Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewIntegrating evolutionary and molecular genetics of aging
Introduction
Aging or senescence is a progressive decline in physiological function, leading to decreased rates of survival and reproduction with increasing age and ultimately to death [1], [2], [3], [4], [5], [6], [7]. We can ask two fundamental questions about aging, one evolutionary, the other mechanistic: why do organisms age, and how do they age? On the evolutionary level, the puzzle is to understand why such an apparently maladaptive trait harbors genetic variation and evolves despite natural selection acting to increase Darwinian fitness. On the mechanistic level, the challenge is to understand the molecular basis of aging. In the last 70 years evolutionary and molecular biologists have made enormous progress in answering these questions, yet largely independently of each other [3], [5], [6], [7].
Why do organisms age? In the 1940s and 1950s J.B.S. Haldane, P.B. Medawar, and G.C. Williams realized that aging might evolve because the force of natural selection declines with age and might thus be inefficient at maintaining function at old age [1], [2], [3], [7], [8], [9]. Subsequent theoretical work in the 1960s and 1970s, chiefly by W.D. Hamilton and B. Charlesworth, put the evolutionary theory of aging on a firm population genetic basis [[3], [10], [11]], and by the 1980s and 1990s the theory had received major empirical support [3], [11], [12], [13]. The major lessons from this work were that (1) aging is not “programmed”, but an inevitable, maladaptive byproduct of the strength of selection declining with age; (2) life span is a polygenic and genetically variable trait which responds readily to selection; and (3) evolutionary changes in life span often trade off with changes in early-life fitness traits [3], [5], [6], [7], [9], [11]. Evolutionary biologists also speculated that aging should not be affected by mutations of large effect and that different species are unlikely to share the same mechanisms of aging [2], [5], [6], [7]. However, by traditionally treating the genetics of aging as a black box, progress in the evolutionary genetics of aging has to a large extent stalled and been overshadowed by advances in molecular biogerontology.
How do organisms age? In the 1980s and 1990s several geneticists decided to apply the powerful tools of molecular genetics to the problem of aging [6], [7], [14], [15], [16], [17]. They reasoned that, if one can understand the sophisticated process of development from a fertilized egg to a complex adult by mutation analysis, one might be able to use the same approach to elucidate the mechanisms whereby organisms age. Using the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the yeast Saccharomyzes cerevisiae as models, they had remarkable success at identifying mutations that can extend life span, in some cases more than ten-fold [18], [19], [20], [21], [22], [23]. At least three major lessons emerged from these experiments, several of which contradicted evolutionary predictions or intuitions. First, although many genes affect life span, mutations in major signaling pathways can have large effects on life span. Second, several longevity mechanisms seem to be conserved among species, from invertebrates to mammals. Third, mutations influencing life span can have antagonistic pleiotropic effects on reproduction or other fitness traits; however, not all of them display such effects, and trade-offs between life span and reproduction or other fitness components are either not ubiquitous or can be uncoupled [6], [14], [15], [16], [17], [24]. However, by focusing on mutants in laboratory models, molecular biologists have traditionally neglected to ask questions about the genetic basis of variation in aging within and among species.
Here we argue that some of the most interesting questions in the biology of aging today are directly at the interface between evolution and molecular mechanisms [[6], [7], [9]]. Evolutionary biologists can use the extensive knowledge about mechanisms of aging to assess whether the assumptions and predictions of the evolutionary theory have been met or whether they need refinement [[6], [7], [9]]. At the same time, molecular biologists have become interested in asking questions about aging that are inspired by evolutionary concepts. Are candidate genes affecting life span in the laboratory genetically variable and under selection in natural populations [[25], [26]]? Are the mechanisms of aging evolutionarily conserved or lineage-specific [[6], [7], [27], [28]]? What is the genetic basis of the remarkable variation in life span among species [3], [6], [9]? How many genes affecting longevity have antagonistic pleiotropic effects [9], [24]? Are trade-offs between life span and reproduction (or other fitness components) due to differential resource allocation or signaling processes independent of metabolism [29], [30], [31]? What are the age-dependent effects of mutations on aging [7]? What is the molecular basis of plasticity in life span and is this response to the environment adaptive [[6], [7], [32]]? Answering these and other fundamental questions about aging will require a synthesis of molecular and evolutionary approaches.
Section snippets
The evolutionary theory of aging
As we far as we know, most organisms probably age, from bacteria to humans [[3], [33], [34]]. But why we must age and die has puzzled scientists for centuries. Since aging affects survival and reproduction deleteriously, it was difficult to envision how natural selection would favor it. Two thousand years ago, the Greek poet and philosopher Lucretius argued that aging and death existed for the good of society, noting that death ensured that there would always be room for the next generation [35]
Candidate aging genes in natural populations
Two general approaches, distinct yet highly complementary, have been used to identify the genes and molecular pathways that regulate aging and life span. The first is mutational analysis, where mutants are screened for life span extension or a correlated trait and then the gene is identified by forward genetics [124]. Such analyses have generated an extensive list of “aging genes” that extend life and/or reduce age-specific mortality rates when gene function is impaired (hypomorphic expression
Conclusions
Together with Partridge and Gems [6] and Ackermann and Pletcher [7] we believe that the time is ripe for a synthesis of evolutionary and molecular genetics of aging. In recent years molecular genetics has shed light upon many aspects of aging of major interest to evolutionary biologists, while molecular geneticists have become increasingly interested in answering questions with an evolutionary angle [[6], [7], [9]]. Although the core ideas of the evolutionary theory of aging are well supported
Acknowledgements
We thank Ed Masoro and the editors of BBA for inviting us to write this review; Daniel Promislow, Marc Tatar, and Anne Bronikowski for stimulating discussions; Ed Masoro and two anonymous reviewers for helpful feedback on a previous version of the manuscript; and the Swiss National Science Foundation (PA00A-113087/2 to TF), the Austrian Science Foundation (FWF, P 21498-B11 to TF), the National Science Foundation (DEB-0542859 to PSS), and the American Federation for Aging Research (junior
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