidney were inversely correlated with maximum life span [FREE RADICAL BIOLOGY & MEDICINE; Ku,HH; 15(6):621-627 (1993)]. A similar study of 8 non-primate mammals showed a direct correlation between maximum lifespan and oxidative damage to mtDNA in heart & brain. There was a 4-fold difference in levels of oxidative damage and a 13-fold difference in longevity, supportive of the idea that mtDNA oxidative damage is not the only cause of aging [THE FASEB JOURNAL; Barja,G; 14(2):312-318 (2000)]."

Note that in the last reference the tissues studied were non-proliferative: heart & brain. Not only mtDNA oxidative damage, but also mtDNA damage are highest in heart & brain: [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Cortopassi,GA; 89(16):7370-7374 (1992)]. But from the point of view of protecting mtDNA by making modified copies in the nucleus, it should not matter whether the damage is oxidation or deletion. Am I correct in assuming that you think mtDNA deletions are also mainly due to free-radicals?

[Aubrey]Similarly, atherosclerosis is best considered part of aging because foam cell formation, a necessary precursor to atherosclerotic plaques, is an intrinsic side-effect of normal lipid metabolism in the artery wall. Both cancer and atherosclerosis are sometimes caused or exacerbated by extrinsic causes, but intrinsic causes are the dominant influence on their progression.

I think that an extrinsic cause could cause aging-type damage. Whether you called it "aging" matters less than the universality of the damage to cells & tissues and the contribution of that damage to mortality. 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.

[Aubrey]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.

The half-life of lead in the skeleton is in excess of 20 years, and the fraction of lead in bone increases with age from about 70% in children to nearly 95%. Lead in the CNS is highest in the hippocampus. Unlike iron, which accumulates in mitochondria, lead is most disruptive to synapse function [NEUROTOXICITY; Suszkiw,JB; 25(4):599-604 (2004)] and therefore not affected by improved lysosomal enzymes. Mental function is expected to decline with age, and we cannot say how much of this might be due to lead. Similarly, aluminum accumulates in bone. Although the neurofibrillary tangles caused by aluminum are distinct from those found in Alzheimer's Disease [BRAIN RESEARCH; Huang,Y; 771(2):213-220 (1997)], they could similarly disrupt proteasome function. 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".

The point about NFTs, however, does raise the question: 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?

[Ben] I don't think that stem cell-mediated replacement of neurons is a good strategy for the whole brain because I don't think it can be done in a way that retains the synaptic connections that form the basis of memory and personal identity.

[Aubrey]If we needed to connect a new neuron to exactly the same other neurons as the one it's replacing was connected to, I would agree, but I think we can say with confidence that memory and personal identity are stored more "holographically" than that.

The recovery of some memories by stroke victims is evidence for some redundancy, but I still believe that every lost set of connections is a loss of information. I am more conservative about preserving neurons & synapses than you are, but this is too complex a topic to open here.

[Ben] If you are so sanguine about stem-cell mediated replacement for neurons, then why include strategies for cell repair in SENS at all?

[Aubrey]Because there will be a limit to the rate at which cells can be replaced without compromising tissue function in some tissues - especially the brain, but probably the heart and skeletal muscle too. So it makes sense to use cell repair to minimize the required rate of cell replacement.

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. If cell/tissue repair were efficient enough, you could dispense with stem cells for all tissues. By adding more efficient DNA repair to SENS you could dispense with (6) & (7).

[Ben] If resources were not scarce, then all seven SENS strategies could be achieved tomorrow.

[Aubrey]Even I at my most optimistic would not say that!

But you said "I'm not convinced that prioritizing 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 my full statement was:

"If resources were not scarce, then all seven SENS strategies could be achieved tomorrow. There would be no need for a Methuselah Mouse Prize or an Institute of Biomedical Gerontology."

Time & money are the needed resources, and if those are not present in sufficient quantity to fulfill SENS tomorrow, they are thus scarce. Assuming that you were to get millions of dollars for the Institute of Biomedical Gerontology, priorities should be set for allocating the money if tens of millions are really what's needed. In any case, I disagree that all seven SENSE categories equally impact aging and mortality.

[Aubrey](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.) ... If every SENS category is the dominant one for something that kills us, leaving it out (or letting research to repair/obviate it proceed less rapidly than the others) will delay achievement of the main goal, namely letting people live a lot longer. The measure of the "amount" of damage that makes most sense is the age at which the SENS category kills people, and I'm saying that age is roughly the same for all categories.

The gap in perception and communication between us on this issue is very great. In order to begin to reply to you, I need to have specifics. So I request that you tell me what is in the last column of the following table -- which lists each SENS damage-type and corresponding strategy, but omits the major age-related cause of death to which you refer which kills people at roughly the same age. (I answer the last: cancer.)

(1)cell lossstem cells         
(2)senescent cellsimmune activation         
(3)protein cross-linksdrugs/enzymes         
(4)extracellular junkimmune activation         
(5)intracellular junkbetter lysosome enzymes         
(6)mtDNA damagemtDNA to nDNA         
(7)cancerdelete genes for telomerase/ALT  cancer         

To Advertise     Find Products

Science of Aging Knowledge Environment. ISSN 1539-6150