Expression of the methionine sulfoxide reductase lost during evolution extends Drosophila lifespan in a methionine-dependent manner.

Accumulation of oxidized amino acids, including methionine, has been implicated in aging. The ability to reduce one of the products of methionine oxidation, free methionine-R-sulfoxide (Met-R-SO), is widespread in microorganisms, but during evolution this function, conferred by the enzyme fRMsr, was lost in metazoa. We examined whether restoration of the fRMsr function in an animal can alleviate the consequences of methionine oxidation. Ectopic expression of yeast fRMsr supported the ability of Drosophila to catalyze free Met-R-SO reduction without affecting fecundity, food consumption, and response to starvation. fRMsr expression also increased resistance to oxidative stress. Moreover, it extended lifespan of flies in a methionine-dependent manner. Thus, expression of an oxidoreductase lost during evolution can enhance metabolic and redox functions and lead to an increase in lifespan in an animal model. More broadly, our study exposes the potential of a combination of genetic and nutritional strategies in lifespan control.

Comparative transcriptomics across 14 Drosophila species reveals signatures of longevity.

Lifespan varies dramatically among species, but the biological basis is not well understood. Previous studies in model organisms revealed the importance of nutrient sensing, mTOR, NAD/sirtuins, and insulin/IGF1 signaling in lifespan control. By studying life-history traits and transcriptomes of 14 Drosophila species differing more than sixfold in lifespan, we explored expression divergence and identified genes and processes that correlate with longevity. These longevity signatures suggested that longer-lived flies upregulate fatty acid metabolism, downregulate neuronal system development and activin signaling, and alter dynamics of RNA splicing. Interestingly, these gene expression patterns resembled those of flies under dietary restriction and several other lifespan-extending interventions, although on the individual gene level, there was no significant overlap with genes previously reported to have lifespan-extension effects. We experimentally tested the lifespan regulation potential of several candidate genes and found no consistent effects, suggesting that individual genes generally do not explain the observed longevity patterns. Instead, it appears that lifespan regulation across species is modulated by complex relationships at the system level represented by global gene expression.

Age-associated molecular changes are deleterious and may modulate life span through diet.

Transition through life span is accompanied by numerous molecular changes, such as dysregulated gene expression, altered metabolite levels, and accumulated molecular damage. These changes are thought to be causal factors in aging; however, because they are numerous and are also influenced by genotype, environment, and other factors in addition to age, it is difficult to characterize the cumulative effect of these molecular changes on longevity. We reasoned that age-associated changes, such as molecular damage and tissue composition, may influence life span when used in the diet of organisms that are closely related to those that serve as a dietary source. To test this possibility, we used species-specific culture media and diets that incorporated molecular extracts of young and old organisms and compared the influence of these diets on the life span of yeast, fruitflies, and mice. In each case, the "old" diet or medium shortened the life span for one or both sexes. These findings suggest that age-associated molecular changes, such as cumulative damage and altered dietary composition, are deleterious and causally linked with aging and may affect life span through diet.

The zebrafish cornea: structure and development.

PURPOSE: To evaluate the zebrafish as a model for the studies of corneal development and disease. METHODS: Zebrafish embryos and larvae at various stages of development were used for documenting corneal morphogenesis and differentiation. Corneal samples were collected from embryos, larvae, and adult zebrafish for histologic and electron microscopy analysis. Expression patterns of corneal polypeptides were investigated by immunostaining of sections. RESULTS: The zebrafish cornea develops rapidly during embryogenesis, so that its three major layers, the epithelium, the stroma, and the endothelium, are well formed by day 3 postfertilization. The subsequent steps of corneal differentiation, such as the thickening of the corneal stroma, proceed relatively slowly. Several polypeptides are highly enriched in the epithelium or the stroma of the larval and adult zebrafish cornea and are excellent markers of corneal differentiation. CONCLUSIONS: Development and differentiation of the zebrafish cornea are easily accessible to analysis. Anatomic and ultrastructural characterization of the zebrafish cornea demonstrates many similarities to the human cornea and provides the basis for the use of the zebrafish model both to analyze the basic genetic mechanisms of corneal development and to study the causes of corneal disease.

Age- and diet-associated metabolome remodeling characterizes the aging process driven by damage accumulation.

Aging is thought to be associated with increased molecular damage, but representative markers vary across conditions and organisms, making it difficult to assess properties of cumulative damage throughout lifespan. We used nontargeted metabolite profiling to follow age-associated trajectories of >15,000 metabolites in Drosophila subjected to control and lifespan-extending diets. We find that aging is associated with increased metabolite diversity and low-abundance molecules, suggesting they include cumulative damage. Remarkably, the number of detected compounds leveled-off in late-life, and this pattern associated with survivorship. Fourteen percent of metabolites showed age-associated changes, which decelerated in late-life and long-lived flies. In contrast, known metabolites changed in abundance similarly to nontargeted metabolites and transcripts, but did not increase in diversity. Targeted profiling also revealed slower metabolism and accumulation of lifespan-limiting molecules. Thus, aging is characterized by gradual metabolome remodeling, and condition- and advanced age-associated deceleration of this remodeling is linked to mortality and molecular damage.DOI: http://dx.doi.org/10.7554/eLife.02077.001.