Variation In Lifespan Research Articles

Coefficient of Variation of Lifespan Across the Tree of Life: Is It a Signature of Programmed Aging?

Measurements of variation are of great importance for studying the stability of pathological phenomena and processes. For the biology of aging, it is very important not only to determine average mortality, but also to study its stability in time and the size of fluctuations that are indicated by the variation coefficient of lifespan (CVLS). It is believed that a relatively small (~20%) value of CVLS in humans, comparable to the coefficients of variation of other events programmed in ontogenesis (for example, menarche and menopause), indicates a relatively rigid determinism (N. S. Gavrilova et al. (2012) Biochemistry (Moscow), 77, 754-760). To assess the prevalence of this phenomenon, we studied the magnitude of CVLS, as well as the coefficients of skewness and kurtosis in diverse representatives of the animal kingdom using data provided by the Institute for Demographic Research (O. R. Jones et al. (2014) Nature, 505, 169-173). We found that, unlike humans and laboratory animals, in most examined species the values of CVLS are rather high, indicating heterogeneity of the lifespan in the cohorts studied. This is probably due to the large influence of background mortality, as well as the non-monotonicity of total mortality in the wild, especially at the earliest ages. One way to account for this influence is to "truncate" the data (removing the earliest and latest ages from consideration). To reveal the effect of this procedure, we proposed a new indicator, the stability coefficient of mortality dynamics, which indicates how quickly CVLS is reduced to values that characterize a relatively homogeneous population (33%) when the data are "truncated". Such indicators facilitate the use of the parameters of survival curves for analysis of the effects of geroprotectors, lifestyle, and other factors on lifespan, and for the quantification of relative contributions of genetic and environmental factors to the dynamics of aging in human and animal populations, including those living in the wild.

The cultural evolution of national constitutions

We explore how ideas from infectious disease and genetics can be used to uncover patterns of cultural inheritance and innovation in a corpus of 591 national constitutions spanning 1789–2008. Legal “ideas” are encoded as “topics”—words statistically linked in documents—derived from topic modeling the corpus of constitutions. Using these topics we derive a diffusion network for borrowing from ancestral constitutions back to the US Constitution of 1789 and reveal that constitutions are complex cultural recombinants. We find systematic variation in patterns of borrowing from ancestral texts and “biological”‐like behavior in patterns of inheritance, with the distribution of “offspring” arising through a bounded preferential‐attachment process. This process leads to a small number of highly innovative (influential) constitutions some of which have yet to have been identified as so in the current literature. Our findings thus shed new light on the critical nodes of the constitution‐making network. The constitutional network structure reflects periods of intense constitution creation, and systematic patterns of variation in constitutional lifespan and temporal influence.

Neurobiology: A genetic cause of age-related decline.

Genetic variation in a neuropeptide signalling pathway regulates age-related declines in health in nematode worms. This discovery points to a mechanism that influences individual differences in ageing. See Article p.198 The rate at which we age is highly variable. The roundworm Caenorhabditis elegans also shows variability in lifespan and age-related decline. Shi-Qing Cai and colleagues now show that polymorphisms in regulatory-gene-for-behavioural-ageing-1 (rgba-1) and the neuropeptide receptor gene npr-28 result in changes in the rate at which the worms age. rgba-1 encodes neuropeptides in glial cells that activate receptors encoded by npr-28 in neurons, leading to a reduction of SIR-2.1-mediated activation of UPRmt, which modulates ageing.

Desistance and Severity of Alcohol Use Disorder: A Lifespan-Developmental Investigation.

Key to an understanding of alcohol use disorder (AUD) are the drinking-related reductions that begin in young adulthood and continue throughout the adult lifespan. Research is needed to precisely characterize the form of these reductions, including possible developmental differences across the lifespan. Using U.S.-representative data, we estimated multiple-group Markov models characterizing longitudinal transitions among five drinking statuses and differences in transition patterns across six adult age periods. While past research indicates relative developmental stability in overall AUD-desistance rates, we found far higher rates of Severe-AUD desistance in young adulthood relative to later ages. Especially considering the dramatic change reflected by Severe-AUD desistance (from 6+ symptoms to 0-1 symptoms), this result indicates a substantial developmental shift, with Severe-AUD-desistance rates peaking at 43-50% across ages 25-34 and then dropping to 22-24% across ages 35-55. We discuss implications regarding practical significance of young-adult "maturing out" and predictions regarding lifespan variability in desistance mechanisms.

What do early life deaths contribute to the lifespan variation gap? A population based study

What do early life deaths contribute to the lifespan variation gap? A population based study

Detection of barriers to dispersal is masked by long lifespans and large population sizes.

Population genetic analyses of species inhabiting fragmented landscapes are essential tools for conservation. Occasionally, analyses of fragmented populations find no evidence of isolation, even though a barrier to dispersal is apparent. In some cases, not enough time may have passed to observe divergence due to genetic drift, a problem particularly relevant for long‐lived species with overlapping generations. Failing to consider this quality during population structure analyses could result in incorrect conclusions about the impact of fragmentation on the species. We designed a model to explore how lifespan and population size influence perceived population structure of isolated populations over time. This iterative model tracked how simulated populations of variable lifespan and population size were affected by drift alone, using a freshwater mussel, Quadrula quadrula (mapleleaf), as a model system. In addition to exhibiting dramatic lifespan variability among species, mussels are also highly imperiled and exhibit fragmentation by dams throughout the range of many species. Results indicated that, unless population size was small (<50 individuals) or lifespan short (<22 years), observing genetic divergence among populations was unlikely. Even if wild populations are isolated, observing population structure in long‐lived mussels from modern damming practices is unlikely because it takes longer for population structure to develop in these species than most North American dams have existed. Larger population sizes and longer lifespans increase the time needed for significant divergence to occur. This study helps illuminate the factors that influence genetic responses by populations to isolation and provides a useful model for conservation‐oriented research.

Highly variable lifespan in an annual reptile, Labord\u2019s chameleon (Furcifer labordi)

Among tetrapods, the current record holder for shortest lifespan is Labord’s chameleon, Furcifer labordi. These reptiles from the arid southwest of Madagascar have a reported lifespan of 4–5 months during the annual rainy season and spend the majority of their life (8–9 months) as a developing embryo. This semelparous, annual life history is unique among tetrapods, but only one population (Ranobe) in the southernmost distribution range has been studied. We therefore investigated the potential for environmentally-dependent variability in lifespan in a population in Kirindy Forest, which has a much longer warm rainy season. While no adults were found after March in Ranobe, the disappearance of adults was delayed by several months in Kirindy. Our data also revealed sex-biased mortality, suggesting that females have a longevity advantage. Furthermore, we found that, after an unusually long previous rainy season, one female was capable of surviving until a second breeding season. Keeping F. labordi in cages under ambient conditions demonstrated that also males can also survive until the next season of activity under these conditions. Our study therefore revealed considerable variability in the extreme life history of this tetrapod that is linked to variation in ecological factors.

Age-related changes of physiological performance and survivorship of bank voles selected for high aerobic capacity

Variation in lifespans is an intriguing phenomenon, but how metabolic rate influence this variation remains unclear. High aerobic capacity can result in health benefits, but also in increased oxidative damage and accelerated ageing. We tested these contradictory predictions using bank voles (Myodes=Clethrionomys glareolus) from lines selected for high swim-induced aerobic metabolism (A), which had about 50% higher maximum metabolic rate and a higher basal and routine metabolic rates, than those from unselected control lines (C). We measured sprint speed (VSmax), forced-running maximum metabolic rate (VO2run), maximum long-distance running speed (VLmax), running speed at VO2run (VVO2), and respiratory quotient at VO2run (RQ) at three age classes (I: 3–5, II: 12–14, III: 17–19months), and analysed survivorship. We asked if ageing, understood as the age-related decline of the performance traits, differs between the A and C lines. At age class I, voles from A lines had 19% higher VO2run, and 12% higher VLmax, but tended to have 19% lower VSmax, than those from C lines. RQ was nearly 1.0 for both A and C lines. The pattern of age-related changes differed between the lines mainly between age classes I and II, but not in older animals. VSmax increased by 27% in A lines and by 10% in C lines between age class I and II, but between classes II and III, it increased by 16% in both selection directions. VO2run decreased by 7% between age class I and II in A lines only, but in C lines it remained constant across all age classes. VLmax decreased by 8% and VVO2 by 12% between age classes II and III, but similarly in both selection directions. Mortality was higher in A than in C lines only between the age of 1 and 4months. The only trait for which the changes in old animals differed between the lines was RQ. In A lines, RQ increased between age classes II and III, whereas in C lines such an increase occurred between age classes I and II. Thus, we did not find obvious effects of selection on the pattern of ageing. However, the physiological performance and mortality of bank voles remained surprisingly robust to ageing, at least until the age of 17–19months, similar to the maximum lifespan under natural conditions. Therefore, it is possible that the selection could affect the pattern of ageing in even older individuals when symptoms of senility might be more profound.

The system capacity view of aging and longevity

BackgroundAging is a complex systems level problem that needs a systems level solution. However, system models of aging and longevity, although urgently needed, are still lacking, largely due to the paucity of conceptual frameworks for modeling such a complex process.ResultsWe propose that aging can be viewed as a decline in system capacity, defined as the maximum level of output that a system produces to fulfill demands. Classical aging hallmarks and anti‐aging strategies can be well‐aligned to system capacity. Genetic variants responsible for lifespan variation across individuals or species can also be explained by their roles in system capacity. We further propose promising directions to develop systems approaches to modulate system capacity and thus extend both healthspan and lifespan.ConclusionsThe system capacity model of aging provides an opportunity to examine aging at the systems level. This model predicts that the extent to which aging can be modulated is normally limited by the upper bound of the system capacity of a species. Within such a boundary, aging can be delayed by moderately increasing an individual’s system capacity. Beyond such a boundary, increasing the upper bound is required, which is not unrealistic given the unlimited potential of regenerative medicine in the future, but it requires increasing the capacity of the whole system instead of only part of it.

Bayesian association scan reveals loci associated with human lifespan and linked biomarkers

The enormous variation in human lifespan is in part due to a myriad of sequence variants, only a few of which have been revealed to date. Since many life-shortening events are related to diseases, we developed a Mendelian randomization-based method combining 58 disease-related GWA studies to derive longevity priors for all HapMap SNPs. A Bayesian association scan, informed by these priors, for parental age of death in the UK Biobank study (n=116,279) revealed 16 independent SNPs with significant Bayes factor at a 5% false discovery rate (FDR). Eleven of them replicate (5% FDR) in five independent longevity studies combined; all but three are depleted of the life-shortening alleles in older Biobank participants. Further analysis revealed that brain expression levels of nearby genes (RBM6, SULT1A1 and CHRNA5) might be causally implicated in longevity. Gene expression and caloric restriction experiments in model organisms confirm the conserved role for RBM6 and SULT1A1 in modulating lifespan.

Computational Analysis of Lifespan Experiment Reproducibility.

Independent reproducibility is essential to the generation of scientific knowledge. Optimizing experimental protocols to ensure reproducibility is an important aspect of scientific work. Genetic or pharmacological lifespan extensions are generally small compared to the inherent variability in mean lifespan even in isogenic populations housed under identical conditions. This variability makes reproducible detection of small but real effects experimentally challenging. In this study, we aimed to determine the reproducibility of C. elegans lifespan measurements under ideal conditions, in the absence of methodological errors or environmental or genetic background influences. To accomplish this, we generated a parametric model of C. elegans lifespan based on data collected from 5,026 wild-type N2 animals. We use this model to predict how different experimental practices, effect sizes, number of animals, and how different “shapes” of survival curves affect the ability to reproduce real longevity effects. We find that the chances of reproducing real but small effects are exceedingly low and would require substantially more animals than are commonly used. Our results indicate that many lifespan studies are underpowered to detect reported changes and that, as a consequence, stochastic variation alone can account for many failures to reproduce longevity results. As a remedy, we provide power of detection tables that can be used as guidelines to plan experiments with statistical power to reliably detect real changes in lifespan and limit spurious false positive results. These considerations will improve best-practices in designing lifespan experiment to increase reproducibility.

Regulation of Drosophila Lifespan by bellwether Promoter Alleles

Longevity varies among individuals, but how natural genetic variation contributes to variation in lifespan is poorly understood. Drosophila melanogaster presents an advantageous model system to explore the genetic underpinnings of longevity, since its generation time is brief and both the genetic background and rearing environment can be precisely controlled. The bellwether (blw) gene encodes the α subunit of mitochondrial ATP synthase. Since metabolic rate may influence lifespan, we investigated whether alternative haplotypes in the blw promoter affect lifespan when expressed in a co-isogenic background. We amplified 521 bp upstream promoter sequences containing alternative haplotypes and assessed promoter activity both in vitro and in vivo using a luciferase reporter system. The AG haplotype showed significantly greater expression of luciferase than the GT haplotype. We then overexpressed a blw cDNA construct driven by either the AG or GT haplotype promoter in transgenic flies and showed that the AG haplotype also results in greater blw cDNA expression and a significant decrease in lifespan relative to the GT promoter haplotype, in male flies only. Thus, our results show that naturally occurring regulatory variants of blw affect lifespan in a sex-specific manner.

Towards ageing well: Use it or lose it: Exercise, epigenetics and cognition

More and more people are living into the 90s or becoming centenarians. But, the gift of increased ‘age span’ seldom equates with an improved ‘health-span’. Governments across the world are expressing concern about the epidemic of chronic disease, and have responded by initiating policies that make prevention, reduction and treatment of chronic disease, a public health priority. But understanding, how to age long and well, with the avoidance of chronic disease and later life complex disease morbidity is challenging. While inherited genes have an undoubted role to play in the chance of maintaining good health or conversely a predilection to developing disease and chronic ill health, there is increasing evidence that behavioural and environmental life-style choices may contribute up to 50% of the variability of human lifespan. Physical exercise is readily available to everyone, and is a simple cheap and effective form of life-style intervention. Exercise appears to help maintain good health and to reduce the risk of developing chronic disease and ill health. Evidence suggests that physical activity improves well-being across many health domains through out life, continues to offer important health benefits in older age groups and tracks with a ‘healthy ageing’ profile. Although many of the molecular pathways remain to be fully identified, here we discuss how physical activity and exercise is understood to produce changes in the human epigenome, which have the potential to enhance cognitive and psychological health, improve muscular fitness, and lead to better ageing with improved quality of life in older age.

Socially disparate trends in lifespan variation: a trend study on income and mortality based on nationwide Danish register data

BackgroundSocial inequality trends in life expectancy are not informative as to changes in social disparity in the age-at-death distribution. The purpose of the study was to investigate social differentials in...

環境条件に応じた葉寿命の種内変異 : 一般的傾向と機能型間の差異( なぜいま葉寿命なのか?)

環境条件に応じた葉寿命の種内変異 : 一般的傾向と機能型間の差異( なぜいま葉寿命なのか?)

Trends in Education-Specific Life Expectancy, Data Quality, and Shifting Education Distributions: A Note on Recent Research.

Several recent articles have reported conflicting conclusions about educational differences in life expectancy, and this is partly due to the use of unreliable data subject to a numerator-denominator bias previously reported as ranging from 20% to 40%. This article presents estimates of life expectancy and lifespan variation by education in the United States using more reliable data from the National Health Interview Survey. Contrary to prior conclusions in the literature, I find that life expectancy increased or stagnated since 1990 among all education-race-sex groups except for non-Hispanic white women with less than a high school education; there has been a robust increase in life expectancy among white high school graduates and a smaller increase among black female high school graduates; lifespan variation did not increase appreciably among high school graduates; and lifespan variation plays a very limited role in explaining educational gradients in mortality. I also discuss the key role that educational expansion may play in driving future changes in mortality gradients. Because of shifting education distributions, within an education-specific synthetic cohort, older age groups are less negatively selected than younger age groups. We could thus expect a greater concentration of mortality at younger ages among people with a high school education or less, which would be reflected in increasing lifespan variability for this group. Future studies of educational gradients in mortality should use more reliable data and should be mindful of the effects of shifting education distributions.

Mechanisms of increased lifespan in hypoxia

Genetic variation accounts for a relatively small amount of the variation in lifespan (generally 15–30%), while environmental stressors are very strong predictors (Finch and Kirkwood 2000). Hypoxia is an environmental stress that increases longevity in some contexts, but the mechanisms remain poorly understood. Our long‐term goal is to understand the mechanisms by which hypoxia extends lifespan. In the bee Megachile rotundata, lifespan doubles upon rearing in hypoxia (Abdelrahman et al. 2014). We hypothesize that that hypoxia increases longevity by limiting telomere loss from reactive oxygen species (ROS). In this study, prepupal bees were maintained in 10, 21 or 24% oxygen for 9 months. Each month, two subsets of bees were removed. One group was immediately frozen for processing. A second subset of bees was reared to adulthood and then frozen for processing. Similar to our previous findings, all bees had extended lifespans compared to bees in the wild, but bees exposed to hypoxia had high survival after 9 months in 10% oxygen. At nine months, bees reared in 24% oxygen had 14% survival, while those in normoxia had 41% survival. Because they survived better than bees in normoxia or hyperoxia, we predicted that bees in hypoxic conditions would have reduced telomere loss rates, lower levels of ROS, and/or higher levels of telomerase activity than bees exposed to normoxia. We measured total antioxidant activity and found no differences among treatments from either prepupal or adult bees, indicating that oxidative stress is not regulated at the level of antioxidants. Because antioxidants are invariant, we predict that increased oxidative damage to proteins will be observed under normoxic and hyperoxic conditions. We expect bees reared in hypoxia to have longer telomeres than bees reared in normoxia or hyperoxia. In addition, we expect bees reared in hypoxia to have lower levels of oxidative damage than bees reared in normoxia or hyperoxia.Support or Funding InformationNIH COBRE to NDSU, USDA‐ARS

Parallel evolution of genes controlling mitonuclear balance in short-lived annual fishes.

SummaryThe current molecular understanding of the aging process derives almost exclusively from the study of random or targeted single‐gene mutations in highly inbred laboratory species, mostly invertebrates. Little information is available as to the genetic mechanisms responsible for natural lifespan variation and the evolution of lifespan, especially in vertebrates. Here, we investigated the pattern of positive selection in annual (i.e., short‐lived) and nonannual (i.e., longer‐lived) African killifishes to identify a genomic substrate for evolution of annual life history (and reduced lifespan). We identified genes under positive selection in all steps of mitochondrial biogenesis: mitochondrial (mt) DNA replication, transcription from mt promoters, processing and stabilization of mt RNAs, mt translation, assembly of respiratory chain complexes, and electron transport chain. Signs of paralleled evolution (i.e., evolution in more than one branch of Nothobranchius phylogeny) are observed in four out of five steps. Moreover, some genes under positive selection in Nothobranchius are under positive selection also in long‐lived mammals such as bats and mole‐rats. Complexes of the respiratory chain are formed in a coordinates multistep process where nuclearly and mitochondrially encoded components are assembled and inserted into the inner mitochondrial membrane. The coordination of this process is named mitonuclear balance, and experimental manipulations of mitonuclear balance can increase longevity of laboratory species. Our data strongly indicate that these genes are also casually linked to evolution lifespan in vertebrates.

Abstract P104: Genetic Factors Influence Glycated Hemoglobin, Fasting Glucose, and Fasting Insulin Levels in the Population Architecture Using Genomics and Epidemiology Consortium

Elevated levels of fasting glucose and fasting insulin precede the development type 2 diabetes (T2D). While T2D and cardiovascular disease share common risk factors, dysregulation of glucose metabolism is of particular concern because it can result in end-organ damage including the heart, nerves, kidneys, and eyes. The prevalence of diabetes is higher in American minority populations. Through genome-wide association studies, approximately 60 loci have been identified for fasting glucose, fasting insulin, and glycated hemoglobin. To better understand the genetic basis of glucose dysregulation, the Population Architecture using Genomics and Epidemiology (PAGE) Consortium genotyped 12,801 Hispanic/Latinos, 5,696 African Americans, 1,405 Native Hawaiians, 398 Native Americans, and 1,727 Asians without diabetes using the approximately 1.3 million variants on the Multi-Ethnic Global Array (MEGA), which is enriched for coding variation and ancestral diverse content. Through ancestry-combined single variant association testing with fasting glucose, fasting insulin, and glycated hemoglobin (HbA1c), we identified a novel potential association between decreased HbA1c and the minor A allele of rs11887523 ( p = 4.51x10 -9 , MFSD2B p.A60T, minor allele frequency (MAF) 7% in African Americans, MAF 2% in Hispanics). Other associations with HbA1c included hemoglobin genes, further highlighting the importance of considering variation in hemoglobin and red-blood cell lifespan when using HbA1c as a measure of glucose control. We also replicated several known associations including between fasting glucose and variants near G6PC2, GCKR, MTNR1B, and FOXA2 ; and between fasting insulin and the GRB14/COBLL1 locus. Further analyses including imputing the data out to 1000 Genomes phase3 and gene-based tests of rare variants are underway. These will increase power to detect associations with ancestry-specific rare variants.

Environmental Canalization of Life Span and Gene Expression in Caenorhabditis elegans.

Animals, particularly poikilotherms, exhibit distinct physiologies at different environmental temperatures. Here, we hypothesized that temperature-based differences in physiology could affect the amount of variation in complex quantitative traits. Specifically, we examined, in Caenorhabditis elegans, how different temperatures (15°C, 20°C, and 25°C) affected the amount of interindividual variation in life span and also expression of three reporter genes-transcriptional reporters for vit-2, gpd-2, and hsp-16.2 (a life-span biomarker). We found the expected inverse relationship between temperature and average life span. Surprisingly, we found that at the highest temperature, there were fewer differences between individuals in life span and less interindividual variation in expression of all three reporters. We suggest that growth at 25°C might canalize (reduce interindividual differences in) life span and expression of some genes by eliciting a small constitutive heat shock response. Growth at 25°C requires wild-type hsf-1, which encodes the main heat shock response transcriptional activator. We speculate that increased chaperone activity at 25°C may reduce interindividual variation in gene expression by increasing protein folding efficiency. We hypothesize that reduced variation in gene expression may ultimately cause reduced variation in life span.