Ageless Quest: One Scientist's Search for Genes That Prolong Youth
by: Leonard Guarente
Topics include: yeast aging, insulin pathway, mating genes, mammalian aging, petri plates, insulin signaling, mother cells, nuclear transplantation, yeast genome
From Publishers Weekly
Science can be like sausage-sure, you like it, but you're better off not knowing how it's made. But with the arrival this year of a number of tell-all science memoirs, readers can't help but take a peek, deriving a certain lurid thrill. Given the potentially explosive subject matter, one would expect Guarente's account of his pursuit of a genetic "cure" for aging to dish up controversy, but it doesn't. Rather, this slim book delivers pure work-a-day science, without any insider dramatics. Guarente, a biologist at MIT whose work on aging has been featured in the Wall Street Journal, the New York Times and the Boston Globe, does gripe now and again about such things as the hardships of the tenure track. But the balance of the book details the author's intellectual adventure, touching along the way on theories of aging and the workings of the biotech industry. At the heart of his story is a gene called SIR2, which has been found to slow aging in yeast in animals. Could it eventually be used on humans? Possibly. Guarente views aging as a disease that someday might be treatable with new drugs, which raises further provocative questions about the ripple effect treatment could have on population, economics and other social factors. But the author, who excels as a diarist but less as a popular-science pitchman, leaves these questions largely untapped. This, admittedly, makes for sedate though quite amiable, utilitarian reading.
Copyright 2003 Reed Business Information, Inc.
Book Info
Massachusetts Institute of Technology, Cambridge. Pocket-sized account of the research by one of the pioneer researchers in the aging field. Explores the possibility that the aging process found in yeast might reveal principles that can be applied to other, more complex organisms.
From the Publisher
From Nature (February 20, 2003):
Scientists in their later years sometimes enter a philosopause, characterized by armchair speculations and the writing of autobiographies. Ageless Quest, although having this appearance, is an interesting exception, because it is written by a scientist at the peak of his powers. Part autobiography, part social commentary, part science, the book does an excellent job of explaining and extolling the use of model organisms for research into ageing.
The common features of ageing are a decline in fecundity and increased vulnerability to death during adulthood. Many different kinds of damage and pathology accumulate with age, the precise spectrum varying between individuals. The complexity and variability of the ageing process have often led it to be regarded not as one process, but as many. For these reasons, ageing has seemed intractable, both to experimental analysis and to medical amelioration. Although many researchers studying ageing would not sign up to an agenda that aimed to increase lifespan per se, they would agree that their aim is to improve health in old age. The message of Agelesss Quest is that the prospects for improving health in the elderly are far greater than has been supposed, and that these improvements are, in turn, likely to extend lifespan.
The recent history of scientific thinking about ageing is mirrored in the choices that Lenny Guarente has made in his own research career, a story that he tells with candour and insight. Initially he played safe, focusing his research on the regulation of gene expression, to win tenure at the Massachusetts Institute of Technology, a process akin to dodging a carefully aimed bullet. After tenure and security, he cast around for a riskier, less mature research area, and considered working both on AIDS (too crowded) and the human brain (too difficult). Several straws in the wind suggested that ageing could be amenable to the standard methods of genetic analysis. Slow-ageing, mutant strains of yeast and the nematode worm Caenorhabditis elegans had been described. And caloric restriction, in which food intake is reduced to about half of normal levels, had long been known to slow down ageing in rodents and other organisms, a phenomenon that is presumably mediated by altered gene expression.
So graduate students Brian Kennedy and Nick Austriaco were given a year to establish the yeast ageing system in Guarentes lab. (An engaging feature of the book is the prominence given to the role of successive graduate students in shaping the science, along with Guarentes thumbnail sketches of their characters.) Kennedy and Austriaco found that different yeast strains aged at characteristically different rates. The team isolated four long-lived mutant yeast strains, one of which was also unable to mate, which allowed the mutation to be pinpointed to a gene whose protein product was already known to be involved in the regulation of gene expression.
The quest to understand how this mutation slows ageing required tenacity, technical ingenuity and considerable thought. It wasnt the mutated gene itself that turned out to be critical, but a partner gene called SIR2. The original mutation had resulted in over- rather than under-activity of SIR2. The SIR2 gene therefore acts to promote the survival of the yeast.
SIR2 turned out to have two telling characteristics. First, a homologue in C. elegans also increased lifespan, suggesting that the effect of SIR2 on ageing is conserved over huge evolutionary distances. Guarente has had what he terms "consistent mentoring" from successive departmental chairmen, and this latest discovery was greeted with: "Just what we need, a long-lived worm." Second, SIR2 encodes an enzyme (NAD-dependent histone deacetylase) that is involved in chromosomal compaction; when a chromosomal region is condensed, its genes become inaccessible and are turned off. As the enzyme requires NAD, high levels of which may indicate that cellular nutrient supplies are low, it would probably be most active when energy is in short supply. In accordance with this idea, the lifespan of yeast that overexpress SIR2 is not extended by reduced glucose availability, as it is in wild-type yeast.
Writing about caloric restriction in the late 1980s, David Harrison and Robin Holliday pointed out that mammals and other animals have evolved methods of surviving hard times, particularly food shortage. Starved organisms can suppress processes that lead to reproduction, and enhance processes that protect against environmental stress. These changes may in turn slow down ageing, increasing the likelihood of successful reproduction when the food supply is restored.
Guarente makes a good case that SIR2 epitomizes one kind of gene action of the sort that Harrison and Holliday envisaged. It is responsive to cellular nutrient status, and reacts to high NAD levels (and hence food shortage) by shutting down gene activity. Precisely which genes are turned off may differ between organisms. Genes in the insulin/IGF-like pathway, of which SIR2 may be part, are also nutrient-sensitive regulators of gene expression, and affect the rate of ageing in worm, fruitfly and mouse.
The indications so far from model organisms are that interventions that slow down ageing can also improve age-specific health. Caloric restriction, for example, slows down the accumulation of multiple forms of age-related damage and pathology in rodents.
Guarente is an optimist. He thinks that drugs targeted at products of genes such as SIR2 will become available in the next 10 or 20 years to improve age-specific health and slow down ageing. Although voluntary caloric restriction is not a feasible approach to improving human health, it may be possible to target the pathway that mediates the response. Indeed, Guarente devotes much of his time to his biotech company Elixir, and has much of interest to say about the synergies and conflicts of interest between academia and business. Ageless Quest conveys some quite difficult ideas and complex experimental results with a clarity and freshness that deserve to make it widely read.
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