American Scientist

The Molecular Genetics of Aging: Results and Problems in Cell Differentiation. Siegfried Hekimi (ed.). xxv + 240 pp. Springer, 2000. $135.

En route to Sardinia for a meeting on centenarians and eager for a preview of findings that might be presented there, I turned to the first chapter of this collection, an essay on "Centenarians and the Genetics of Longevity" by Tom Perls and associates. I learned that centenarians are not a new phenomenon (although there are a lot more of them now than ever before), and I was reminded of the surprising fact that centenarians are often clustered in a single lineage. Four such families are discussed here, one with five centenarians and another with seven, one with eight siblings living beyond the age of 90, and one with 23 out of 46 in the third generation living to 90 or beyond. Although as a geneticist I would like to believe that this proves that there are major additive genes that control extreme longevity in human beings (as the age-1 gene does in the nematode Caenorhabditis elegans), the data do not convince me that this must be so; other explanations are possible. Indeed, on our flight back to the United States, Perls confided to me that he agrees and would write the chapter differently now. Toward the end of the chapter, the authors suggest that late menopause indicates a slower rate of aging overall, and they theorize that "menopause may be the evolutionary fulcrum that determines human life span." Here a section subhead erroneously implies that menopause occurs only in people; the text does acknowledge pilot whales as an exception to this, but cessation of female reproduction has been documented in numerous other organisms as well.

The second chapter, by S. Michal Jazwinski, presents a cohesive, though incomplete, description of the genes specifying the reproductive life span of yeast. His thesis that the metabolic and stress response pathways are integrated by means of the retrograde response (a pathway facilitating mitochondrial regulation of nuclear genes) makes increasing sense to me. I would like to see yeast-aging researchers exploit the stationary-phase (nongrowing) phenotype as well. The overview provided in this chapter is less than complete because it ignores work from the laboratories of Lenny Guarente and Cathy Clarke, among others.

Next, Rajinder S. Sohal (a pioneer in this area) and his colleagues discuss the role of oxidative stress in aging. I was eager to see a coherent overview of Sohal's work, but in this I was disappointed. Instead I learned that there are "vast" bodies of literature (too vast to be reviewed, I guess) that support the oxidative-stress theory of aging. The authors maintain that most genetic research on longevity (including my own—so I may be prejudiced) is for naught, because "no reliable inferences can be drawn about aging in homeotherms [which have relatively stable metabolic rates] solely on the basis of chronological life-span variations in poikilotherms" (such as insects and nematodes, which have variable rates of metabolism). An odd statement for Sohal, who has spent his life working on flies! Sohal's major point here is that in interpreting the results of experimental regimens that purport to affect the rate of aging, we should consider whether the metabolic rate has been affected. More important is his contrarian point, that "extension of life span without simultaneously increasing metabolic potential is of questionable biological significance." He seems to think that genetics has little to offer.

Stephen Helfand and Blanka Rogina review their work on gene expression in Drosophila. Their observations that most genes show age-specific expression still surprise me; I expect the expression level of most genes not to change during adulthood. I'd like to see the characterization of the transcriptome in Drosophila. Unfortunately, the work of many laboratories (for example, those of John Tower, Jim Curtsinger and Linda Partridge) is left out of this chapter. This is characteristic of the book's anecdotal nature and is a major shortcoming.

C. elegans is amply represented with four chapters. These add up to a fairly detailed, in-depth review of most of the work that has been done in the nematode, starting with my own and ending with a variety of unpublished results from the contributors' own research. Siegfried Hekimi reviews his own work and does a good job of it. He emphasizes clk genes (which is not surprising) and constructs a plausible unifying hypothesis for understanding the factors that determine life span in worms.

Perhaps the best two chapters in the book are "Contributions of Cell Death to Aging in C. elegans," by Laura A. Herndon and Monica Driscoll, in which they link necrotic-like cell death and aging; and "Stress Response and Aging in Caenorhabditis elegans," by Gordon Lithgow. If the book weren't so expensive, it might almost be worth buying for these reviews alone, particularly for those working in this area. Lithgow shows that longevity mutants can be identified using a surrogate marker—heat resistance—and suggests that heat-shock proteins play a role in life prolongation. He emphasizes the role of response to stress in life prolongation, as do Naoaki Ishii and Philip S. Hartman in their chapter on oxidative stress and aging in C. elegans (none of them have read Sohal's chapter, I guess). Ishii and Hartman provide a good review of oxidative stress and include physiological studies of carbonyls in their chapter. Again, numerous laboratories and points of view are not represented—for example, those of Cynthia Kenyon, Gary Ruvkun and myself.

Martihn E. T. Dollé, Heidi Giese, Harry van Steeg and Jan Vijg review their work testing the role of somatic mutation in the specification of mouse life span. They describe several mouse strains that have been genetically engineered to facilitate measures of mutation rates during organismic aging. The data just now appearing in the literature from the use of this technique are reviewed here and turn out to be less supportive of the hypothesis for "general" aging than I would have anticipated.

In the last two chapters, which are well done, Andrzej Bartke and Gary Van Zant describe their longevity research. Bartke's excellent review of work on dwarf mice discusses the surprising finding that their life span is extended over that of their normal siblings by as much as 49 percent in males (so that they live about a year longer) and 64 percent in females. He concludes that "direct application of findings in Ames or Snell dwarf mice, and, parenthetically, also in the [calorically restricted] animals, to the human is exceedingly unlikely." Van Zant provides some interesting data supporting the thesis that stem cells may play a key role in organismic longevity; however, few of his tests are critical. I'd like to see how the stem cell populations change in the various longevity mutants discussed in the previous chapter.

The richness and depth that characterize modern aging research are apparent in this book. It's hard to believe that the paradigm initiated some 20 years ago to look for "worthless," long-lived mutants has paid off with so many top-notch research results. It's unfortunate that the work of many key laboratories was omitted from this volume.