Biological Aging Is No Longeran Unsolved ProblemLEONARD HAYFLICKDepartment of Anatomy, University of California, San Francisco, Schoolof Medicine, The Sea Ranch, California 95497, USAABSTRACT: The belief that aging is still an unsolved problem in biologyis no longer true. Of the two major classes of theories, the one classthat is tenable is derivative of a single common denominator that re-sults in only one fundamental theory of aging. In order to address thiscomplex subject, it is necessary to first define the four phenomena thatcharacterize the finitude of life. These phenomena are aging, the deter-minants of longevity, age-associated diseases, and death. There are onlytwo fundamental ways in which age changes can occur. Aging occurs ei-ther as the result of a purposeful program driven by genes or by eventsthat are not guided by a program but are stochastic or random, acci-dental events. The weight of evidence indicates that genes do not drivethe aging process but the general loss of molecular fidelity does. Poten-tial longevity is determined by the energetics of all molecules presentat and after the time of reproductive maturation. Thus, every molecule,including those that compose the machinery involved in turnover, re-placement, and repair, becomes the substrate that experiences the ther-modynamic instability characteristic of the aging process. However, thedeterminants of the fidelity of all molecules produced before and afterreproductive maturity are the determinants of longevity. This processis governed by the genome. Aging does not happen in a vacuum. Agingmust be the result of changes that occur in molecules that have existedat one time with no age changes. It is the state of these pre-existingmolecules that governs longevity determination. The distinction betweenthe aging process and age-associated disease is not only based on themolecular definition of aging described above but it is also rooted inseveral practical observations. Unlike any disease, age changes (a) occurin every multicellular animal that reaches a fixed size at reproductivematurity, (b) cross virtually all species barriers, (c) occur in all membersof a species only after the age of reproductive maturation, (d) occur in allanimals removed from the wild and protected by humans even when thatspecies probably has not experienced aging for thousands or even mil-lions of years, (e) occur in virtually all animate and inanimate matter, and(f ) have the same universal molecular etiology, that is, thermodynamicinstability. Unlike aging, there is no disease or pathology that shares thesesix qualities. Because this critical distinction is poorly understood, thereAddress for correspondence: Leonard Hayflick, Department of Anatomy, University of California,San Francisco, School of Medicine, P.O. Box 89, The Sea Ranch, CA 95497. fax: [email protected]. N.Y. Acad. Sci. 1100: 1–13 (2007).C2007 New York Academy of Sciences.doi: 10.1196/annals.1395.00112 ANNALS OF THE NEW YORK ACADEMY OF SCIENCESis a continuing belief that the resolution of age-associated diseases willadvance our understanding of the fundamental aging process. It will not.The distinction between disease and aging is also critical for establishingscience policy because although policy makers understand that the fund-ing of research on age-associated diseases is an unquestioned good, theyalso must understand that the resolution of age-associated diseases willnot provide insights into understanding the fundamental biology of agechanges. They often believe that it will and base decisions on that mis-understanding. The impact has been to fund research on age-associateddiseases at several orders of magnitude greater than what is available forresearch on the biology of aging. There is an almost universal belief bygeriatricians and others that the greatest risk factor for all of the leadingcauses of death is old age. Why then are we not devoting significantlygreater resources to understanding more about the greatest risk factorfor every age-associated pathology by attempting to answer this funda-mental question—“What changes occur in biomolecules that lead to themanifestations of aging at higher orders of complexity and then increasevulnerability to all age-associated pathology?”KEYWORDS: aging; age-associated disease; longevityINTRODUCTIONAs his inaugural professorial lecture in 1951 at University College London,Sir Peter Medawar gave one of the most influential discourses on the biologyof aging. It was entitled, “An Unsolved Problem in Biology.”1The unsolvedproblem was the failure to understand how and why biological aging occurs.In the more than half century that has elapsed since Medawar’s notablelecture, research on the biology of aging has gone from virtual obscurity to alevel of popularity that today can only be characterized as remarkable.For the first 25 years after Medawar’s lecture most studies on aging weredescriptive. But, in the subsequent 25 years the enormous advances that havebeen made in our understanding of fundamental biological mechanisms hasbeen exploited by biogerontologists to provide us with new insights into theimmediate cause of age changes. As these insights emerged, the field of agingresearch became inundated with many theories on the cause of aging. See,for example, Hayflick (1985).2So many theories were formulated that cynicsremarked that there are as many theories of aging as there are biogeronto-logists.However, that belief is no longer true. Of the two major classes of theories,the one class that is tenable is derivative of a single common denominator thatresults in only one fundamental theory of aging. I will discuss these two classesof theories subsequently. The huge body of knowledge in biogerontology thathas been revealed in the last 25 years has resulted in a high level of confidencethat the cause of biological aging is now understood. This knowledge is theresult of the work of many researchers.HAYFLICK 3In order to address this complex subject it will be necessary to first definethe four phenomena that characterize the finitude of life. These phenomenaare aging, the determinants of longevity, age-associated diseases, and death. Iwill not discuss the biology of death other than to say that even for this conceptthere is no single universally accepted definition. In order to avoid a definitionof biological death one wag observed that death is nature’s way of telling youto slow down.THE AGING