Geroscience: the need to address some issues.

The geroscience field hypothesises that it could be possible to delay all age-related diseases by delaying the ageing process itself, and not by curing each age-related disease individually. While this perspective is attracting, some issues provisionally prohibit to fully adhere to it, such as the risk for some over-enthusiasm or scientism and the tendency to accept that results observed in animal models can be easily translated in human beings. Particularly, it is not clear whether geroscience plans to delay or suppress ageing, or if healthspan could become very close to lifespan. This article lists some of these issues, in the hope that supporters of geroscience will grasp them to allow a full development of the field, and argues that geroscience should avoid reductionist approaches not taking into account social and behavioural complex aspects of human ageing.

New life expectancy forecasts are too optimistic.

Life expectancy at birth (e0) forecasts are used to estimate future pension costs. Previous French official forecasts have often overestimated e0. Recent forecasts published by demographers provide higher e0 estimates than official forecasts for France, Sweden, Japan and the USA, and do not consider that e0 could decrease, as in previous years because of flus, heatwaves, or other outbreaks. Too optimistic forecasts make that governments may overestimate future pension needs.

Is lifespan linked with developmental viability in Drosophila melanogaster?

Long-lived lines of flies have been selected by reproduction at older ages and correlated responses observed, and particularly whether development of flies was modified. Using these selected lines or flies subjected to larval crowding of food restriction during development, two studies have computed, among lines, a correlation between viability of eggs and larvae and mean lifespan of adults: mean lifespan was longer when the viability was lower, showing a selection of fittest flies. The present study correlates viability and mean lifespan observed during three decades in a single wild-type strain. Contrary to the previous studies, a slight but not significant positive correlation is observed, showing that lifespan can hardly increase when viability increases. Therefore, it is not clear whether development and lifespan are linked, as hypothesised by some authors.

Covid-19 and the next outbreak: decreasing frailty by using mild stress?

The coronavirus disease 2019 (Covid-19) has resulted in many deaths, particularly of very old or obese people. These people are at risk to die in the event of an outbreak, like under one-year old babies were at risk to die one century ago from various diseases. It is argued that mild stress could help people to resist new outbreaks. The people who are obese because of bad feeding habits (snacking, junk food, overfeeding) and inactivity should adopt more healthy behaviours. Because an inactive way of life at old age can increase frailty, physical and mental activities should be kept at the highest possible level in elderly people, particularly if they live in retirement homes. In the event of an outbreak, management staff of these homes should not confine residents in their room for weeks or months, as it can increase inactivity, under-nutrition, sarcopenia, and depressive symptoms. People with or without co-morbidities should be active and one could wonder whether other mild stresses such as sauna bathing could help to better resist infection.

A mild heat stress increases resistance to heat of dFOXO Drosophila melanogaster mutants but less in wild-type flies.

While severe stresses have deleterious effects, mild stresses can have beneficial effects called hormetic effects. This study observed survival time at 37.5 °C and at 13-16 days of age of wild-type Drosophila melanogaster flies and dFOXO mutants, after they were subjected to 5 or 10 min daily at 37.5 °C for 5 days starting at 5 days of age. This mild stress increased survival time of the mutants, this effect being nearly not observed in wild-type flies. Previous studies showed that another mild stress, the cold, can increase survival time to heat of wild-type flies, but not of dFOXO mutants, while hypergravity increased survival time of mutants but not of wild-type flies. Therefore, three mild stresses, cold, hypergravity, and heat can increase resistance to heat but the pathways mediating this effect are seemingly different, as cold does not increase resistance in dFOXO mutants but increases it in wild-type flies, while hypergravity and heat have opposite effects. It appears that dFOXO may be needed or not to observe hormetic effects.

Neglecting larval rearing conditions in Drosophila melanogaster can negatively impact research on ageing.

The developmental conditions of Drosophila melanogaster flies can modify the phenotypic traits of adults. However, the control of these conditions is neglected by some authors in their articles and the readers are unaware, for instance, whether flies developed in crowded cultures or fed on a new or used medium. Controlling developmental conditions allows to know precisely the viability of flies, their duration of development and sex-ratio, which can be warning signals of bad rearing conditions. As developmental conditions can modify the results of experiments on the effects of ageing it is necessary to strictly control them.

Covid-19 Mortality: A Matter of Vulnerability Among Nations Facing Limited Margins of Adaptation.

Context: The human development territories have been severely constrained under the Covid-19 pandemic. A common dynamics has been observed, but its propagation has not been homogeneous over each continent. We aimed at characterizing the non-viral parameters that were most associated with death rate. Methods: We tested major indices from five domains (demography, public health, economy, politics, environment) and their potential associations with Covid-19 mortality during the first 8 months of 2020, through a Principal Component Analysis and a correlation matrix with a Pearson correlation test. Data of all countries, or states in federal countries, showing at least 10 fatality cases, were retrieved from official public sites. For countries that have not yet finished the first epidemic phase, a prospective model has been computed to provide options of death rates evolution. Results: Higher Covid death rates are observed in the [25/65°] latitude and in the [-35/-125°] longitude ranges. The national criteria most associated with death rate are life expectancy and its slowdown, public health context (metabolic and non-communicable diseases (NCD) burden vs. infectious diseases prevalence), economy (growth national product, financial support), and environment (temperature, ultra-violet index). Stringency of the measures settled to fight pandemia, including lockdown, did not appear to be linked with death rate. Conclusion: Countries that already experienced a stagnation or regression of life expectancy, with high income and NCD rates, had the highest price to pay. This burden was not alleviated by more stringent public decisions. Inherent factors have predetermined the Covid-19 mortality: understanding them may improve prevention strategies by increasing population resilience through better physical fitness and immunity.

Characterisation of the positive effects of mild stress on ageing and resistance to stress.

The positive effects of mild stress on ageing, lifespan and resistance to stress have been studied mainly in Drosophila melanogaster flies and in the nematode Caenorhabditis elegans. These studies now allow to know the effects of the strength of the mild stress and of the number of exposures, the duration of the positive effects, if mild stress is effective when applied at any age, and whether combining two or three mild stresses is more efficient than a single one. This article summarises these results.

Hypergravity increases resistance to heat in dFOXO Drosophila melanogaster mutants and can lower FOXO translocation in wild-type males.

Severe stresses have deleterious effects, but mild stresses can have beneficial effects called hormetic effects. This study observed survival time of wild-type Drosophila melanogaster flies and dFOXO mutants exposed to 37 °C, a severe stress for flies, after they lived or not for 2 weeks in hypergravity (3 or 5 g), a mild stress with hormetic effects in flies. Hypergravity increased survival time of the mutants, this effect being less observed in wild-type flies. The heat stress increased dFOXO translocation similarly in all gravity groups in a wild-type strain, and hypergravity decreased dFOXO translocation similarly in heat-stressed or not heat-stressed males, no clear effect of the gravity level being observed in females. Because hypergravity increases resistance to heat in dFOXO mutants and the translocation is not tightly dependent on the gravity level, one can conclude that dFOXO does not mediate the effect of hypergravity on resistance to heat. A previous study showed that another mild stress, the cold, can increase survival time at 37 °C of wild-type D. melanogaster flies, but this was not observed in dFOXO mutants. Therefore, two mild stresses, cold and hypergravity, can increase resistance to heat but the pathways mediating this effect are seemingly different, as cold does not increase resistance in dFOXO mutants while hypergravity increases it.

Is Life Expectancy of French Women Going to Plateau and Oscillate?

Some authors have hypothesised that life expectancy at birth could reach 100 years in developed countries in the next decades. Using recent data for French women, it is shown that life expectancy changes from 1993 to 2016 are mainly linked to mortality rates of oldest women. In recent years, it happened that life expectancy of French women oscillated, because of for instance influenza epidemics killing mainly oldest frail people. It is hypothesised that in coming years, life expectancy of French women (and one day of men?) will only very slightly increase and will show oscillations because of increased mortality the years of severe influenza, heatwave and other events threatening the life of frail oldest people. This fate could also be that of the other developed countries in the future, which would mean that life expectancy has begun to plateau.

Does Calorie Restriction in Primates Increase Lifespan? Revisiting Studies on Macaques (Macaca mulatta) and Mouse Lemurs (Microcebus murinus).

The effects of calorie restriction have now been studied in two non-human primates, the macaque Macaca mulatta and the mouse lemur Microcebus murinus. The study on lemurs and one of the two studies on macaques have reported a lifespan increase. In this review, I argue that these results are better explained by a lifespan decrease in the control group because of a bad diet and/or overfeeding, rather than by a real lifespan increase in calorie-restricted animals. If these results can be readily translated to humans, it would mean that no beneficial effect of calorie restriction on lifespan can be expected in normal-weight or lean people, but that overweight and/or obese people could benefit to some extent from a decrease in excessive food intake.

Are We Reaching the Limits of Homo sapiens?

Echoing scientific and industrial progress, the Twentieth century was an unprecedented period of improvement for human capabilities and performances, with a significant increase in lifespan, adult height, and maximal physiological performance. Analyses of historical data show a major slow down occurring in the most recent years. This triggered large and passionate debates in the academic scene within multiple disciplines; as such an observation could be interpreted as our upper biological limits. Such a new phase of human history may be related to structural and functional limits determined by long term evolutionary constraints, and the interaction between complex systems and their environment. In this interdisciplinary approach, we call into question the validity of subsequent forecasts and projections through innovative and related biomarkers such as sport, lifespan, and height indicators. We set a theoretical framework based on biological and environmental relevance rather than using a typical single-variable forecasting approach. As demonstrated within the article, these new views will have major social, economical, and political implications.