Grandma plays favourites: X-chromosome relatedness and sex-specific childhood mortality

Biologists use genetic relatedness between family members to explain the evolution of many behavioural and developmental traits in humans, including altruism, kin investment and longevity. Women''s post-menopausal longevity in particular is linked to genetic relatedness between family members. According to the ‘grandmother hypothesis’, post-menopausal women can increase their genetic contribution to future generations by increasing the survivorship of their grandchildren. While some demographic studies have found evidence for this, others have found little support for it. Here, we re-model the predictions of the grandmother hypothesis by examining the genetic relatedness between grandmothers and grandchildren. We use this new model to re-evaluate the grandmother effect in seven previously studied human populations. Boys and girls differ in the per cent of genes they share with maternal versus paternal grandmothers because of differences in X-chromosome inheritance. Here, we demonstrate a relationship between X-chromosome inheritance and grandchild mortality in the presence of a grandmother. With this sex-specific and X-chromosome approach to interpreting mortality rates, we provide a new perspective on the prevailing theory for the evolution of human female longevity. This approach yields more consistent support for the grandmother hypothesis, and has implications for the study of human evolution.     

Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging

Several human progerias, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by the accumulation at the nuclear envelope of farnesylated forms of truncated prelamin A, a protein that is also altered during normal aging. Previous studies in cells from individuals with HGPS have shown that farnesyltransferase inhibitors (FTIs) improve nuclear abnormalities associated with prelamin A accumulation, suggesting that these compounds could represent a therapeutic approach for this devastating progeroid syndrome. We show herein that both prelamin A and its truncated form progerin/LADelta50 undergo alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition, which could explain the low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models. We also show that a combination of statins and aminobisphosphonates efficiently inhibits both farnesylation and geranylgeranylation of progerin and prelamin A and markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid syndromes associated with nuclear-envelope abnormalities.     

Visual Saliency Prediction and Evaluation across Different Perceptual Tasks

Saliency maps produced by different algorithms are often evaluated by comparing output to fixated image locations appearing in human eye tracking data. There are challenges in evaluation based on fixation data due to bias in the data. Properties of eye movement patterns that are independent of image content may limit the validity of evaluation results, including spatial bias in fixation data. To address this problem, we present modeling and evaluation results for data derived from different perceptual tasks related to the concept of saliency. We also present a novel approach to benchmarking to deal with some of the challenges posed by spatial bias. The results presented establish the value of alternatives to fixation data to drive improvement and development of models. We also demonstrate an approach to approximate the output of alternative perceptual tasks based on computational saliency and/or eye gaze data. As a whole, this work presents novel benchmarking results and methods, establishes a new performance baseline for perceptual tasks that provide an alternative window into visual saliency, and demonstrates the capacity for saliency to serve in approximating human behaviour for one visual task given data from another.     

Metabolic Signatures of Extreme Longevity in Northern Italian Centenarians Reveal a Complex Remodeling of Lipids,Amino Acids,and Gut Microbiota Metabolism

The aging phenotype in humans has been thoroughly studied but a detailed metabolic profiling capable of shading light on the underpinning biological processes of longevity is still missing. Here using a combined metabonomics approach compromising holistic ¹H-NMR profiling and targeted MS approaches, we report for the first time the metabolic phenotype of longevity in a well characterized human aging cohort compromising mostly female centenarians, elderly, and young individuals. With increasing age, targeted MS profiling of blood serum displayed a marked decrease in tryptophan concentration, while an unique alteration of specific glycerophospholipids and sphingolipids are seen in the longevity phenotype. We hypothesized that the overall lipidome changes specific to longevity putatively reflect centenarians'' unique capacity to adapt/respond to the accumulating oxidative and chronic inflammatory conditions characteristic of their extreme aging phenotype. Our data in centenarians support promotion of cellular detoxification mechanisms through specific modulation of the arachidonic acid metabolic cascade as we underpinned increased concentration of 8,9-EpETrE, suggesting enhanced cytochrome P450 (CYP) enzyme activity. Such effective mechanism might result in the activation of an anti-oxidative response, as displayed by decreased circulating levels of 9-HODE and 9-oxoODE, markers of lipid peroxidation and oxidative products of linoleic acid. Lastly, we also revealed that the longevity process deeply affects the structure and composition of the human gut microbiota as shown by the increased extrection of phenylacetylglutamine (PAG) and p-cresol sulfate (PCS) in urine of centenarians. Together, our novel approach in this representative Italian longevity cohort support the hypothesis that a complex remodeling of lipid, amino acid metabolism, and of gut microbiota functionality are key regulatory processes marking exceptional longevity in humans.     

Model selection as a tool for phylogeographic inference: an example from the willow Salix melanopsis

Phylogeographic inference has typically relied on analyses of data from one or a few genes to provide estimates of demography and population histories. While much has been learned from these studies, all phylogeographic analysis is conditioned on the data, and thus, inferences derived from data that represent a small sample of the genome are unavoidably tenuous. Here, we demonstrate one approach for moving beyond classic phylogeographic research. We use sequence capture probes and Illumina sequencing to generate data from >400 loci in order to infer the phylogeographic history of Salix melanopsis, a riparian willow with a disjunct distribution in coastal and the inland Pacific Northwest. We evaluate a priori phylogeographic hypotheses using coalescent models for parameter estimation, and the results support earlier findings that identified post‐Pleistocene dispersal as the cause of the disjunction in S. melanopsis. We also conduct a series of model selection exercises using IMa2, Migrate‐n and ?a?i. The resulting ranking of models indicates that refugial dynamics were complex, with multiple regions in the inland regions serving as the source for postglacial colonization. Our results demonstrate that new sources of data and new approaches to data analysis can rejuvenate phylogeographic research by allowing for the identification of complex models that enable researchers to both identify and estimate the most relevant parameters for a given system.     

How does marriage affect length of life? Analysis of a French historical dataset from an evolutionary perspective

There are broadly two explanations for why human longevity appears to be extended by marriage. First, there is the social explanation, whereby the companionship, division of labour and the economic support that marriage offers is thought to extend life. Second, there is a selective explanation, whereby those individuals with high potential longevity are more attractive to the opposite sex and therefore more likely to get married. Here we analyse the “TRA” dataset from 19th century France, using an evolutionary approach to address the question of why marriage is linked to longevity, focussing particularly on sex differences. The dataset is based on death and marriage records from all of France between 1798 and 1901 and includes information on age at death, marriage and wealth for individuals whose surnames began with the letters TRA. We find that marriage is positively associated with longevity, particularly for men. In part, this is related to the higher rate of deaths for single males during marriageable age, as compared to a higher rate of deaths for females during marriage. There is a positive association between wealth (at death) and longevity for individuals who were single or married at death, with a stronger effect for singles. Analysis of the effect of spousal age gap on duration of survival after first marriage indicates that men who were married to younger women lived longer, whereas the longevity of women was not associated with the spousal age gap. We put forward an evolutionary perspective on marriage and longevity, hypothesizing that there is an important role for sexual selection in the association between marriage and longevity, with women selecting on characteristics associated with longevity, whilst men select on characteristics associated with reproductive potential.     

The effect of pharmaceutical innovation on longevity: Evidence from the U.S. and 26 high-income countries

This study examines the impact that pharmaceutical innovation, which accounts for most private biomedical research expenditure, has had on longevity. We perform two types of two-way fixed-effects analyses, which control for the effects of many potentially confounding variables. First, we analyze long-run (2006–2018) changes in longevity associated with different diseases in a single country: the U.S. Then, we analyze relative longevity levels associated with different diseases in 26 high-income countries during a single time period (2006–2016). The measure of longevity we analyze, mean age at time of death, is strongly positively correlated across countries with life expectancy at birth. The measure of pharmaceutical innovation we use is the mean vintage (year of initial world launch) of the drugs used to treat each disease in each country. Changes in the vintage distribution of drugs are due to both entry of new drugs and exit of old drugs. Our analysis of U.S. data indicates that the diseases for which there were larger increases in drug vintage tended to have larger increases in the longevity of Americans of all races and both sexes. In other words, the lower the mean age of the drugs, the higher the mean age at death. We test, and are unable to reject, the “parallel trends” hypothesis. We estimate that the 2006–2018 increase in drug vintage increased the mean age at death of Americans by about 6 months (66% of the observed increase). Controlling for sex, race, and education has only a small effect on the estimate of the vintage coefficient. The estimates indicate that drug vintage did not have a significant effect on the mean age at death of decedents with less than 9 years of education. Drug vintage had a positive and significant effect on the mean age at death of decedents with at least 9 years of education, and a larger effect on the mean age at death of decedents with at least 13 years of education. The finding that pharmaceutical innovation has a larger effect on the longevity of people with more education is consistent with previous evidence that more educated people are more likely to use newer drugs. Our analysis of data on 26 high-income countries indicates that the higher the vintage of drugs available to treat a disease in a country, the higher mean age at death was, controlling for fixed disease and country effects. The increase in drug vintage is estimated to have increased mean age at death in the 26 countries by 1.23 years between 2006 and 2016—73% of the observed increase. We obtain estimates of the cost of pharmaceutical innovation—its impact on drug expenditure—as well as estimates of an important benefit of pharmaceutical innovation—the number of life-years gained from it—and of their ratio, i.e., the incremental cost-effectiveness ratio. Estimates of the cost per life-year gained for the U.S. and the 26 countries are $35,817 and $13,904, respectively. Both figures are well below per capita GDP in the respective regions, suggesting that, overall, pharmaceutical innovation was highly cost-effective.     

Genealogical data and the biodemography of human longevity

Biodemography of human longevity is an emerging interdisciplinary field of sociobiological research with deep historical roots. Two research questions are examined in this article: (1) What evidence is there for the familial transmission of human longevity?, and (2) what are the effects of parental age at reproduction on offspring longevity, and in particular, are there long-term adverse health consequences associated with the trend toward delayed reproduction? The ability of scientists to conduct biodemographic studies depends not only on merging theoretical and methodological elements from the biological and demographic/actuarial sciences, but unique sources of data and statistical methods must also be developed. In this article we describe how gencalogical data have been used for over a century to explore basic questions about human longevity, and how similar kinds of data now being developed are driving the formation of new testable research hypotheses in the field of biodemography.     

Bitter Taste Receptor Polymorphisms and Human Aging

Several studies have shown that genetic factors account for 25% of the variation in human life span. On the basis of published molecular, genetic and epidemiological data, we hypothesized that genetic polymorphisms of taste receptors, which modulate food preferences but are also expressed in a number of organs and regulate food absorption processing and metabolism, could modulate the aging process. Using a tagging approach, we investigated the possible associations between longevity and the common genetic variation at the three bitter taste receptor gene clusters on chromosomes 5, 7 and 12 in a population of 941 individuals ranging in age from 20 to 106 years from the South of Italy. We found that one polymorphism, rs978739, situated 212 bp upstream of the TAS2R16 gene, shows a statistically significant association (p = 0.001) with longevity. In particular, the frequency of A/A homozygotes increases gradually from 35% in subjects aged 20 to 70 up to 55% in centenarians. These data provide suggestive evidence on the possible correlation between human longevity and taste genetics.     

Human longevity and early reproduction in pre‐industrial Sami populations

Senescence is predicted to be associated with the intensity and timing of reproduction at an earlier age. Here, we examine the phenotypic association between reproduction and post‐reproductive survival in three pre‐industrial human populations that lived in Northern Scandinavia during 1640–1870. In both sexes longevity was independent of the total number of born or adult children, whereas early reproduction was negatively associated with the longevity of females and males. Our results thus do not support the view that reproductive investment as such has a negative impact on longevity, but suggest that survival costs are associated with the scheduling of reproduction. We discuss, however, an alternative point of view suggesting that less intense selection for early reproduction, extended parental care, and social structure allowing kin selection through the effects of close relatives are factors that have selected for the long post‐reproductive life span in humans.     

Evidence of sex-linked effects on the inheritance of human longevity: a population-based study in the Valserine valley (French Jura), 18-20th centuries

A long-standing puzzle in gerontology is the sex dependence of human longevity and its inheritance. We have analysed the sex-linked pattern of inheritance of longevity from 643 nuclear families on the historical population register of a French valley. We have focused on mean conditional life expectancy at a minimum age of 50 years, thus, in the present study, longevity refers to late or post-reproductive survival. A comparison of parents' and offspring's longevity has shown the existence of a heritable component of late survival in this population. We have found that the heritable component was substantially larger for daughters compared to sons. Moreover, this result appeared to be specific to late survival, that is, when only post-reproductive mortality for parental and offspring generations is taken into account. The stronger resemblance of parents to their daughters was no longer observed when considering younger ages at death for the offspring. This observation explains the hitherto unaccountable diversity of data in previous studies.     

How general is cognitive ability in non-human animals? A meta-analytical and multi-level reanalysis approach

General intelligence has been a topic of high interest for over a century. Traditionally, research on general intelligence was based on principal component analyses and other dimensionality reduction approaches. The advent of high-speed computing has provided alternative statistical tools that have been used to test predictions of human general intelligence. In comparison, research on general intelligence in non-human animals is in its infancy and still relies mostly on factor-analytical procedures. Here, we argue that dimensionality reduction, when incorrectly applied, can lead to spurious results and limit our understanding of ecological and evolutionary causes of variation in animal cognition. Using a meta-analytical approach, we show, based on 555 bivariate correlations, that the average correlation among cognitive abilities is low (r = 0.185; 95% CI: 0.087–0.287), suggesting relatively weak support for general intelligence in animals. We then use a case study with relatedness (genetic) data to demonstrate how analysing traits using mixed models, without dimensionality reduction, provides new insights into the structure of phenotypic variance among cognitive traits, and uncovers genetic associations that would be hidden otherwise. We hope this article will stimulate the use of alternative tools in the study of cognition and its evolution in animals.     

A new computational approach to analyze human protein complexes and predict novel protein interactions

We propose a new approach to identify interacting proteins based on gene expression data. By using hypergeometric distribution and extensive Monte-Carlo simulations, we demonstrate that looking at synchronous expression peaks in a single time interval is a high sensitivity approach to detect co-regulation among interacting proteins. Combining gene expression and Gene Ontology similarity analyses enabled the extraction of novel interactions from microarray datasets. Applying this approach to p21-activated kinase 1, we validated α-tubulin and early endosome antigen 1 as its novel interactors.     

Estimating Root Longevity at Sites with Long Periods of Low Root Mortality

Minirhizotron technique is capable of providing median root longevity. The use of the median longevity might overestimate root longevity if the distribution of survival times is very skewed or irregular, as is the case at sites where root mortality is very low during the long winter. In this paper we illustrate the case theoretically and compare that with field observation in northern Sweden to show an alternative procedure for such sites. Hypothetical root cohorts were constructed to investigate and show some technical problems with estimating median root longevity at a Swedish northern site where root mortality is very low during long winter time (8 months), and to investigate whether these problems could be overcome by discarding winter time from the survival analysis and include only the growing season in which the roots are at risk of mortality. Authentic root data, gathered in a minirhizotron study at such a site, were analysed on a whole year basis and on season basis. By analysing longevity based only on the season when there is a risk for root death, the median longevity became a more reliable estimate of the true mean longevity. When this method was applied to root data from northern Sweden, the estimated root longevity in different treatments became between 17% lower and 8% higher compared to the longevity estimated on a whole year basis.We conclude that the reliability of the median longevity as an estimate of the true mean longevity can be increased by basing the survival analysis only on the parts of the year when fine roots are at risk of mortality at sites with long winter and low root mortality.     

Seed size in relation to phylogeny,growth form and longevity in a subalpine meadow on the east of the Tibetan plateau

This study examined seed size distribution, and seed size in relation to phylogeny, growth form and longevity, where seed size is expected to be approximately of a log-normal frequency distribution and correlate dwith phylogeny, growth form and longevity. We made use of a data set of 229 species from alpine meadow on the east of the Tibetan plateau. Species spanned 10⁴ range of seed size, and the frequency of seed mass classes on a logarithmic scale produced an approximately normal distribution, but largely shifted towards smaller-sized seeds compared to those of the temperate zone and the tropics. It was evident that seed size was strongly related to phylogeny, where order, family, genus and species accounted for 2%, 32.9%, 48.9% and 16.2% of total variation in log seed mass. However, both growth form and longevity did not account for variation in log seed mass, which was opposite to the previously reported patterns of trait correlation. The implications of our results are discussed.     

Microbial Interaction Network Estimation via Bias-Corrected Graphical Lasso

With the increasing availability of microbiome 16S data, network estimation has become a useful approach to studying the interactions between microbial taxa. Network estimation on a set of variables is frequently explored using graphical models, in which the relationship between two variables is modeled via their conditional dependency given the other variables. Various methods for sparse inverse covariance estimation have been proposed to estimate graphical models in the high-dimensional setting, including graphical lasso. However, current methods do not address the compositional count nature of microbiome data, where abundances of microbial taxa are not directly measured, but are reflected by the observed counts in an error-prone manner. Adding to the challenge is that the sum of the counts within each sample, termed “sequencing depth,” is an experimental technicality that carries no biological information but can vary drastically across samples. To address these issues, we develop a new approach to network estimation, called BC-GLASSO (bias-corrected graphical lasso), which models the microbiome data using a logistic normal multinomial distribution with the sequencing depths explicitly incorporated, corrects the bias of the naive empirical covariance estimator arising from the heterogeneity in sequencing depths, and builds the inverse covariance estimator via graphical lasso. We demonstrate the advantage of BC-GLASSO over current approaches to microbial interaction network estimation under a variety of simulation scenarios. We also illustrate the efficacy of our method in an application to a human microbiome data set.

     

Noggin maintains pluripotency of human embryonic stem cells grown on Matrigel

Objective:  Spontaneous differentiation of human embryonic stem cell (hESC) cultures is a major concern in stem cell research. Physical removal of differentiated areas in a stem cell colony is the current approach used to keep the cultures in a pluripotent state for a prolonged period of time. All hESCs available for research require unidentified soluble factors secreted from feeder layers to maintain the undifferentiated state and pluripotency. Under experimental conditions, stem cells are grown on various matrices, the most commonly used being Matrigel.
Materials and Methods:  We propose an alternative method to prevent spontaneous differentiation of hESCs grown on Matrigel that uses low amounts of recombinant noggin. We make use of the porosity of Matrigel to serve as a matrix that traps noggin and gradually releases it into the culture to antagonize bone morphogenetic proteins (BMP). BMPs are known to initiate differentiation of hESCs and are either present in the conditioned medium or are secreted by hESCs themselves.
Results:  hESCs grown on Matrigel supplemented with noggin in conditioned medium from feeder layers (irradiated mouse embryonic fibroblasts) retained both normal karyotype and markers of hESC pluripotency for 14 days. In addition, these cultures were found to have increased cell proliferation of stem cells as compared to hESCs grown on Matrigel alone.
Conclusion:  Noggin can be utilized for short term prevention of spontaneous differentiation of stem cells grown on Matrigel.     

RNA Editing Genes Associated with Extreme Old Age in Humans and with Lifespan in C. elegans

Background

The strong familiality of living to extreme ages suggests that human longevity is genetically regulated. The majority of genes found thus far to be associated with longevity primarily function in lipoprotein metabolism and insulin/IGF-1 signaling. There are likely many more genetic modifiers of human longevity that remain to be discovered.

Methodology/Principal Findings

Here, we first show that 18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study of centenarians, the New England Centenarian Study. We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity. Some SNPs in ADARB2 replicate consistently in the four populations and suggest a strong effect that is independent of the different genetic backgrounds and environments. To evaluate the functional association of these genes with lifespan, we demonstrate that inactivation of their orthologues adr-1 and adr-2 in C. elegans reduces median survival by 50%. We further demonstrate that inactivation of the argonaute gene, rde-1, a critical regulator of RNA interference, completely restores lifespan to normal levels in the context of adr-1 and adr-2 loss of function.

Conclusions/Significance

Our results suggest that RNA editors may be an important regulator of aging in humans and that, when evaluated in C. elegans, this pathway may interact with the RNA interference machinery to regulate lifespan.