Finch CE et al. (2001) Annu Rev Genomics Hum Genet "The genetics of aging."

Ruvkun G, Finch CE

[Annu Rev Genomics Hum Genet, 2001]

The genetic analysis of life span has only begun in mammals, invertebrates, such as Caenorhabditis elegans and Drosophila, and yeast. Even at this primitive stage of the genetic analysis of aging, the physiological observations that rate of metabolism is intimately tied to life span is supported. In many examples from mice to worms to flies to yeast, genetic variants that affect life span also modify metabolism. Insulin signaling regulates life span coordinately with reproduction, metabolism, and free radical protective gene regulation in C. elegans. This may be related to the findings that caloric restriction also regulates mammalian aging, perhaps via the modulation of insulin-like signaling pathways. The nervous system has been implicated as a key tissue where insulin-like signaling and free radical protective pathways regulate life span in C. elegans and Drosophila. Genes that determine the life span could act in neuroendocrine cells in diverse animals. The involvement of insulin-like hormones suggests that the plasticity in life spans evident in animal phylogeny may be due to variation in the timing of release of hormones that control vitality and mortality as well as variation in the response to those hormones. Pedigree analysis of human aging may reveal variations in the orthologs of the insulin pathway genes and coupled pathways that regulate invertebrate aging. Thus, genetic approaches may identify a set of circuits that was established in ancestral metazoans to regulate their longevity.

Margalit A et al. (2005) Novartis Found Symp "A lamin-dependent pathway that regulates nuclear organization, cell cycle progression and germ cell development."

Wilson KL, Gruenbaum Y, Fridkin A, Liu J, Margalit A

[Novartis Found Symp, 2005]

The C. elegans genome encodes a single lamin protein (Ce-lamin), three LEM domain proteins (Ce-emerin, Ce-MAN1 and LEM-3) and a single BAF protein (Ce-BAF). Down-regulation of Ce-lamin causes embryonic lethality. Abnormalities include rapid changes in nuclear morphology during interphase, inability of cells to complete mitosis, abnormal condensation of chromatin, clustering of nuclear pore complexes (NPCs), and missing or abnormal germ cells. Ce-emerin and Ce-MAN1 are both embedded in the inner nuclear membrane, and both bind Ce-lamin and Ce-BAF; in addition, both require Ce-lamin for their localization. Mutations in human emerin cause X-linked recessive Emery-Dreifuss muscular dystrophy. In C. elegans, loss of Ce-emerin alone has no detectable phenotype, while loss of 90% Ce-MAN1 causes approximately 15% embryonic lethality. However in worms that lack Ce-emerin, a approximately 90% reduction of Ce-MAN1 is lethal to all embryos by the 100-cell stage, with a phenotype involving chromatin condensation and repeated cycles of anaphase chromosome bridging and cytokinesis. The anaphase-bridged chromatin retained a mitosis-specific phosphohistone H3 epitope, and failed to recruit detectable Ce-lamin or Ce-BAF. Down-regulation of Ce-BAF showed similar phenotypes. These findings suggest that lamin, LEM-domain proteins and BAF are part of a lamina network essential for chromatin organization and cell division, and that Ce-emerin and Ce-MAN1 share at least one and possibly multiple overlapping functions, which may be relevant to Emery-Dreifuss muscular dystrophy.

Longo VD et al. (2003) Science "Evolutionary medicine: from dwarf model systems to healthy centenarians?"

Finch CE, Longo VD

[Science, 2003]

Restriction of the number of calories consumed extends longevity in many organisms. In rodents, caloric restriction decreases the levels of plasma glucose and insulin-like growth factor I (IGF-1) and postpones or attenuates cancer, immunosenescence, and inflammation without irreversible side effects. In organisms ranging from yeast to mice, mutations in glucose or IGF-I-like signaling pathways extend life-span but also cause glycogen or fat accumulation and dwarfism. This information suggests a new category of drugs that could prevent or postpone diseases of aging with few adverse effects.

Palmer AR (2016) Philos Trans R Soc Lond B Biol Sci "What determines direction of asymmetry: genes, environment or chance?"

Palmer AR

[Philos Trans R Soc Lond B Biol Sci, 2016]

Conspicuous asymmetries seen in many animals and plants offer diverse opportunities to test how the development of a similar morphological feature has evolved in wildly different types of organisms. One key question is: do common rules govern how direction of asymmetry is determined (symmetry is broken) during ontogeny to yield an asymmetrical individual? Examples from numerous organisms illustrate how diverse this process is. These examples also provide some surprising answers to related questions. Is direction of asymmetry in an individual determined by genes, environment or chance? Is direction of asymmetry determined locally (structure by structure) or globally (at the level of the whole body)? Does direction of asymmetry persist when an asymmetrical structure regenerates following autotomy? The answers vary greatly for asymmetries as diverse as gastropod coiling direction, flatfish eye side, crossbill finch bill crossing, asymmetrical claws in shrimp, lobsters and crabs, katydid sound-producing structures, earwig penises and various plant asymmetries. Several examples also reveal how stochastic asymmetry in mollusc and crustacean early cleavage, in Drosophila oogenesis, and in Caenorhabditis elegans epidermal blast cell movement, is a normal component of deterministic development. Collectively, these examples shed light on the role of genes as leaders or followers in evolution.This article is part of the themed issue 'Provocative questions in left-right asymmetry'.