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BOOK REVIEW |
Associate Dean for Research College of Biological Sciences University of Minnesota St. Paul, MN 55108
Handbook of the Biology of Aging, 6th Edition, edited by Edward J. Masoro & Steven N. Austad. Academic Press, San Diego, CA, 2006, 660 pp., $99.95 (cloth).
The purpose of the Handbooks of Aging series is "to encourage integration of information from across disciplines and methods of gathering data about aging" (Birren, 2006, p. xvi). This 6th edition of the Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad, succeeds very well in achieving that goal, and will be a welcome addition to the library shelves of the biogerontologist. It is not possible in these handbooks to cover the entire field of the biology of aging in every edition; neither is it desirable to repeat all topics each year. Although the editors point out that "the content of the work is virtually 100% new," it is useful to briefly review what's particularly new and/or unique in this 6th edition.
Although the 5th edition (Masoro & Austad, 2001) included a chapter on the "Effect of Age on Gene Expression," the 6th edition has recognized the increasing use of microarrays in such experiments with its chapter on "Microarray Analysis of Gene Expression Changes in Aging," by Noel Hudson et al. The 5th edition's chapter on "Dietary Restriction: An Experimental Approach to the Study of the Biology of Aging," has been replaced by a chapter titled "Dietary Restriction, Hormesis, and Small Molecule Mimetics," by David Sinclair and Konrad Howitz. Although this chapter describes a "major shift in thinking" about dietary restriction (DR), this new approach embraces many of the current theories on DR under one umbrella. Edward Masoro has provided a nicely argued chapter on an old and divisive subject—"Are Age-Associated Diseases an Integral Part of Aging?" A chapter on "Computer Modeling in the Study of Aging," by Thomas Kirkwood et al., is new, as is a chapter on "Reliability Theory of Aging and Longevity," by Leonid Gavrilov and Natalia Gavrilova. A chapter on "Hematopoietic Stem Cells, Aging and Cancer," by Deborah Bell and Gary Van Zant, reflects the increasing interest in and knowledge about the possible roles of stem cells in aging.
Given the editors, it is not surprising that a good part of this Handbook (9 out of 21 chapters) is focused on the use of short-lived models (yeast, nematodes, fruit flies, birds, and mice and other mammals) in aging research. The overall list is rounded out with chapters on mitochondria, evolutionary biology, skeletal muscle, fat and carbohydrate metabolism, insulin-signaling, and the female reproductive system. Although I will only discuss a selected number of the chapters here, mainly those with relevance to longevity regulation, the overall lineup well represents most of the current directions in non-neurological biogerontology research today.
Are Age-Associated Diseases an Integral Part of Aging?
As pointed out by Masoro in his chapter, gerontologists have been debating for over 100 years whether age-associated diseases are an integral part of aging. Yet, the issue remains far from settled. Masoro provides a very thoughtful discussion of the issue, but in the summary he concludes that the question is yet to be definitively answered (and perhaps never will be). I agree with his view that "rigidly holding to the view that age-associated diseases are not an integral part of aging may have had, and is likely to continue to have, an adverse effect on aging research" (p. 56).
Furthermore, as Masoro observes at the end of his chapter, such a view tends to eliminate the use of experimental models that might well provide useful insights into the aging process. For example, there is widespread skepticism that Hutchinson-Gilford progeria syndrome (HGPS) is a useful model in which to study aging (Miller, 2004). I suspect, however, that the so-called accelerated aging models in general, and HGPS in particular, may have something useful to teach us about aging phenotypes in humans (see Warner & Sierra, 2003; Scaffidi & Mistelli, 2006), particularly with regard to the roles of cell death and stem cells in aging, as well as in age-related pathology.
This theme is briefly picked up later in a chapter titled "p53 and Mouse Aging Models," by Catherine Gatza et al., who discuss the relevance of a particular p53 mutant to aging. This mouse is unusual because it is cancer resistant, but has a life span that is only 80% of normal. Several other mice deficient in a variety of other enzymes involved in DNA metabolism are discussed in this chapter because they also have early onset of aging phenotypes affecting bone, muscle, and skin. Why tissues of mesenchymal origin are particularly affected is not clear, but the causal mechanisms may be relevant to understanding the onset of osteoporosis and sarcopenia in older people.
Finally, to come back to the question addressed by Masoro about whether age-associated diseases are an integral part of aging, I would counter with: Does it really matter? What's important is to understand that studying the causes of aging can be a surrogate for studying the causes of age-related disease and pathology and vice versa. The two seem inextricably linked to me, and not easily amenable to separation.
Dietary Restriction, Hormesis and Small Molecule Mimetics
Without a doubt, the most robust intervention to alter the rate of aging and the extend the maximum life span in animals is the intervention known as DR or caloric restriction (CR) (McCay, Crowell, & Maynard, 1935). The general protocol is to reduce caloric intake by 20%–40%, while maintaining the required intake of essential vitamins, minerals, essential amino acids and fatty acids, and so forth. This intervention works in almost every species in which it has been adequately tested (Weindruch & Walford, 1988), although the experiments in rhesus monkeys are not yet far enough along for an unequivocal conclusion about this species. Not surprisingly, the search for DR mimetics has become a hot topic in gerontology because few people are likely to initiate such a nutritional regimen in young adulthood, and maintain it for a lifetime, in the hope of adding 10 more years or so to their lives. They might feel differently about that, however, when they reach age 70 and older.
Sinclair and Howitz describe a new approach to finding a DR mimetic. In this chapter, they provide a comprehensive review of the history of DR research, and then move on to present a novel hypothesis that represents a recent major shift in thinking, but embraces many of the current theories about DR. "The hormesis theory of DR proposes that the diet imposes a low intensity stress on the organism, which elicits a defense response that helps protect it against the causes of aging," (p. 78) as suggested earlier by Lithgow (2001). Apparently, organisms possess pathways to promote survival during periods of adversity, and activation of such a pathway can ultimately affect longevity.
Earlier attempts to mimic DR included the use of 2-deoxyglucose, a nonmetabolizeable form of glucose. Toxicity is a concern with this compound, however, so it has not been proposed for human clinical trials. Sinclair and Howitz entered this field by screening for compounds that could stimulate a class of enzymes known as sirtuins. Sirtuins are deacetylating enzymes that remove acetyl groups from a variety of other proteins, including histones and transcription factors. Acetylation is one of several biochemical modifications used to modulate the function of proteins, and altering the acetylation patterns of histones and transcription factors has the potential to globally alter the activity of hundreds of other proteins. In their screen, Howitz and colleagues (Howitz, Bitterman, Cohen, et al., 2003) identified a small number of polyphenolic compounds that activate SIRT1, the mammalian equivalent of the yeast Sir2 protein that had already been shown to promote longevity in yeast and nematodes. These sirtuin-activating compounds (STACs) include the polyphenols resveratrol, butein, and quercetin, all of which are only made in plants.
How and whether STACs help plants survive is not known, but this finding increases our appreciation of the importance of plants in our diet beyond supplying vitamins and fiber. STACs may work in animals because they activate an evolutionarily ancient mechanism that allows animals to respond to stress as do plants that have no direct control over their environment. This stimulation of a hormesis signal transduction pathway in animals is very different from the previously much-discussed "actions that directly counteract proximate causes of cellular damage" (p. 90), such as those caused by production of reactive oxygen species in vivo. Thus, the Sinclair and Howitz chapter points out the importance of 1) identifying the components of these putative hormetic signaling pathways, and 2) investigating the possible roles of animal proteins already known to interact with phytochemicals such as these polyphenols in the search not only for the mechanism for how DR works, but also for understanding mechanisms involved in longevity regulation.
Microarray Analysis of Gene Expression Changes in Aging
This topic is new in this 6th edition of the Handbook, and receives a lengthy and very comprehensive treatment by Noel Hudson and colleagues. When gene expression microarray technology came on the scene about 10 years ago (DeRisi, Iyer, & Brown, 1997), these authors predicted that this system should find numerous uses in genome-wide genetic mapping, physical mapping, and gene expression studies. There was an immediate appreciation by the biogerontology community of the potential of this technology in aging research in the area of documenting changes in gene expression patterns with increasing age.
The race was on, and Lee, Klopp, Weindruch, and Prolla (1999) were the first to publish with their paper on changes in the gene expression profile in mouse skeletal muscle with aging and its retardation by dietary restriction. This was quickly followed by other papers from this group on gene expression patterns in mouse brain, rhesus skeletal muscle, mouse heart, mouse adipose tissue, and others, using age and dietary restriction as independent variables. These papers from the University of Wisconsin were joined in the literature by papers from the University of Michigan, the University of Texas Health Science Center in San Antonio, the University of Rochester, the Buck Institute, and the Geron Corporation, to name a few. This rapid production of results generated considerable debate about proper strategies for identifying which data are meaningful and which are not from among the thousands of genes included on the microarray chips (Miller et al., 2001). This debate has therefore emphasized the need for rigorous statistical and bioinformatic analysis of the data obtained.
As Hudson and colleagues point out in their Handbook chapter, the opportunities are almost limitless, but the rate-limiting steps remain: 1) determining what differences are significant and which aren't; 2) determining what the significant differences actually mean; and 3) confirming whether the gene expression changes are actually reflected in changes in the levels of proteins. So far, the field is characterized by more data than answers, but the potential usefulness of the technology remains promising. An immense breakthrough would be development of a biomarker panel of genes on a gene expression microarray chip that could be used to assess physiological age of an individual from analysis of gene expression patterns in either their fibroblasts or lymphocytes.
A Critical Evaluation of Nonmammalian Models for Aging Research
A chapter by Steven Austad and Andrej Podlutsky provides the most thoughtful discussion of this topic that I can recall reading. They start with the obvious question about what "is the extent to which underlying mechanisms of aging will overlap among invertebrate models, in which the majority of progress has been made, and to the species of ultimate interest to most researchers: humans" (p. 449). They begin their analysis by describing new (at least to me) information about evolutionary relationships. Apparently, new DNA sequence information from a multitude of organisms has now thrown previous phylogenetic relationships based on morphological traits into question. The traditional view has been that nematodes and fruit flies shared their last common ancestor with mammals. Now it is thought that mammals diverged before the nematodes and fruit flies diverged from each other. Thus, a trait shared by both could have arisen well after the mammalian lineage diverged. However, if a trait is shared by nematodes and fruit flies AND yeast—as is the longevity extension induced by over-expression of sirtuins—this would increase the probability that the mechanism may also obtain in mammals (unless secondarily lost during subsequent evolution). In the context of this new evolutionary information, the potential relevance of yeast research in understanding human biology is considerably augmented.
The authors go on to propose that it would be useful to develop an animal model for aging research that diverged from the human lineage prior to worms and flies. They suggest that Cnidarians (hydra, corals, jellyfish, anemones) fill the bill as they share some human genes that do not exist in nematodes and fruit flies. Whereas yeast to a certain extent fills this role, as a unicellular organism it lacks a host of other genes involved in such things as cell–cell interactions. However, until someone develops a Cnidarian model, we are likely to continue to rely on yeast, nematodes, and fruit flies to discover concepts that we want to test in mammalian and primate models.
Austad and Podlutsky also suggest that "progress would be greatly accelerated ... if we knew more about the phenotypic details about deterioration and death in our model organisms" (p. 461). Until we know more about these details, we will not know whether we are studying "private" or "public" mechanisms of aging. ("Private" means a mechanism specific for the organism under study, rather than for animals in general.) A couple of examples of this concern are the electron microscopic demonstration by Herndon and colleagues (Herndon, Schmeissner, Dudaronik, et al., 2002) that aging in nematodes is accompanied primarily by muscle deterioration, and that over-expression of superoxide dismutase only in neurons is sufficient to extend longevity in fruit flies (Parkes, Elia, Dickinson, Helliker, Phillips, & Boulianne, 1998). Is aging in these models mainly about muscle deterioration? When the focus is on nematodes and fruit flies at biogerontological meetings, a frequently asked question is: What do these animals die from? It's time we found out!
This Handbook also contains one other chapter on nematodes ("Dissecting the Processes of Aging Using the Nematode Caenorhabditis elegans"), and no fewer than four chapters on fruit flies ("Complex Genetic Architecture of Drosophila Longevity"; "Biodemography of Aging and Age-Specific Mortality in Drosophila"; "Genetic Manipulation of Life Span in Drosophila melanogaster"; "Juvenile and Steroid Hormones in Drosophila melanogaster"). All of these chapters were written by recognized experts in the field.
Growth and Aging: Why Do Big Dogs Die Young?
This title of the chapter written by Richard Miller and Steven Austad is somewhat counter-intuitive in view of the well-known association between body size and longevity among species. So why is this association reversed within a species? The most likely explanation is that the positive correlation of body size with longevity among species, and the negative correlation within a species, have different causes.
One focus of this chapter is comparisons of animals that resemble each other, but age at different rates. Through a variety of experimental approaches, many performed in Miller's own laboratory, Miller and Austad conclude that insulin0like growth factor (IGF-I) levels are a critical factor in the differences in aging rates and longevity among individual genetically heterogeneous mice, and that early growth rate is a predictor of life span. Dramatic increases in longevity are observed for mice deficient in pituitary development, and smaller increases are observed for mice lacking the growth hormone receptor, as both of these mutant mouse stocks have very low IGF-I levels (about 20% of normal). Similarly, many wild-derived mouse stocks have subnormal levels of IGF-I, and also live longer than laboratory mice.
Whereas dogs have not been genetically manipulated in the same way, they have been bred based on size, and an unintended consequence has been to generate breeds that have significantly different life spans. There is a strong inverse correlation between size and life span in dogs, and a strong correlation between size and IGF-I levels. All of these results "suggest that the pace of aging may be regulated by hormonal pathways that also control growth and body size" (p. 529), but the exact mechanisms remain to be elucidated.
Fibroblasts taken from long-lived mice with low IGF-I levels and grown in culture are remarkably more resistant to multiple forms of cytotoxic stress, but the mechanism(s) of this resistance are not unknown. Similar resistance has been observed in bird fibroblasts, reflecting their exceptional longevity when compared to mammalian species of comparable size. This resistance may reflect what Sinclair and Howitz called "actions that directly counteract proximate causes of cellular damage" (p. 90). It may also explain why DR further increases the exceptional longevity of dwarf mice, that is, why low IGF-I and DR effects are additive, thereby producing very long-lived mice (Bartke, Wright, Mattison, Ingram, Miller, Kinney, et al., 2001). The reader who wants to learn more about the role of insulin-signaling in aging will find Christy Carter and William Sonntag's chapter on "Growth Hormone, Insulin-Like Growth Factor-1 and Biology of Aging" of considerable interest as well.
Miller and Austad suggest that longevity differences among different species appear to "reflect co-evolutionary pressures that promote anti-aging mechanisms among species large enough, or ... agile enough to avoid predation" (p. 524). Overall, this chapter provides an insightful update on the relationship between size and longevity in mammalian species. However, it does not tackle the basis for exceptional longevity in some nonmammalian species such as birds—neither are answers to this question found in the chapter on "Senescence in Wild Populations of Mammals and Birds," by Brunet-Rossinni and Austad. This Handbook also does not address the issue of species that appear to show negligible senescence with increasing age, for example, lobsters and some fish, which appear to simply increase in size until predation or accidental death occurs. Perhaps in a future edition?
In summary, I have chosen to discuss only a few of the chapters in this Handbook because I am most familiar with these areas of gerontology. The other chapters are equally well done, and a reviewer with more expertise in physiological systems might have chosen to comment on these chapters instead of the ones I have chosen.
References
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