Invertebrates as model organisms for research on aging biology

Invertebrate model systems, such as nematodes and fruit flies, have provided valuable information about the genetics and cellular biology involved in aging. However, limitations of these simple, genetically tractable organisms suggest the need for other model systems, some of them invertebrate, to facilitate further advances in the understanding of mechanisms of aging and longevity in mammals, including humans. This paper introduces 10 review articles about the use of invertebrate model systems for the study of aging by authors who participated in an ‘NIA-NIH symposium on aging in invertebrate model systems’ at the 2013 International Congress for Invertebrate Reproduction and Development. In contrast to the highly derived characteristics of nematodes and fruit flies as members of the superphylum Ecdysozoa, cnidarians, such as Hydra, are more ‘basal’ organisms that have a greater number of genetic orthologs in common with humans. Moreover, some other new model systems, such as the urochordate Botryllus schlosseri, the tunicate Ciona, and the sea urchins (Echinodermata) are members of the Deuterostomia, the same superphylum that includes all vertebrates, and thus have mechanisms that are likely to be more closely related to those occurring in humans. Additional characteristics of these new model systems, such as the recent development of new molecular and genetic tools and a more similar pattern to humans of regeneration and stem cell function suggest that these new model systems may have unique advantages for the study of mechanisms of aging and longevity.     

Organelle aging:Lessons from model organisms

Most cellular processes descend into failure during aging. While a large collection of longevity pathways has been identified in the past decades, the mechanism for age-related decline of cellular homeostasis and organelle function remains largely unsolved. It is known that many organelles undergo structural and functional changes during normal aging, which significantly contributes to the decline of tissue function at old ages. Since recent studies have revealed an emerging role of organelles as regulatory hubs in maintaining cellular homeostasis, understanding of organelle aging will provide important insights into the cellular basis of organismal aging. Here we review current progress on the characterization of age-dependent structural and functional alterations in the more well-studied organelles, as well as the known mechanisms governing organelle aging in model organisms, with a special focus on the fruit fly Drosophila melanogaster.     

Reproductive aging: insights from model organisms

Aging was once thought to be the result of a general deterioration of tissues as opposed to their being under regulatory control. However, investigations in a number of model organisms have illustrated that aspects of aging are controlled by genetic mechanisms and are potentially manipulable, suggesting the possibility of treatment for age-related disorders. Reproductive decline is one aspect of aging. In model organisms and humans of both sexes, increasing age is associated with both a decline in the number of progeny and an increased incidence of defects. The cellular mechanisms of reproductive aging are not well understood, although a number of factors, both intrinsic and extrinsic to an organism's germline, may contribute to aging phenotypes. Recent work in a variety of organisms suggests that nuclear organization and nuclear envelope proteins may play a role in these processes.     

Genetic approaches for understanding virulence in Toxoplasma gondii

Virulence of the protozoan parasite Toxoplasma gondii is highly variable and dependent upon the genotype of the parasite. The application of forward and reverse genetic approaches for understanding the genetic basis of virulence has resulted in the identification of several members of the ROP family as key mediators of virulence. More recently, modern genomic techniques have been used to address strain differences in virulence and have also identified additional members of the ROP family as likely mediators. The development of forward and reverse genetic, as well as modern genomic techniques, and the path to the discovery of the ROP genes as virulence factors is reviewed here.     

Genomic instability in laminopathy-based premature aging

Premature aging syndromes often result from mutations in nuclear proteins involved in the maintenance of genomic integrity. Lamin A is a major component of the nuclear lamina and nuclear skeleton. Truncation in lamin A causes Hutchinson-Gilford progerial syndrome (HGPS), a severe form of early-onset premature aging. Lack of functional Zmpste24, a metalloproteinase responsible for the maturation of prelamin A, also results in progeroid phenotypes in mice and humans. We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents. Bone marrow cells isolated from Zmpste24-/- mice show increased aneuploidy and the mice are more sensitive to DNA-damaging agents. Recruitment of p53 binding protein 1 (53BP1) and Rad51 to sites of DNA lesion is impaired in Zmpste24-/- MEFs and in HGPS fibroblasts, resulting in delayed checkpoint response and defective DNA repair. Wild-type MEFs ectopically expressing unprocessible prelamin A show similar defects in checkpoint response and DNA repair. Our results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging.     

Genomic data integration for ecological and evolutionary traits in non-model organisms

Why is it needed to develop system biology initiatives such as ENCODE on non-model organisms?     

A framework for understanding physical ecosystem engineering by organisms

While well‐recognized as an important kind of ecological interaction, physical ecosystem engineering by organisms is diverse with varied consequences, presenting challenges for developing and using general understanding. There is also still some uncertainty as to what it is, and some skepticism that the diversity of engineering and its effects is amenable to conceptual integration and general understanding. What then, are the key cause/effect relationships and what underlies them? Here we develop, enrich and extend our extant understanding of physical ecosystem engineering into an integrated framework that exposes the essential cause/effect relationships, their underpinnings, and the interconnections that need to be understood to explain or predict engineering effects. The framework has four cause/effect relationships linking four components: 1. An engineer causes structural change; 2. Structural change causes abiotic change; 3. Structural and abiotic change cause biotic change; 4. Structural, abiotic and biotic change can feedback to the engineer. The first two relationships describe an ecosystem engineering process and abiotic dynamics, while the second two describe biotic consequence for other species and the engineer. The four relationships can be parameterized and linked using time‐indexed equations that describe engineered system dynamics. After describing the relationships we discuss the utility of the framework; how it might be enriched; and briefly how it can be used to identify intersections of ecosystem engineering with fields outside ecology.     

Genomic determinants of protein folding thermodynamics in prokaryotic organisms

Here we investigate how thermodynamic properties of orthologous proteins are influenced by the genomic environment in which they evolve. We performed a comparative computational study of 21 protein families in 73 prokaryotic species and obtained the following main results. (i) Protein stability with respect to the unfolded state and with respect to misfolding are anticorrelated. There appears to be a trade-off between these two properties, which cannot be optimized simultaneously. (ii) Folding thermodynamic parameters are strongly correlated with two genomic features, genome size and G+C composition. In particular, the normalized energy gap, an indicator of folding efficiency in statistical mechanical models of protein folding, is smaller in proteins of organisms with a small genome size and a compositional bias towards A+T. Such genomic features are characteristic for bacteria with an intracellular lifestyle. We interpret these correlations in light of mutation pressure and natural selection. A mutational bias toward A+T at the DNA level translates into a mutational bias toward more hydrophobic (and in general more interactive) proteins, a consequence of the structure of the genetic code. Increased hydrophobicity renders proteins more stable against unfolding but less stable against misfolding. Proteins with high hydrophobicity and low stability against misfolding occur in organisms with reduced genomes, like obligate intracellular bacteria. We argue that they are fixed because these organisms experience weaker purifying selection due to their small effective population sizes. This interpretation is supported by the observation of a high expression level of chaperones in these bacteria. Our results indicate that the mutational spectrum of a genome and the strength of selection significantly influence protein folding thermodynamics.     

Current understanding of ovarian aging

The reproductive system of human female exhibits a much faster rate of aging than other body systems. Ovarian aging is thought to be dominated by a gradual decreasing numbers of follicles, coinciding with diminished quality of oocytes. Menopause is the final step in the process of ovarian aging. This review focuses on the mechanisms underlying the ovarian aging involving a poor complement of follicles at birth and a high rate of attrition each month, as well as the alternated endocrine factors. We also discuss the possible causative factors that contribute to ovarian aging, e.g., genetic factors, accumulation of irreparable damage of microenvironment, pathological effect and other factors. The appropriate and reliable methods to assess ovarian aging, such as quantification of follicles, endocrine measurement and genetic testing have also been discussed. Increased knowledge of the ovarian aging mechanisms may improve the prevention of premature ovarian failure.     

Formal Darwinism as a tool for understanding the status of organisms in evolutionary biology

This paper uses the framework of Formal Darwinism (FD) to evaluate organism-centric critiques of the Modern Synthesis (MS). The first section argues that the FD project reconciles two kinds of selective explanations in biology. Thus it is not correct to say that the MS neglects organisms—instead, it explains organisms’ design, as argued in the second section. In the third section I employ a concept of the organism derived from Kant that has two aspects: the parts presupposing the whole, and the productivity of the parts in relation to the whole. The first aspect corresponds to the “design” that FD explains, whereas the second aspect is something about which the MS is largely silent.     

Genomic adaptation of prokaryotic organisms at high temperature

One of the central issues of evolutionary genomics is to find out the adaptive strategies of microorganisms to stabilize nucleic acid molecules under high temperature. Thermal adaptation hypothesis gives a link between G+C content and growth temperature if there is a considerable variation of guanine and cytosine content between species. However, there has been a long-standing debate regarding the correlations between genomic GC content and optimal growth temperature (Topt). We urged that adaptation to growth at high temperature requires a coordinated set of evolutionary changes affecting: (i) nucleic acid thermostability and (ii) stability of codon-anticodon interactions. Moreover, in Bacillaceae family we have demonstrated that a higher genomic GC level do not have any role in stabilizing mRNA secondary structure at high growth temperature. Comparative analysis between homologous sequences of thermophilic Thermus thermophilus and mesophilic Deinococcus radiodurans suggests that increased levels of GC contents in the coding sequence corresponding to strand structure of Thermus thermophilus genes have stabilizing effect on the mRNA secondary structure, whereas increased levels of GC contents in coding sequences corresponding to aperiodic structure have destabilizing effect on the mRNA secondary structure. In this perspective, a critical review of thermal adaptation hypothesis is further advocated.     

Genomic approaches to research in pulmonary hypertension

Genomics, or the study of genes and their function, is a burgeoning field with many new technologies. In the present review, we explore the application of genomic approaches to the study of pulmonary hypertension (PH). Candidate genes, important to the pathobiology of the disease, have been investigated. Rodent models enable the manipulation of selected genes, either by transgenesis or targeted disruption. Mutational analysis of genes in the transforming growth factor-β family have proven pivotal in both familial and sporadic forms of primary PH. Finally, microarray gene expression analysis is a robust molecular tool to aid in delineating the pathobiology of this disease.     

Genomic approaches to research in lung cancer

The medical research community is experiencing a marked increase in the amount of information available on genomic sequences and genes expressed by humans and other organisms. This information offers great opportunities for improving our understanding of complex diseases such as lung cancer. In particular, we should expect to witness a rapid increase in the rate of discovery of genes involved in lung cancer pathogenesis and we should be able to develop reliable molecular criteria for classifying lung cancers and predicting biological properties of individual tumors. Achieving these goals will require collaboration by scientists with specialized expertise in medicine, molecular biology, and decision-based statistical analysis.     

Complex life cycles of multicellular eukaryotes: new approaches based on the use of model organisms

A wide variety of life cycles can be found in the different groups of multicellular eukaryotes. Here we provide an overview of this variety, and review some of the theoretical arguments that have been put forward to explain the evolutionary stability of different life cycle strategies. We also describe recent progress in the analysis of the haploid-diploid life cycle of the model angiosperm Arabidopsis thaliana and show how new molecular data are providing a means to test some of the theoretical predictions. Finally, we describe an emerging model organism from the brown algae, Ectocarpus siliculosus, and highlight the potential of this system for the investigation of the mechanisms that regulate complex life cycles.     

Rules for the use of model organisms in anti-aging pharmacology

The use of animal models for initially screening anti-aging drugs is a promising approach for drug discovery. However, there a number of potential artifacts, confounds and errors that can arise in such research programs. The following rules are intended to minimize such problems: (1) since aging occupies an increasing proportion of human adulthood, data that conflate aging and late life should not be extrapolated to human aging; (2) the response to candidate medications should show a normal dose-response pattern, although not necessarily a linear response; (3) medicated animal models should not be hypometabolic; (4) medicated animal models should not show pronounced reductions in fertility; (5) medicated animal models should not exhibit general nervous system depression; (6) the effect of the medication should not be highly sensitive to the culture environment; (7) the effect of the medication should not be highly dependent on the genetic ancestry of the stock employed, leaving aside inbreeding, which should be avoided because humans are not generally inbred. While these rules do not guarantee successful extrapolation of successful drug results from the animal model to humans in a clinical setting, the failure to adhere to these rules should raise doubts about such extrapolation.     

Theoretical approaches to the description of the morphology of organisms

Theoretical morphology should include methods that allow to determine limits of discrete variability of organisms of the given taxon. It is possible to determine the multitude of possible factors based on the demands of natural selection to the given structure under given conditions. The author presents a number of such multitudes that describe the variability of salamander tongue apparatus, kinematics of flapping flight in insects and wing shape of birds from the order Ciconiiformes. Another approach is based on mechanisms that rule the morphogenesis of individuals of the given taxon in particulate environment. Examples of morphogenetic multitude are illustrated by the variability of location of organs on plant stems, morphology of mollusc shells and colonies of hydroids polyps. All examples show that existing phenotypes occupy a compact area in the space of theoretically possible forms so the multitude of realized phenotypes does not have free space. If some free space is discovered it means that corresponding forms of life exist in nature but still are not registered and investigated.