Normalized lifespan inequality: disentangling the longevity–lifespan variability nexus

Previous studies have documented a historically strong and negative association between countries’ life expectancy (i.e., average longevity) and length-of-life inequality (i.e., variability in ages at death). The relationship between both variables might be partially explained by life expectancy increasing at a faster pace than maximal length of life, a phenomenon that mechanically compresses the age-at-death distribution and has not been taken into consideration in previous studies. In this paper, we propose a new approach to lifespan inequality measurement that accounts for the (uncertainly) bounded nature of length-of-life. Applying the new approach to the countries of the Human Mortality Database, we observe that the decline in overall lifespan variability typically associated with increases in longevity seems to stop and even reverse at higher levels of life expectancy. This suggests the emergence of worrying ethical dilemmas, whereby higher achievements in longevity would only be possible at the expense of higher lifespan variability.

Endogenous DAF-16 Spatiotemporal Activity Quantitatively Predicts Lifespan Extension Induced by Dietary Restriction

In many organisms, dietary restriction (DR) leads to lifespan extension through the activation of cell protection and pro-longevity gene expression programs. In the nematode C. elegans, the DAF-16 transcription factor is a key aging regulator that governs the Insulin/IGF-1 signaling pathway and undergoes translocation from the cytoplasm to the nucleus of cells when animals are exposed to food limitation. In this work, we assess the endogenous activity of DAF-16 under various DR regimes by coupling CRISPR/Cas9-enabled fluorescent tagging of DAF-16 with quantitative image analysis and machine learning. Our results indicate that lifelong DAF-16 endogenous activity is a robust predictor of mean lifespan in C. elegans, and it accounts for 78% of the lifespan variability induced by DR. We found that this lifespan-extending mechanism occurs mainly in the intestine and neurons, and that DR drives DAF-16 activity in unexpected locations such as the germline and intestinal nucleoli.

The Interplay Between Stress Related Genes and Its Role in Human Longevity: Insights for Translational Studies

Human lifespan is a multifactorial trait resulted from complicated interplay among many genetic and environmental factors. Despite substantial progress in clarifying many aspects of lifespan’ variability the mechanism of its multifactorial regulation remains unclear. In this paper we investigate the role of genes from integrated stress response (ISR) pathway in such regulation. Experimental studies showed that persistent cellular stress may result in cellular senescence (for proliferating cells), or in apoptosis (for post-mitotic cells) which may affect health and lifespan in laboratory animals. These studies also showed which ISR genes are likely to interplay to produce joint effects on these traits. Note that in humans, the interplay between these genes does not necessarily influence these traits. This is because biological mechanisms regulating these traits in laboratory animals and humans may differ. This means that, when possible, the experimentally detected connections promising for human applications, should be verified using available human data before their testing in expensive clinical trials. In this paper we used HRS data to test connection between SNPs from the EIF2AK4 gene that senses cellular stress signals and the DDIT3 gene from the apoptosis regulation part of the ISR. We found genome wide significant associations between interacting SNPs from these genes and longevity. This result shows that available human data may be successfully used for making important steps in translation of experimental research findings towards their application in humans. Following this strategy may increase efficiency of clinical trials aiming to find appropriate medications to promote human health and longevity.

Changes in life expectancy and lifespan variability by income quartiles in four Nordic countries: a study based on nationwide register data

ObjectivesLevels, trends or changes in socioeconomic mortality differentials are typically described in terms of means, for example, life expectancies, but studies have suggested that there also are systematic social disparities in the dispersion around those means, in other words there are inequalities in lifespan variation. This study investigates changes in income inequalities in mean and distributional measures of mortality in Denmark, Finland, Norway, and Sweden over two decades.DesignNationwide register-based study.SettingThe Danish, Finnish, Norwegian and Swedish populations aged 30 years or over in 1997 and 2017.Main outcome measuresIncome-specific changes in life expectancy, lifespan variation and the contribution of ‘early’ and ‘late’ deaths to increasing life expectancy.ResultsIncreases in life expectancy has taken place in all four countries, but there are systematic differences across income groups. In general, the largest gains in life expectancy were observed in Denmark, and the smallest increase among low-income women in Sweden and Norway. Overall, life expectancy increased and lifespan variation decreased with increasing income level. These differences grew larger over time. In all countries, a marked postponement of early deaths led to a compression of mortality in the top three income quartiles for both genders. This did not occur for the lowest income quartile.ConclusionIncreasing life expectancy is typically accompanied by postponement of early deaths and reduction of lifespan inequality in the higher-income groups. However, Nordic welfare societies are challenged by the fact that postponing premature deaths among people in the lowest-income groups is not taking place.

Global, cell non-autonomous gene regulation drives individual lifespan among isogenic C. elegans

Across species, lifespan is highly variable among individuals within a population. Even genetically identical Caenorhabditis elegans reared in homogeneous environments are as variable in lifespan as outbred human populations. We hypothesized that persistent inter-individual differences in expression of key regulatory genes drives this lifespan variability. As a test, we examined the relationship between future lifespan and the expression of 22 microRNA promoter::GFP constructs. Surprisingly, expression of nearly half of these reporters, well before death, could effectively predict lifespan. This indicates that prospectively long- vs. short-lived individuals have highly divergent patterns of transgene expression and transcriptional regulation. The gene-regulatory processes reported on by two of the most lifespan-predictive transgenes do not require DAF-16, the FOXO transcription factor that is a principal effector of insulin/insulin-like growth factor (IGF-1) signaling. Last, we demonstrate a hierarchy of redundancy in lifespan-predictive ability among three transgenes expressed in distinct tissues, suggesting that they collectively report on an organism-wide, cell non-autonomous process that acts to set each individual’s lifespan.

Reducing Results Variance in Lifespan Machines: An Analysis of the Influence of Vibrotaxis on Wild-Type Caenorhabditis elegans for the Death Criterion

Nowadays, various artificial vision-based machines automate the lifespan assays of C. elegans. These automated machines present wider variability in results than manual assays because in the latter worms can be poked one by one to determine whether they are alive or not. Lifespan machines normally use a “dead or alive criterion” based on nematode position or pose changes, without poking worms. However, worms barely move on their last days of life, even though they are still alive. Therefore, a long monitoring period is necessary to observe motility in order to guarantee worms are actually dead, or a stimulus to prompt worm movement is required to reduce the lifespan variability measure. Here, a new automated vibrotaxis-based method for lifespan machines is proposed as a solution to prompt a motion response in all worms cultured on standard Petri plates in order to better distinguish between live and dead individuals. This simple automated method allows the stimulation of all animals through the whole plate at the same time and intensity, increasing the experiment throughput. The experimental results exhibited improved live-worm detection using this method, and most live nematodes (>93%) reacted to the vibration stimulus. This method increased machine sensitivity by decreasing results variance by approximately one half (from ±1 individual error per plate to ±0.6) and error in lifespan curve was reduced as well (from 2.6% to 1.2%).

Alternative Forecasts of Danish Life Expectancy

In the last three decades, considerable progress in mortality forecasting has been achieved, with new and more sophisticated models being introduced. Most of these forecasting models are based on the extrapolation of past trends, often assuming linear (or log-linear) development of mortality indicators, such as death rates or life expectancy. However, this assumption can be problematic in countries where mortality development has not been linear, such as in Denmark. Life expectancy in Denmark experienced stagnation from the 1980s until the mid-1990s. To avoid including the effect of the stagnation, Denmark’s official forecasts are based on data from 1990 only. This chapter is divided into three parts. First, we highlight and discuss some of the key methodological issues for mortality forecasting in Denmark. How many years of data are needed to forecast? Should linear extrapolation be used? Second, we compare the forecast performance of 11 models for Danish females and males and for period and cohort data. Finally, we assess the implications of the various forecasts for Danish society, and, in particular, their implications for future lifespan variability and age at retirement.

Germline burden of rare damaging variants negatively affects human healthspan and lifespan

Genome-wide association studies often explore links between particular genes and phenotypes of interest. Known genetic variants, however, are responsible for only a small fraction of human lifespan variation evident from genetic twin studies. To account for the missing longevity variance, we hypothesized that the cumulative effect of deleterious variants may affect human longevity. Here, we report that the burden of rarest protein-truncating variants (PTVs) negatively impacts both human healthspan and lifespan in two large independent cohorts. Longer-living subjects have both fewer rarest PTVs and less damaging PTVs. In contrast, we show that the burden of frequent PTVs and rare non-PTVs is less deleterious, lacking association with longevity. The combined effect of rare PTVs is similar to that of known variants associated with longer lifespan and accounts for 1 − 2 years of lifespan variability. We further find that somatic accumulation of PTVs accounts for a minute fraction of mortality and morbidity acceleration and hence provides little support for its causal role in aging. Thus, damaging mutations, germline and somatic, can only contribute to aging as a result of higher-order effects including interactions of multiple forms of damage.