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A Response to Estep in Technology Review

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#1 Michael

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Posted 15 February 2005 - 01:06 AM

Dear Editors and Dr. Estep,

First, I thank Dr. Estep for his contribution to the debate. Leaving aside the naked ad hominem attacks proffered by Pontin in his editiorial, Dr. Nuland's original article was unfortunately typical of the responses one gets from many persons with at least some scientific background: vague hand-waving about the complexity of biological systems without any attempt to address the specific interventions advocated by Dr. de Grey. A specific, science-based objection to the feasibility of the SENS project from a scientist actually working in the science of aging is therefore welcome.

That said, I do believe that Estep's concerns are ungrounded. While de Grey has already addressed most of these quite competently, I do have some additional comments.

Preston Estep III, Ph.D. wrote:

> the SENS plan does not address the primary -- and maybe the most difficult to control -- general aspect of aging: entropy ...

> including cellular dedifferentiation or transdifferentiation

> ..., nuclear and mitochondrial mutation,
> chromosomal instability, aberrant methylation and other directed modification of the genome, loss of chromatin meta-structure, or changes in other aspects of transcriptional or signaling networks that render them more noisy and less robust over time.

But to the contrary: it is the very essence of the SENS platform that it proposes precisely that entropic decay should be addressed *directly*, as the primary therapeutic target, rather than by perturbing metabolism -- a mischaracterization asserted, and indeed used as the basis of a straw-man fallacy, in the Nuland article. That is, the SENS platform (4,5) embraces a series of interventions designed precisely to reverse the stochastic decay of biomolecules and (at an emergent level) biological processes by either the direct undoing of the original lesion (as eg. through the reversal of advanced glycation endproduct crosslinks via small molecules of which ALT-711 (6) is the prototype) or by severing the link between such lesions and pathology (as eg. the allotopic expression of the 13 mtDNA-encoded proteins from nuclear transgenes, thus rendering harmless mtDNA deletions inflicted by nonenzymatic mitochondrial free radicals (7)).

The SENS platform addresses each of the specific examples of entropic decay cited by Estep, with the seeming exception of gene dysregulation:

> Many recent experiments,
> especially large-scale microarray transcript profiles of aging, support
> this general concept of time-dependent decay of orderliness (for
> examples, see references 1, 2, and 3).

However, such changes are in fact almost certainly addressed by the SENS platform because there is a very strong case to be made that such shifts in gene expression with age are secondary to other changes whcih are themselves subject to the SENS panel of interventions.

That is: such shifts are either the result of an "aging program," or they are secondary to some primary, and fundamentally entropic, aging process. Since the former is rejected on theoretical grounds by the consensus of researchers into the role of evolutionary pressure into aging (8), the latter must hold. And indeed, the most useful investigations into such shifts -- those in which shifts in gene expression associated with normal aging are compared with those undergone in animals subjected to calorie restriction (CR) (9), which (as Estep well knows) is the sole intervention known to retard biological aging in mammals. These studies have found that the most prominent classes of genes undergoing shifts which both occur with aging are retarded by CR (and which are thus most likely related, as cause or as effect, to primary aging processes) are those involved in inflammation and antioxidant defense -- gene classes, that is, whose natures imply precisely that their expression has been altered in response to underlying molecular lesion(s). But all such entropic processes appear to be embraced by the SENS platform (4,5); therefore, the redressing of such processes via the SENS panel of interventions is predicted to obviate the secondary shifts in gene expression associated with aging.

Similar logic applies to Estep's question as to by what by what signals the stem cells to be used therapeutically in the SENS platform are to be guided to assume their proper role. Not only is it the case (as de Grey has now indicated in his reply of 2/3/2005 3:53:17 PM) that this restoration can be expected occur in part via the information which is imparted to the system by the infusion of new, youthful cells, but it is also the case that such signals will be provided precisely (as Estep phrases it) "by the highly orderly signaling that already exists in vivo," since (again) the obviation, via the SENS interventions, of the cellular pathology induced by primary age changes can be confidently predicted to normalize the secondary shifts in signaling networks which occur in biological aging.

Estep also states more broadly that "mainstream scientists have produced substantial evidence not addressed by de Grey and his plan." Presuming that this evidence is not addressed either in de Grey's scientific papers, or by the replies which he or I have given to Estep's comments in the present forum, it would be of interest to hear from Estep of what further evidence he was thinking. As in all scientific endeavor, only through the uncovering of such weaknesses in the SENS platform can the panel of proposals be strengthened and its flaws addressed before its application to experimental animals and, ultimately, human clinical use.


> 1. Ly DH, Lockhart DJ, Lerner RA, Schultz PG. Mitotic misregulation and
> human aging. Science. 2000 Mar 31;287(5462):2486-92.
> 2. Whitney AR, Diehn M, Popper SJ, Alizadeh AA, Boldrick JC, Relman DA,
> Brown PO. Individuality and variation in gene expression patterns in
> human blood. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1896-901. Epub
> 2003 Feb 10.
> 3. Welle S, Brooks AI, Delehanty JM, Needler N, Thornton CA. Gene
> expression profile of aging in human muscle. Physiol Genomics. 2003 Jul
> 07;14(2):149-59.
4: De Grey AD.
Challenging but essential targets for genuine anti-ageing drugs.
Expert Opin Ther Targets. 2003 Feb;7(1):1-5.
PMID: 12556198 [PubMed - in process]

5: de Grey AD, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJ, Stock G.
Time to talk SENS: critiquing the immutability of human aging.
Ann N Y Acad Sci. 2002 Apr;959:452-62; discussion 463-5.
PMID: 11976218 [PubMed - indexed for MEDLINE]

6. Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S.
Advanced glycation end-product cross-link breakers: a novel approach to
cardiovascular pathologies related to the aging process.
Am J Hypertens. 2004 Dec;17(12 Pt 2):23S-30S.
PMID: 15607432 [PubMed - in process]

7. de Grey AD.
Mitochondrial gene therapy: an arena for the biomedical use of inteins.
Trends Biotechnol. 2000 Sep;18(9):394-9. Review.
PMID: 10942964 [PubMed - indexed for MEDLINE]

8. Kirkwood TB, Austad SN.
Why do we age?
Nature. 2000 Nov 9;408(6809):233-8. Review.
PMID: 11089980 [PubMed - indexed for MEDLINE]

9. Weindruch R, Kayo T, Lee CK, Prolla TA.
Gene expression profiling of aging using DNA microarrays.
Mech Ageing Dev. 2002 Jan;123(2-3):177-93.
PMID: 11718811 [PubMed - indexed for MEDLINE]


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Posted 15 February 2005 - 02:44 AM

Nicely written, Michael.

You have also captured Aubrey's key strategy which is to avoid "perturbing", as you say metabolism, which I take it to also mean avoid directly dealing with the causes of perturbation in gene expression and instead deal with their effects.

This is the essence of Aubrey's SENS philosophy - get the job done with as little information as possible. A shrewdly efficient system with one proviso - as the information landscape changes so too should the intervention route if greater efficiencies are to be realized.

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