A Means to an End

The New York Times, August 15, 1999. Reviewed by John Horgan.
Almost four years ago a political scientist, Harvey Sapolsky, fretted in the journal Technology Review over the fate of American science in the post-Soviet era. The end of the cold war, he argued, had eliminated a major justification for American research and development; to keep their funding levels high, scientists needed to find another bogeyman to replace the Evil Empire. Sapolsky's candidate? Mortality. Most taxpayers, he pointed out, want to live longer or even forever; moreover, scientists will almost ceratinly never defeat mortality, so they can remain on the public dole forever.

Sapolsky must be pleased with his prescience. Over the past few years federal funding has subsided for physics - the primary beneficiary of the cold war - and soared for biomedical research. Senescence in particular has become one of science's most glamorous topics. Virtually every week, it seems, researchers announce the discovery of a new gene or protein or something related to aging. Given the frenzy of media speculation unleashed by these findings, one would think we are on the verge of becoming a race of Methuselahs. "Can you live forever?" Esquire asked on the front of its May issue. "Probably. Do you want to? See inside."

Those who want a clear-eyed appraisal of aging research can now choose between two solid books on the topic (issued by the same publisher). Both convey the excitement of the science of senescence, but both also emphasize how far investigators are from discovering the fountain of youth.

"Times Of Our Lives", by Tom Kirkwood...

An obvious difference between Kirkwood's book and "A Means to an End", by William R. Clark, is stylistic. A professor emeritus of immunology at the University of California, Los Angeles, Clark serves up his facts and theories more or less straight. His view of aging also diverges from Kirkwood's in interesting ways. Clark portrays senescence as an unfortunate side effect of oxygen-based metabolism. Oxygen provides cells with a powerful energy source, but it is also a volatile, corrosive mutagen that can wreak havoc on DNA and other vital cellular components. Natural selection provided us with mechanisms for minimizing the damage from oxygen, but all are imperfect. Even vigorous exercise, in spite of its obvious benefits, might accelerate senescence in subtle ways by increasing our oxygen consumption, Clark warns.

He cautiously concludes that certain foods and dietary supplements called antioxidants might reduce the risk of cancer heart disease and other afflictions of age by countering oxygen damage. He has a sensible take on so-called caloric restriction experiments, in which researchers, by sharply curtailing the diets of mice and other animals, have boosted their life span by more than 50 percent. Although many of us could benefit from eating less, Clark says, caloric restriction is unlikely to let us live 150 years or more, as some enthusiasts claim. The research suggests that "excess caloric intake shortens lifespan, not that caloric restriction extends it, he asserts.

He has a more sanguine view than Kirkwood of the genetics of senescence. After all, researchers have discovered genes that, when manipulated, can stretch the life span of fruit flies, worms and other simple organisms; genes with similar structures have been identified in humans. Moreover, human diseases like Werner's syndrome, which mimics the symptoms of advanced aging, are caused by a single mutant gene. These findings persuade Clark that human senescence may stem not from innumerable genetic factors - as Kirkwood thinks - but from as few as seven genes. Clark is thus more optimistic about the prospects for boosting longevity through gene therapies.

But he deflates the hype about telomeres, bundles of DNA that cap the ends of chromosomes. Telomeres apparently play a crucial role in limiting cells' ability to replicate; every time cells divide, telomeres get a little shorter, until finally cells stop dividing altogether after 50 or so divisions. Researchers hope that if they can prevent telomeres from shortening, they might make individual cells and even entire organisms immortal. Clark points out two problems: First, making cells immortal also makes them more likely to become cancerous. Second, some rather important cells - like those in our brains - stop dividing long before adulthood, so telomere therapy would have no impact on them.

Many recent articles on aging tease us with the thought that telomere therapy and other breakthroughs might let us live longer than Mme. Calment. "The first immortal man," Esquire proclaimed last spring, is "about 40. Nothing special….Like you." So far, these prophesies are wishful thinking. But remember, mortality has a silver lining - at least for scientists. As long as we keep growing old and dying, science lives!

Kirkus Reviews , February 15, 1999 (Staff review)
Clark, Professor Emeritus of Immunology at Univ. of Calif., Los Angeles, describes in detail how the process of aging, or senescence, takes place at the level of individual cells and what is known about the internal regulation of that process by our genes. He relates how research into various genetic disorders that mimic the human aging process, such as Hutchinson-Gilford progeria and Werner's syndrome, is providing clues to the involvement of genes in the aging process; and he dismisses claims that rejuvenation or immortality can be achieved through the manipulation of telomeres, those segments of DNA at the tip ends of chromosomes that have been called the cell's internal timekeepers. The effects of caloric restriction on lifespan are considered, as is the role of antioxidants in reducing the risk of deadly cancers and cardiovascular disease. What is clear from Clark's text is that more is known about how and why we age than has ever been known before, and that with the coming completion of the Human Genome Project, knowledge of the genes involved in aging will greatly expand. In his final chapter, which is the book's least technical and most thought-provoking, Clark considers briefly what the impact on society will be as that knowledge is applied and leads to a longer, healthier average human lifespan. A scientist's careful, unsensational account of the current status of research into aging that requires from the reader a level of commitment well beyond mere curiosity.

Library Journal May 1, 1999. Reviewed by Margaret Henderson.
As in his previous books, Clark does not hesitate to introduce the lay reader to complex concepts in cell and molecular biology. The news media and popular magazines tend to overestimate the impact of aging research on humans, but Clark looks at things realistically, especially the effects of reduced caloric intake and antioxidants at the cellular level. Clark concludes his book with an interesting discussion of the economic and social impact longer lifespan might have on humans. Clark's is less anecdotal than some of the other aging books on the market: Steve Austad's Why We Age, Leonard Hayflick and Robert Butler's How and Why We Age, and John Medina's The Clock of Ages. He sticks to the scientific research and refers to articles published in top-ranked, peer-reviewed scientific publications in his bibliography. Recommended for larger public libraries.

Booklist, March 15, 1999 Reviewed by William Beatty.
Clark believes that the study of aging is one of the most mysterious and exciting areas of biomedical research. His fascinating and informative book conveys his belief, if the reader is willing to stay with its close reasoning and scientific terminology. Clark examines aging and death at the cellular level. Cellular processes that deal with "programmed" and accidental death began far down in the evolutionary chain; indeed, one of the most remarkable aspects of the subject is how closely those processes resemble one another in the simplest and most complex organisms. As Clark works his way through recent research, he points out difficulties in separating cause and effect and the many questions that still remain unanswered. How cells keep time is only one of the provocative questions he raises. Other subjects include the roles of genes and environment, of free radicals and antioxidants, and of unbounded and restricted eating. One of the books most engaging elements is Clark's ability to show how scientists think about problems and approaches in the field.

Publisher's Weekly, March 22, 1999. Staff review
A Professor Emeritus of Immunology at UCLA, Clark here examines "the process of aging from a new and important perspective, that of cell and molecular biology, and the underlying discipline of genetics. When addressing each of these biological subfields, Clark effortlessly takes readers from the simple to the complex. from a discussion of single-cell organisms to human beings. Along the way, he summarizes the latest scientific information while outlining prospects for future research. Although this is a scholarly book, not a how-to manual, Clark does discuss strategies for extending the average human life by caloric restrictions and the use of antioxidants. He also does a nice job of exploring the causes of Alzheimer's disease, various forms of cancer, and an array of genetic disorders that afflict the young by making them age prematurely. Finally, in this neatly informative work, Clark uses a sociological and political perspective to probe the tensions likely to arise between length of life and quality of life as medical advances continue to accumulate, and to consider the broader ramifications inherent in an aging population.

Journal of Anti-Aging Medicine May/June 1999
This broad?ranging book treats the topic of aging through a wide range of model organisms from in vitro tissue cultures to paramecia (one of Clark's strengths), nematodes, fruit flies, guppies, salmon, and finally human progeria patients. First, Clark begins by making the point that humans are uniquely endowed with the knowledge that their individual members are compelled to die. Then, he explains that the key to death from aging lies in our genes, not the environment. Next, he points out that gerontic genes (those that contribute to longevity or conversely to senescence) out of the approximately 100,000 genes in the human genome are few in number, perhaps in the low hundreds; Clark cites George Martin as saying 70 such genes is not an unreasonable number (page 194)]. Finally, he explains that, although different genes have recently been demonstrated to "evolve" at different rates, gerontic genes have been remarkably conserved across many species over millions of years. (Thus, knowing what they are in lower phyla should help us identify these same genes in humans.) What also simplifies our problem somewhat is the fact that the 100 trillion cells of an adult human, which undergo replicative senescence at different rates, all have one set of identical gerontic genes in their nucleus. Thus, by implication, systematic interventions in these genes by genetic engineering could be a big win for biologists. With respect to the issue of teleology in the Darwinian evolution of aging, Clark says (on page 45), "Natural selection has no other basis for "decision making" than the impact of natural variation ? mutations ? on the survival and reproduction of [individual] genes. It is worth remembering that [higher] evolution is not the 'purpose" of natural selection. Natural selection ultimately adheres to the same principals of thermodynamics [entropy] that govern all other activities in the physical universe; evolution is simply an epiphenomenon perceived by humans. In other words, mutations that would increase the pre?reproductive lifespan of an individual are of no inherent value unless they in some way increase the efficiency with which the inherited DNA will be passed on to yet another generation. Whereas a pair of mice may have to produce forty copies of themselves to maintain a population equilibrium consistent with the available food supply, a pair of humans need only produce three. Across a wide range of species there is a correlation of maximum lifespan with reproductive efficiency and low accidental death rates [from predation of one's young]."

But how exactly do organisms age from their genes upward to their tissues? One cellular clock appears to be hidden in the {TTAGGG} telomeric repeat units (about 1500 to 2000 times in most cells) at the tips of our chromo- somes. Clark shows graphically that continual telomere loss secondary to repeated divisions (if not restored by the enzyme telomerase) can lead to random chromosomal clumping, a serious show?stopper for future mitoses. However, Clark quickly points out that most aging organisms are filled with post?mitotic cells, so "the claim that restoring telomerase activity in humans could lead to rejuvenation or immortality cannot be taken seriously; there is no obvious role for telomerase to play in the majority of the cells in our bodies." Question: How could a cell?cycle block (like GI/S for example) explain gray hair, wrinkled skin, heart disease, and cataracts, all of which occur in cells that are for the most part no longer dividing? Clark answers: "We simply do not know at present."

On the other hand, Clark has profound insights into the relation between metabolic rate (graphically shown for different species), oxidative stress (the oxygen?utilizing bacteria that we now call "mitochondria," which we procured at an early stage of evolutionary history and then, to prevent them from replicating autonomously, disabled by swapping a good portion of their genome into our own nuclei), and caloric restriction (balanced undemutrition without malnutrition). He treats the topic of Alzheimer's Disease with equal precision. An original idea at the end of the book posits a system of antagonistic sets of regulatory gerontic genes ?? some of which initiate the onset of senescence and some of which repress the onset of senescence, and which, as a side effect, dictate maximum lifespan. The Werner's Syndrome (WS) helicase gene might be an example of this sort of gene. Catalase, glutathione, and SOD genes are also important in this regard. A comparable argument could be made for the presence of a system of antagonistic genes to control the onset of puberty, menopause, and parity (average litter size) in different species. vIn the concluding chapter, Clark ranges from discussing the biological significance of human centenarians to the role of the human genome project in our search for the "fountain of youth." "There are nay?sayers who would like to turn back the clock... but that is not the way human beings go about their business. Molecular medicine will be an important part of the 21st century. It may require some adjustment in our thinking, and even in our social institutions. But we will do it. We will do it.

Natural History Magazine, April 1999.
Cell biologist Clark dissects the process of human aging, examining what goes on at a cellular level when an individual is stricken by genetic disorders, like Werner Syndrome and Alzheimer's Disease, that mimic human senescence. He also provides explanations as to why caloric restriction and reduction of oxidative stress may increase an individual's lifespan.