SUMMARY Sex differences in longevity can provide insights into novel mechanisms of aging, yet they have been little studied. Surprisingly, sex-specific longevity patterns are better known in wild animals. Evolutionary hypotheses accounting for longevity patterns in natural populations include differential vulnerability to environmental hazards, differential intensity of sexual selection and distinct patterns of parental care. Mechanistic hypotheses focus on asymmetric inheritance of sex chromosomes and mitochondria. Virtually all intensively studied species show conditional sex differences in longevity. Humans are the only species in which one sex is known to have a ubiquitous survival advantage. Paradoxically, although women live longer, they suffer greater morbidity particularly late in life. This mortality-morbidity paradox may be a consequence of greater connective tissue responsiveness to sex hormones in women. Human females’ longevity advantage may result from hormonal influences on inflammatory and immunological responses, or greater resistance to oxidative damage; current support for these mechanisms is weak.

This study compared trends in body size, life span, metabolic rate, and ecology of bats and marsupials with those from mammals generally, using a 580 species data base. The linear logarithmic relationship between mammalian body mass and maximum longevity, deleting bats and marsupials, is used as a standard against which to measure life spans of particular mammal groups. Bats have maximum life spans a minimum of 3 times those of nonflying eutherians--a trend resulting from neither low basal metabolic rate, the ability to enter torpor, nor large relative brain size. Marsupials live about 80% as long as nonflying eutherians despite averaging lower basal metabolic rates; similarly, there is no effect of heterothermy or relative brain size. These results directly conflict with predictions of both "rate of living" and brain-size mediated theories of aging. However, they are consistent with an evolutionary theory that posits exceptionally long life spans among mammals with reduced environmental vulnerability.

Target of rapamycin inhibition by rapamycin feeding has previously been shown to extend life in genetically heterogeneous mice. To examine whether it similarly affected mouse health, we fed encapsulated rapamycin or a control diet to C57BL/6Nia mice of both sexes starting at 19 months of age. We performed a range of health assessments 6 and 12 months later. Rapamycin feeding significantly reduced mTOR activity in most but not all tissues. It also reduced total and resting metabolic rate during the light (inactive) phase of the light:dark cycle in females only but had no effect on spontaneous activity or metabolism during the dark (active) phase of either sex. Males only had less fragmented sleep when fed rapamycin, whereas stride length and rotarod performance were improved in both sexes. Survival was also improved by this late-life rapamycin feeding, and some pathological lesions were delayed. We found no adverse health consequences associated with rapamycin treatment.

Without bioadhesive delivery devices, complex compounds are typically degraded or cleared from mucosal tissues by the mucus layer. 1-3 While some chemically-modified, micro-structured surfaces have been studied in aqueous environments, 4,5 adhesion due to geometry alone has not been investigated. Silicon nanowire-coated beads show significantly better adhesion than those with targeting agents under shear, and can increase the lift-off force 100-fold. We have shown that nanowire coatings, paired with epithelial physiology, significantly increase adhesion in mucosal conditions. KeywordsNanowire; nano-structure; bioadhesion; mucoadhesion; gecko-inspired; drug delivery; mucosa Because of their easy accessibility, large surface area, and rich blood supply, mucous membranes (mucosae), such as intestinal, nasal, ocular, vaginal, and buccal tissues, are frequently targeted for therapeutic drug delivery. 1,6 However, the mucosae present significant barriers to permeation, including a 1-450 μm motile mucous gel layer, tight junctions, and in some tissues, harsh enzymes and low pH. 7 Delivery devices have been able to protect compounds from chemical degradation, but without adhesion to the underlying epithelium, the *Additional contact information for Tejal A. Desai: -Tejal. Desai@ucsf.edu, phone -415-514-9695, fax -415-476-2414 Under nanoadhesive conditions, as the number of adhesive elements per surface area increases (ie: diameter of individual elements decreases), the surface area to volume ratio increases and van der Waals adhesion is predicted to increase 24,25 . Furthermore, because mucosal epithelia exhibit nano-structured microvilli, available surface area contact is considerably increased on the cell surface [26][27][28][29] . Thus, by decreasing the diameter of the elements on the device surface to the nano-scale and targeting a microvilliated surface, it may be possible to generate strong bioadhesive forces due to geometric features alone.To test the interaction of microvilli and nano-structures, a prototype device was created to couple the adhesive characteristics of nanowires with the drug delivery capacity of beads. A standard vapor liquid solid method for synthesizing silicon nanowires on flat wafer surfaces was modified to achieve growth of size-specific nanowires on the surface of 30-50 micron diameter glass beads (Figure 1). 30A Caco-2 cell monolayer was used as an in vitro model of the intestinal mucosa because the cells display a microvilliated structure which closely corresponds to that found in vivo 31 . From scanning electron microscopy ( Figure 1b), significant interdigitation of the nanowires and microvilli was visible at the cell-nano-structure interface, showing significant areas of contact between the cells and nanowires.In order to characterize the effects of geometric and chemical modifications of the nanowires, three nanowire test geometries and a control group with no nanowires (See Table 1 in Supporting Information) were fabricated. A subset of the long nanowire group and the contr...

Background:The current structural model of Streptococcus pneumoniae lipoteichoic acid reveals inconsistencies. Results: High resolution NMR and MS analysis of O-deacylated pnLTA allowed a precise revision of its structure. Conclusion:The novel structure presented here is in complete agreement with known structural, biosynthetic, and immunological data. Significance: This study will aid in further understanding the biosynthesis and inflammatory potency of pneumococcal (lipo)teichoic acids.

Fischer, K. E. and Chapman, C. A. 1993. Frugivores and fruit syndromes: differences in patterns at the genus and species level.-Oikos 66: 472-482. Comparative studies have suggested that fruit traits, such as color, size, and protection, have evolved as covarying character complexes ("dispersal syndromes") in response to selection by frugivorous dispersers. However, many comparative studies of disperser-specific syndromes have used species as sampling units, a method which implicitly assumes that character complexes evolve de novo in each species. This approach overestimates the number of times a character complex has evolved because covariation that results from common ancestry (plesiomorphy) is confounded with covariation across independent lineages (convergence). We compiled data on fleshy fruit traits from five regional floras to test the hypothesis that fruit traits form character complexes which covary independently of phylogeny (i.e. across lineages). Our results suggest that such character complexes are rare, and that analyses of covariation among these character complexes are extremely sensitive to the investigator's choice of sampling unit. When syndromes derived from observations of the foraging behavior of frugivores are analyzed using species as sampling units, our data show significant associations among traits at four out of five locations. In contrast, when genera are used as sampling units, there is no significant association among traits at any of the sites. Theories of coevolution between fruits and frugivores have proposed that fruit morphology is a response to selective pressures exerted by frugivorous birds and mammals. If these frugivores have shaped fruit morphology into dispersal-related character complexes or syndromes, then traits associated with a syndrome should be absent or much reduced in frequency in regions lacking that guild of dispersers. To test this prediction, we examined the flora of New Guinea, which lacks primates and other diurnal mammalian frugivores, and found no difference in the frequency of traits associated with dispersal by diurnal mammals.

Herein, we demonstrate that nanotopographical cues can be utilized to enable biologics >66 kDa to be transported across epithelial monolayers. When placed in contact with epithelial monolayers, nanostructured thin films loosen the epithelial barrier and allow for significantly increased transport of FITC-albumin, FITC-IgG, and a model therapeutic, etanercept. Our work highlights the potential to use drug delivery systems which incorporate nanotopography to increase the transport of biologics across epithelial tissue.

Mutation of a single copy of the adenomatous polyposis coli (APC) gene results in familial adenomatous polyposis (FAP), which confers an extremely high risk for colon cancer. ApcMin/+ mice exhibit multiple intestinal neoplasia (MIN) that causes anemia and death from bleeding by 6 months. Mechanistic target of rapamycin complex 1 (mTORC1) inhibitors were shown to improve ApcMin/+ mouse survival when administered by oral gavage or added directly to the chow, but these mice still died from neoplasia well short of a natural life span. The National Institute of Aging Intervention Testing Program showed that enterically targeted rapamycin (eRapa) extended life span for wild type genetically heterogeneous mice in part by inhibiting age-associated cancer. We hypothesized that eRapa would be effective in preventing neoplasia and extend survival of ApcMin/+ mice. We show that eRapa improved survival for ApcMin/+ mice in a dose-dependent manner. Remarkably, and in contrast to previous reports, most of the ApcMin/+ mice fed 42 ppm eRapa lived beyond the median life span reported for wild type syngeneic mice. Furthermore, chronic eRapa did not cause detrimental immune effects in mouse models of cancer, infection or autoimmunity; thus, assuaging concerns that chronic rapamycin treatment suppresses immunity. Our studies suggest that a novel formulation (enteric targeting) of a well-known and widely used drug (rapamycin) can dramatically improve its efficacy in targeted settings. eRapa or other mTORC1 inhibitors could serve as effective cancer preventatives for people with FAP without suppressing the immune system, thus reducing the dependency on surgery as standard therapy.