Ageing as a two-phase process: theoretical framework.

Human ageing, along with the ageing of conventional model organisms, is depicted as a continuous and progressive decline of biological capabilities accompanied by an exponentially increasing mortality risk. However, not all organisms experience ageing identically and our understanding of the phenomenon is coloured by human-centric views. Ageing is multifaceted and influences a diverse range of species in varying ways. Some undergo swift declines post-reproduction, while others exhibit insubstantial changes throughout their existence. This vast array renders defining universally applicable "ageing attributes" a daunting task. It is nonetheless essential to recognize that not all ageing features are organism-specific. These common attributes have paved the way for identifying "hallmarks of ageing," processes that are intertwined with age, amplified during accelerated ageing, and manipulations of which can potentially modulate or even reverse the ageing process. Yet, a glaring observation is that individuals within a single population age at varying rates. To address this, demographers have coined the term 'frailty'. Concurrently, scientific advancements have ushered in the era of molecular clocks. These innovations enable a distinction between an individual's chronological age (time since birth) and biological age (physiological status and mortality risk). In 2011, the "Smurf" phenotype was unveiled in Drosophila, delineating an age-linked escalation in intestinal permeability that presages imminent mortality. It not only acts as a predictor of natural death but identifies individuals exhibiting traits normally described as age-related. Subsequent studies have revealed the phenotype in organisms like nematodes, zebrafish, and mice, invariably acting as a death predictor. Collectively, these findings have steered our conception of ageing towards a framework where ageing is not linear and continuous but marked by two distinct, necessary phases, discernible in vivo, courtesy of the Smurf phenotype. This framework includes a mathematical enunciation of longevity trends based on three experimentally measurable parameters. It facilitates a fresh perspective on the evolution of ageing as a function. In this article, we aim to delineate and explore the foundational principles of this innovative framework, emphasising its potential to reshape our understanding of ageing, challenge its conventional definitions, and recalibrate our comprehension of its evolutionary trajectory.

Smurfness-based two-phase model of ageing helps deconvolve the ageing transcriptional signature.

Ageing is characterised at the molecular level by six transcriptional 'hallmarks of ageing', that are commonly described as progressively affected as time passes. By contrast, the 'Smurf' assay separates high-and-constant-mortality risk individuals from healthy, zero-mortality risk individuals, based on increased intestinal permeability. Performing whole body total RNA sequencing, we found that Smurfness distinguishes transcriptional changes associated with chronological age from those associated with biological age. We show that transcriptional heterogeneity increases with chronological age in non-Smurf individuals preceding the other five hallmarks of ageing that are specifically associated with the Smurf state. Using this approach, we also devise targeted pro-longevity genetic interventions delaying entry in the Smurf state. We anticipate that increased attention to the evolutionary conserved Smurf phenotype will bring about significant advances in our understanding of the mechanisms of ageing.

Demographic models of the reproductive process: Past, interlude, and future.

After 30 years of active development, mechanistic models of the reproductive process nearly stopped attracting scholarly interest in the early 1980s. In the following decades, fertility research continued to thrive, relying on solid descriptive work and detailed analysis of micro-level data. The absence of systematic modelling efforts, however, has also made the field more fragmented, with empirical research, theory building, and forecasting advancing along largely disconnected channels. In this paper we outline some of the drivers of this process, from the popularization of user-friendly statistical software to the limitations of early family building models. We then describe a series of developments in computational modelling and statistical computing that can contribute to the emergence of a new generation of mechanistic models. Finally, we introduce a concrete example of this new kind of model, and show how they can be used to formulate and test theories coherently and make informed projections.

Socioeconomic development predicts a weaker contraceptive effect of breastfeeding.

The contraceptive effect of breastfeeding remains essential to controlling fertility in many developing regions of the world. The extent to which this negative effect of breastfeeding on ovarian activity is sensitive to ecological conditions, notably maternal energetic status, has remained controversial. We assess the relationship between breastfeeding duration and postpartum amenorrhea (the absence of menstruation following a birth) in 17 World Fertility Surveys and 284 Demographic Health Surveys conducted between 1975 and 2019 in 84 low- and middle-income countries. We then analyze the resumption of menses in women during unsupplemented lactation. We find that a sharp weakening of the breastfeeding-postpartum amenorrhea relationship has globally occurred over the time period analyzed. The slope of the breastfeeding-postpartum amenorrhea relationship is negatively associated with development: higher values of the Human Development Index, urbanization, access to electricity, easier access to water, and education are predictive of a weaker association between breastfeeding and postpartum amenorrhea. Low parity also predicts shorter postpartum amenorrhea. The association between exclusive breastfeeding and maintenance of amenorrhea in the early postpartum period is also found in rapid decline in Asia and in moderate decline in sub-Saharan Africa. These findings indicate that the effect of breastfeeding on ovarian function is partly mediated by external factors that likely include negative maternal energy balance and support the notion that prolonged breastfeeding significantly helps control fertility only under harsh environmental conditions.

[Ethical and social consequences of biomarkers that predict impending death in humans]. / Conséquences éthiques et sociales de biomarqueurs prédictifs de la mort chez l'homme - La vieillesse et la mort, problématiques comportementales et sociétales.

Fundamental research on ageing has taken an interesting turn in recent years with the rapid development of biomarkers predicting mortality in model organisms, particularly Drosophila, as well as in humans through improvements in approaches to the identification of circulating molecules in mass. These developments lead to a shift in our ability to predict the occurrence of death from the historically population level to the individual level. We question here the ethical, medical and social implications of this change of scale.

TITLE: Conséquences éthiques et sociales de biomarqueurs prédictifs de la mort chez l'homme - La vieillesse et la mort, problématiques comportementales et sociétales. ABSTRACT: La recherche fondamentale sur le vieillissement a pris un tour intéressant ces dernières années avec un développement rapide des biomarqueurs prédictifs de mortalité chez les organismes modèles, notamment la drosophile, ainsi que chez l'être humain à travers les améliorations des approches d'identification en masse de molécules circulantes. Ces développements conduisent à un déplacement de notre capacité de prédiction de survenue de la mort, du niveau historiquement populationnel au niveau individuel. Nous interrogeons ici les implications éthiques, médicales et sociales de ce changement d'échelle.

Ethical and social implications of approaching death prediction in humans - when the biology of ageing meets existential issues.

BACKGROUND: The discovery of biomarkers of ageing has led to the development of predictors of impending natural death and has paved the way for personalised estimation of the risk of death in the general population. This study intends to identify the ethical resources available to approach the idea of a long-lasting dying process and consider the perspective of death prediction. The reflection on human mortality is necessary but not sufficient to face this issue. Knowledge about death anticipation in clinical contexts allows for a better understanding of it. Still, the very notion of prediction and its implications must be clarified. This study outlines in a prospective way issues that call for further investigation in the various fields concerned: ethical, psychological, medical and social. METHODS: The study is based on an interdisciplinary approach, a combination of philosophy, clinical psychology, medicine, demography, biology and actuarial science. RESULTS: The present study proposes an understanding of death prediction based on its distinction with the relationship to human mortality and death anticipation, and on the analogy with the implications of genetic testing performed in pre-symptomatic stages of a disease. It leads to the identification of a multi-layered issue, including the individual and personal relationship to death prediction, the potential medical uses of biomarkers of ageing, the social and economic implications of the latter, especially in regard to the way longevity risk is perceived. CONCLUSIONS: The present study work strives to propose a first sketch of what the implications of death prediction as such could be - from an individual, medical and social point of view. Both with anti-ageing medicine and the transhumanist quest for immortality, research on biomarkers of ageing brings back to the forefront crucial ethical matters: should we, as human beings, keep ignoring certain things, primarily the moment of our death, be it an estimation of it? If such knowledge was available, who should be informed about it and how such information should be given? Is it a knowledge that could be socially shared?

Correction to: Fetal growth is associated with CpG methylation in the P2 promoter of the IGF1 gene.

[This corrects the article DOI: 10.1186/s13148-018-0489-9.].

Fetal growth is associated with CpG methylation in the P2 promoter of the IGF1 gene.

Background: There are many reasons to think that epigenetics is a key determinant of fetal growth variability across the normal population. Since IGF1 and INS genes are major determinants of intrauterine growth, we examined the methylation of selected CpGs located in the regulatory region of these two genes. Methods: Cord blood was sampled in 159 newborns born to mothers prospectively followed during their pregnancy. A 142-item questionnaire was filled by mothers at inclusion, during the last trimester of the pregnancy and at the delivery. The methylation of selected CpGs located in the promoters of the IGF1 and INS genes was measured in cord blood mononuclear cells collected at birth using bisulfite-PCR-pyrosequencing. Results: Methylation at IGF1 CpG-137 correlated negatively with birth length (r = 0.27, P = 3.5 × 10-4). The same effect size was found after adjustment for maternal age, parity, and smoking: a 10% increase in CpG-137 methylation was associated with a decrease of length by 0.23 SDS. Conclusion: The current results suggest that the methylation of IGF1 CpG-137 contributes to the individual variation of fetal growth by regulating IGF1 expression in fetal tissues.

Impact of social inequalities at birth on the longevity of children born 1914-1916: A cohort study.

BACKGROUND: Testing whether familial socioeconomic status (SES) in childhood is a predictor of mortality has rarely been done on historical cohorts. METHODS: The birth certificates of 4,805 individuals born 1914-1916 in 16 districts of the Paris region were retrieved. The handwritten information provided the occupation of parents, the legitimacy status, life events (e.g. marriage, divorce), and the precise date of death when after 1945 (i.e. age 31 years (y) in the cohort). We used the median age at death (MAD) as a global measure of mortality, then studied separately survival to and after 31 y. Multivariate Imputation by Chained Equations (MICE), Generalized Additive Models (GAMs) and mixed effect Cox models were used. RESULTS: MAD showed large variations according to paternal occupation. The lowest MAD in both sexes was that of workers' children: it was 56.3 y (95% CI: [48.6-62.7]) in men and 67.4 y (95% CI: [60.8-72.7]) in women, respectively (95% CI: 13.4 y [5.7-21.3]) and 12.3 y (95% CI: [4.0-19.2]) below the highest MAD attained. MAD experienced by illegitimate children was 18.9 y (95% CI: [13.3-32.3]) shorter than of legitimate children. The multivariate analysis revealed that in both sexes survival to age 31 y was predicted independently by legitimacy and paternal occupation. Paternal occupation was found significantly associated with mortality after age 31 y in females only: accordingly difference in life expectancy at age 31 y was 4.4 y (95% CI: [1.2-7.6]) between upper class and workers' daughters. CONCLUSIONS: Paternal occupation and legitimacy status were strong predictors of offspring longevity in this one-century historical cohort born during World War One.

Comparison of the temperature-mortality relationship in foreign born and native born died in France between 2000 and 2009.

The daily temperature-mortality relationship is typically U shaped. The temperature of minimum mortality (MMT) has been shown to vary in space (higher at lower latitudes) and time (higher in recent periods). This indicates human populations adapt to their local environment. The pace of this adaptation is unknown. The objective of this study was to investigate the differences in the temperature-mortality relationship in continental France between foreign born and natives. Source data were the 5,273,005 death certificates of individuals living in continental France between 2000 and 2009 at the time of their death. Foreign-born deaths (N = 573,384) were matched 1:1 with a native-born death based on date of birth, sex, and place of death. Four regions of France based on similarity of their temperatures profiles were defined by unsupervised clustering. For each of these four regions, variations of all causes mortality with season and temperature of the day were modeled and compared between four groups of foreign born (Maghreb, sub-Saharan Africa, Southern Europe, and Northern Europe) and matched groups of natives. Overall, the temperature-mortality relationship and MMT were close in foreign born and in native born: The only difference between foreign born and native born concerned the attributable mortality to cold, found in several instances larger in foreign born. There are little differences in France between the temperature-mortality relationships in native born and in foreign born. This supports the hypothesis of an adaptation of these populations to the temperature patterns of continental France, which for those born in Africa differ markedly from the climatic pattern of their birth country.

Prenatal loss of father during World War One is predictive of a reduced lifespan in adulthood.

Although early-life stress is known to alter health, its long-term consequences on mortality remain largely unknown. Thanks to unique French legislation established in 1917 for war orphans and children of disabled soldiers, we were able to study the adult mortality of individuals born in 1914-1916 whose fathers were killed during World War 1. Vital information and socio-demographic characteristics were extracted manually from historical civil registers for 5,671 children born between 1 August 1914 and 31 December 1916 who were granted the status of "pupille de la Nation" (orphan of the Nation). We used a database comprising 1.4 million deceased soldiers to identify war orphans and collect information on their fathers and then paired each orphan with a nonorphan from the same birth register matched for date of birth, sex, and mother's age at the infant's birth. Mortality between ages 31 and 99 y was analyzed for 2,365 orphan/nonorphan pairs. The mean loss of adult lifespan of orphans who had lost their father before birth was 2.4 y (95% CI: 0.7, 3.9 y) and was the result of increased mortality before age 65 y. Adult lifespan was not reduced when the father's death occurred after the infant's birth. These results support the notion that intrauterine exposure to a major psychological maternal stress can affect human longevity.

Space-Time Covariation of Mortality with Temperature: A Systematic Study of Deaths in France, 1968-2009.

BACKGROUND: The temperature-mortality relationship has repeatedly been found, mostly in large cities, to be U/J-shaped, with higher minimum mortality temperature (MMT) at low latitudes being interpreted as indicating human adaptation to climate. OBJECTIVES: Our aim was to partition space with a high-resolution grid to assess the temperature-mortality relationship in a territory with wide climate diversity, over a period with notable climate warming. METHODS: The 16,487,668 death certificates of persons > 65 years of age who died of natural causes in continental France (1968-2009) were analyzed. A 30-km × 30-km grid was placed over the map of France. Generalized additive model regression was used to assess the temperature-mortality relationship for each grid square, and extract the MMT and the RM25 and RM25/18 (respectively, the ratios of mortality at 25°C/MMT and 25°C/18°C). Three periods were considered: 1968-1981 (P1), 1982-1995 (P2), and 1996-2009 (P3). RESULTS: All temperature-mortality curves computed over the 42-year period were U/J-shaped. MMT and mean summer temperature were strongly correlated. Mean MMT increased from 17.5°C for P1 to 17.8°C for P2 and to 18.2°C for P3 and paralleled the summer temperature increase observed between P1 and P3. The temporal MMT rise was below that expected from the geographic analysis. The RM25/18 ratio of mortality at 25°C versus that at 18°C declined significantly (p = 5 × 10-5) as warming increased: 18% for P1, 16% for P2, and 15% for P3. CONCLUSIONS: Results of this spatiotemporal analysis indicated some human adaptation to climate change, even in rural areas.