CRer-CR agnostic point-counterpoint

[Guest guest]

Hi All,

See the below papers regarding points-counterpoints between a CRer and a CR

agnostic.

Rae MJ.

Anti-Aging Medicine: Fallacies, Realities, Imperatives.

J Gerontol A Biol Sci Med Sci. 2005 Oct;60(10):1223-1227. No abstract available.

PMID: 16282551

LAST year's double special sections of the Journal on " Anti-Aging Medicine "

featured

several contributions from the distinguished experimentalist Leonard Hayflick.

Among

these was " ‘Anti-Aging’ is an Oxymoron, " (1) which ends with a question that

clearly

lays out the importance of the subject of these issues: since there is an

" almost

universal belief by geriatricians that the greatest risk factor for all of the

leading causes of death is old age[,] why then are we not devoting significant

resources to understanding more about the greatest risk factor for every

age-associated pathology by attempting to answer this fundamental question: ‘Why

are

old cells more vulnerable to pathology than are young cells?’ "

However pointed Dr. Hayflick's rhetorical question may be, it can only strike

its

reader as an Herculean non sequitur as a conclusion to this essay. For the

thesis of

the remainder of the article is that " No intervention will slow, stop, or

reverse

the aging process in humans " —indeed, that the very notion of such intervention

violates the laws of both logic and physics. If, as Hayflick contends,

understanding

why old cells are more vulnerable to pathology than are young cells will not

allow

us to intervene in the process, then understanding aging is a purely

curiosity-driven venture of no practical biomedical value—in which case

politicians,

the publicly-funded research bureaucracy, and the taxpaying public are right to

refuse to invest scarce resources into advancing our knowledge in the field.

Fortunately, the arguments supporting the " Oxymoron " thesis are fundamentally

flawed

in their logic—and sometimes in their representations of experimental data as

well.

That there is likely to be erroneous argumentation somewhere in the article

should

be clear from the outset to most readers of the Journal, since—in response to

Hayflick's challenge that " When it becomes possible to slow, stop, or reverse

the

aging process in the simpler molecules that compose inanimate objects, such as

machines, then that prospect may become tenable for the complex molecules that

compose life forms " —anyone familiar with the biogerontological literature can

readily cite examples in which the latter has already been accomplished in model

organisms. The most obvious example is calorie restriction (CR), through which

researchers have been intervening in the rate of loss of molecular fidelity and

of

age-associated acceleration of vulnerability to pathology in mammals for seven

decades. As Hayflick—and most readers—must be aware, CR has been robustly

documented

to retard the accumulation of a wide range of the molecular lesions suspected to

underlie aging, and to thereby extend youthful physiological function and

species'

maximum life span to a degree proportional to the duration and severity of the

restriction of energy intake (2)—an effect that appears to be inducible to

similar

results throughout the life span, including very late in middle age (3). A

variety

of genetic interventions—primarily based on modulation of signaling by the

insulin

and insulin-like growth factor-1 axes—also slow down key aspects of biological

aging

in laboratory rodents (somewhat less certainly) (4) and lower organisms (5,6).

Hayflick's conclusion being untenable, we must look to his arguments to see how

they

fail to lead to it. The present essay is devoted to this task.

THE AGING OF WHOLES AND OF PARTS

Much of the article is centered on an argument that rests on a fallacy of

composition. Hayflick defines aging as " a stochastic process ... caused by the

escalating loss of molecular fidelity that ultimately exceeds repair capacity

and

increases vulnerability to pathology or age-associated diseases " whose

" fundamental

cause ... is rooted in the intrinsic thermodynamic instability of most complex

biological molecules whose precise three-dimensional folded structures cannot be

maintained with accuracy indefinitely " (1). From this springboard, he makes the

quite breathtaking leap of logic to the conclusion that " because the aging

process

is a universal property of all molecules ... intervention in the aging process

borders on the likelihood of violating fundamental laws of physics, " rendering

" being ‘anti-aging’ comparable to being ‘anti-gravity’ or oppose[d to] other

fundamental laws of physics and chemistry " (1).

The error in this reasoning is readily apparent. Hayflick is asserting that

because

the " aging " of each individual biomolecule in the organism is an inevitability

of

the Second Law of Thermodynamics, therefore " No intervention will slow, stop, or

reverse the aging process in humans. " But of course, humans are not identical to

each of their constituent biomolecules or even to a simple sum thereof

(composition

fallacy), but are integrated wholes whose constituent biomolecules are in a

continuous process of turnover.

The aging of an organism is thus not the same as the aging of each of the

organism's

transiently constituent biomolecules, and true anti-aging medicine does not

necessitate violation of the physical law that dictates the vulnerability of

each

such biomolecule to entropy. Rather, such intervention would either slow the

rate at

which these biomolecules are damaged, or increase the rate of their repair and

replacement, leading to a slowing or reversal of the rate at which the overall

molecular fidelity of the organism is lost. Any intervention that accomplishes

these

goals at the molecular level, leading to the reduction, arrest, or reversal of

the

age-associated acceleration of vulnerability to pathology of the organism, would

constitute " anti-aging medicine " —despite the fact that individual biomolecules

would

continue to ultimately fall prey to entropic decay.

GENES: REGULATORS OF THE RATE OF AGING

Closely related errors are perpetrated in the sections " The Determinants of

Longevity " and " Genes Do Not Govern Aging. " Hayflick begins by making an

uncontroversial distinction:

Potential longevity is determined by the energetics of all molecules present at

and

after the time of reproductive maturation ... The determinants of the fidelity

of

all [such] molecules ... are, of course, governed by the genome ... by the

excess or

reserve physiological capacity reached at the time of sexual maturation that,

through natural selection, was achieved to better guarantee survival to that age

....

[but] the determination of longevity is incidental to the main goal of reaching

reproductive maturity and is only indirectly determined by the genome. Thus,

genes

do not drive the aging process but they indirectly determine potential longevity

[my

emphasis] (1).

However, Hayflick then proceeds to draw from this distinction a quite

unjustified

conclusion: that " Longevity determination is an entirely different process from

aging and is independent of it " (1).

It is clear that the use of this distinction to advance the " Oxymoron " thesis

rests

on a fallacy of ambiguity, again relying on the composition fallacy outlined

above.

Again: the fact of " aging " of individual biomolecules is not the same as the

rate of

aging of the organism. To suggest that " Longevity determination is an entirely

different process from aging and is independent of it " is to erect a " Chinese

wall. "

For while it is true that the " determinants of longevity " to which Hayflick

refers

in distinction to " the aging process " do not drive the aging of individual

biomolecules—which is, indeed, the inevitable result of entropy— " longevity

determination " transparently constitutes the genome's role in regulating the

rate of

accumulation of molecular damage—that is, of aging.

Reference to a statement in one of his previous publications (7) might serve to

remind Hayflick of the artificiality of claiming longevity determination to be

" an

entirely different " and " independent " process from aging: " One class of animals

that

may provide some answers to the determination of longevity are those animals

that do

not reach a fixed size in adulthood and age slowly or not at all. If these

animals

do age, the process is either negligible or it occurs below the limits of

detection

[my emphasis]. "

Moreover, by focusing only on the genome's role in the initial determination of

the

intrinsic thermodynamic properties of the organism's constituent biomolecules,

Hayflick presents a misleading picture of biological quietism in the face of the

stochastic forces of aging, in which the genome simply creates biomolecules of

greater or lesser thermodynamic stability, and then (like the Deist God)

releases

its creatures to an unregulated biochemical process of entropic " unwinding. "

This

quite partial image lends illusory plausibility to Hayflick's thesis of the

impossibility of modulating the rate of aging. In fact, however, the genome's

involvement in the determination of longevity also includes the regulation of

the

intensity of the biochemical forces of aging to which those biomolecules are

exposed, and the rate at which damage is interdicted and repaired.

Regarding the former: as many definitions of aging [e.g., Strehler's (8)]

clarify, a

distinguishing feature of aging per se is that it is intrinsic to the organism.

The

reason for this is not only because their constituent biomolecules are subject

to

the Second Law of Thermodynamics, but also because the very biochemistry

underlying

normal metabolism entails the production of reactive intermediates, such as the

stochastic mitochondrial generation of reactive oxygen species (mtROS) during

oxidative phosphorylation, or the reactive chemistry of glucose that leads to

the

nonenzymatic glycation of proteins. And of course, the intensity of these

metabolic

forces varies according to specifications laid out in the organism's underlying

genetic inheritance, as can be observed via interspecies comparisons (9,10).

Since key forces of stochastic damage are partly subject to genetic regulation,

they

can be modulated by interventions that alter the expression of the relevant

genes.

As an example, consider the rate of formation of mtROS. It is determined by the

genetically established design of the mitochondrion; it therefore varies from

species to species; it is negatively correlated with species maximum life span;

and

it can be strongly argued to be a key driver of aging (10,11). Consistent with

both

the mitochondrial free radical theory of aging and the biomedical tractability

of

aging, the two experimental interventions that most clearly slow aging in

mammals

(CR and the Prop-1 gene mutation of the Ames dwarf mouse) lead to reduced

generation

of mtROS, and lower accumulation of resulting molecular lesions, relative to

controls (10,12).

Hayflick's article also neglects the other side of the balance sheet of aging:

the

machinery—antioxidant enzymes, DNA repair systems, molecular chaperones, the

lysosome and proteasome, and so forth—that exists precisely to prevent aging

damage

from occurring, and/or to remove, repair, or replace damaged biomolecules. While

alluding to the existence of molecules " that compose the machinery involved in

turnover, maintenance, and repair, " Hayflick notes only that they are, like all

other biomolecules, " the substrate that incurs the thermodynamic instability, "

rendering them vulnerable to the stochastic forces of aging (1)—ignoring their

contribution to the prevention of " aging " in the rest of the body's

biomolecules.

Again, the existence of this machinery implies the ability to modulate the aging

process. As is the case with the rate of production of molecular damage, so the

species-specific efficacy of the mechanisms that retard or reverse the systemic

accumulation of damaged biomolecules is correlated with the rate of aging in

that

species (13), and can be manipulated experimentally. CR alters the activity of

many

of these maintenance mechanisms, and it is widely accepted that these

optimizations

contribute to the decelerated loss of molecular fidelity and physiological

function—and resultant extensions of youthful and total life span—upon which the

conclusion that CR retards the aging process is founded (2,14). Likewise, we now

know of numerous stress resistance genes whose manipulation retards biological

aging

in yeasts, Caenorhabditis elegans, and Drosophila—and possibly the laboratory

mouse

(5,6,15,16) [but see (4)].

Hayflick himself presents a more complete picture of evolutionarily determined,

genetically regulated maintenance of the organism's molecular fidelity in a

separate

article in the same issue of the Journal, where he is not concerned with the

promulgation of the " Oxymoron " thesis:

Most complex biological molecules are constantly renewed in order to replace

preexisting forms whose energetics will only permit short lives, or to replace

and

dispose of molecules that have incurred errors and may be harmful. Thus, the

complex

mechanisms that drive turnover, repair, quality control, and waste disposal also

have evolved to guarantee that their molecules will retain functional capacity

long

enough for their possessor to reach reproductive success ... After reproductive

success, the random loss of molecular fidelity continues to escalate and, for

many

molecules, soon exceeds repair and turnover capacity ... [M]any of these

stochastic

processes ... occur prior to sexual maturation. ... However, repair processes

must

be capable of managing these losses in molecular fidelity with such efficiency

that

reproductive success is reached by most members of a species, otherwise the

species

would vanish (17).

Hayflick's statement that " Longevity determination is an entirely different

process

from aging and is independent of it " is thus clearly unjustified. Rather, as we

have

seen, while the " determinants of longevity " are not the cause of the simple fact

of

molecular aging, they are precisely the determinants of the rate of organismal

aging—and it is this rate that is the target of biomedical gerontological

intervention. And while the thermodynamic stability of the body's constituent

biomolecules is unlikely to be susceptible to modulation without harm to the

organism, the two other determinants of longevity—the rate at which the body's

metabolic biochemistry induces damage, and the rate at which such damage is

prevented, interdicted, or removed—clearly are susceptible to experimental

manipulation in lower organisms. Just as there are mechanisms of aging, so there

are

mechanisms of anti-aging—and both are therapeutic targets for genuine anti-aging

medicine.

" ANTI-AGING MEDICINE " : PRESENT REALITY AND EMERGING PROBABILITY

Hayflick next attempts to illustrate the impossibility of retarding aging

through

the use of an analogy between the aging of a person and the " aging " of an

automobile:

Because of the randomness of the aging process, the rate of loss of molecular

fidelity varies from organ to organ, from tissue to tissue, and from cell to

cell

.... result[ing] in a few human tissues ... that become the weakest links and

whose

failure ultimately leads to pathology and death ... It is analogous to what

occurs

in the varying rates of aging in components of ... automobiles. ... In the

vernacular of engineers, the time when the weakest link in a complex system

fails is

called the ‘mean time to failure.’ For a cheap car, it might be 4 or 5 years,

and

for Americans born today, it is about 76 years (1).

This analogy is a good one as far as it goes, but it is misused to again assert

either the logical impossibility or the hopeless impracticability of anti-aging

intervention: " we cannot even slow, stop, or reverse the aging process in such

far

simpler entities than ourselves as are, for example, our own automobiles " (1),

he

claims—much less that of so complex a system as a living organism. But to the

contrary: we are fully capable of doing so, as any antique car enthusiast can

attest. We do so at the molecular level by applying anti-rust treatments to the

body-in-white, or by using sophisticated lubricants that reduce metal fatigue,

or by

purchasing gasoline additives that remove deposits of less stable or heavier

gasoline components. We also reverse the effects of aging in automobiles by

replacing aged components with new ones [for analogous biological advances

toward

which, see e.g., (18)].

Hayflick is aware of all of this, but attempts to dismiss it with the comment

that

" our repair processes also age, and ... no one has yet solved the aging problem

in

cars or in the repair shops themselves, who like all else in the universe,

suffer

the same fate " (1). This is yet another extension of the composition fallacy

outlined above. Again, the inevitability of the fact of aging of individual

biomolecules does not render impossible the alteration of the rate of aging of

the

organism/automobile as a whole. If our tools (whether they be small molecule

agents

or sprocket wrenches) themselves " age " with time in some sense, we will continue

to

maintain and repair the organism/automobile by replacing our worn tools with new

ones. The only absolute entropic impediment to ongoing maintenance of organism

or

automobile that readily presents itself is the projected " heat death " of the

universe.

THE BIOMARKER BUGABOO: AGAINST COPENHAGEN

After observing (correctly) that " None of the products or services touted by

[current " anti-aging " hucksters] has ever been demonstrated to perturb " aging,

Hayflick proceeds to assert that " Common sense should dictate that this must be

true " [my emphasis]—that is, that we could not have biogerontological

interventions

available at this time—because " Absent [verifiable biomarkers of aging], it is

impossible to demonstrate an effect on a rate " of aging (1)—and that, therefore,

the

assessment of the efficacy of a putative anti-aging intervention is presently

impossible.

Before addressing this argument, it should be pointed out that it actually does

not

support the " Oxymoron " thesis that there is a logical inconsistency in the very

notion of the development of such interventions. However, because acceptance of

these arguments have implications for the practical feasibility of the

development

of genuine anti-aging medicine, they should be assessed.

While there is some epistemological merit to the assertion that biomarkers of

aging

are required to assess the efficacy of an alleged anti-aging medicine, the

absence

of verifiable biomarkers does not constitute an insurmountable heuristic

impediment

to the development of such. It has not, for example, prevented biogerontologists

from reaching the clear conclusion that CR retards aging in laboratory animals,

precisely because CR's effects on the aging phenotype (19)—and on age-associated

acceleration of vulnerability to pathology and mortality—are so manifestly clear

as

to obviate the need for a surrogate metric of the process. Clinical trials of

candidate anti-aging medicines may likewise lead to results that, while

difficult to

quantitate, are (like the material placed before Justice Potter in 1973)

readily identified when seen.

Certainly, however, a more systematic set of endpoints for such trials would be

preferable. A reasonably clear, short-term path forward for developers of

biomedical

gerontological interventions is implicit in Hayflick's careful definition of

biological aging. Biogerontology has identified many—and perhaps all—of the

molecular lesions that contribute to the aging process (13,20,21). Many of these

same lesions also contribute to specific diseases or pathologies of aging, as in

the

case of nonenzymatic glycation of renal basement membrane collagen in renal

disease

and atherosclerosis, or the accumulation of insoluble aggregates in

atherosclerosis

and neurodegenerative disease.

Suppose, then, that an intervention were demonstrated (a) to retard aging in

rodents

on similar evidence as that on which CR is already acknowledged to do, ( to

retard

or reverse the accumulation of one or more of these molecular lesions in both

experimental animals and humans, and © to retard or reverse the development of

specific pathologies associated with such lesions in the diseases of aging in

humans. In such an instance, the gerontologist might well be justified in

concluding

(while wearing the engineer's hardhat) that aspects of aging were indeed being

slowed, delayed, arrested, or reversed in persons administered the intervention,

even while acknowledging (while wearing the theoretician's mortarboard) that

this

conclusion may remain tinged with uncertainty for decades.

Again, however, Hayflick's arguments here, even were they sound, represent

potential

technical hurdles to the development of anti-aging medical interventions, rather

than demonstrations of the logical inconsistency of the goal itself.

AGING VERSUS DEVELOPMENT

After briefly repeating previous objections to the tractability of the problem

already demonstrated to be factually or logically untenable, Hayflick attempts

to

demonstrate that the goal itself is misguided in his sections on " Desirability

and

Probability " and " Curiosity Does Not Imply Intervention. " As these objections

are to

the sociological or ethical implications of the project rather than to its

scientific feasibility or logical consistency, they fall outside of the focus of

the

present essay; fortunately, nearly all have been refuted elsewhere (22,23,24).

Suffice it to say that these worries are unfounded, and certainly do not

represent a

convincing counterweight to the unimaginably great burden of morbidity and

mortality

that intervention would alleviate.

But these sections also voice the most grossly transparent error in reasoning in

the

article—an error that is all the more astounding granted its rejection of the

key

premises on which Hayflick's other, more difficult-to-disentangle, a priori

arguments against biogerontological intervention's logical possibility are

founded.

Here Hayflick attempts to deny the desirability of intervention in the aging

process

by a false analogy with intervening in the childhood development: " If

replacement of

organs is an undesirable means of circumventing the aging process, slowing the

process might be viewed more favorably. However, slow physical or mental

development

at any age is viewed universally as a serious pathology. If retarding the mental

and

physical development of someone from birth to age 20 years for, say, 10 years,

in

order to gain a decade of additional life is unattractive, then slowing one's

aging

processes in later life will not be attractive for the same reasons " [emphasis

mine]

(1).

One finds oneself flabbergasted that Dr. Leonard Hayflick should be the author

of

these sentences. Having painstakingly established and pedantically repeated the

careful definition of aging as a purely stochastic process of entropic decline

from

the peak of molecular fidelity and physiological structural perfection attained

at

reproductive maturity, leading to increasing vulnerability to pathology and

death,

he suddenly and without argumentation renounces this definition and reverts to a

biologically naïve picture of aging as a stage in organismal development.

Anyone who has read and understood Hayflick's definition of aging should be able

to

see that the two bear no relationship to one another. To think of aging in terms

of

a developmental program is a widespread intuition, often rationalized in terms

of

group selection as a mechanism that would ensure adaptation to changing

environmental conditions by increasing generational turnover; however, such

formulations are now understood to be fundamentally inconsistent with the

evolutionary theory, which instead understands that senescence is not a selected

trait, but the result of either entropic biochemical decay against which

evolution

selects in accordance with the rate of extrinsic mortality, or the result of the

pleiotropic effects of genes over the life history (25). Indeed, Hayflick in

fact

argues for the former view throughout the rest of the " Oxymoron " article, only

to

unexpectedly revert to the " programmed aging " position in this section. But

clearly,

genetic teleology is not analogous to physical entropy; random molecular decay

is

not analogous to an exquisitely orchestrated sequence of anabolic and catabolic

events; and the process of taking a defenseless infant—incapable of speech,

reproduction, self-propelled motion, or even bladder control—and transforming it

into an adult in the peak of physical and mental capacity and health, is

transparently not analogous to " a stochastic process ... caused by the

escalating

loss of molecular fidelity that ultimately exceeds repair capacity and increases

vulnerability to pathology or age-associated diseases " and at some point the

loss of

the aforementioned capacities.

This false analogy is then used to deny the desirability of intervention in the

aging process, equating it with " the goal of understanding how to stop, slow, or

reverse the development of embryos, fetuses, or the growth of children " (1). To

use

Hayflick's vehicular analogy: it is as if, having devoted an entire article to

the

factors underlying the gradual mechanical decay of an automobile, he were to end

the

document by asserting that an enhanced program of maintenance of the vehicle

would

be undesirable, by equating such an intervention with the halting of the

vehicle's

construction midway along the assembly line.

MORALITY IMPLIES INTERVENTION

Hayflick ends his article with the previously quoted question: granted that

there is

an " almost universal belief by geriatricians that the greatest risk factor for

all

of the leading causes of death is old age[,] Why then are we not devoting

significant resources to understanding more about the greatest risk factor for

every

age-associated pathology by attempting to answer this fundamental question: ‘Why

are

old cells more vulnerable to pathology than are young cells?’ " (1).

Of course, the " Oxymoron " article provides us with the (erroneous) answer to

Hayflick's rhetorical question. If, as the article asserts, intervention in the

aging process is ruled out by the laws of both physics and logic, then

biogerontology research will lead only to increasingly detailed explanations of

the

inescapability of accelerating morbidity and mortality with every passing year.

This

is an endeavor to which politicians, funding bureaucracies, and the public are

rightly reluctant to allocate scarce resources.

However, the arguments alleging the impossibility of intervention in aging on

logical and physical grounds having been seen to be in error, the urgent need to

make research into genuine " anti-aging medicine " the top priority on the

biomedical

research agenda becomes clear. Once this reorientation in research priorities

has

taken place, we can begin to better answer Hayflick's question, and ultimately

develop therapies that uncouple the passage of time from accelerating disease,

disability, suffering, and death.

Hayflick L.

Anti-Aging Medicine: Fallacies, Realities, Imperatives.

J Gerontol A Biol Sci Med Sci. 2005 Oct;60(10):1228-1232. No abstract available.

PMID: 16282552

For a critic who peppers his complaints and his reasoning with the language of a

logician, it should come as some surprise to readers, as it did to me, that all

seven of his most important complaints rest on false premises.

The critic claims that because I believe that, at the time of my writing, " ...

no

intervention will slow, stop, or reverse the aging process in humans, " (1) that

this

is to him " ... an Herculean non sequitur because I have argued that a

fundamental

question in biogerontology should be, ‘Why are old cells more vulnerable to

pathology than are young cells?’ "

The logician has invented a non sequitur where none exists. There are countless

known biological processes where human intervention is either presently not

possible

or ethically undesirable.

The critic might also benefit from knowing that I have never maintained that

intervening in the aging process in humans is impossible, as he falsely alleges.

But, I have, and still do, maintain that it cannot be done today and that it is

highly improbable in the future. For example, time dilation, a major conclusion

from

the special theory of relativity, indisputably results in a slowing of the aging

process (2). In addition, the increase in brain weight/body weight ratios in

animals

for which there exists a continuous fossil record strongly implies that on an

evolutionary time scale, animal and human life spans increase (2). However, I

doubt

that many readers will find that these theoretical possibilities would benefit

them.

The critic concludes that, because I believe that intervention in the human

aging

process is remote, he interprets this to mean that " ... understanding aging is a

purely curiosity driven venture of no practical biomedical value ... " and that

" ...

the taxpaying public are right to refuse to invest scarce resources into

advancing

our knowledge in the field. "

Contrary to this position, research into the fundamental biology of age changes

is,

in the view of many, " ... a purely curiosity driven venture of no practical

biomedical value ... " but, that observation most certainly should not diminish

its

importance. Biologists who, for example, conduct research in human embryology or

development are not motivated to explore these fields with the goal of

intervening

in these fundamental processes. They are driven by the same curiosity that

motivates

most biogerontologists. My embryology and developmental biology colleagues

looked at

me in disbelief when I asked them if the goal of their research was to slow,

stop,

or reverse embryological or developmental processes in humans. The scientific

community accepts without question that curiosity, and not intervention, drives

these and other biologists. Why should the goal of research on the biology of

later

life be any different?

Unlike biologists who study life's earliest stages, the goal for

biogerontologists

is, first, to satisfy their curiosity by understanding the etiology of age

changes.

Once that goal is achieved (it has been achieved but has not been widely

appreciated) (Holliday, R., Hayflick, L., Unpublished observations), then it

might

become possible to learn why the properties that distinguish old cells from

young

cells makes them more vulnerable to pathology.

As for the critic's complaints that I have undervalued caloric restriction (CR)

as a

means of intervening in the aging process, there is not a single research result

that proves unequivocally the critic's claims that caloric restriction slows,

stops,

or reverses the aging process. What CR experiments may have shown is that

gluttony

(or some arbitrary high caloric control) reduces longevity because CR more

closely

mimics the common " feast or famine " lifestyle of feral animals. This lifestyle

differs significantly from that of inbred laboratory controls. Thus, CR may be

revealing the " true " longevity of animals that would occur if predation,

accidents,

and pathology were controlled under feral conditions as they are in the

laboratory.

It is also tenable to hold that CR has not been proven to slow, stop, or reverse

the

aging process but that it has been shown to indirectly delay its appearance by

directly effecting longevity determinants (1,2). It is also likely that the

increase

in longevity that CR produces is due, in whole or in part, to delaying the

manifestations of pathology.

Because CR is known to extend the chronological time during which early

developmental changes occur, and to do this well before age changes appear, it

is

evident that CR affects longevity determinants and not the aging process (3).

The critic, like other practitioners of CR, might reflect on the facts that (a)

being extremely underweight has the same negative effect on longevity as obesity

does in humans (4,5) and that ( libido is reduced (6). I suspect that I am not

alone in observing that a gain of more years spent in a condition of

semistarvation

and with a reduced libido is not much fun.

If the critic, like his hypothetical " anyone, " is so " ... familiar with the

biogerontological literature (that he) can readily cite examples in which (aging

has

been slowed, stopped, or reversed) ... in model organisms, " then his failure to

provide a single reference substantiating this claim is compelling.

Contrary to the critic's sweeping claim, no CR intervention " ... has been

robustly

documented to retard the accumulation of a wide range of the molecular lesions

suspected to underlie aging, and to thereby extend youthful physiological

function

and species' maximum life span ... " In fact, no one has proven unequivocally how

CR

works nor does the critic give any references for what he states is so " ...

robustly

documented ... "

Also, contrary to the critics claim, no " ... genetic intervention(s) ... " has

ever

been shown to " ... slow down key aspects of biological aging ... " What genetic

manipulation and CR have shown is that longevity determinants are tractable—a

fact

that has been known for more than a century by invoking less sophisticated

techniques such as temperature manipulation, crowding, food deprivation, and

hybrid

vigor (2). No one has described a genetic intervention made after proven age

changes

appear that has indisputably slowed, stopped, or reversed the process.

The critic devotes a section called " The Aging of Wholes and of Parts " by

committing

the identical error that he has committed at the outset of his

peroration—asserting

a false premise. I did not write that " ... ‘aging’ of each individual

biomolecule in

the organism is an inevitability of the Second Law of Thermodynamics, " therefore

" ... no intervention will slow, stop, or reverse the aging process in humans. "

No reference to the Second Law of Thermodynamics appears in my article! For the

second time, the critic has invented a false premise upon which rests his

subsequent

arguments.

However, the critic might benefit from knowing that the Second Law of

Thermodynamics

does not apply to living organisms because living organisms are open systems.

Furthermore, his statement that " ... constituent biomolecules are in a

continuous

process of turnover " is erroneous. For example, most of the collagen that

constitutes a huge amount of all protein mass in humans does not turn over, nor

does

eye lens protein, tendon, cartilage, and most muscle cells and bone mass. Thus,

his

obscure " composition fallacy " is not only untenable for attributing to me

something

that I never wrote but it also is untenable because his argument is not based on

fact.

The critic claims that " any intervention that ... at the molecular level, ...

lead(s) to the reduction, arrest, or reversal of the age-associated acceleration

of

vulnerability to pathology of the organism, would constitute ‘anti-aging

medicine’—despite the fact that individual biomolecules would continue to

ultimately

fall prey to entropic decay. "

This fatuous assertion is as useful as Herbert Hoover's logic that proposed:

" When

many people are out of work, unemployment results. " But, then the critic

torpedoes

his own statement by admitting that " ... individual biomolecules would continue

to

ultimately fall prey to entropic decay, " which is, of course, aging.

In his next section entitled " Genes: Determinants of the Rate of Aging, " the

critic,

for the third time, fabricates a false premise upon which rests a major

argument.

Nowhere in my article do I claim that " ... the fact of ‘aging’ of individual

biomolecules is ... the same as the rate of aging of the organism. " This

invention,

like his preceding two, invites the same response: All that follows from this

third

false premise does not require comment.

The critic's ex cathedra statement that " ... longevity determination ...

transparently constitutes the genome's role in regulating the rate of

accumulation

of molecular damage—that is, of aging " has no basis in experimental fact. His

use of

the word " transparently " is simply a glib (transparent?) effort to use derision

as a

tool to persuade readers unquestioningly to accept his bias. The fact that no

references are given for his claim speaks louder than does his weak effort to

ridicule.

The critic's quotation from a prior publication by me (7) in no way supports his

contention of my alleged " ... artificiality in claiming longevity determination

to

be ‘an entirely different’ and ‘independent’ process from aging. " The quoted

statement refers to the class of animals that do not reach a fixed size in

adulthood

and do not age at all, or do so negligibly. Unlike animals that do age, the

maintenance, repair, and turnover capacity (longevity determinants) that exist

after

reproductive maturation in these animals simply continue to exceed the rate of

loss

of molecular fidelity in their substrates. Longevity determination is an

anabolic

process. Aging is a catabolic process. There is nothing " artificial " about this

simple distinction.

After suffering through " biological quietism " (whatever that is) and the " Deist

God "

(whoever this tautology is) who " ... releases its creatures ... " (whatever they

are)

and " entropic unwinding " (whatever that is) and " ... intensity of the

biochemical

forces ... (whatever they are), " the misquote that follows after this avalanche

of

cryptic verbiage, one arrives at the fourth example of the critic's production

of

false premises. He writes " ... Hayflick's thesis of the impossibility of

modulating

the rate of aging. "

I challenge the critic to find this position stated in any of my publications.

In respect to the intrinsicality of organismal aging, the critic's statement

that

" ... their constituent biomolecules are subject to the Second Law of

Thermodynamics

.... " is yet another revelation of fundamental ignorance of biological systems.

As

stated above, living organisms are open systems to which the Second Law does not

apply. The Second Law applies only to closed systems. Once again, all of the

critics

arguments and conclusions that follow from his spurious belief do not require

further comment.

Other than attempting to dazzle readers with what appears to be language

designed to

impress, what does the critic really mean by such ambiguous phrases as " ... of

course, the intensity of the metabolic forces varies according to specifications

laid out in the organism's underlying genetic inheritance ...? " " Of course "

connotes

the belief that everyone must surely know what follows. However, most do not

because

they understand that the genome contains a code and not a recipe.

Most of the critic's arguments are replete with canonical statements that

represent

his world view but most are unsupported by fact and simply represent bias or

misunderstanding. The section that contains the following quotes reveals some of

the

dozens of examples that could be given: " ... key forces of stochastic damage are

partly subject to genetic regulation ..., " " ... they can be modulated by

interventions that alter the expression of relevant genes, " " ... it is

determined by

the genetically established design of the mitochondrion ..., " and " ... it

therefore

varies from species to species ... " There is no unequivocal proof for any of

these

statements in the two cited references, whose use for alleged support serves

more to

mislead than to edify.

What follows in this same paragraph is the statement that " ... the rate of

formation

of mtROS ... is determined by the genetically established design of the

mitochondrion; it therefore varies from species to species; it is negatively

correlated with species maximum life span; and it can be strongly argued to be a

key

driver of aging. "

The strength of an argument rests upon the facts that support it. In fact, there

is

absolutely no direct evidence that mtROS, or any other ROS, is " ... a key driver

of

aging. " All such " evidence " may prove that ROS are associated with aging and

make

good intellectual sense that they may be causative, but it is still a theory,

lacks

proof, and thus remains pure conjecture.

The critic makes the further claim that two interventions (CR and the prop-1

gene

mutation of the Ames dwarf mouse) " ... most clearly slow aging in mammals ... "

by

.... " lead(ing) to reduced generation of mtROS, and lower accumulation of

resulting

molecular lesions, relative to controls. "

It is difficult to understand how this conclusion can be reached when 1) there

are

no universally accepted biomarkers to measure the rate of age changes in these

laboratory animals, 2) no evidence has been provided that would exclude the

possibility that these interventions might delay or prevent pathology and not

aging,

and 3) no evidence has been provided to eliminate the greater likelihood that

these

two interventions affect longevity determinants and not the aging process (1).

The critic's argument that I have " neglected " to consider the processes that he

says

" ... prevent(s) aging damage from occurring ... " is grotesque and represents the

fourth fabrication of a false premise in his list of complaints.

I have specifically used the words " ... maintenance, repair, and turnover ... "

as

processes that maintain molecular fidelity (1). Again, another false premise

results

in the conclusion that the critic's arguments that are derivative of this false

premise require no further comment.

Despite the critic's claim to the contrary, there is no direct evidence that " CR

alters the activity of many of these maintenance mechanisms ... " The fact that

the

critic asserts that " ... it is widely accepted that these optimizations (which

he

does not define) contribute to the decelerated loss of molecular fidelity and

physiological function ... " does not make it true. It was once " widely accepted

that " humans had 48 chromosomes and " widely accepted that " normal cells are

immortal

and " widely accepted that " humans had 100,000 genes. All are untrue. It is a

further

revelation that a logician would depend not only on false premises but also on

alleged " wide acceptance " to constitute evidence.

Contrary to the critic's belief, none of the " ... numerous stress resistance

genes

.... ‘directly' ... retards (sic) biological aging in yeasts, Caenorhabditis

elegans,

and Drosophila—and possibly the laboratory mouse ... " What these genes may

affect

are the molecular determinants of longevity such as those involved in

development,

maintenance, turnover, and repair (1).

The continued use by the critic throughout his peroration of language such as

" ...

clearly unjustified ..., " " rather, as we have seen ..., " " ... we now know of

...., "

" ... it is widely accepted ..., " and " ... composition fallacy ... " represents

efforts intended to persuade the reader that his positions are well supported

and

that those who disagree are simply ignorant. It is to be hoped that most readers

will realize that this style of argumentation by fiat does not trump facts or

alternative interpretations of facts.

Without providing any support for his dogmatic statement, the critic argues that

" ... the determinants of longevity are not the cause of the simple fact of

molecular

aging, they are precisely the determinants of the rate of organismal aging ... "

Furthermore, and implicit in this statement, is his recognition that there is a

difference between aging and longevity determinants that, in several former

arguments, he claims is " artificial, " " a Chinese wall, " or otherwise denies. The

logician thus exposes his self-contradicting positions.

Although recognizing that " ... the thermodynamic stability of the body's

constituent

biomolecules is unlikely to be susceptible to modulation without harm to the

organism, ... " the critic embraces rate interventions while neglecting to

understand

that biological rates are governed by " ... the body's constituent biomolecules

...., "

which he admits are " ... unlikely to be susceptible to modulation without harm

to

the organism ... " This circuitous reasoning results in the illogic of the

critic/logician having his cake and eating it too.

A fifth false premise appears in the section " ‘Anti-Aging Medicine’: Present

Reality

and Emerging Probability. " Nowhere in my article (1) have I tried " ... to

illustrate

the impossibility of retarding aging, " and, for the fifth time, and for the same

reason, it becomes unnecessary to comment on the author's long discourse that

follows from this false premise.

Contrary to the critic's unsubstantiated claim, parts replacement is in no way

an

intervention in the aging process. No fundamental manipulation of the molecules

in

an aging inanimate part is achieved by replacing it. The aged replaced part will

continue to age. Thus, parts replacement in no way is a valid example of

intervention in the aging process.

None of the antique car enthusiasts with whom I have consulted have degrees in,

or

more than a passing interest in, biology, yet, unlike the critic, they agree

unanimously that replacing parts does not intervene in the fundamental molecular

changes that continue to occur in those parts as they repose on the scrap heap.

They

went on to advise that most of their " antique " cars were not old at all, but

were

quite new because all or most of the old parts had been replaced with new parts

or

remanufactured old parts. The critic might benefit from reflecting on these

questions: " How many (and which) parts must be replaced in an inanimate object

or

living form to arrest the aging process in the entire entity? " and " How many

parts

must be replaced with new before that entity can no longer be considered to be

original? "

Neither antique car enthusiasts nor biogerontologists have an answer.

Longevity determination and the aging process in any complex inanimate object

are

perfectly analogous to similar events occurring in biological material because

both

are rooted first in the establishment of molecular fidelity (longevity

determination) and, second, in the loss of that fidelity (aging).

The critic's belief that, " applying anti-rust treatments ... or ... using

sophisticated lubricants ..., or ... purchasing gasoline additives ... can

intervene

in the fundamental aging process, " ignores the fact that none of these

interventions

reaches the preponderance of molecules in the treated parts that will continue

to

age. Cosmetics and facelifts may make you look young but they do not make you

young.

Car manufacturers wisely list " anti-rust treatments, sophisticated lubricants

....,

or ... gasoline additives " as maintenance procedures and not as anti-aging

procedures. Unlike the critic, biologically untrained car manufacturers

understand

that the aging process is not only different from longevity determinants but

also

unavoidable. Longevity determination in cars is appreciated by designating for

different car models (analogous to different species) different warranty

periods. By

recognizing that the aging process is similar within models (analogous to a

single

species), however, the same warranty period is applied to all cars within a

model.

For the sixth time, the critic has fabricated a false premise by misstating my

position. Nowhere in my article did I assert that altering the rate of aging is

" impossible. " Like the previous five straw men manufactured by the critic,

further

comment by me on what follow from this misstatement of fact is unnecessary.

After enduring the critic's efforts to dazzle readers with his putative

erudition in

the section marked " The Biomarker Bugaboo: Against Copenhagen " ( " ... against

Copenhagen, " " ... some epistemological merit ..., " " ... an insurmountable

heuristic

impediment ..., " and " ... a surrogate metric ... " ), his argument finally

surfaces.

That is " ... the absence of verifiable biomarkers ... has not ... prevented

biogerontologists from reaching the clear conclusion that CR retards aging in

laboratory animals ... "

This statement forces restating that the critic's orthodox interpretation of CR

experiments has 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.

Second, 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 (1).

Third, 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 (Holliday, R., Hayflick, L., Unpublished

observations).

The critic's argument that " ... the absence of verifiable biomarkers ... has not

....

prevented biogerontologists from reaching the clear conclusion that CR retards

aging

in laboratory animals ... " becomes considerably less clear when one considers

that

at least three alternative conclusions are tenable.

The critic holds that " ... biogerontology has identified many—and perhaps all—of

the

molecular lesions that contribute to the aging process. " This position is either

based on an article of faith or a misunderstanding of what constitutes evidence

capable of distinguishing between age changes and pathology. This is at the root

of

the critic's dilemma. There are many manifestations of aging in humans that are

not

considered to be pathology. No one has ever died from wrinkled skin, age spots,

gray

hair, or many other nonpathological equivalents.

Furthermore, the critic accepts without question that interfering with the aging

process has no serious unintended consequences. I have discussed many of these

previously (2,7). In addition, by increasing the stability of some but not all

classes of molecules, which is likely to be the first " success, " then having

some

tissues, or even entire organs, age at slower rates may be fruitless. If the

class(es) of affected molecules results in only one or two vital organs like the

heart or cardiovascular system becoming more resistant to age changes, the

resulting

" age mosaicism " in organs would not have enormous benefit because the aging

process

would continue in other vital organs. Resolving all of the leading causes of

death

(cardiovascular disease, stroke, and cancer could only result in approximately a

15-year increase in life expectancy (8). The only way that substantial increases

in

life expectancy beyond 15 years can be achieved is by increasing the stability

of

virtually all biomolecules and not just a few classes. In consideration of our

present state of ignorance, the likelihood of intervening in the energetics of

many

classes of biomolecules approaches the vanishing point.

In what has become, by now, a boringly repetitive debating style, the critic

continues his strategy of dismissing in cavalier prose those arguments with

which he

disagrees while providing no evidence in support of his biases. This strategy

incorporates pontifical statements and/or the citation of inappropriate

references

in the hope that their mere mention will be persuasive.

For example, in the next section of his complaints, the critic dismisses my

belief

that intervening in the aging process has many potential downsides by stating

that,

" they fall outside of the focus of the present essay; fortunately, nearly all

have

been refuted elsewhere, " or his dogmatic dismissal— " suffice it to say that these

worries are unfounded ... "

In following sections, we find further examples of argument by ridicule,

belittlement, or derision, all of which should fail to persuade because no data

is

given: " ... voice the most grossly transparent error in reasoning ..., " " ... an

error that is all the more astounding ..., " " ... its rejection of the key

premises

...., " " ... by a false analogy ..., " and " ... demonstrated to be factually or

logically untenable ... "

Strident and emotional prose is no substitute for data.

The critic's next assertion is an iteration of his chronic failure to understand

the

difference between aging and age-associated pathology. This is revealed by his

statement that there is an " ... unimaginably great burden of morbidity and

mortality

that intervention would alleviate. " Like most platitudes, this one is

incontrovertible. It is prevention of, or intervention in, age-associated

diseases

that has been proven to relieve these burdens—not intervention in the underlying

aging process itself. Intervention in disease processes is the only method by

which

human life expectancy has been increased through human intervention. In this

country, the increase was 27 years during the last century (1), and it did not

occur

from any advance made in our understanding of the fundamental biology of aging.

As indicated above, once all of the leading causes of death are resolved in this

country, the maximum increase in human life expectation possible from that of

today

is approximately 15 years (1,8). When that miracle occurs, the only remaining

means

of increasing human life expectancy will be to intervene in the fundamental

biology

of aging or the determinants of longevity. It is this distinction that the

critic

appears unable to grasp.

All of the biomedical establishments on the planet are engaged in finding,

and/or

implementing, interventions that would prevent, delay, reduce, or eliminate the

" ...

burden of morbidity and mortality that intervention would alleviate. " When

applied

to old people, these practices are called geriatric medicine and not

biogerontology.

Only a microscopic fraction of the world's biological research efforts are

directed

toward an understanding of the fundamental aging process, which increases

vulnerability to the entire " ... burden of morbidity and mortality. " I do not

oppose

research on age-associated pathology, as the critic seems to imply. I do oppose

the

enormous imbalance in resources, which has been created under the all-inclusive

rubric " aging research. " Most of the research conducted under this rubric

supports

geriatric medicine. Only a fraction is devoted to the study of the biology of

aging.

The budget of the National Institute on Aging is a good example. More than 50%

is

spent on Alzheimer's disease research and less than 5% on studies directed

toward an

understanding of the fundamental biology of aging (1).

Reducing the " ... burden of morbidity and mortality ... " would be better served

by

understanding the molecular changes that distinguish old cells from young cells

and

that subsequently increase their vulnerability to pathology. This quest is

called

research on the fundamental biology of aging, or biogerontology. However, the

support available for its pursuit is too trivial to expect that an answer will

be

forthcoming soon.

The last few paragraphs of the critic's complaints continue the repetitive

practice

of employing derision and ex cathedra statements in place of fact and scientific

discourse in order to persuade. These paragraphs contain, perhaps, the best

examples

of this unconvincing strategy: " ... taking a defenseless infant—incapable of

speech,

reproduction, self-propelled motion, or even bladder control—and transforming it

into an adult in the peak of physical and mental capacity and health, is

transparently not analogous to ‘a stochastic process ...,' " " this false analogy

...., " " the ‘Oxymoron’ article provides us with the (erroneous) answer ..., " " ...

however, the arguments alleging the impossibility of intervention in aging on

logical and physical grounds having been seen to be in error ..., " " one finds

oneself flabbergasted ..., " and finally, " ... pedantically repeated. "

The arguments made in this section of the critic's discourse are based on his

failure to understand the definition of " analogy, " which leads the

critic/logician

to a reductio ad absurdum. For someone who prides himself in " wearing the

theoretician's mortarboard, " I suggest that he consult his beginning course

syllabus

where he should find the definition of " analogy. " It also appears in the Oxford

American Dictionary and Thesaurus as follows: " logic, a process of arguing from

similarity in known respects to similarity in other respects. "

The logician/critic bases his final paragraphs on his absurd belief that I do

not

understand the difference between development and aging. This is the seventh and

most preposterous false premise to be added to the six described above. I leave

to

readers the decision whether or not I might know the difference between

development

and aging. If I do not, the critic's arguments are tenable. If I do, then

further

comment on these latter paragraphs is unnecessary.

In his final effort to persuade, the critic argues that because I believe that

aging

is a fundamental property of all matter, this will make " ... politicians,

funding

bureaucracies, and the public ... rightly reluctant to allocate scarce

resources " to

study the basic biology of aging. The critic might reflect on the fact that

these

groups have not turned their backs on funding research on the fundamental

properties

of matter such as gravity, the electromagnetic spectrum, magnetism, and the weak

and

strong forces. Nor have they turned their backs on funding fundamental research

on

embryology (homeotic " hox " genes) or development, all of which are pursued in an

effort to understand how the world works (often called curiosity) and not in a

direct effort to relieve pain or suffering. Basic research precedes applied

research.

The critic has based seven of his arguments, or about half of his criticisms, on

false premises. A third quarter contains efforts to persuade by using

unsupported

statements based on faith, bias, ignorance of published data, or refusal to

consider

alternative interpretations. For the remaining quarter, which consists of

statements

made ex cathedra and efforts to denigrate, deride, disparage, scorn, mock, or

ridicule, I choose not to dignify with rebuttal.

Al Pater, PhD; email: old542000@...

__________________________________

- PC Magazine Editors' Choice 2005

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