The genomics of exceptional longevity in rockfishes refine genetic foundations of human lifespan variation

Longevity is a defining, heritable trait that varies dramatically between species. To resolve the genetic regulation of this trait, we have mined genomic variation in rockfishes, ranging in longevity from 11 to over 205 years. Shifts in rockfish longevity occurred multiple times independently, and in a short evolutionary time frame, thus empowering convergence analyses. Our analyses reveal a common network of genes under convergent restricted evolution in long-lived lineages, encompassing established aging regulators such as insulin-signaling, yet also identify flavonoid (aryl-hydrocarbon) metabolism as a novel pathway modulating longevity. Further, these genes were used to refine human longevity GWAS, identifying the aryl-hydrocarbon metabolism pathway to be significantly associated with the 99th percentile of human longevity, independently validating its importance and conservation. This evolutionary intersection highlights a novel, conserved genetic architecture that associates with the evolution of longevity across vertebrates and provides actionable targets for research into lifespan and healthspan modulation.

The Cross-sectional Average Inequality in Lifespan (CAL†): A Lifespan Variation Measure That Reflects the Mortality Histories of Cohorts

Lifespan variation is a key metric of mortality that describes both individual uncertainty about the length of life and heterogeneity in population health. We propose a novel and timely lifespan variation measure, which we call the cross-sectional average inequality in lifespan, or CAL†. This new index provides an alternative perspective on the analysis of lifespan inequality by combining the mortality histories of all cohorts present in a cross-sectional approach. We demonstrate how differences in the CAL† measure can be decomposed between populations by age and cohort to explore the compression or expansion of mortality in a cohort perspective. We apply these new methods using data from 10 low-mortality countries or regions from 1879 to 2013. CAL† reveals greater uncertainty in the timing of death than the period life table–based indices of variation indicate. Also, country rankings of lifespan inequality vary considerably between period and cross-sectional measures. These differences raise intriguing questions as to which temporal dimension is the most relevant to individuals when considering the uncertainty in the timing of death in planning their life courses.

Evolution of Natural Lifespan Variation and Molecular Strategies of Extended Lifespan

To understand the genetic basis and the selective forces acting on longevity, it is useful to employ ecologically diverse individuals of the same species, widely different in lifespan. This way, we may capture the experiment of Nature that modifies the genotype arriving at different lifespans. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered wide diversity of lifespan. We sequenced the genomes of these organisms and analyzed how their replicative lifespan is shaped by nutrients and transcriptional and metabolite patterns. By identifying genes, proteins and metabolites that correlate with longevity across these isolates, we found that long-lived strains elevate intermediary metabolites, differentially regulate genes involved in NAD metabolism and adjust control of epigenetic landscape through conserved, rare histone modifier. Our data further offer insights into the evolution and mechanisms by which caloric restriction regulates lifespan by modulating the availability of nutrients without decreasing fitness.

Evolution of natural lifespan variation and molecular strategies of extended lifespan

To understand the genetic basis and selective forces acting on longevity, it is useful to examine lifespan variation among closely related species, or ecologically diverse isolates of the same species, within a controlled environment. In particular, this approach may lead to understanding mechanisms underlying natural variation in lifespan. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered a wide diversity of replicative lifespan. Phylogenetic analyses pointed to genes and environmental factors that strongly interact to modulate the observed aging patterns. We then identified genetic networks causally associated with natural variation in replicative lifespan across wild yeast isolates, as well as genes, metabolites and pathways, many of which have never been associated with yeast lifespan in laboratory settings. In addition, a combined analysis of lifespan-associated metabolic and transcriptomic changes revealed unique adaptations to interconnected amino acid biosynthesis, glutamate metabolism and mitochondrial function in long-lived strains. Overall, our multi-omic and lifespan analyses across diverse isolates of the same species shows how gene-environment interactions shape cellular processes involved in phenotypic variation such as lifespan.

Lifespan Extension in Long-Lived Vertebrates Rooted in Ecological Adaptation

Contemporary studies on aging and longevity have largely overlooked the role that adaptation plays in lifespan variation across species. Emerging evidence indicates that the genetic signals of extended lifespan may be maintained by natural selection, suggesting that longevity could be a product of organismal adaptation. The mechanisms of adaptation in long-lived animals are believed to account for the modification of physiological function. Here, we first review recent progress in comparative biology of long-lived animals, together with the emergence of adaptive genetic factors that control longevity and disease resistance. We then propose that hitchhiking of adaptive genetic changes is the basis for lifespan changes and suggest ways to test this evolutionary model. As individual adaptive or adaptation-linked mutations/substitutions generate specific forms of longevity effects, the cumulative beneficial effect is largely nonrandom and is indirectly favored by natural selection. We consider this concept in light of other proposed theories of aging and integrate these disparate ideas into an adaptive evolutionary model, highlighting strategies in decoding genetic factors of lifespan control.

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.

Divergent Trends of Lifespan Variation During Mortality Crises

Lifespan variation has been attracting increasingly greater attention as a measure of population health and mortality. Several studies have analysed periods of steady mortality decline, highlighting a strong inverse relationship between lifespan variation and life expectancy. Recent research has found that this association weakens, and even reverses, when mortality does not improve equally over age. However, to date no study has comprehensively explored the behaviour of lifespan variation when mortality increases significantly. Analysing three epidemics and two famines in Europe from the eighteenth to the twentieth centuries, we find that, during these events, relative lifespan variation increases, while absolute variation declines, and that subsequently both quickly revert to pre-crisis levels. Using decomposition techniques, we show that mortality at older ages leads to a temporary increase in absolute – but not relative – variation. Moreover, female lifespan variation is less affected by the crises than that of males, because of the higher impact of infant and child mortality on male lifespan variation. By underlining different trends of lifespan variation by sex and indicator, we offer new insight into the consequences of mortality crises. Contrary to what is often asserted, we also show that the choice of lifespan variation indicator is not always inconsequential.

What can lifespan variation reveal that life expectancy hides? Comparison of five high-income countries

Objectives In most countries, life expectancy at birth (e0) has improved for many decades. Recently, however, progress has stalled in the UK and Canada, and reversed in the USA. Lifespan variation, a complementary measure of mortality, increased a few years before the reversal in the USA. To assess whether this measure offers additional meaningful insights, we examine what happened in four other high-income countries with differing life expectancy trends. Design We calculated life disparity (a specific measure of lifespan variation) in five countries -- USA, UK, France, Japan and Canada -- using sex- and age specific mortality rates from the Human Mortality Database from 1975 to 2017 for ages 0--100 years. We then examined trends in age-specific mortality to identify the age groups contributing to these changes. Setting USA, UK, France, Japan and Canada Participants aggregate population data of the above nations. Main Outcome Measures Life expectancy at birth, life disparity and age-specific mortality. Results The stalls and falls in life expectancy, for both males and females, seen in the UK, USA and Canada coincided with rising life disparity. These changes may be driven by worsening mortality in middle-age (such as at age 40). France and Japan, in contrast, continue on previous trajectories. Conclusions Life disparity is an additional summary measure of population health providing information beyond that signalled by life expectancy at birth alone.