For a decade we have known that Alzheimer's (AD) amyloid-beta protein (Abeta) exists normally as a soluble, molecule and is associated in blood and CSF with high density lipoproteins (HDL) [detailed in 2].

Lipoproteins provide the proper thermodynamic environment for Abeta, which shares with other apolipoproteins the unique structural property of amphipathicity [2]. In the absence of lipids, such molecules easily cross- and self- aggregate and undergo oligomerization. Some also form amyloid fibrils, structures that are present in separate types of human amyloidosis (for ex., apoA-I, serum amyloid A). Previous reports have indicated that natural Abeta does not cross link with other apoliporoteins in normal cerebrospinal fluid (CSF) high density lipoproteins (HDL), but does crosslink with HDL apolipoproteins in CSF samples from Alzheimer's patients [2]. The AD condition thus may represent a pathological alteration of the lipoprotein structural integrity in a way that breaks monomeric Abeta-to-lipid interaction and favors the interaction of Abeta-to-apolipoprotein (shown for ApoE and ApoJ) [2] or Abeta-to-Abeta, which creates the oligomers that are the subject of the Science study (18 April, p. 486).

Of major importance for this report, in our view, is the potent inhibition by lipoproteins of the neural toxicity of Abeta [3, 4, 5]. Such inhibition of Abeta toxicity by lipoproteins was shown in SH-SY5Y cells [3]. These same cells were used in the Science study under different experimental conditions to prove Abeta oligomer toxicity; the effect of lipoproteins on oligomer toxicity was not tested in this report.

We also think that introducing a control of specificity (perhaps by pre-adsorbing anti-oligomer antibodies with Abeta oligomers) in an immunofluorescent staining of Alzheimer's brain tissue would add confidence that the structures detected are indeed Abeta oligomers. This is especially important, because the micellar Abeta used for production of the anti-oligomer antibodies may mimic the conformation of lipid-bound Abeta (and of other membrane-bound proteins [6]), which was similarly shown to have distinct immunoreactivity [7].

Sincerely,

Alexei Koudinov, MD, PhD
neuroscientist and editor
http://anzwers.org/free/neurology
http://neurobiologyoflipids.org

Footnote: This 300 word letter was first submitted to Science magazine (online submission no. 30545, April 21, 2003; rejected on May 1, 2003).

Competing financial interests: I do not have any competing financial interest. I aim free information dissemination and an unbiased development of Alzheimer's neuroscience. I observe the Society for Neuroscience Guidelines for Responsible Conduct Regarding Scientific Communication. Discussed herein Science report (18 April, p. 486) and earlier Science viewpoint article on oligomeric Ab by Dennis J Selkoe (25 Oct 2002, p. 789) lack appropriate competing interest declaration. Such interests are disclosed in Forbes magazine and in Science (Corrections and clarifications. Science 27 Sept 2002, 297: 2209), respectively. For further details please see my Open letter to Public Citizen's Health Research Group on Alzheimer's disease research (SAGE KE, 21 Feb 2003).

References:

1. Shuster AM, Gololobov GV, Kvashuk OA, Bogomolova AE, Smirnov IV, Gabibov AG. DNA hydrolyzing autoantibodies. Science 256: 665-7 (1992) [ PubMed ].

2. Koudinov AR, Berezov TT, Koudinova NV. The levels of soluble Ab in different HDL subfractions distinguish Alzheimer's and normal aging CSF: implication for brain cholesterol pathology? Neurosci Lett. 314: 115-118 (2001) [ PubMed ][ Author Related Articles and Scientific Correspondence ].

3. Cedazo-Minguez A, Huttinger M, Cowburn RF. Beta-VLDL protects against A beta(1-42) and apoE toxicity in human SH-SY5Y neuroblastoma cells. NeuroReport 12: 201-206 (2001) [ PubMed ].

4. Farhangrazi ZS, Ying H, Bu G, Dugan LL, Fagan AM, Choi DW, Holtzman DM. High density lipoprotein decreases beta-amyloid toxicity in cortical cell culture. NeuroReport 8: 1127-1130 (1997) [ PubMed ].

5. Koldamova RP, Lefterov IM, Lefterova MI, Lazo JS. Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits Abeta aggregation and toxicity. Biochemistry. 40: 3553-3560 (2001) [ PubMed ].

6. Soreghan B, Pike C, Kayed R, Tian W, Milton S, Cotman C, Glabe CG. The influence of the carboxyl terminus of the Alzheimer Abeta peptide on its conformation, aggregation, and neurotoxic properties. Neuromolecular Med. 1: 81-94 (2002) [ PubMed ].

Friday, April 21, 2006

Dear Dr. Gray and Dr. Bürkle:

I enjoyed your article in SAGE-KE about the recent SENS-II conference, which gave a nice overview of the meeting and the areas of controversy around Aubrey’s ideas and activities.

As one of the authors of the EMBO Reports article, I thought I ought to respond to your speculation about an area of apparent ambiguity. You write:

[quotation] Positing that the SENS agenda is 'so far from plausible that it commands no respect at all within the informed scientific community,' these authors wish to 'dissociate themselves from the cadre of those impressed by de Grey's ideas in their present state.' This statement is both forceful and ambiguous. It can be read as the relatively benign wish to be placed in a nonoverlapping circle on the Venn diagram of who believes what in aging-related research, or it can be read as a more sinister threat of shunning the apostates. If the authors intended the latter, what are the requirements for admission into the shunned cadre? It could not be attendance at one SENS conference, for some of the signatories have attended. Would attendance at both suffice? Further, is it not possible to express interest in or contribute to some of the scientific objectives of SENS without being judged a SENS acolyte? [end quotation]

I am very sorry that the article may have left the misimpression of its cosignators as sinister and threatening bullies, the kind of people who take attendance at meetings and make lists of evil-doers destined to be confined to some scientific Guantanamo, where they are denied access to their copies of Rejuvenation Research, and from which much-needed shipments of liquid nitrogen and telomerase are diverted to other purposes. It was intended, as you speculated, to express a fully benign wish, inviting comrades to see the light and step into the part of the Venn diagram where people support aging research, do some of it themselves, go to any conferences they want to attend, and talk to and be friendly with anyone they wish, but are careful to try to distinguish fact from speculation, and speculation from fantasy.

I don’t see any need to define a shunned cadre, with or without admission requirements. Nearly all of the scientific objectives on the SENS menu are interesting, and people working on them are likely to make discoveries of great importance. But when colleagues, like Aubrey, feel a need to exaggerate the speed with which biogerontology will produce practical advances, or exaggerate the likelihood that old people can be converted into spanking new ones, I think this is in general bad for society and harmful to the scientific enterprise. I think it’s important for scientists to do their part to help administrators, journalists, and interested laypersons distinguish strategy from wish-fulfillment, and critical thought from advertising. Your SAGE-KE article is, in my view anyway, a fine example of how to approach this kind of knotty issue.

First, I have never remotely suggested that participation in my SENS conferences constitutes tacit agreement with me as to SENS's feasibility. (It is not clear from Gray and Buerkle's text whether they think I have been doing this, but a reader might easily form such an impression.) That would be a ludicrous inference, given that I am on abundant record as knowing full well how radical SENS is, and also that I have repeatedly taken a decidedly more established approach when I seek to determine whether other scientists support a component of SENS, namely, first to expose them to it for a whole day and then to ask them to co-author a paper on it [2-5]. (It is notable that only one of my co-authors on any of these papers signed Warner et al.'s recent denunciation of SENS [6]; one can draw one's own conclusions from the fact that her name was mis-spelled in the list of authors.) There is no reason whatever for a SENS conference participant to be concerned that his or her opinions regarding SENS will be misrepresented either by me or by any other SENS advocate. If some of my more energetic detractors seek to make such a link, it is those detractors who should be condemned for impugning the reputations of eminent scientists in an attempt to marginalise me, and if anything, scientists should resist that intimidation by attending SENS conferences in greater numbers than ever. Perhaps this was Gray and Buerkle's point, but if so, I fear that some readers might have missed it.

The converse point also merits a slight correction. While attendance at the SENS conferences means nothing about support for SENS, it does confer at least circumstantial authority to opine on the matters that were presented there. Gray and Buerkle point out that some of the 28 signatories to the recent denunciation of SENS [6] attended, but this may give an exaggerated impression; in fact, and as I pointed out in my response to Warner et al. [7], not one of them attended SENS 2 and only five attended its altogether less SENS-centric predecessor, IABG10, in 2003 (when SENS had less notoriety).

Gray and Buerkle quote the "Position Statement on Human Aging" [8] out of context: the comment there about humans living forever referred to literally that, i.e. no death from age-independent causes either. My agreement with that paper's main thrust, the present non-existence of any true life- extending products, is the reason I endorsed it. I and some other endorsers lobbied the authors vigorously to remove assertions about the probability of such products arriving within our lifetime, but without success; but that was not the paper's main theme, so I judged that an endorsement was still appropriate.

I am perplexed at Gray and Buerkle's implication that I have in some way been tarred with the Hwang brush as a result of his participation in a conference that I organised. If I have, all I can say is that I am in very good company.

Finally, I must take sharp exception to Gray and Buerkle's assessment of the SENS Challenge. When scientists disagree as to the plausibility of a hypothesis or the feasibility of an experiment, they generally do so in cautious terms, and in such circumstances it is entirely proper to be able to express one's view without being required to justify it rigorously. When they express their opinion of a colleague's work using words like "fantasy" and "pretence," however, the object of their derision is entitled to ask for an explanation - and, if years pass with no explanation being forthcoming, to bring his critics' reticence to public notice. Gray and Buerkle say that the terms of the Challenge mean that it allows me to taunt my detractors "baselessly," but that is not true at all: rather, the conclusion that a submission must persuade a panel of independent experts of in order to win (namely, that SENS is so absurd that it should not be dignified with learned debate) is precisely the view that my critics have been expressing off the record for some years and more recently (though only after my strong criticism of their public silence [9]) in print. It is public knowledge [10] that Technology Review began the search for a mainstream gerontologist's demolition of SENS entirely on its own initiative, as a result of having been given a strongly negative but non- specific evaluation of it by experts whom they consulted during 2004, and that the SENS Challenge was begun (with input from the Methuselah Foundation, yes) only after a number of experts declined to write such an article and Technology Review began to wonder whether they had been misled. Thus, Gray and Buerkle are absolutely wrong to suggest that "[t]he TR Challenge serves no purpose but to attract attention to Aubrey de Grey and the increasingly bitter dispute with his detractors" -- rather, it serves the wholly legitimate purpose of testing the hypothesis that my detractors have formed their negative opinions of SENS without the attention to its details that their audience will tend to presume that they have paid. If Gray and Buerkle know of a better way to distinguish that hypothesis from the competing one, advanced by my detractors, that no such commentary has been written simply because experts are too busy to ridicule something so ridiculous, they should suggest it.

In conclusion, my high media profile results from the coherence of the SENS agenda and the incoherence of the criticism that SENS has so far received [7]. This is demonstrated by the fact that SENS has been accorded an almost uniformly positive media treatment (Technology Review's articles in February 2005 being almost the only exception). I am not a soundbite expert, nor am I fond of them. The SENS conferences will thus continue to bring together the world's best science in areas that I consider relevant to extreme life extension, and participants will continue to be able to make up their own minds as to whether that science adds up to a viable approach to greatly postponing aging.

1. D. A. Gray, A. Buerkle, SENS and the Polarization of Aging-Related Research. Sci. Aging Knowl. Environ. 2006 (7), pe8 (2006).

2. de Grey ADNJ, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJM, Stock G. Time to talk SENS: critiquing the immutability of human aging. Annals NY Acad Sci 2002; 959:452-462.

3. de Grey ADNJ, Baynes JW, Berd D, Heward CB, Pawelec G, Stock G. Is human aging still mysterious enough to be left only to scientists? BioEssays 2002; 24(7):667-676.

4. de Grey ADNJ, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CAB, Porter ACG. Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers. Annals NY Acad Sci 2004; 1019:147-170.

5. de Grey ADNJ, Alvarez PJJ, Brady RO, Cuervo AM, Jerome WG, McCarty PL, Nixon RA, Rittmann BE, Sparrow JR. Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age- related diseases. Ageing Res Rev 2005; 4(3):315-338.

6. H. Warner, J. Anderson, S. Austad, E. Bergamini, D. Bredesen, R. Butler, B. A. Carnes, B. F. Clark, V. Cristofalo, J. Faulkner et al., Science fact and the SENS agenda. What can we reasonably expect from ageing research? EMBO Rep. 6, 1006-1008 (2005).

7. de Grey ADNJ. Like it or not, life extension research extends beyond biogerontology. EMBO Reports 2005; 6(11):1000.

8. S. J. Olshansky, L. Hayflick, B. A. Carnes, Position statement on human aging. J. Gerontol. A Biol. Sci. Med. Sci. 57, B292-B297 (2002).

9. de Grey ADNJ. Resistance to debate on how to postpone ageing is delaying progress and costing lives. EMBO Rep 2005; 6(S1):S49-S53.