Interview with Dr. Leonid A. Gavrilov

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Interview with Dr. Leonid A. Gavrilov This is an original transcript of the interview with Dr. Leonid A. Gavrilov, Ph. D. The edited and abridged version of this interview is published in the scientific peer-reviewed Journal of Anti-Aging Medicine: PIECES OF THE PUZZLE. An Interview with Leonid A. Gavrilov, Ph.D. Journal of Anti-Aging Medicine, 2002, 5(3): 255-263.
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   JOURNAL OF ANTI-AGING MEDICINEVolume 5, Number 3, 2002© Mary Ann Liebert, Inc. Pieces of the Puzzle An Interview with Leonid A. Gavrilov, Ph.D. 255 Leonid A. Gavrilov, Ph.D., is a Research Associateat the Center on Aging, National Opinion ResearchCenter, University of Chicago. He received his Mas-ter’s degree in chemistry, with a specialization inmathematical modeling and chemical kinetics, andhis Ph.D. in genetics from Moscow State Univer-sity. Dr. Gavrilov’s areas of specialization includethe biodemography of human longevity and analy-sis of human mortality and aging, the mathemati-cal modeling of aging and mortality, and the ge-netics of aging and longevity. He is on the editorialboards of   Journal of Anti-Aging Medicine,Sci-entificWorld  Journal , and Experimental Geron-tology. Dr. Gavrilov and his wife, NataliaGavrilova, co-authored the book The Biology ofLife Span: A Quantitative Approach. Dr. Gavrilov, please provide our readerssome insight into your background and how you became interested in studying agingand longevity. I have a Master’s degree in chemistry (chem-ical kinetics and enzymology) and a Ph.D. in biology (genetics), both from Moscow StateUniversity, Russia. I then spent a decade of in-tensive research and self-education, duringwhich I wrote a book entitled The Biology of LifeSpan , 1 which was published in the UnitedStates in 1991. While working on this book, Itried to understand what happens in aging, andwhy we age and die. I performed an extensiveand critical review of abundant scientific liter-ature on aging and longevity, trying to recon-cile different findings and theories. I also col-lected and analyzed thousands of life tables(lifespan survival data) for various human pop-ulations and other biological species. It was atremendous amount of work, which was donein collaboration with Dr. Natalia Gavrilova, mywife. We were fortunate to make a number ofnew findings, which have since been cited inthe scientific literature.Writing a book was a good method of self-education in aging studies. How do I know thatthis self-education was correct? Well, indica-tors include the fact that our book was selectedand cited by the Encyclopedia Britannica as a rec-ommended reference on longevity. The bookalso received positive reviews in a dozen sci-entific journals, including Nature , the British Medical Journal , and BioEssays , and more than100 citations in the scientific literature. We be-lieve that our research and self-education ef-forts were not in vain.Another very good test of our scientific cre-dentials occurred five years ago, when Nataliaand I immigrated to the United States from Rus-sia and applied for research funding in this newand highly competitive environment. We werelucky to be awarded research grants from theNational Institute on Aging, of the NIH, to studyfamilial transmission of human longevity, andthe effects of parental age at conception on a per-son’s lifespan. With this funding, we were ableto continue our research and to publish our find-ings. I find it somewhat ironic that my scientific background is now featured in “Who’s Who inAmerica” (Marquis Who’s Who, 2002 edition),despite the fact that I am still a citizen of Russia.Now please allow me to answer the secondpart of your question: how I became interestedin studying aging and longevity. The decisionto study aging was made early in my life, whenmy school years were coming to an end andthe question of what I should do next was be-coming an urgent one. I was very idealistic atthat time and I had read a lot of science fiction.  I thought that perhaps the only way to succeedin a really worthwhile project, such as under-standing how the human brain thinks or prob-ing deep space exploration was to have enoughtime to accomplish the necessary research. Thisled me to confront the aging problem as a wayto overcome natural time constraints. I alsothought that in order to be able to understandthe chemistry of aging and to make an anti-ag-ing drug, I would first need to study chemistryin a university. I certainly do not regret that de-cision.I received a free and rather good initial edu-cation at the Department of Chemical Kinetics,founded by the Nobel laureate Nicolai Semy-onov—discoverer of free radical chain reac-tions. Thus, I became familiar with the free-rad-ical theory of aging and the mechanisms ofdamage protection by antioxidants at the very beginning of my scientific career.I was also very much impressed by the powerof quantitative approaches to science. I find itamazing that it is possible to discriminate be-tween intricate, competing mechanisms (hy-potheses) of chemical reactions, simply by quan-titatively analyzing the exact time trajectories(kinetics) of concentrations of reaction compo-nents and the products of the reaction. My im-mediate thought was that perhaps a similarquantitative approach could be applied to the biological aging problem, in an effort to uncoverthe mechanisms of aging through quantitativeanalysis of age-related mortality kinetics.It was this concept of quantitative analysis thatshaped all of my future research efforts. This ap-preciation of the great power of quantitativeanalysis was reinforced by my subsequent edu-cation and research work toward obtaining aPh.D. in genetics. It is truly amazing that the veryidea of genes, their existence in pairs (alleles),their random and independent segregation inoffspring, and the concept of dominance all cameto Gregor Mendel as a result of his thoughtfulquantitative analysis of simple observations oftrait frequencies in parents and offspring. Later,this purely quantitative approach to the analysisof trait frequencies also allowed the Nobel lau-reate Thomas Hunt Morgan to discover thatgenes are organized in groups in a linear fash-ion (in chromosomes), to create the first genemaps, and to describe the crossing-over phe-nomenon. Finally, another Nobel laureate, Bar- bara McClintock, discovered the phenomenon ofgenetic instability and “jumping genes” (trans-posons) through the quantitative analysis of ob-servations on color variation among kernels ofmaize.I find a special charm in these elegant stud-ies, in which great scientific discoveries weremade through the clever use of quantitativeanalysis of very simple observations, ratherthen fancy and expensive cutting-edge tech-niques. These historical examples convincedme in the very beginning of my scientific ca-reer that the most powerful scientific instru-ment is still the human brain. I based all of myfuture research work on this precept, placingthe main emphasis on human scientific intelli-gence. This quantitative approach can be sum-marized by the following motto: “Think, mea-sure and count; count, measure and think.”This is why the title of our book is not The Bi-ology of Life Span , but rather The Biology of LifeSpan: A Quantitative Approach . The quantitativeapproach became a cornerstone of all our sci-entific studies. Please describe your current position and yourscientific responsibilities. I am fortunate to be a recipient (Principal In-vestigator) of the Independent Scientist Awardfrom the National Institute on Aging, whichprovides five years of funding for research onaging and longevity. My scientific responsibil-ity, as I understand it, is to do good science andto publish new relevant findings in peer-re-viewed journals. For example, recently we havedeveloped and published a new unifying the-ory of aging and longevity based on a reliabil-ity approach. This new theory provides a gen-eral explanation of aging for organisms as wellas for technical devices. It was published in the  Journal of Theoretical Biology . 2 I also developeda course, “Biodemography of Human Mortal-ity and Longevity,” which I teach at the Uni-versity of Chicago. Teaching activities are veryuseful for scientific research, because they stim-ulate teachers to clarify scientific issues for theirstudents to the extent that they begin to un-derstand those issues themselves. For example,our recent scientific article, “Evolutionary The- PIECES OF THE PUZZLE256  ories of Aging and Longevity,” 3 was written andpublished largely thanks to teaching activities. Dr. Gavrilov, in your view, what is aging, howdoes it occur, and how does it express itself inhuman clinical disease? Aging is a term used to define a set of pro-cesses that contribute to health deterioration and,with the passage of time, ultimately, to death. Inother words any process that contributes to age-related decline in performance, productivity, andhealth is a component of the aging process thatdeserves our attention and intervention. One canthink of aging as a group of processes responsi- ble for such manifestations asincreasing risk of frailty, dis-ability, morbidity (for age-re-lated degenerative diseases,in particular), and, ultimately,increasing mortality rates.This interpretation of aging isconsistent with the generaldefinition of aging systems inmathematical reliability the-ory and reliability engineer-ing: an aging system is a sys-tem that demonstrates anage-dependent increase infailure rates. Failure occurswhen the systems deviatefrom anticipated and desired behavior.The main problem withstudying aging is that it is amany-headed monster and manifests manytypes of failures and often multiple failures.Therefore, attempts to describe this complex,multidimensional phenomenon through thechange of just one index—described as biologi-cal age, physiological age, or real age—may bemisleading and even a deceptive oversimplifica-tion. More adequate scientific language to de-scribe the aging phenomenon can be found ingeneral system theory, and in reliability theory,in particular. Interestingly, reliability theorypredicts that a system may deteriorate with ageeven if it is built from non-aging elements withconstant failure rates. The key issue here is thesystem’s redundancy for irreplaceable ele-ments, which is responsible for the aging phe-nomenon. In other words, each particular stepin system destruction/deterioration may ap-pear to be random (occasional failure bychance, and not actual aging), but if system fail-ure requires a sequence of several such steps,then the system as a whole may demonstrateaging behavior.Why is this important? Because the signifi-cance of beneficial anti-aging interventions isoften undermined by claims that these inter-ventions are not proven to delay the process ofaging itself, but instead that they simply delayor “cover-up” particular manifestations of ag-ing. In contrast to these pessimistic views, reli-ability theory states that there may be no spe-cific underlying, elementaryaging process itself, insteadaging may be largely a prop-erty of a redundant system asa whole, because it has a net-work of destruction path-ways, each being associatedwith particular manifestationsof aging (types of failure).Therefore, we should not bediscouraged by only partialsuccess of any particular anti-aging intervention. Instead,we can appreciate the avail-ability of so many opportuni-ties to oppose aging in nu-merous different ways.Thus, efforts to understandthe routes and early stages ofage-related degenerative dis-eases should not be discardedas irrelevant to our understanding of “true bi-ological aging.” On the contrary, attempts to build a wall between biogerontology and clin-ical medicine are counterproductive. After all,the main reason people are concerned about ag-ing is because it is related to health deteriora-tion and increased morbidity. The most impor-tant pathways linked to age-related changes arethose that make older people sick.  How has the scientific community’s view of agingin general evolved in recent years? Is there aconsensus on what aging is and how it occurs?What are the most important controversies in the field at present? PIECES OF THE PUZZLE257 Leonid A. Gavrilov, Ph.D.  Views on aging have changed dramatically.They have also become more diverse and po-larized in recent years. Just a decade ago, theconsensus was to consider aging as an irre-versible, universal, and intrinsic process. Ag-ing was often thought of as an immutable, fun-damental process, about which little could bedone. For example, there was a belief that mu-tations could only shorten lifespan, not increaseit. Even if some mutants lived longer lives, the belief was that this life extension came with thecost of having a crippled life.Aging was considered to be a generalized de-terioration. Therefore, the search for specific in-terventions that would have broadly applica- ble, positive effects on lifespan was considereda completely futile task, destined for failure forfundamental reasons. There was also a beliefthat each biological species has a specific max-imal lifespan, which is immutable within agiven species.I remember well the 1980s, when we firstchallenged the concept of species-specific max-imal lifespan, argued that there was no fixedlimit to longevity, and even suggested a relia- bility theory of aging that predicted late-lifemortality deceleration and leveling off. The de- bates were heated. Our own arguments wereonly taken seriously after publication of our book in 1991. We are pleased now to observethat the idea of a fixed maximal lifespan limithas been rejected by many other researches,and there has been a real fuss over the conceptof late-life mortality deceleration. The idea ofimmutability of aging is also being challengednow in professional scientific journals.Aging studies are now undergoing a para-digm shift, and frankly, I would call it a scien-tific revolution. Controversies are inevitable insuch transition periods and they do indeed ex-ist. The most important current controversy isrelated to an evolutionary explanation of ag-ing. Evolutionary biologists were always verygenerous with gerontologists in providing ad-vice and guidance on how to do aging research.Surprisingly, this generous intellectual assis-tance proved to be extremely injurious for ag-ing studies. The reason is that evolutionary the-ory was interpreted in such a way that thesearch for single gene mutations, or life-ex-tending interventions, with very large positiveeffects on lifespan was considered a completelyfutile task, destined for failure for fundamen-tal evolutionary reasons. Researchers were con-vinced by the forceful, evolutionary argumentsof George Williams, which held that “ ... nat-ural selection will always be in greatest opposi-tion to the decline of the most senescence-pronesystem.” Therefore, he continued, “senescenceshould always be a generalized deterioration,and never due largely to changes in a single sys-tem. ... This conclusion banishes the ‘fountainof youth’ to the limbo of scientific impossibilitieswhere other human aspirations, like the perpet-ual motion machine and Laplace’s ‘superman’have already been replaced by other theoreticalconsiderations. Such conclusions are always dis-appointing, but they have the desirable conse-quence of channeling research in directions thatare likely to be fruitful. 4 ”As a result of this triumphant evolutionaryindoctrination, many exciting research oppor-tunities for lifespan extension were squanderedfor half a century until the recent and aston-ishing discovery of single gene mutants withprofoundly extended longevity. This shiftedthe tide in aging research, despite all discour-aging predictions and warnings based on evo-lutionary arguments.Recent discoveries of lifespan-extending mu-tations are spectacular. A single-gene mutation, daf-2 , more than doubles the lifespan of nema-todes, keeping them active, fully fertile (contraryto predictions of some evolutionary theories),and with normal metabolic rates. Another sin-gle gene mutation, called methuselah, extendsthe average lifespan of fruit flies by about 35%;it also enhances their resistance to variousforms of stress, including starvation, high tem-perature, and toxic chemicals. Finally, a single-gene mutation was found in mice that extendstheir lifespans by about 30% and also increasestheir resistance to toxic chemicals.Researchers involved in these studies cameto the following conclusion: “The field of age-ing research has been completely transformedin the past decade. ... When single genes arechanged, animals that should be old stayyoung. In humans, these mutants would beanalogous to a ninety-year-old who looks andfeels forty-five. On this basis we begin to thinkof ageing as a disease that can be cured, or at PIECES OF THE PUZZLE258
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