Mendelian randomization analyses implicate biogenesis of translation machinery in human aging.

Reduced provision of protein translation machinery promotes healthy aging in a number of animal models. In humans, however, inborn impairments in translation machinery are a known cause of several developmental disorders, collectively termed ribosomopathies. Here, we use casual inference approaches in genetic epidemiology to investigate whether adult, tissue-specific biogenesis of translation machinery drives human aging. We assess naturally occurring variation in the expression of genes encoding subunits specific to the two RNA polymerases (Pols) that transcribe ribosomal and transfer RNAs, namely Pol I and III, and the variation in expression of ribosomal protein (RP) genes, using Mendelian randomization. We find each causally associated with human longevity (ß = -0.15 ± 0.047, P = 9.6 × 10-4, q = 0.015; ß = -0.13 ± 0.040, P = 1.4 × 10-3, q = 0.023; ß = -0.048 ± 0.016, P = 3.5 × 10-3, q = 0.056, respectively), and this does not appear to be mediated by altered susceptibility to a single disease. We find that reduced expression of Pol III, RPs, or Pol I promotes longevity from different organs, namely visceral adipose, liver, and skeletal muscle, echoing the tissue specificity of ribosomopathies. Our study shows the utility of leveraging genetic variation in expression to elucidate how essential cellular processes impact human aging. The findings extend the evolutionary conservation of protein synthesis as a critical process that drives animal aging to include humans.

Epigenetic clocks indicate that kidney transplantation and not dialysis mitigate the effects of renal ageing.

BACKGROUND: Chronic kidney disease (CKD) is an age-related disease that displays multiple features of accelerated ageing. It is currently unclear whether the two treatment options for end-stage kidney disease (dialysis and kidney transplantation [KT]) ameliorate the accelerated uremic ageing process. METHODS: Data on clinical variables and blood DNA methylation (DNAm) from CKD stage G3-G5 patients were used to estimate biological age based on blood biomarkers (phenotypic age [PA], n = 333), skin autofluorescence (SAF age, n = 199) and DNAm (Horvath, Hannum and PhenoAge clocks, n = 47). In the DNAm cohort, we also measured the change in biological age 1 year after the KT or initiation of dialysis. Healthy subjects recruited from the general population were included as controls. RESULTS: All three DNAm clocks indicated an increased biological age in CKD G5. However, PA and SAF age tended to produce implausibly large estimates of biological age in CKD G5. By contrast, DNAm age was 4.9 years (p = 0.005) higher in the transplantation group and 5.9 years (p = 0.001) higher in the dialysis group compared to controls. This age acceleration was significantly reduced 1 year after KT, but not after 1 year of dialysis. CONCLUSIONS: Kidney failure patients displayed an increased biological age as estimated by DNAm clocks compared to population-based controls. Our results suggest that KT, but not dialysis, partially reduces the age acceleration.

Inter-individual variation in mitochondrial phosphorylation efficiency predicts growth rates in ectotherms at high temperatures.

There is increasing evidence that aquatic ectotherms are especially vulnerable to global warming since their metabolic demands increase with ambient temperature while water-oxygen content decreases. The possible role of shrinking aerobic scope in limiting performance has been much discussed; however, less attention has been given to whether tissue-level changes in the efficiency of oxygen usage occur at elevated temperatures. Here, we show that this varies widely among individuals, with consequences for performance. We examined the inter-individual variation in growth rate and mitochondrial function from white muscle and liver of brown trout (Salmo trutta) acclimated to either high (19.5°C) or near-optimal temperature (12°C). Liver (but not muscle) mitochondria showed a positive relationship between growth rate and maximal oxidative phosphorylation at both temperatures, and a negative relationship between growth rate and ROS release. There was a positive correlation in both tissues between individual mitochondrial phosphorylation efficiency and growth rate, but only at 19.5°C. In this representative of aquatic ectotherms, an individual's liver mitochondrial efficiency thus seems to dictate its capacity to grow at elevated temperatures. This suggests that individual heterogeneity in cellular function may cause variation in the thermal limits of aquatic ectotherms and could adversely affect wild populations in warming environments.

The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing.

Improvements in hygiene and health management have driven significant increases in human lifespan over the last 50 years. Frustratingly however, this extension of lifespan has not been matched by equivalent improvements in late-life health, not least due to the global pandemic in type-2 diabetes, obesity and cardiovascular disease, all ageing-associated conditions exacerbated and accelerated by widespread adoption of the high calorie Western diet (HCD). Recently, evidence has begun to emerge that parasitic worm infection might protect against such ageing-associated co-morbidities, as a serendipitous side-effect of their evolution of pro-survival, anti-inflammatory mechanisms. As a novel therapeutic strategy, we have therefore investigated the potential of ES-62, an anti-inflammatory secreted product of the filarial nematode Acanthocheilonema viteae, to improve healthspan (the period of life before diseases of ageing appear) by targeting the chronic inflammation that drives metabolic dysregulation underpinning ageing-induced ill-health. We administered ES-62 subcutaneously (at a dose of 1 µg/week) to C57BL/6J mice undergoing HCD-accelerated ageing throughout their lifespan, while subjecting the animals to analysis of 120 immunometabolic responses at various time-points. ES-62 improved a number of inflammatory parameters, but markedly, a range of pathophysiological, metabolic and microbiome parameters of ageing were also successfully targeted. Notably, ES-62-mediated promotion of healthspan in male and female HCD-mice was associated with different mechanisms and reflecting this, machine learning modelling identified sex-specific signatures predictive of ES-62 action against HCD-accelerated ageing. Remarkably, ES-62 substantially increased the median survival of male HCD-mice. This was not the case with female animals and unexpectedly, this difference between the two sexes could not be explained in terms of suppression of the chronic inflammation driving ageing, as ES-62 tended to be more effective in reducing this in female mice. Rather, the difference appeared to be associated with ES-62's additional ability to preferentially promote a healthier gut-metabolic tissue axis in male animals.

Hydrogen sulfide in ageing, longevity and disease.

Hydrogen sulfide (H2S) modulates many biological processes, including ageing. Initially considered a hazardous toxic gas, it is now recognised that H2S is produced endogenously across taxa and is a key mediator of processes that promote longevity and improve late-life health. In this review, we consider the key developments in our understanding of this gaseous signalling molecule in the context of health and disease, discuss potential mechanisms through which H2S can influence processes central to ageing and highlight the emergence of novel H2S-based therapeutics. We also consider the major challenges that may potentially hinder the development of such therapies.

Growth acceleration results in faster telomere shortening later in life.

There is a wealth of evidence for a lifespan penalty when environmental conditions influence an individual's growth trajectory, such that growth rate is accelerated to attain a target size within a limited time period. Given this empirically demonstrated relationship between accelerated growth and lifespan, and the links between lifespan and telomere dynamics, increased telomere loss could underpin this growth-lifespan trade. We experimentally modified the growth trajectory of nestling zebra finches (Taeniopygia guttata), inducing a group of nestlings to accelerate their growth between 7 and 15 days of age, the main phase of body growth. We then sequentially measured their telomere length in red blood cells at various time points from 7 days to full adulthood (120 days). Accelerated growth between 7 and 15 days was not associated with a detectable increase in telomere shortening during this period compared with controls. However, only in the treatment group induced to show growth acceleration was the rate of growth during the experimental period positively related to the amount of telomere shortening between 15 and 120 days. Our findings provide evidence of a long-term influence of growth rate on later-life telomere shortening, but only when individuals have accelerated growth in response to environmental circumstances.

Measurement of mitochondrial respiration in permeabilized fish gills.

Physiological investigations of fish gills have traditionally centred on the two principal functions of the gills: gas exchange and ion regulation. Mitochondrion-rich cells (MRCs) are primarily found within the gill filaments of fish, and are thought to proliferate in order to increase the ionoregulatory capacity of the gill in response to environmentally induced osmotic challenges. However, surprisingly little attention has been paid to the metabolic function of mitochondria within fish gills. Here, we describe and validate a simple protocol for the permeabilization of fish gills and subsequent measurement of mitochondrial respiration rates in vitro Our protocol requires only small tissue samples (8 mg), exploits the natural structure of fish gills, does not require mechanical separation of the gill tissue (so is relatively quick to perform), and yields accurate and highly reproducible measurements of respiration rates. It offers great potential for the study of mitochondrial function in gills over a wide range of fish sizes and species.

Photoperiodic regulation in a wild-derived mouse strain.

MSM/Ms (MSM) is a mouse strain derived from Japanese wild mice, Mus musculus molossinus, that maintains the ability to synthesize melatonin in patterns reflecting the ambient photoperiod. The objective of this study was to characterize the effects of photoperiodic variation on metabolic and reproductive traits, and the related changes in pituitary-hypothalamic gene expression in MSM mice. MSM mice were kept in long (LP) or short photoperiod (SP) for 6 weeks. Our results demonstrate that MSM mice kept in LP, as compared with mice kept in SP, display higher expression of genes encoding thyrotropin (TSH) in the pars tuberalis, thyroid hormone deiodinase 2 (dio2) in the tanycytes and RFamide-related peptide (RFRP3) in the hypothalamus, and lower expression of dio3 in the tanycytes, along with larger body and reproductive organ mass. Additionally, to assess the effects of the gestational photoperiodic environment on the expression of these genes, we kept MSM mice in LP or SP from gestation and studied their offspring. We show that the gestational photoperiod affects the TSH/dio pathway in newborn MSM mice in a similar way to adults. This result indicates a transgenerational effect of photoperiod from the mother to the fetus in utero Overall, these results indicate that photoperiod can influence neuroendocrine regulation in a melatonin-proficient mouse strain, in a manner similar to that documented in other seasonal rodent species. MSM mice may therefore become a useful model for research into the molecular basis of photoperiodic regulation of seasonal biology.

Differences in mitochondrial efficiency explain individual variation in growth performance.

The physiological causes of intraspecific differences in fitness components such as growth rate are currently a source of debate. It has been suggested that differences in energy metabolism may drive variation in growth, but it remains unclear whether covariation between growth rates and energy metabolism is: (i) a result of certain individuals acquiring and consequently allocating more resources to growth, and/or is (ii) determined by variation in the efficiency with which those resources are transformed into growth. Studies of individually housed animals under standardized nutritional conditions can help shed light on this debate. Here we quantify individual variation in metabolic efficiency in terms of the amount of adenosine triphosphate (ATP) generated per molecule of oxygen consumed by liver and muscle mitochondria and examine its effects, both on the rate of protein synthesis within these tissues and on the rate of whole-body growth of individually fed juvenile brown trout (Salmo trutta) receiving either a high or low food ration. As expected, fish on the high ration on average gained more in body mass and protein content than those maintained on the low ration. Yet, growth performance varied more than 10-fold among individuals on the same ration, resulting in some fish on low rations growing faster than others on the high ration. This variation in growth for a given ration was related to individual differences in mitochondrial properties: a high whole-body growth performance was associated with high mitochondrial efficiency of ATP production in the liver. Our results show for the first time, to our knowledge, that among-individual variation in the efficiency with which substrates are converted into ATP can help explain marked variation in growth performance, independent of food intake. This study highlights the existence of inter-individual differences in mitochondrial efficiency and its potential importance in explaining intraspecific variation in whole-animal performance.

Allostatic load and ageing: linking the microbiome and nutrition with age-related health.

Ageing is a process of decline in physiological function and capability over time. It is an anticipated major burden on societal health-care costs due to an increasingly aged global population. Accelerated biological ageing is a feature of age-related morbidities, which also appear to share common underpinning features, including low-grade persistent inflammation, phosphate toxicity, diminished Nrf2 activity, a depleted metabolic capability, depressed mitochondrial biogenesis and a low diversity gut microbiome.Social, psychological, lifestyle and nutritional risk factors can all influence the trajectory of age-related health, as part of an individual's exposome, which reflects the interplay between the genome and the environment. This is manifest as allostatic (over)load reflecting the burden of lifestyle/disease at both a physiological and molecular level. In particular, age-related genomic methylation levels and inflammatory status reflect exposome differences. These features may be mediated by changes in microbial diversity. This can drive the generation of pro-inflammatory factors, such as TMAO, implicated in the 'diseasome' of ageing. Additionally, it can be influenced by the 'foodome', via nutritional differences affecting the availability of methyl donors required for maintenance of the epigenome and by the provision of nutritionally derived Nrf2 agonists. Both these factors influence age-related physiological resilience and health. This offers novel insights into possible interventions to improve health span, including a rage of emerging senotherapies and simple modifications of the nutritional and environmental exposome. In essence, the emerging strategy is to treat ageing processes common to the diseasome of ageing itself and thus preempt the development or progression of a range of age-related morbidities.

Proteostasis and ageing: insights from long-lived mutant mice.

The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age-related disease, and thus improving late-life health and vitality. While several mechanisms have been proposed as conserved lifespan determinants, the loss of proteostasis - where proteostasis is defined here as the maintenance of the proteome - appears highly relevant to both ageing and disease. Several studies have shown that multiple proteostatic mechanisms, including the endoplasmic reticulum (ER)-induced unfolded protein response (UPR), the ubiquitin-proteasome system (UPS) and autophagy, appear indispensable for longevity in many long-lived invertebrate mutants. Similarly, interspecific comparisons suggest that proteostasis may be an important lifespan determinant in vertebrates. Over the last 20 years a number of long-lived mouse mutants have been described, many of which carry single-gene mutations within the growth-hormone, insulin/IGF-1 or mTOR signalling pathways. However, we still do not know how these mutations act mechanistically to increase lifespan and healthspan, and accordingly whether mechanistic commonality occurs between different mutants. Recent evidence supports the premise that the successful maintenance of the proteome during ageing may be linked to the increased lifespan and healthspan of long-lived mouse mutants.

Marker-dependent associations among oxidative stress, growth and survival during early life in a wild mammal.

Oxidative stress (OS) is hypothesized to be a key physiological mechanism mediating life-history trade-offs, but evidence from wild populations experiencing natural environmental variation is limited. We tested the hypotheses that increased early life growth rate increases OS, and that increased OS reduces first-winter survival, in wild Soay sheep (Ovis aries) lambs. We measured growth rate and first-winter survival for four consecutive cohorts, and measured two markers of oxidative damage (malondialdehyde (MDA), protein carbonyls (PC)) and two markers of antioxidant (AOX) protection (total AOX capacity (TAC), superoxide dismutase (SOD)) from blood samples. Faster lamb growth was weakly associated with increased MDA, but not associated with variation in the other three markers. Lambs with higher SOD activity were more likely to survive their first winter, as were male but not female lambs with lower PC concentrations. Survival did not vary with MDA or total TAC. Key predictions relating OS to growth and survival were therefore supported in some OS markers, but not others. This suggests that different markers capture different aspects of the complex relationships between individual oxidative state, physiology and fitness, and that overarching hypotheses relating OS to life-history variation cannot be supported or refuted by studying individual markers.

Inadequate food intake at high temperatures is related to depressed mitochondrial respiratory capacity.

Animals, especially ectotherms, are highly sensitive to the temperature of their surrounding environment. Extremely high temperature, for example, induces a decline of average performance of conspecifics within a population, but individual heterogeneity in the ability to cope with elevating temperatures has rarely been studied. Here, we examined inter-individual variation in feeding ability and consequent growth rate of juvenile brown trout Salmo trutta acclimated to a high temperature (19°C), and investigated the relationship between these metrics of whole-animal performances and among-individual variation in mitochondrial respiration capacity. Food was provided ad libitum, yet intake varied ten-fold amongst individuals, resulting in some fish losing weight whilst others continued to grow. Almost half of the variation in food intake was related to variability in mitochondrial capacity: low intake (and hence growth failure) was associated with high leak respiration rates within liver and muscle mitochondria, and a lower coupling of muscle mitochondria. These observations, combined with the inability of fish with low food consumption to increase their intake despite ad libitum food levels, suggest a possible insufficient capacity of the mitochondria for maintaining ATP homeostasis. Individual variation in thermal performance is likely to confer variation in the upper limit of an organism's thermal niche and might affect the structure of wild populations in warming environments.

Variation in the link between oxygen consumption and ATP production, and its relevance for animal performance.

It is often assumed that an animal's metabolic rate can be estimated through measuring the whole-organism oxygen consumption rate. However, oxygen consumption alone is unlikely to be a sufficient marker of energy metabolism in many situations. This is due to the inherent variability in the link between oxidation and phosphorylation; that is, the amount of adenosine triphosphate (ATP) generated per molecule of oxygen consumed by mitochondria (P/O ratio). In this article, we describe how the P/O ratio can vary within and among individuals, and in response to a number of environmental parameters, including diet and temperature. As the P/O ratio affects the efficiency of cellular energy production, its variability may have significant consequences for animal performance, such as growth rate and reproductive output. We explore the adaptive significance of such variability and hypothesize that while a reduction in the P/O ratio is energetically costly, it may be associated with advantages in terms of somatic maintenance through reduced production of reactive oxygen species. Finally, we discuss how considering variation in mitochondrial efficiency, together with whole-organism oxygen consumption, can permit a better understanding of the relationship between energy metabolism and life history for studies in evolutionary ecology.

Individuals with higher metabolic rates have lower levels of reactive oxygen species in vivo.

There is increasing interest in the effect of energy metabolism on oxidative stress, but much ambiguity over the relationship between the rate of oxygen consumption and the generation of reactive oxygen species (ROS). Production of ROS (such as hydrogen peroxide, H2O2) in the mitochondria is primarily inferred indirectly from measurements in vitro, which may not reflect actual ROS production in living animals. Here, we measured in vivo H2O2 content using the recently developed MitoB probe that becomes concentrated in the mitochondria of living organisms, where it is converted by H2O2 into an alternative form termed MitoP; the ratio of MitoP/MitoB indicates the level of mitochondrial H2O2 in vivo. Using the brown trout Salmo trutta, we tested whether this measurement of in vivo H2O2 content over a 24 h-period was related to interindividual variation in standard metabolic rate (SMR). We showed that the H2O2 content varied up to 26-fold among fish of the same age and under identical environmental conditions and nutritional states. Interindividual variation in H2O2 content was unrelated to mitochondrial density but was significantly associated with SMR: fish with a higher mass-independent SMR had a lower level of H2O2. The mechanism underlying this observed relationship between SMR and in vivo H2O2 content requires further investigation, but may implicate mitochondrial uncoupling which can simultaneously increase SMR but reduce ROS production. To our knowledge, this is the first study in living organisms to show that individuals with higher oxygen consumption rates can actually have lower levels of H2O2.

Polr3b heterozygosity in mice induces both beneficial and deleterious effects on health during ageing with no effect on lifespan.

The genetic pathways that modulate ageing in multicellular organisms are typically highly conserved across wide evolutionary distances. Recently RNA polymerase III (Pol III) was shown to promote ageing in yeast, C. elegans and D. melanogaster. In this study we investigated the role of Pol III in mammalian ageing using C57BL/6N mice heterozygous for Pol III (Polr3b+/-). We identified sexually dimorphic, organ-specific beneficial as well as detrimental effects of the Polr3b+/- mutation on health. Female Polr3b+/- mice displayed improved bone health during ageing, but their ability to maintain an effective gut barrier function was compromised and they were susceptible to idiopathic dermatitis (ID). In contrast, male Polr3b+/- mice were lighter than wild-type (WT) males and had a significantly improved gut barrier function in old age. Several metabolic parameters were affected by both age and sex, but no genotype differences were detected. Neither male nor female Polr3b+/- mice were long-lived compared to WT controls. Overall, we find no evidence that a reduced Pol III activity extends mouse lifespan but we do find some potential organ- and sex-specific benefits for old-age health.

Timing of TORC1 inhibition dictates Pol III involvement in Caenorhabditis elegans longevity.

Organismal growth and lifespan are inextricably linked. Target of Rapamycin (TOR) signalling regulates protein production for growth and development, but if reduced, extends lifespan across species. Reduction in the enzyme RNA polymerase III, which transcribes tRNAs and 5S rRNA, also extends longevity. Here, we identify a temporal genetic relationship between TOR and Pol III in Caenorhabditis elegans, showing that they collaborate to regulate progeny production and lifespan. Interestingly, the lifespan interaction between Pol III and TOR is only revealed when TOR signaling is reduced, specifically in adulthood, demonstrating the importance of timing to control TOR regulated developmental versus adult programs. In addition, we show that Pol III acts in C. elegans muscle to promote both longevity and healthspan and that reducing Pol III even in late adulthood is sufficient to extend lifespan. This demonstrates the importance of Pol III for lifespan and age-related health in adult C. elegans.