Gross ways to live long: parasitic worms as an anti-inflammaging therapy?

Evolutionary medicine argues that disease can arise because modern conditions do not match those in which we evolved. For example, a decline in exposure to commensal microbes and gastrointestinal helminths in developed countries has been linked to increased prevalence of allergic and autoimmune inflammatory disorders (the hygiene hypothesis). Accordingly, probiotic therapies that restore ‘old friend’ microbes and helminths have been explored as Darwinian treatments for these disorders. A further possibility is that loss of old friend commensals also increases the sterile, aging-associated inflammation known as inflammaging, which contributes to a range of age-related diseases, including cardiovascular disease, dementia, and cancer. Interestingly, Crowe et al., 2020 recently reported that treatment with a secreted glycoprotein from a parasitic nematode can protect against murine aging by induction of anti-inflammatory mechanisms. Here, we explore the hypothesis that restorative helminth therapy would have anti-inflammaging effects. Could worm infections provide broad-spectrum protection against age-related disease

Mutation of daf‐2 extends lifespan via tissue‐specific effectors that suppress distinct life‐limiting pathologies

In aging Caenorhabditis elegans, as in higher organisms, there is more than one cause of death. C. elegans exhibit early death with a swollen, infected pharynx (P death), and later death with pharyngeal atrophy (p death). Interventions that alter lifespan can differentially affect frequency and timing of each type of death, generating complex survival curve shapes. Here, we use mortality deconvolution analysis to investigate how reduction of insulin/IGF-1 signaling (IIS), which increases lifespan (the Age phenotype), affects different forms of death. All daf-2 insulin/IGF-1 receptor mutants exhibit increased lifespan in the p subpopulation (p Age), while pleiotropic class 2 daf-2 mutants show an additional marked reduction in P death frequency. The latter is promoted by pharyngeal expression of the IIS-regulated DAF-16 FOXO transcription factor, and at higher temperature by reduced pharyngeal pumping rate. Pharyngeal DAF-16 also promotes p Age in class 2 daf-2 mutants, revealing a previously unknown role for the pharynx in the regulation of aging. Necropsy analysis of daf-2 interactions with the daf-12 steroid receptor implies that previously described opposing effects of daf-12 on daf-2 longevity are attributable to internal hatching of larvae, rather than complex interactions between insulin/IGF-1 and steroid signaling. These findings support the view that wild-type IIS acts through multiple distinct mechanisms which promote different life-limiting pathologies, each of which contribute to late-life mortality. This study further demonstrates the utility of mortality deconvolution analysis to better understand the genetics of lifespan

A physical approach on flood risk vulnerability of buildings

The design of efficient hydrological risk mitigation strategies and their subsequent implementation relies on a careful vulnerability analysis of the elements exposed. Recently, extensive research efforts were undertaken to develop and refine empirical relationships linking the structural vulnerability of buildings to the impact forces of the hazard processes. These empirical vulnerability functions allow estimating the expected direct losses as a result of the hazard scenario based on spatially explicit representation of the process patterns and the elements at risk classified into defined typological categories. However, due to the underlying empiricism of such vulnerability functions, the physics of the damage-generating mechanisms for a well-defined element at risk with its peculiar geometry and structural characteristics remain unveiled, and, as such, the applicability of the empirical approach for planning hazard-proof residential buildings is limited. Therefore, we propose a conceptual assessment scheme to close this gap. This assessment scheme encompasses distinct analytical steps: modelling (a) the process intensity, (b) the impact on the element at risk exposed and (c) the physical response of the building envelope. Furthermore, these results provide the input data for the subsequent damage evaluation and economic damage valuation. This dynamic assessment supports all relevant planning activities with respect to a minimisation of losses, and can be implemented in the operational risk assessment procedure

Excessive folate synthesis limits lifespan in the C. elegans: E. coli aging model

Background: Gut microbes influence animal health and thus, are potential targets for interventions that slow aging. Live E. coli provides the nematode worm Caenorhabditis elegans with vital micronutrients, such as folates that cannot be synthesized by animals. However, the microbe also limits C. elegans lifespan. Understanding these interactions may shed light on how intestinal microbes influence mammalian aging. Results: Serendipitously, we isolated an E. coli mutant that slows C. elegans aging. We identified the disrupted gene to be aroD, which is required to synthesize aromatic compounds in the microbe. Adding back aromatic compounds to the media revealed that the increased C. elegans lifespan was caused by decreased availability of para-aminobenzoic acid, a precursor to folate. Consistent with this result, inhibition of folate synthesis by sulfamethoxazole, a sulfonamide, led to a dose-dependent increase in C. elegans lifespan. As expected, these treatments caused a decrease in bacterial and worm folate levels, as measured by mass spectrometry of intact folates. The folate cycle is essential for cellular biosynthesis. However, bacterial proliferation and C. elegans growth and reproduction were unaffected under the conditions that increased lifespan. Conclusions: In this animal:microbe system, folates are in excess of that required for biosynthesis. This study suggests that microbial folate synthesis is a pharmacologically accessible target to slow animal aging without detrimental effects

What are the effects of maternal and pre-adult environments on ageing in humans, and are there lessons from animal models?

An open issue in research on ageing is the extent to which responses to the environment during development can influence variability in life span in animals, and the health profile of the elderly in human populations. Both affluence and adversity in human societies have profound impacts on survivorship curves, and some of this effect may be traceable to effects in utero or in infancy. The Barker Hypothesis that links caloric restriction in very early life to disruptions of glucose-insulin metabolism in later life has attracted much attention, as well as some controversy, in medical circles. It is only rarely considered by evolutionary biologists working on phenotypic plasticity, or by biogerontologists studying model organisms such as C. elegans or Drosophila. One crucial mechanism by which animals can respond in an adaptive manner to adverse conditions, for example in nutrition or infection, during development is phenotypic plasticity. Here we begin with a discussion of adaptive plasticity in animals before asking what such phenomena may reveal of relevance to rates of ageing in animals, and in humans. We survey the evidence for effects on adult ageing of environmental conditions during development across mammalian and invertebrate model organisms, and ask whether evolutionary conserved mechanisms might be involved. We conclude that the Barker Hypothesis is poorly supported and argue that more work in human populations should be integrated with multi-disciplinary studies of ageing-related phenomena in experimental populations of different model species that are subjected to nutritional challenges or infections during pre-adult development

Two forms of death in ageing Caenorhabditis elegans

Ageing generates senescent pathologies, some of which cause death. Interventions that delay or prevent lethal pathologies will extend lifespan. Here we identify life-limiting pathologies in Caenorhabditis elegans with a necropsy analysis of worms that have died of old age. Our results imply the presence of multiple causes of death. Specifically, we identify two classes of corpse: early deaths with a swollen pharynx (which we call ‘P deaths’), and later deaths with an atrophied pharynx (termed ‘p deaths’). The effects of interventions on lifespan can be broken down into changes in the frequency and/or timing of either form of death. For example, glp-1 mutation only delays p death, while eat-2 mutation reduces P death. Combining pathology and mortality analysis allows mortality profiles to be deconvolved, providing biological meaning to complex survival and mortality profiles

The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing

Inhibiting insulin/IGF-1 signalling extends lifespan and delays age-related disease in species throughout the animal kingdom. This life-extension pathway, the first to be defined, was discovered through genetic studies in the small roundworm Caenorhabditis elegans. This discovery is described here

Lifespan extension and the doctrine of double effect

Recent developments in biogerontology—the study of the biology of ageing—suggest that it may eventually be possible to intervene in the human ageing process. This, in turn, offers the prospect of significantly postponing the onset of age-related diseases. The biogerontological project, however, has met with strong resistance, especially by deontologists. They consider the act of intervening in the ageing process impermissible on the grounds that it would (most probably) bring about an extended maximum lifespan—a state of affairs that they deem intrinsically bad. In a bid to convince their deontological opponents of the permissibility of this act, proponents of biogerontology invoke an argument which is grounded in the doctrine of double effect. Surprisingly, their argument, which we refer to as the ‘double effect argument’, has gone unnoticed. This article exposes and critically evaluates this ‘double effect argument’. To this end, we first review a series of excerpts from the ethical debate on biogerontology in order to substantiate the presence of double effect reasoning. Next, we attempt to determine the role that the ‘double effect argument’ is meant to fulfil within this debate. Finally, we assess whether the act of intervening in ageing actually can be justified using double effect reasoning

Dramatic age-related changes in nuclear and genome copy number in the nematode Caenorhabditis elegans

The nematode Caenorhabditis elegans has become one of the most widely used model systems for the study of aging, yet very little is known about how C. elegans age. The development of the worm, from egg to young adult has been completely mapped at the cellular level, but such detailed studies have not been extended throughout the adult lifespan. Numerous single gene mutations, drug treatments and environmental manipulations have been found to extend worm lifespan. To interpret the mechanism of action of such aging interventions, studies to characterize normal worm aging, similar to those used to study worm development are necessary. We have used 4′,6′-diamidino-2-phenylindole hydrochloride staining and quantitative polymerase chain reaction to investigate the integrity of nuclei and quantify the nuclear genome copy number of C. elegans with age. We report both systematic loss of nuclei or nuclear DNA, as well as dramatic age-related changes in nuclear genome copy number. These changes are delayed or attenuated in long-lived daf-2 mutants. We propose that these changes are important pathobiological characteristics of aging nematodes

Optimizing Dietary Restriction for Genetic Epistasis Analysis and Gene Discovery in C. elegans

Dietary restriction (DR) increases mammalian lifespan and decreases susceptibility to many age-related diseases. Lifespan extension due to DR is conserved across a wide range of species. Recent research has focused upon genetically tractable model organisms such as C. elegans to uncover the genetic mechanisms that regulate the response to DR, in the hope that this information will provide insight into the mammalian response and yield potential therapeutic targets. However, no consensus exists as to the best protocol to apply DR to C. elegans and potential key regulators of DR are protocol-specific. Here we define a DR method that better fulfills criteria required for an invertebrate DR protocol to mirror mammalian studies. The food intake that maximizes longevity varies for different genotypes and informative epistasis analysis with another intervention is only achievable at this ‘optimal DR’ level. Importantly therefore, the degree of restriction imposed using our method can easily be adjusted to determine the genotype-specific optimum DR level. We used this protocol to test two previously identified master regulators of DR in the worm. In contrast to previous reports, we find that DR can robustly extend the lifespan of worms lacking the AMP-activated protein kinase catalytic subunit AAK2 or the histone deacetylase SIR-2.1, highlighting the importance of first optimizing DR to identify universal regulators of DR mediated longevity