Highlights d DSB repair, but not NER, coevolves with maximum lifespan (MLS) in rodents d The activity of SIRT6 in stimulating DSB repair coevolves with MLS in rodent species d Five amino acids determine the differential activities of mouse and beaver SIRT6 d Stronger SIRT6 leads to a longer lifespan

In some animal groups, the secondary embryonic axis is patterned by a small group of cells, often called an organizer, that signals to other cells to establish the correct pattern of cell fates. The Dpp/BMP2-4 pathway plays a central role in secondary axis patterning in many animals [1-11], but it has not been examined during early axial patterning in spiralian embryogenesis. This is a deeply conserved mode of development found in mollusks, annelids, nemerteans, entoprocts, and some marine platyhelminth groups (reviewed in [12, 13]). In the spiralian embryo of the mollusk Ilyanassa, we find that the Dpp ortholog (IoDpp) is expressed most strongly on the dorsal side, in cells of the embryonic organizer and its neighbors. Phospho-smad staining indicates that the pathway is active in all lineages during organizer signaling, but activation is strongest on the dorsal side. Knockdown of IoDpp by morpholino oligos prevents the development of all structures that require organizer signaling and ventralizes the embryo. Ectopic activation of the pathway can induce eyes and external shell, which require organizer signaling. These results indicate that Dpp/BMP2-4 signaling is a key part of the spiralian organizer and suggest similarity with other metazoan organizers. However, the fact that IoDpp/BMP2-4 is inducing, rather than repressing, the neuroectoderm is a surprising difference that may be conserved among spiralians. These results connect the spiralian organizer to this general aspect of secondary axis patterning but highlight the significant variation across animals in effects of the pathway on particular cell types and tissues.

Estrogen has been shown to attenuate the inflammatory response following injury or lipopolysaccharide treatment in several organ systems. Estrogen's actions are transduced through two estrogen receptor sub-types, estrogen receptor (ER) -alpha and estrogen receptor-beta, whose actions may be overlapping or independent of each other. The present study examined the effects of ERα-and ERβ-specific ligands in regulating the inflammatory response in primary astrocyte cultures. Pre-treatment with 17β-estradiol (ERα/ERβ agonist), HPTE (ERα agonist/ERβ antagonist) and DPN (ERβ agonist) led to attenuation of IL-1β, TNFα, and MMP-9 in astrocyte media derived from young adult (3-4 mos.) and reproductive senescent female (9-11 mos., acyclic) astrocyte cultures, while pretreatment with PPT (ERα agonist) attenuated IL-1β (but not TNFα or MMP-9) in both young and senescent-derived astrocyte cultures. Our previous work determined that 17β-estradiol was unable to attenuate the LPS-induced increase in IL-1β in olfactory bulb primary microglial cultures derived from either young adult or reproductive senescent females. In young adult-derived microglial cultures, the LPS-induced increase in IL-1β was not attenuated by pre-treatment with 17β-estradiol, PPT or HPTE. Interestingly, the ERβ agonist, DPN significantly decreased IL-1β following LPS treatment in young adult-derived microglia. Thus while both microglia and astrocytes synthesize and release inflammatory mediators, the present data shows that compounds which bind ERβ are more effective in attenuating proinflammatory cytokines in both cell types and may therefore be a more effective agent for future therapeutic use.

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SummaryWhether errors in protein synthesis play a role in aging has been a subject of intense debate. It has been suggested that rare mistakes in protein synthesis in young organisms may result in errors in the protein synthesis machinery, eventually leading to an increasing cascade of errors as organisms age. Studies that followed generally failed to identify a dramatic increase in translation errors with aging. However, whether translation fidelity plays a role in aging remained an open question. To address this issue, we examined the relationship between translation fidelity and maximum lifespan across 17 rodent species with diverse lifespans. To measure translation fidelity, we utilized sensitive luciferase‐based reporter constructs with mutations in an amino acid residue critical to luciferase activity, wherein misincorporation of amino acids at this mutated codon re‐activated the luciferase. The frequency of amino acid misincorporation at the first and second codon positions showed strong negative correlation with maximum lifespan. This correlation remained significant after phylogenetic correction, indicating that translation fidelity coevolves with longevity. These results give new life to the role of protein synthesis errors in aging: Although the error rate may not significantly change with age, the basal rate of translation errors is important in defining lifespan across mammals.

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Gastropod shell morphologies are famously diverse but generally share a common geometry, the logarithmic coil. Variations on this morphology have been modeled mathematically and computationally but the developmental biology of shell morphogenesis remains poorly understood. Here we characterize the organization and growth patterns of the shell-secreting epithelium of the larval shell of the basket whelkTritia(also known asIlyanassa). Despite the larval shell’s relative simplicity, we find a surprisingly complex organization of the shell margin in terms of rows and zones of cells. We examined cell division patterns with EdU incorporation assays and found two growth zones within the shell margin. In the more anterior aperture growth zone, we find that inferred division angles are biased to lie parallel to the shell edge, and these divisions occur more on the margin’s left side. In the more posterior mantle epithelium growth zone, inferred divisions are significantly biased to the right, relative to the anterior–posterior axis. These growth zones, and the left–right asymmetries in cleavage patterns they display, can explain the major modes of shell morphogenesis at the level of cellular behavior. In a gastropod with a different coiling geometry,Planorbellasp., we find similar shell margin organization and growth zones asTritia, but different left–right asymmetries than we observed in the helically coiled shell ofTritia. These results indicate that differential growth patterns in the mantle edge epithelium contribute to shell shape in gastropod shells and identify cellular mechanisms that may vary to generate shell diversity in evolution.

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