- Email: [email protected]
Reversing human aging
Experimental Gerontology, Vol. 32, No. 6, pp. 731-734, 1997 Published 1997 by Elsevier Science Inc. Printed in the USA. All rights reserved 0531-5565/97 $17.00 + .00 ELSEVIER
PII S0531-5565(97)00041-7
Book Review
A TALE OF TWO THEORIES
Reversing Human Aging, by Michael Fossel, William M o r r o w and Company, Inc., New York, 1996, 307 pages, ISBN 0-688-14324-5, $25; and The Clock o f Ages, by John J. Me-
dina, Cambridge University Press, New York, 1996, 332 pages, ISBN 0-521-46244-4, $24.95. This is a pitous tale for to heere. But nathelees, passe over, is no fors: I praye to God so save thy gentil cors, And eek thine urinals and thy jurdones, Thyn ipocras and eek thy galiones, And every boiste ful of thy letuarye-God blesse hem, and oure lady Sainte Marye. GEOFFREY CHAUCER
IT IS CURIOUSthat the books by Fossel and Medina appeared contemporaneously. Despite their superficial differences, these works share much in common. This similarity includes a growing interest in the problems of aging and aging research. Reversing Human Aging and The Clock o f Ages should only be read in juxtaposition. For this is the only manner in which their differences will permit the casual reader to grasp their mutual plight. "Science has discovered the true Fountain of Youth--and it is within the reach of all of us," confidently declares the jacket of Fossel's book. It can't get better than that, and indeed, it is all downhill from there. This is really not a book about aging; rather, it is a volume on telomere shortening. In his Introduction, the author apologizes profusely for "overly bold simplifications," "misunderstandings," and "unreasonable conclusions." He begs that: "Much of it [his book] will be criticized harshly." That criticism is justified: "I have gone beyond my facts. I have done so knowingly; perhaps that is the greater fault." This characterization of this oeuvre is all too apt. There are certainly factual errors in Fossel's treatise, such as the stated incidence of Werner's syndrome (p. 51), or "in 1900, life expectancy was 25 y e a r s . . . " (p. 171). More annoying is the unsubstantiated insistence on the presence of a clock that defines maximum life span and on its location in at most only a few genes (p. 48). The relegation of all genetic, epigenetic, and environmental factors as phenomena that are secondary to the actual cause of aging (p. 56), deemed telomere shortening by Fossel, is much more difficult to countenance. This feat of intellectual equilibristics is achieved by the author through his redefinition of aging as telomere shortening. This legerdemain is implicit in the text, and it can even be encountered explicitly (p. 731
732
BOOK REVIEW
123 and 124). If aging is by definition telomere shortening, then telomere shortening can certainly be considered the cause of aging and everything follows neatly. Where telomere shortening does not occur, for example in the fruit fly, the cells are already senescent, according to the author (p. 105). The words of criticism stated above do not detract from the generally useful exposition of telomere biology contained in this book. However, the author does not know when to leave well enough alone. There is a lack of distinction between conjecture and fact that is difficult to swallow [e.g., "The diseases we associate with the nervous system--strokes, Alzheimer's, and other dementias--occur because the glia, unlike neurons that they protect, age and die... The glia age, whereas neurons do not." (p. 136)]. The author professes that such a distinction is not so important in a book aimed at nonscientists (p. xii). This reviewer believes that it is even more important when the audience lacks independent tools with which to distinguish between fact and fancy. The author is so consumed by telomere shortening as the cause of aging that he ignores facts. Unicellular organisms, in particular yeasts, are immortal, according to the plan (p. 100 et seq.). They must be, because their telomeres do not shorten. Fossel cites a reference in support of this lack of telomere shortening in yeasts. This reference contains data and additional citations that demonstrate that yeasts are mortal. A review of the manifestations of aging in a wide array of tissue and organ systems traces the root cause of these phenomena to telomere shortening. "Our maximum life span is determined by our telomeres" (p. 151). "The telomere is [the] only place where all the mechanisms of aging come together, and it is here where we can most efficiently prevent or reverse the myriad dysfunctions that express themselves as aging. It is here that we can reverse aging" (p. 156). This is how the author opens a two-chapter analysis of telomere therapy. A remarkable amount of space has been devoted to speculation on the minute details of a therapeutic approach, which has yet to be firmly grounded in basic experimental fact. Given this lack of foundation, it is probably not surprising that the author seeks "a telomerase analog [that] would be an artificial teiomerase that was tougher and more durable than normal telomerases" (p. 158), forgetting that the enzyme is composed of several protein subunits and contains an RNA component. These ruminations border on the preposterous when Fossel states that human trials will begin by the year 2000, a cure for most cancers will be in hand by 2005 (p. 163), and aging will be reversed by 2015 (pp. 177 and 222), so that "your life span can he extended by several hundred years" (p. 171). All of this will cost us between $50 and $1,000 for a single treatment (p. 172). "In the long run, side effects of telomere therapy will be few" (p. 210). In contrast to a lack of appreciation of the details of telomere therapy, this reviewer found the discussion of the social, political, economic, religious, and ethical ramifications of life extension to be thoughtful and very worthwhile. This may constitute the beginning of an important public dialog. Fossel's observation that: "Presently, anyone who makes it to eighty is experienced, but we think of them as dependent. The majority of eighty-year-olds are healthy, but there is little respect for age. We associate age with what we fear rather than what we respect," (p. 239) nicely sums up current attitudes toward aging and the aged. Whereas Fossel's book is confident about the imminence of dramatic gains in human longevity, John Medina demurs in his book. Indeed, scant attention is paid to this potential issue, lifting the need to discuss its ramifications. Medina provides a brief, standard recitation of the benefits of diet and exercise, and a touch of hormone therapy. This therapy is placed in its proper context of an unproven experimental approach. "We just don't know enough" to make accurate projections concerning gains in human longevity is the author's sage conclusion (p. 315). This
BOOK REVIEW
733
conclusion is based on the multifactorial nature of aging enunciated here and in several other places in the book. There are similarities between the two books. Both stress an intemal clock that dictates the course of aging. Medina calls it the "Clock of Ages." This clock chimes incessantly throughout his volume. We are never quite sure what the nature of this clock really is. A fleeting glimpse is finally provided toward the end of the book (p. 275 et seq.), though without the conviction and certainly without the certainty that Fossel musters. "The genes and biochemicals of the Clock of Ages are involved with a cellular timing event that is intimately associated with the cell cycle," states Medina. This timing event we learn is telomere shortening. To his credit, the author acknowledges one of the major difficulties with this aging timer. However, he does not leave well enough alone. He muddies the waters of evolutionary and developmental biology, not to mention biogerontology, by brokering a marriage between error accumulation and genetic programming theories of aging with telomerase as dowery. "In most non-tumor cells, the genes that encode the complex [telomerase] are turned off and the cell subsequently ages and dies. Is this turn-off an error? Or the very beginning of a genetic program?" (p. 278). The weak attempt to define the "Clock of Ages" really appears to constitute a perceived necessity to justify scientifically the use of this term, which clearly functions as a literary device in Medina's book. This leads to one of the major difficulties with this work. Medina's desire to achieve literary heights leads to a panoply of diversions and digressions that make the otherwise reasonable arguments he makes difficult to follow. Almost every thought is introduced or embedded within an anecdote from the life of the author or a biographical vignette of a famous, infamous, or remote character. Used much more sparingly, this approach would make a difficult topic easier to assimilate. However, Medina's propensity for this device becomes an example of a diversionary tactic, to use military terminology to match the embroilment of the unresolved circumstances surrounding the death of Napoleon into a discourse on programmed organismal death (chapter 14). It is a sorry commentary that this may not be the most remote of the connections the author attempts to establish. Medina's book opens with an attempt to define aging. He succumbs to his desire to be anecdotal. He devotes some 50 pages (chapters 1 and 2) to this exercise, and roams the phylogenetic landscape in the process. The cellular slime mold becomes an animal during this joumey, and the definition of "organism" is called into question. The author cannot resist bringing Dukas' "The Sorcerer's Apprentice" into the fray, and revealing that this raised the question in his mind of"how babies were made" (pp. 13 and 16). His argument (p. 21) that aging and death are the price of sexual reproduction does not sit well with subsequent evolutionary arguments. The difficulty of defining aging and death would have been brought home much more clearly and succinctly had the author limited himself to his considerations of clinical death in humans and cause of death on death certificates. Furthermore, this would have led very directly to the main topic of this book: the aging of various organ and tissue systems (pp. 71 to 224). Medina's brief treatment of the evolutionary biology of aging (chapter 3) comes as a pleasant surprise. The nature of this surprise is not the fact that he clearly explicates the notion that "the force of natural selection declines with age" (p. 65). Rather, it is the differentiation, which others have often found difficult to grasp, between the early and later thoughts of August Weismann on this subject (p. 62). The section of the book by Medina to which most readers of Experimental Gerontology will skip is his treatment of "why" we age. This section is preceded by a clear, authoritative, and almost unadulterated by anecdote molecular biology primer. The author groups the mechanisms
734
BOOK REVIEW
of aging into two categories: error accumulation and genetic programming (chapters 13 and 14). He laudably resists the compulsion of most authors to further subdivide these to virtual atomic resolution. These are well-reasoned chapters that still suffer from anecdotal overload. Some umbrage may be taken with certain formulations, such as "the overabundance of waste products can affect normal processes that, if left alone, would never [author's emphasis] age" (p. 251). Medina's summary of the role of mitochondrial DNA mutations in aging (p. 256) is a popularly held, though unsubstantiated, view. His description of antioxidants as "molecular 'firefighters' " or " 'assassins,' " and "the job of these heroic--if violent--biochemicals is to destroy ROS molecules" (p. 256) brings a chuckle to the reader. The author's discussion of glycosylation and glycation (pp. 262 and 263) suggests a confusion of these two distinct processes. The major difficulty with this section of the book, and with Medina's book in general, is the equation, tempered to some extent by error accumulation, of apoptosis with organismal aging and death. This equation is intimated early and is maintained throughout this book. It is often implicit, but it is also explicity stated. "How does the protein encoded by the bcl-2 gene work? It affects molecular programs in different ways, depending upon the cell type being examined. In one cell type (nerves), the mechanisms of its life-saving action has caused proponents of both Error Accumulation theory and Programmed Death advocates to leap with pure scientific joy. It joins the two ideas together" (p. 284). The author's theory becomes a developmental program theory of aging in a thoroughly explicit identification of aging and apoptosis in the second paragraph of conclusions on p. 291. It is more than likely that apoptosis, or better deficits in programmed cell death, contribute to aging. However, there is no basis for the author's insistence that suicide genes function to program organismal death (p. 291). The books by Fossel and Medina will provide a brief diversion for the biogerontologist. They will be serious reading for the uninitiated. For the latter, they will appear authoritative. As pointed out above, each of these volumes contains a fatal scientific flaw: whether or not telomeres or apoptosis prove ultimately to be the end all of aging, and it is doubtful they will. Beyond that, there is style. One can trade the minutiae of telomere therapy of Fossel for the incessant anecdotal dispersion of Medina. What is the source of the difficulties with these otherwise promising works? It would seem that these books have been written by individuals who are knowledgeable and enthusiastic about aging research. What they appear to lack is the intimate understanding of true practitioners of biogerontology. S. MICHALJAZWINSK1 Department of Biochemistry and Molecular Biology Louisiana State University Medical Center 1901 Perdido Street, Box P7-2 New Orleans, LA 70112 E-mail: [email protected]
PII S0531-5565(97)00041-7
Book Review
A TALE OF TWO THEORIES
Reversing Human Aging, by Michael Fossel, William M o r r o w and Company, Inc., New York, 1996, 307 pages, ISBN 0-688-14324-5, $25; and The Clock o f Ages, by John J. Me-
dina, Cambridge University Press, New York, 1996, 332 pages, ISBN 0-521-46244-4, $24.95. This is a pitous tale for to heere. But nathelees, passe over, is no fors: I praye to God so save thy gentil cors, And eek thine urinals and thy jurdones, Thyn ipocras and eek thy galiones, And every boiste ful of thy letuarye-God blesse hem, and oure lady Sainte Marye. GEOFFREY CHAUCER
IT IS CURIOUSthat the books by Fossel and Medina appeared contemporaneously. Despite their superficial differences, these works share much in common. This similarity includes a growing interest in the problems of aging and aging research. Reversing Human Aging and The Clock o f Ages should only be read in juxtaposition. For this is the only manner in which their differences will permit the casual reader to grasp their mutual plight. "Science has discovered the true Fountain of Youth--and it is within the reach of all of us," confidently declares the jacket of Fossel's book. It can't get better than that, and indeed, it is all downhill from there. This is really not a book about aging; rather, it is a volume on telomere shortening. In his Introduction, the author apologizes profusely for "overly bold simplifications," "misunderstandings," and "unreasonable conclusions." He begs that: "Much of it [his book] will be criticized harshly." That criticism is justified: "I have gone beyond my facts. I have done so knowingly; perhaps that is the greater fault." This characterization of this oeuvre is all too apt. There are certainly factual errors in Fossel's treatise, such as the stated incidence of Werner's syndrome (p. 51), or "in 1900, life expectancy was 25 y e a r s . . . " (p. 171). More annoying is the unsubstantiated insistence on the presence of a clock that defines maximum life span and on its location in at most only a few genes (p. 48). The relegation of all genetic, epigenetic, and environmental factors as phenomena that are secondary to the actual cause of aging (p. 56), deemed telomere shortening by Fossel, is much more difficult to countenance. This feat of intellectual equilibristics is achieved by the author through his redefinition of aging as telomere shortening. This legerdemain is implicit in the text, and it can even be encountered explicitly (p. 731
732
BOOK REVIEW
123 and 124). If aging is by definition telomere shortening, then telomere shortening can certainly be considered the cause of aging and everything follows neatly. Where telomere shortening does not occur, for example in the fruit fly, the cells are already senescent, according to the author (p. 105). The words of criticism stated above do not detract from the generally useful exposition of telomere biology contained in this book. However, the author does not know when to leave well enough alone. There is a lack of distinction between conjecture and fact that is difficult to swallow [e.g., "The diseases we associate with the nervous system--strokes, Alzheimer's, and other dementias--occur because the glia, unlike neurons that they protect, age and die... The glia age, whereas neurons do not." (p. 136)]. The author professes that such a distinction is not so important in a book aimed at nonscientists (p. xii). This reviewer believes that it is even more important when the audience lacks independent tools with which to distinguish between fact and fancy. The author is so consumed by telomere shortening as the cause of aging that he ignores facts. Unicellular organisms, in particular yeasts, are immortal, according to the plan (p. 100 et seq.). They must be, because their telomeres do not shorten. Fossel cites a reference in support of this lack of telomere shortening in yeasts. This reference contains data and additional citations that demonstrate that yeasts are mortal. A review of the manifestations of aging in a wide array of tissue and organ systems traces the root cause of these phenomena to telomere shortening. "Our maximum life span is determined by our telomeres" (p. 151). "The telomere is [the] only place where all the mechanisms of aging come together, and it is here where we can most efficiently prevent or reverse the myriad dysfunctions that express themselves as aging. It is here that we can reverse aging" (p. 156). This is how the author opens a two-chapter analysis of telomere therapy. A remarkable amount of space has been devoted to speculation on the minute details of a therapeutic approach, which has yet to be firmly grounded in basic experimental fact. Given this lack of foundation, it is probably not surprising that the author seeks "a telomerase analog [that] would be an artificial teiomerase that was tougher and more durable than normal telomerases" (p. 158), forgetting that the enzyme is composed of several protein subunits and contains an RNA component. These ruminations border on the preposterous when Fossel states that human trials will begin by the year 2000, a cure for most cancers will be in hand by 2005 (p. 163), and aging will be reversed by 2015 (pp. 177 and 222), so that "your life span can he extended by several hundred years" (p. 171). All of this will cost us between $50 and $1,000 for a single treatment (p. 172). "In the long run, side effects of telomere therapy will be few" (p. 210). In contrast to a lack of appreciation of the details of telomere therapy, this reviewer found the discussion of the social, political, economic, religious, and ethical ramifications of life extension to be thoughtful and very worthwhile. This may constitute the beginning of an important public dialog. Fossel's observation that: "Presently, anyone who makes it to eighty is experienced, but we think of them as dependent. The majority of eighty-year-olds are healthy, but there is little respect for age. We associate age with what we fear rather than what we respect," (p. 239) nicely sums up current attitudes toward aging and the aged. Whereas Fossel's book is confident about the imminence of dramatic gains in human longevity, John Medina demurs in his book. Indeed, scant attention is paid to this potential issue, lifting the need to discuss its ramifications. Medina provides a brief, standard recitation of the benefits of diet and exercise, and a touch of hormone therapy. This therapy is placed in its proper context of an unproven experimental approach. "We just don't know enough" to make accurate projections concerning gains in human longevity is the author's sage conclusion (p. 315). This
BOOK REVIEW
733
conclusion is based on the multifactorial nature of aging enunciated here and in several other places in the book. There are similarities between the two books. Both stress an intemal clock that dictates the course of aging. Medina calls it the "Clock of Ages." This clock chimes incessantly throughout his volume. We are never quite sure what the nature of this clock really is. A fleeting glimpse is finally provided toward the end of the book (p. 275 et seq.), though without the conviction and certainly without the certainty that Fossel musters. "The genes and biochemicals of the Clock of Ages are involved with a cellular timing event that is intimately associated with the cell cycle," states Medina. This timing event we learn is telomere shortening. To his credit, the author acknowledges one of the major difficulties with this aging timer. However, he does not leave well enough alone. He muddies the waters of evolutionary and developmental biology, not to mention biogerontology, by brokering a marriage between error accumulation and genetic programming theories of aging with telomerase as dowery. "In most non-tumor cells, the genes that encode the complex [telomerase] are turned off and the cell subsequently ages and dies. Is this turn-off an error? Or the very beginning of a genetic program?" (p. 278). The weak attempt to define the "Clock of Ages" really appears to constitute a perceived necessity to justify scientifically the use of this term, which clearly functions as a literary device in Medina's book. This leads to one of the major difficulties with this work. Medina's desire to achieve literary heights leads to a panoply of diversions and digressions that make the otherwise reasonable arguments he makes difficult to follow. Almost every thought is introduced or embedded within an anecdote from the life of the author or a biographical vignette of a famous, infamous, or remote character. Used much more sparingly, this approach would make a difficult topic easier to assimilate. However, Medina's propensity for this device becomes an example of a diversionary tactic, to use military terminology to match the embroilment of the unresolved circumstances surrounding the death of Napoleon into a discourse on programmed organismal death (chapter 14). It is a sorry commentary that this may not be the most remote of the connections the author attempts to establish. Medina's book opens with an attempt to define aging. He succumbs to his desire to be anecdotal. He devotes some 50 pages (chapters 1 and 2) to this exercise, and roams the phylogenetic landscape in the process. The cellular slime mold becomes an animal during this joumey, and the definition of "organism" is called into question. The author cannot resist bringing Dukas' "The Sorcerer's Apprentice" into the fray, and revealing that this raised the question in his mind of"how babies were made" (pp. 13 and 16). His argument (p. 21) that aging and death are the price of sexual reproduction does not sit well with subsequent evolutionary arguments. The difficulty of defining aging and death would have been brought home much more clearly and succinctly had the author limited himself to his considerations of clinical death in humans and cause of death on death certificates. Furthermore, this would have led very directly to the main topic of this book: the aging of various organ and tissue systems (pp. 71 to 224). Medina's brief treatment of the evolutionary biology of aging (chapter 3) comes as a pleasant surprise. The nature of this surprise is not the fact that he clearly explicates the notion that "the force of natural selection declines with age" (p. 65). Rather, it is the differentiation, which others have often found difficult to grasp, between the early and later thoughts of August Weismann on this subject (p. 62). The section of the book by Medina to which most readers of Experimental Gerontology will skip is his treatment of "why" we age. This section is preceded by a clear, authoritative, and almost unadulterated by anecdote molecular biology primer. The author groups the mechanisms
734
BOOK REVIEW
of aging into two categories: error accumulation and genetic programming (chapters 13 and 14). He laudably resists the compulsion of most authors to further subdivide these to virtual atomic resolution. These are well-reasoned chapters that still suffer from anecdotal overload. Some umbrage may be taken with certain formulations, such as "the overabundance of waste products can affect normal processes that, if left alone, would never [author's emphasis] age" (p. 251). Medina's summary of the role of mitochondrial DNA mutations in aging (p. 256) is a popularly held, though unsubstantiated, view. His description of antioxidants as "molecular 'firefighters' " or " 'assassins,' " and "the job of these heroic--if violent--biochemicals is to destroy ROS molecules" (p. 256) brings a chuckle to the reader. The author's discussion of glycosylation and glycation (pp. 262 and 263) suggests a confusion of these two distinct processes. The major difficulty with this section of the book, and with Medina's book in general, is the equation, tempered to some extent by error accumulation, of apoptosis with organismal aging and death. This equation is intimated early and is maintained throughout this book. It is often implicit, but it is also explicity stated. "How does the protein encoded by the bcl-2 gene work? It affects molecular programs in different ways, depending upon the cell type being examined. In one cell type (nerves), the mechanisms of its life-saving action has caused proponents of both Error Accumulation theory and Programmed Death advocates to leap with pure scientific joy. It joins the two ideas together" (p. 284). The author's theory becomes a developmental program theory of aging in a thoroughly explicit identification of aging and apoptosis in the second paragraph of conclusions on p. 291. It is more than likely that apoptosis, or better deficits in programmed cell death, contribute to aging. However, there is no basis for the author's insistence that suicide genes function to program organismal death (p. 291). The books by Fossel and Medina will provide a brief diversion for the biogerontologist. They will be serious reading for the uninitiated. For the latter, they will appear authoritative. As pointed out above, each of these volumes contains a fatal scientific flaw: whether or not telomeres or apoptosis prove ultimately to be the end all of aging, and it is doubtful they will. Beyond that, there is style. One can trade the minutiae of telomere therapy of Fossel for the incessant anecdotal dispersion of Medina. What is the source of the difficulties with these otherwise promising works? It would seem that these books have been written by individuals who are knowledgeable and enthusiastic about aging research. What they appear to lack is the intimate understanding of true practitioners of biogerontology. S. MICHALJAZWINSK1 Department of Biochemistry and Molecular Biology Louisiana State University Medical Center 1901 Perdido Street, Box P7-2 New Orleans, LA 70112 E-mail: [email protected]