| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|---|
|
|
|
|||||||
|
|||||||||
AUTHOR'S RESPONSE TO COMMENTARY |
Department of Anatomy, University of California, San Francisco, School of Medicine.
Address correspondence to Leonard Hayflick, PhD, Department of Anatomy, University of California, San Francisco, School of Medicine, P.O. Box 89, The Sea Ranch, CA 95497. E-mail: len{at}gene.com
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 (b) 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.
References
| ||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|---|
| All GSA journals | The Gerontologist |
| Journals of Gerontology Series B: Psychological Sciences and Social Sciences | |
