1 reply to this topic

[Michael]

All:

Last year, as part of the special double issue on "anti-aging medicine," Leonard Hayflick (of "Hayflick limit" fame) wrote a remarkably fallacy-laden paper entitled '"Anti-aging" is an oxymoron' (1), in which he argued that "No intervention will slow, stop, or reverse the aging process in humans." I took issue with this -- both the arguments and the conclusions -- and, along with a briefer piece critiquing the rampaging pessimism running thru' the entire double edition (2), wrote a detailed critique of this particular paper which has finally been published (3), along with Hayflick's response (4).

Hayflick's response is again riddled with fallacious arguments -- mostly repeating fallacies in the first paper (2) already pointed out in my commentary (3) (most notably the composition fallacy of aging of confounding the aging of an organism as a structured whole with the aging of its constituent biomolecules, but also including the transparently self-contradictory statement that he has "never maintained that intervening in the aging process in humans is impossible" (4), despite re-quoting his own dictum that "no intervention will slow, stop, or reverse the aging process in humans," because (a) "it cannot be done today", (b) "it is highly improbable in the future", and "There are countless known biological processes where human intervention is either [c] presently not possible or [d] ethically undesirable" -- when he didn't merely say that no CURRENTLY-AVAILABLE intervention CAN slow aging, or that doing so would be unethical, or that it is merely IMPROBABLE that such interventions will be available in the future, but that NO interventioin WILL do it -- full stop. And reading the full texat of his paper (1) makes it very clear that he is saying that it is not only pragmatically, but LOGICALLY and PHYSICALLY impossible to do so -- hence the "Oxymoron" of his title. (English majors will point out that an oxymoron is not a mere contradiction in terms, but that is a quibble for another forum).

But he then goes on to dispute that CR retards aging -- and not just in humans, which is of course a point still very much open to debate and in desperate need of experimental verification (which, unfortunately, will ultimately not be forthcoming for logistical, sociological, and structural reasons -- and IAC the proof would arrive long after WE are dead unless (as seems reassonable) true, robust, age-REVERSING biotechnology of the SENS type becomes available)), but which certainly seems very highly probable on the balance of evidence (see eg my forthcoming paper in AGE). No, Hayflick is denying that we can conclude that CR retards aging in RODENTS! Indeed, he goes on to say that my comment "fails to provide a single reference substantiating this claim" that "aging has been slowed, stopped, or reversed ... in model organisms," when I gave numerous such -- including, of course, the CR paradigm.

Here is what he says about the subject. Against my "orthodox interpretation of CR experiments" (ie, that they show the retardation of biological aging), he offers "several alternative explanations."

"First, gluttony (or some arbitrary high caloric intake) reduces longevity because CR more closely mimics the common "feast or famine" lifestyle of feral animals. Thus, CR may reveal the "true" longevity of animals that would occur if predation, accidents, and pathology were controlled in the wild as they are in the laboratory." I was aware that H had made this argument in the past, but am surprised that he would still advance it today, when we know perfectly well that it isn't true -- as shown, eg, by the monotonic reductioin in the rate of aging in proportion to the reduction of Caloric intake to levels of CR well below the mere 20% at which mice cease menstrual cycling (5) (which would mean the end of the species if animals were thus CRed in nature) and (more debatably) (b) by Austad's recent experiments in wild-derived mice (6,6a,6b).

Hayflick's second objection: "CR, absent biomarkers, has not been demonstrated to slow, stop, or reverse the aging process but it has been shown to increase average life expectancy by delaying or preventing pathology or, more likely, directly effecting longevity determinants ". Anyone who has read my original comment (3) will know that I have already shown that what H means by "longevity determinants " amounts to "deteminants of the rate of aging." Also, of course, one of the reasons that we can confidently say that CR retards aging in rodents is that it does NOT jut increase AV'G life expectancy, but species-specific maximum lifespan, and that it genuinely extends the curve in mice and increases MRDT in rats -- along with reducing the entropic decay of the organism's constitutent biomolecules that underlie aging (a point that Hayflick disputes, again using the composition fallacy pointed out in my commentary) and preserving youthful physiological function on many parameters.

Third, H argues, "CR, when administered early in life, is known to extend the chronological time during which early developmental changes occur. This effect occurs well before age changes appear, thus providing evidence that CR affects longevity determinants and not the aging process" -- which is nonsense, since (aside from the fact that (again) "longevity determinants " ARE the determinants of the aging rate, and that the proffered counterexplanation (interventioin in development) is based on a long-debunked "programmed aging" "developmental program" paradigm) it was shown over 20 yrs ago by Walford's and Weindruch's seminal paper (7), by several groups since, and most strikingly of all just recently by Spindler's group (8), that CR also slows down aging (as shown by extended species-specific maximum lifespan, extension of physiological function, and reduced molecular lesions to the organism (not, as Hayflick would fallaciously counter, the individual constituent biomolecules) when instituted long after such changes are long over.

This guy did one really seminal series of experiments on replicative senescence in cultured cells 40 years ago, and has ever since maintained the public profile of an "authority" on biological aging, despite putting out this kind of thing. The mind boggles.

If anyone would like a copy of Hayflick's original, my comment, and his reply, for personal research purposes, please PM me. Give me a day or 2 to collect all requests and I'll send 'em off in a batch.


-Michael

1: Hayflick L.
"Anti-aging" is an oxymoron.
J Gerontol A Biol Sci Med Sci. 2004 Jun;59(6):B573-8.
PMID: 15215267 [PubMed - indexed for MEDLINE]

2. Rae MJ.
All hype, no hope? Excessive pessimism in the "anti-aging medicine" special sections.
J Gerontol A Biol Sci Med Sci. 2005 Feb;60(2):139-40; author reply 140-1. No abstract available.
PMID: 15814852 [PubMed - indexed for MEDLINE]

3. Rae MJ.
Anti-Aging Medicine: Fallacies, Realities, Imperatives
J Gerontol A Biol Sci Med Sci. 2005 Oct; 60(10):1222-7.
No PMID yet.

4. Hayflick L.
AUTHOR'S RESPONSE TO COMMENTARY: Anti-Aging Medicine: Fallacies, Realities, Imperatives
J Gerontol A Biol Sci Med Sci. 2005 Oct; 60(10):1228-32
No PMID yet.

5. Nelson JF, Gosden RG, Felicio LS.
Effect of dietary restriction on estrous cyclicity and follicular reserves in aging C57BL/6J mice.
Biol Reprod. 1985 Apr;32(3):515-22.
PMID: 4039610 [PubMed - indexed for MEDLINE]

6. Austad SN, Kristan DM.
Are mice calorically restricted in nature?
Aging Cell. 2003 Aug;2(4):201-7.
PMID: 12934713 [PubMed - indexed for MEDLINE]

6a. Miller RA, Harper JM, Dysko RC, Durkee SJ, Austad SN.
Longer life spans and delayed maturation in wild-derived mice.
Exp Biol Med (Maywood). 2002 Jul;227(7):500-8.
PMID: 12094015 [PubMed - indexed for MEDLINE]

6b. Austad SB.
[GSA Meeting presentation, 2000, and personal correspondence -- no proper refs, and I wish he would $*#!! publish)

7. weindruch R, Walford RL.
Dietary restriction in mice beginning at 1 year of age: effect on life-span and
spontaneous cancer incidence.
Science. 1982 Mar 12;215(4538):1415-8.
PMID: 7063854 [PubMed - indexed for MEDLINE]

8. Dhahbi JM, Kim HJ, Mote PL, Beaver RJ, Spindler SR.
Temporal linkage between the phenotypic and genomic responses to caloric restriction.
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5524-9. Epub 2004 Mar 25.
PMID: 15044709 [PubMed - indexed for MEDLINE]

[John Schloendorn]

Finally got around to reading this, sorry it took so long. Wow, nice battle you two had there... You could really have been nicer to each other, both of you.

I guess it boils down "The rate of aging: a counterproductively undefinable term"[1]. You used your own definition of aging to attack what Hayflick said about his definition and vice versa. (Although do I think a considerable number of inconsistencies in his argument remain even within his own definition).

For example, if Hayflick defines aging as something that happens to individual biomolecules, then indeed no intervention has been shown to affect its rate, and it is not clear how this could be in principle. However, he should have kept pathology completely out of his definition, because pathology clearly can be reversed (and since when does pathology happen to biomolecules??).

I agree with you that the distinction between what Hayflick calls "longevity determinants" and "aging" is artificial, but then again it is legitimate to make such a distinction if you carefully define it. "Aging" in Hayflick's sense thereby ceases to have much in common with what the man in the street thinks when hearing "aging", but then again that's legitimate for an academic.

I think it is in general unwise to write a counterproductively undefinable term on ones flag. "Fight aging" makes a nice catchphrase, but technically it is misleading and could be called arrogant. We all know that SENS isn't about fighting aging (whatever it may be) at all, but about fighting damage that would cause pathology and death if not fought and that's all there is to it.

[1] de Grey AD. "The rate of aging": a counterproductively undefinable term. Rejuvenation Res. 2005 Summer;8(2):77-8.