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Antagonistic pleiotropy hypothesis
About: Antagonistic pleiotropy hypothesis is a research topic. Over the lifetime, 17 publications have been published within this topic receiving 4569 citations.
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TL;DR: August Weismann's theory is subject to a number of criticisms, the most forceful of which are: 1) The fallacy of identifying senescence with mechanical wear, 2) the extreme rarity, in natural populations, of individuals that would be old enough to die of the postulated death-mechanism, 3) the failure of several decades of gerontological research to uncover any deathmechanisms, and 4) the difficulties involved in visualizing how such a feature could be produced
Abstract: A new individual entering a population may be said to have a reproductive probability distribution. The reproductive probability is zero from zygote to reproductive maturity. Later, perhaps shortly...
3,981 citations
TL;DR: Late age-of-onset QTL effects are consistent with the mutation accumulation hypothesis for the evolution of senescence, and sex-specificQTL effects suggest a novel mechanism for maintaining genetic variation for lifespan.
Abstract: Senescence, the decline in survivorship and fertility with increasing age, is a near-universal property of organisms. Senescence and limited lifespan are thought to arise because weak natural selection late in life allows the accumulation of mutations with deleterious late-age effects that are either neutral (the mutation accumulation hypothesis) or beneficial (the antagonistic pleiotropy hypothesis) early in life. Analyses of Drosophila spontaneous mutations, patterns of segregating variation and covariation, and lines selected for late-age fertility have implicated both classes of mutation in the evolution of aging, but neither their relative contributions nor the properties of individual loci that cause aging in nature are known. To begin to dissect the multiple genetic causes of quantitative variation in lifespan, we have conducted a genome-wide screen for quantitative trait loci (QTLs) affecting lifespan that segregate among a panel of recombinant inbred lines using a dense molecular marker map. Five autosomal QTLs were mapped by composite interval mapping and by sequential multiple marker analysis. The QTLs had large sex-specific effects on lifespan and age-specific effects on survivorship and mortality and mapped to the same regions as candidate genes with fertility, cellular aging, stress resistance and male-specific effects. Late age-of-onset QTL effects are consistent with the mutation accumulation hypothesis for the evolution of senescence, and sex-specific QTL effects suggest a novel mechanism for maintaining genetic variation for lifespan.
297 citations
TL;DR: This hypothesis that APOE may represent an example of antagonistic pleiotropy is critically reviewed in light of new research of the impact of APOE on cognition and neural integrity across the lifespan.
Abstract: Research on apolipoprotein E (APOE) has consistently revealed a relationship between the gene's e4 allele and risk for development of Alzheimer's disease (AD). However, research with younger populations of e4 carriers has suggested that the APOE e4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area.
131 citations
TL;DR: This short review portrays the evolutionary theories of aging in the light of the existing discoveries from genomic and molecular genetic studies on aging and longevity in centenarians as well as the proposals for future research in biogerontology.
Abstract: This short review portrays the evolutionary theories of aging in the light of the existing discoveries from genomic and molecular genetic studies on aging and longevity. At the outset, an historical background for the development of the evolutionary theories of aging is presented through the works of August Weismann (programmed death and the germ plasm theories) including his exceptional theoretical postulation, later experimentally validated by the existence of cell division limits. Afterwards, the theory of mutation accumulation of Peter Medawar and the theory modification by Charlesworth (late-life mortality plateau) are presented as well as the antagonistic pleiotropy hypothesis of George Williams, and the disposable soma theory of Kirkwood and Holliday. These theories are discussed in the light of the different research studies, which include studies on insulin signaling and longevity, the possibility that nuclear factor kappa B may be a major mediator of aging, studies of anti-aging Sirtuins and studies on heat shock proteins and longevity and on gene sets as biomarkers of aging. Finally, the proposals for future research in biogerontology, such as studies on the control of protein synthesis, validation of biomarkers of aging, understanding the biochemistry of longevity and research in the field of gerontologic pathology are presented. Likewise, further attention is suggested regarding the work on telomere shortening, stem cells and studies on understanding the biochemical and molecular basis for longevity in centenarians.
108 citations
TL;DR: The discovery that antagonistic pleiotropy is common if not ubiquitous implies that a number of molecular mechanisms of Aging may be widely shared among organisms and that these mechanisms of aging can be potentially alleviated by targeted interventions.
Abstract: Lay Summary: An evolutionary mechanism of aging was hypothesized 60 years ago to be the genetic trade-off between early life fitness and late life mortality. Genetic evidence supporting this hypothesis was unavailable then, but has accumulated recently. These tradeoffs, known as antagonistic pleiotropy, are common, perhaps ubiquitous. George Williams' 1957 paper developed the antagonistic pleiotropy hypothesis of aging, which had previously been hinted at by Peter Medawar. Antagonistic pleiotropy, as it applies to aging, hypothesizes that animals possess genes that enhance fitness early in life but diminish it in later life and that such genes can be favored by natural selection because selection is stronger early in life even as they cause the aging phenotype to emerge. No genes of the sort hypothesized by Williams were known 60 years ago, but modern molecular biology has now discovered hundreds of genes that, when their activity is enhanced, suppressed, or turned off, lengthen life and enhance health under laboratory conditions. Does this provide strong support for Williams' hypothesis? What are the implications of Williams' hypothesis for the modern goal of medically intervening to enhance and prolong human health? Here we briefly review the current state of knowledge on antagonistic pleiotropy both under wild and laboratory conditions. Overall, whenever antagonistic pleiotropy effects have been seriously investigated, they have been found. However, not all trade-offs are directly between reproduction and longevity as is often assumed. The discovery that antagonistic pleiotropy is common if not ubiquitous implies that a number of molecular mechanisms of aging may be widely shared among organisms and that these mechanisms of aging can be potentially alleviated by targeted interventions.
102 citations