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SAGE KE Bulletin Board

Re: Making Sense of SENS: Criticisms and Suggestions

10 October 2005

Aubrey D.N.J. de Grey

Ben, many thanks for your comments. Some replies follow. I apologise if this comes out unformatted; the submission software seems to want to flow it even though I am inserting the requested blank lines between paragraphs.

The question whether age-related diseases (such as cancer) are or are not part of aging is an old one, but I believe that cancer should be included as part of aging because, unlike infections, most cancers become progressively more prevalent with age irrespective of environmental exposure to anything. This is not the same as increased vulnerability, because some of the necessary mutations will typically have occurred early in life. 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.

My proposed approaches to combating both mitochondrial and nuclear mutation accumulation are indeed obviation strategies, rather than repair, and I always say "repair or obviate" whenever I have time/space for more than one word to describe the SENS approach.

Most importantly, I certainly do not say that we need no understanding of the mechanisms of aging in order to combat it by a repair/obviation strategy such as SENS; what I say is that that sort of approach requires a dramatically less thorough undestanding of those mechanisms than would a pre-emption strategy based on improving on evolution's already formidable achievement in making our aging as slow as it is.

Mutations in mitochondrial DNA sometimes lead to increased free radical production, but when the mutation is a deletion (eliminating at least one essential tRNA gene and thus all protein synthesis) it leads to reduced free radical production [e.g. Mutagenesis 18:497], as would indeed be expected since neither of the superoxide-generating complexes of the respiratory chain can even assemble when their mtDNA-encoded subunits are absent. Deletions are by far the most frequent loss-of-function mutation seen in vivo [e.g. Aging Cell 2:1]. However, your argument that lysosomal enhancement is a vital component of SENS still stands, even if it is the wild-type mitochondria that are generating most of the superoxide.

Accelerated nDNA damage indeed causes a wide spectrum of accelerated aging phenotypes, as does accelerated mtDNA damage [Nature 429:417], but this cannot be considered strong evidence that nDNA damage at the natural rate limits lifespan [Med Hypotheses 62:1012]. Also, note that Hamilton et al. measured the steady-state level of 8OHdG, not its rate of formation: when they measured its rate of removal following irradiation there was little difference between young and old. 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.

You are right that organ transplantation is an important component of the delivery of the SENS fixes. It is not listed as one of the SENS strands because it is a delivery technology applicable to several of them, just like gene therapy. The SENS strands are described at the molecular and cellular level because they each occur in many organs and tissues.

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Science of Aging Knowledge Environment. ISSN 1539-6150