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Since its discovery in 1958 in the lens of cows, ophthalmic acid (OPH) has stood in the shadow of its anti‐oxidant analog: glutathione (GSH). Lacking the thiol group that gives GSH many of its important properties, ophthalmic acid's function has remained elusive, and it has been widely presumed to be an accidental product of the same enzymes. In this review, we compile evidence demonstrating that OPH is a ubiquitous metabolite found in bacteria, plants, fungi, and animals, produced through several layers of metabolic regulation. We discuss the limitations of the oft‐repeated suggestions that aberrations in OPH levels should solely indicate GSH deficiency or oxidative stress. Finally, we discuss the available literature and suggest OPH's role in metabolism as a GSH‐regulating tripeptide; controlling both cellular and organelle influx and efflux of GSH, as well as modulating GSH‐dependent reactions and signaling. Ultimately, we hope that this review reinvigorates and directs more research into this versatile metabolite. [ABSTRACT FROM AUTHOR]

The degenerative processes that occur during aging increase the risk of disease and impaired health. Meanwhile, interventions that target aging to promote healthy longevity are gaining interest, both academically and in the public. While nutritional and physical interventions exist, efficacy is often difficult to determine. It is therefore imperative that an aging score measuring the biological aging process is available to the wider public. However, simple, interpret, and accessible biological aging scores are lacking. Here, we developed PhysiAge, a physiological aging score based on five accessible parameters that have influence on or reflect the aging process: (1) average daily step count, (2) blood glucose, (3) systolic blood pressure, (4) sex, and (5) age. Here, we found that compared to calendar age alone, PhysiAge better predicts mortality, as well as established muscle aging markers such as decrease in NAD+ levels, increase in oxidative stress, and decline in physical functioning. In order to demonstrate the usefulness of PhysiAge in identifying relevant factors associated with decelerated aging, we calculated PhysiAges for a cohort of aged individuals and obtained mass spectrometry-based blood plasma metabolomic profiles for each individual. Here, we identified a metabolic signature of decelerated aging, which included components of the TCA cycle, including malate, citrate, and isocitrate. Higher abundance of these metabolites was associated with decelerated aging, in line with supplementation studies in model organisms. PhysiAge represents an accessible way for people to track and intervene in their aging trajectories, and identifies a metabolic signature of decelerated aging in human blood plasma, which can be further studied for its causal involvement in human aging. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Are human ovarian aging and the age-related female fertility decline caused by oxidative stress and mitochondrial dysfunction in oocytes? SUMMARY ANSWER We found oxidative damage in oocytes of advanced maternal age, even at the primordial follicle stage, and confirmed mitochondrial dysfunction in such oocytes, which likely resulted in the use of alternative energy sources. WHAT IS KNOWN ALREADY Signs of reactive oxygen species-induced damage and mitochondrial dysfunction have been observed in maturing follicles, and even in early stages of embryogenesis. However, although recent evidence indicates that also primordial follicles have metabolically active mitochondria, it is still often assumed that these follicles avoid oxidative phosphorylation to prevent oxidative damage in dictyate arrested oocytes. Data on the influence of ovarian aging on oocyte metabolism and mitochondrial function are still limited. STUDY DESIGN, SIZE, DURATION A set of 39 formalin-fixed and paraffin-embedded ovarian tissue biopsies were divided into different age groups and used for immunofluorescence analysis of oxidative phosphorylation activity and oxidative damage to proteins, lipids, and DNA. Additionally, 150 immature oocytes (90 germinal vesicle oocytes and 60 metaphase I oocytes) and 15 cumulus cell samples were divided into different age groups and used for targeted metabolomics and lipidomics analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian tissues used for immunofluorescence microscopy were collected through PALGA, the nationwide network, and registry of histo- and cytopathology in The Netherlands. Comprehensive metabolomics and lipidomics were performed by liquid–liquid extraction and full-scan mass spectrometry, using oocytes and cumulus cells of women undergoing ICSI treatment based on male or tubal factor infertility, or fertility preservation for non-medical reasons. MAIN RESULTS AND THE ROLE OF CHANCE Immunofluorescence imaging on human ovarian tissue indicated oxidative damage by protein and lipid (per)oxidation already at the primordial follicle stage. Metabolomics and lipidomics analysis of oocytes and cumulus cells in advanced maternal-age groups demonstrated a shift in the glutathione-to-oxiglutathione ratio and depletion of phospholipids. Age-related changes in polar metabolites suggested a decrease in mitochondrial function, as demonstrated by NAD+, purine, and pyrimidine depletion, while glycolysis substrates and glutamine accumulated, with age. Oocytes from women of advanced maternal age appeared to use alternative energy sources like glycolysis and the adenosine salvage pathway, and possibly ATP which showed increased production in cumulus cells. LIMITATIONS, REASONS FOR CAUTION The immature oocytes used in this study were all subjected to ovarian stimulation with high doses of follicle-stimulating hormones, which might have concealed some age-related differences. WIDER IMPLICATIONS OF THE FINDINGS Further studies on how to improve mitochondrial function, or lower oxidative damage, in oocytes from women of advanced maternal age, for instance by supplementation of NAD+ precursors to promote mitochondrial biogenesis, are warranted. In addition, supplementing the embryo medium of advanced maternal-age embryos with such compounds could be a treatment option worth exploring. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Amsterdam UMC. The authors declare to have no competing interests. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Remote monitoring technologies (RMTs) allow continuous, unobtrusive, and real-time monitoring of the cardiovascular system. An overview of existing RMTs measuring cardiovascular physiological variables is lacking. This systematic review aimed to describe RMTs measuring cardiovascular functions in community-dwelling adults. An electronic search was conducted via PubMed, EMBASE, and Cochrane Library from January 1, 2020, to April 7, 2022. Articles reporting on non-invasive RMTs used unsupervised in community-dwelling adults were included. Reviews and studies in institutionalized populations were excluded. Two reviewers independently assessed the studies and extracted the technologies used, cardiovascular variables measured, and wearing locations of RMTs. Validation of the RMTs was examined based on the COSMIN tool, and accuracy and precision were presented. This systematic review was registered with PROSPERO (CRD42022320082). A total of 272 articles were included representing 322,886 individuals with a mean or median age from 19.0 to 88.9 years (48.7% female). Of all 335 reported RMTs containing 216 distinct devices, photoplethysmography was used in 50.3% of RMTs. Heart rate was measured in 47.0% of measurements, and the RMT was worn on the wrist in 41.8% of devices. Nine devices were reported in more than three articles, of which all were sufficiently accurate, six were sufficiently precise, and four were commercially available in December 2022. The top four most reported technologies were AliveCor KardiaMobile®, Fitbit Charge 2, and Polar H7 and H10 Heart Rate Sensors. With over 200 distinct RMTs reported, this review provides healthcare professionals and researchers an overview of available RMTs for monitoring the cardiovascular system. [ABSTRACT FROM AUTHOR]

Maintaining mitochondrial function is critical to an improved healthspan and lifespan. Introducing mild stress by inhibiting mitochondrial translation invokes the mitochondrial unfolded protein response (UPRmt) and increases lifespan in several animal models. Notably, lower mitochondrial ribosomal protein (MRP) expression also correlates with increased lifespan in a reference population of mice. In this study, we tested whether partially reducing the gene expression of a critical MRP, Mrpl54, reduced mitochondrial DNA-encoded protein content, induced the UPRmt, and affected lifespan or metabolic health using germline heterozygous Mrpl54 mice. Despite reduced Mrpl54 expression in multiple organs and a reduction in mitochondrial-encoded protein expression in myoblasts, we identified few significant differences between male or female Mrpl54+/− and wild type mice in initial body composition, respiratory parameters, energy intake and expenditure, or ambulatory motion. We also observed no differences in glucose or insulin tolerance, treadmill endurance, cold tolerance, heart rate, or blood pressure. There were no differences in median life expectancy or maximum lifespan. Overall, we demonstrate that genetic manipulation of Mrpl54 expression reduces mitochondrial-encoded protein content but is not sufficient to improve healthspan in otherwise healthy and unstressed mice. [ABSTRACT FROM AUTHOR]

Deregulated energy homeostasis represents a hallmark of aging and results from complex gene-by-environment interactions. Here, we discovered that reducing the expression of the gene ech-6 encoding enoyl-CoA hydratase remitted fat diet-induced deleterious effects on lifespan in Caenorhabditis elegans, while a basal expression of ech-6 was important for survival under normal dietary conditions. Lipidomics revealed that supplementation of fat in ech-6-silenced worms had marginal effects on lipid profiles, suggesting an alternative fat utilization for energy production. Transcriptomics further suggest a causal relation between the lysosomal pathway, energy production, and the longevity effect conferred by the interaction between ech-6 and fat diets. Indeed, enhancing energy production from endogenous fat by overexpressing lysosomal lipase lipl-4 recapitulated the lifespan effects of fat diets on ech-6-silenced worms. Collectively, these results suggest that the gene ech-6 is potential modulator of metabolic flexibility and may be a target for promoting metabolic health and longevity. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: In our current society sedentary behaviour predominates in most people and is associated with the risk of developing type 2 diabetes. It has been suggested that replacing sitting time by standing and walking could be beneficial for individuals with type 2 diabetes but the underlying mechanisms are unknown and direct comparisons with exercise are lacking. Our objective was to directly compare metabolic responses of either sitting less or exercising, relative to being sedentary. Methods: We performed a randomised, crossover intervention study in 12 overweight women who performed three well-controlled 4 day activity regimens: (1) sitting regimen (sitting 14 h/day); (2) exercise regimen (sitting 13 h/day, exercise 1 h/day); and (3) sitting less regimen (sitting 9 h/day, standing 4 h/day and walking 3 h/day). The primary outcome was insulin sensitivity measured by a two-step hyperinsulinaemic–euglycaemic clamp. We additionally performed metabolomics on muscle biopsies taken before the clamp to identify changes at the molecular level. Results: Replacing sitting time by standing and walking over 4 days resulted in improved peripheral insulin sensitivity, comparable with the improvement achieved by moderate-to-vigorous exercise. Specifically, we report a significant improvement in peripheral insulin sensitivity in the sitting less (~13%) and the exercise regimen (~20%), compared with the sitting regimen. Furthermore, sitting less shifted the underlying muscle metabolome towards that seen with moderate-to-vigorous exercise, compared with the sitting regimen. Conclusions/interpretations: Replacing sitting time by standing and walking is an attractive alternative to moderate-to-vigorous exercise for improving metabolic health. Trial registration: ClinicalTrials.gov NCT03912922. [ABSTRACT FROM AUTHOR]

Transcriptome‐based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age‐related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf‐16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA‐approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in Caenorhabditis elegans. This longevity is dependent on both daf‐16 signaling and inhibition of the neuromuscular acetylcholine receptor subunit unc‐38. We found unc‐38 RNAi to improve healthspan, lifespan, and stimulate DAF‐16 nuclear localization, similar to atracurium treatment. Finally, using RNA‐seq transcriptomics, we identify atracurium activation of DAF‐16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF‐16 longevity pathway. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Are genes known to be involved in somatic cell ageing, particularly related to longevity pathways, associated with the accelerated ageing process of the ovary? SUMMARY ANSWER Growth, metabolism, and cell-cycle progression-related pathways that are involved in somatic cell ageing are also associated with ovarian ageing. WHAT IS KNOWN ALREADY Ovarian ageing is characterized by a gradual decline in ovarian follicle quantity, a decline in oocyte quality, and lower chances of pregnancy. Genetic pathways modulating the rate of somatic cell ageing have been researched intensively. Ovarian ageing does not follow the same timeline as somatic cell ageing, as signs of ovarian ageing occur at a younger female age, while the somatic cells are still relatively young. It is not known whether the generally recognized somatic cell longevity genes also play a role during ovarian ageing. Looking at somatic cell longevity genes can lead to new hypotheses and possible treatment options for subfertility caused by ovarian ageing. STUDY DESIGN, SIZE, DURATION In this observational study, we analysed a dataset of individual gene expression profiles of 38 germinal vesicle (GV) oocytes from 38 women aged between 25 and 43 years. We correlated female age (calendar age in years) and biological age (factors known to be associated with ovarian ageing such as dosage of FSH needed for ovarian hyperstimulation, and antral follicle count (AFC)) with gene expression signatures of longevity pathways. PARTICIPANTS/MATERIALS, SETTING, METHODS Transcripts of 38 GV oocytes were used for individual gene expression analysis. R version 3.5.1 was used to process and analyse data. The GeneAge database (build 19) was used to obtain mouse ageing-related genes. Human to mouse orthologues were obtained using the R package biomaRt. Correlations and significance between gene expression data and age were tested for using Pearson's product moment correlation coefficient using ranked expression data. Distributions were compared with an ANOVA, and the Tukey Honest Significant Difference method was used to control for the Type I error rate across multiple comparisons. MAIN RESULTS AND THE ROLE OF CHANCE Of the 136 genes in the GeneAge database, the expression of 15 anti-longevity genes identified in oocytes showed a positive correlation with female calendar age and FSH dosage administered during ICSI treatment, and a negative correlation with AFC. Expression of 32 pro-longevity genes was negatively correlated with calendar age and FSH dosage, and positively correlated with AFC. In general, anti- and pro-longevity genes changed in opposing directions with advancing maternal age in oocytes. Notably, the anti-longevity genes include many 'growth'-related genes involved in the mechanistic target of rapamycin (mTOR) Complex 1 pathway, such as EIF5A2, EIF3H, EIF4E, and mTOR. The pro-longevity genes include many cell-cycle progression-related genes involved in DNA damage repair (e.g. XRCC6, ERCC2, and MSH2) or cell-cycle checkpoint regulation genes (e.g. ATM, BRCA1, TP53, TP63, TP73, and BUB1B). LIMITATIONS, REASONS FOR CAUTION Using mature oocytes instead of GV-stage oocytes discarded from ICSI treatments may provide different results. No correction for multiple testing was carried out on individual genes because a small set of longevity-related genes was selected a priori for the analysis. The global trend was corrected for multiple testing and remained significant. This work was an observational study and, as no additional experimental work was performed, the associations described do not directly demonstrate the involvement of such genes in oocyte ageing. WIDER IMPLICATIONS OF THE FINDINGS Growth, metabolism, and cell-cycle progression-related pathways that are known to be involved in somatic cell ageing were associated with ovarian ageing. If experimental data are obtained to support these associations, we suggest that interventions known to modulate these processes could benefit women suffering from ovarian ageing. STUDY FUNDING/COMPETING INTEREST(S) G.E.J. is supported by a VENI grant from ZonMw (https://www.zonmw.nl). Work in the Houtkooper group is financially supported by an ERC Starting grant (No. 638290), a VIDI grant from ZonMw (No. 91715305), and the Velux Stiftung (No. 1063). M.G. declares several research and educational grants from Guerbet, Merck and Ferring (all location VUmc), outside the scope of the submitted work. The other authors report no competing interest TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Lipid metabolism is under the control of the circadian system and circadian dysregulation has been linked to obesity and dyslipidemia. These factors and outcomes have also been associated to, or affected by, the process of aging. Here, we investigated whether murine white (WAT) and brown (BAT) adipose tissue lipids exhibit rhythmicity and if this is affected by aging. To this end, we have measured the 24 h lipid profiles of WAT and BAT using a global lipidomics analysis of > 1100 lipids. We observed rhythmicity in nearly all lipid classes including glycerolipids, glycerophospholipids, sterol lipids and sphingolipids. Overall, ~ 22% of the analyzed lipids were considered rhythmic in WAT and BAT. Despite a general accumulation of lipids upon aging the fraction of oscillating lipids decreased in both tissues to 14% and 18%, respectively. Diurnal profiles of lipids in BAT appeared to depend on the lipid acyl chain length and this specific regulation was lost in aged mice. Our study revealed how aging affects the rhythmicity of lipid metabolism and could contribute to the quest for targets that improve diurnal lipid homeostasis to maintain cardiometabolic health during aging. [ABSTRACT FROM AUTHOR]

It is hypothesized that treating the general aging population with compounds that slow aging, geroprotectors, could provide many benefits to society, including a reduction of age-related diseases. It is intuitive that such compounds should cause minimal side effects, since they would be distributed to otherwise healthy individuals for extended periods of time. The question therefore emerges of how we should prioritize geroprotectors discovered in model organisms for clinical testing in humans. In other words, which compounds are least likely to cause harm, while still potentially providing benefit? To systematically answer this question we queried the DrugAge database—containing hundreds of known geroprotectors—and cross-referenced this with a recently published repository of compound side effect predictions. In total, 124 geroprotectors were associated to 800 unique side effects. Geroprotectors with high risks of side effects, some even with risk for death, included lamotrigine and minocycline, while compounds with low side effect risks included spermidine and d-glucosamine. Despite their popularity as top geroprotector candidates for humans, sirolimus and metformin harbored greater risks of side effects than many other candidate geroprotectors, sirolimus being the more severe of the two. Furthermore, we found that a correlation existed between maximum lifespan extension in worms and the likelihood of causing a side effect, suggesting that extreme lifespan extension in model organisms should not necessarily be the priority when screening for novel geroprotectors. We discuss the implications of our findings for prioritizing geroprotectors, suggesting spermidine and d-glucosamine for clinical trials in humans. [ABSTRACT FROM AUTHOR]

Lifespan in eukaryotic species can be prolonged by shifting fromcellular states favouring growth to those favouring maintenance and stress resistance. For instance, perturbations in mitochondrial oxidative phosphorylation (OXPHOS) can shift cells into this latter state and extend lifespan. Because mitochondria rely on proteins synthesized from nuclear as well as mitochondrial DNA, they need to constantly send and receive messages from other compartments of the cell in order to function properly andmaintain homeostasis, and lifespan extension is often dependent on this cross-compartmental signalling. Here, we describe the mechanisms of bi-directional mitochondrial cross-compartmental signalling resulting in proteostasis and longevity. These proteostasis mechanisms are highly context-dependent, governed by the origin and extent of stress. Furthermore, we discuss the translatability of these mechanisms and explore therapeutic developments, such as the antibiotic studies targeting mitochondria or mitochondria-derived peptides as therapies for age-related diseases such as neurodegeneration and cancer. [ABSTRACT FROM AUTHOR]

The deregulation of metabolism is a hallmark of aging. As such, changes in the expression of metabolic genes and the profiles of amino acid levels are features associated with aging animals. We previously reported that the levels of most amino acids decline with age in Caenorhabditis elegans (C. elegans). Glycine, in contrast, substantially accumulates in aging C. elegans. In this study we show that this is coupled to a decrease in gene expression of enzymes important for glycine catabolism. We further show that supplementation of glycine significantly prolongs C. elegans lifespan, and early adulthood is important for its salutary effects. Moreover, supplementation of glycine ameliorates specific transcriptional changes that are associated with aging. Glycine feeds into the methionine cycle. We find that mutations in components of this cycle, methionine synthase (metr-1) and S-adenosylmethionine synthetase (sams-1), completely abrogate glycine-induced lifespan extension. Strikingly, the beneficial effects of glycine supplementation are conserved when we supplement with serine, which also feeds into the methionine cycle. RNA-sequencing reveals a similar transcriptional landscape in serine- and glycine-supplemented worms both demarked by widespread gene repression. Taken together, these data uncover a novel role of glycine in the deceleration of aging through its function in the methionine cycle. [ABSTRACT FROM AUTHOR]

Background: Over 80% of women with X-linked adrenoleukodystrophy (ALD) develop spinal cord disease in adulthood for which treatment is supportive only. For future clinical trials quantitative data on disease progression rates are essential. Moreover, diagnosis can be challenging in ALD women, as the most important diagnostic biomarker is normal in 15-20%. Better biomarkers are needed. The purpose of this single centre cross-sectional follow-up study in women with ALD was to assess whether Expanded Disability Status Scale (EDSS), AMC Linear Disability Scale (ALDS) and Short Form (36) Health Survey (SF-36) can detect disease progression and to model the effect of age and duration of symptoms on the rate of progression. Moreover, we performed a pilot study to assess if a semi-targeted lipidomics approach can identify possible new diagnostic biomarkers.Results: In this study 46 women (baseline clinical data published by our group previously) were invited for a follow-up visit. Newly identified women at our center were also recruited. We analysed 65 baseline and 34 follow-up assessments. Median time between baseline and follow-up was 7.8 years (range 6.4-8.7). Mean age at baseline was 49.2 ± 14.2 years, at follow-up 55.4 ± 10.1. EDSS increased significantly (+ 0.08 points/year), but the other outcome measures did not. Increasing age and duration of symptoms were associated with more disability. For the pilot study we analysed plasma of 20 ALD women and 10 controls with ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry, which identified 100 potential biomarker ratios with strong differentiating properties and non-overlapping data distributions between ALD women and controls.Conclusions: Progression of spinal cord disease can be detected with EDSS, but not with ALDS or SF-36 after a follow-up period of almost 8 years. Moreover, age and the duration of symptoms seem positively associated with the rate of progression. Although a significant progression was measurable, it was below the rate generally conceived as clinically relevant. Therefore, EDSS, ALDS and SF-36 are not suitable as primary outcome measures in clinical trials for spinal cord disease in ALD women. In addition, a semi-targeted lipidomics approach can identify possible new diagnostic biomarkers for women with ALD. [ABSTRACT FROM AUTHOR]

There is a large variability in lifespans of individuals even if they are genetically identical and raised under the same environmental conditions. Our recent system wide study of replicative aging in baker’s yeast predicts that protein biogenesis is a driver of aging. Here, we address how the natural variation in replicative lifespan within wild-type populations of yeast cells correlates to three biogenesis-related parameters, namely cell size, ribosomal protein Rpl13A-GFP levels, and division times. Imaging wild type yeast cells in microfluidic devices we observe that in all cells and at all ages, the division times as well as the increase in cell size that single yeast undergo while aging negatively correlate to their lifespan. In the longer-lived cells Rpl13A-GFP levels also negatively correlate to lifespan. Interestingly however, at young ages in the population, ribosome concentration was lowest in the cells that increased the most in size and had shorter lifespans. The correlations between these molecular and cellular properties related to biogenesis and lifespan explain a small portion of the variation in lifespans of individual cells, consistent with the highly individual and multifactorial nature of aging. [ABSTRACT FROM AUTHOR]

The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C. elegans , independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo , via reduction of translation and ATF-4. [Display omitted] • The anti-retroviral zidovudine extends healthy longevity in C. elegans • Lifespan extension with NRTIs zidovudine and didanosine depends on ATF-4 • Zidovudine alters pyrimidine metabolism and reduces cytosolic translation • ATF-4 regulates reduced translation upon zidovudine treatment McIntyre et al. report on the longevity-extending effects of the anti-retroviral pharmaceutical zidovudine in the worm C. elegans. Zidovudine reduces translation in treated worm populations, and both this reduced translation and the lifespan extension are dependent on the transcription factor ATF-4. [ABSTRACT FROM AUTHOR]

24 h whole-body substrate metabolism and the circadian clock within skeletal muscle are both compromised upon metabolic disease in humans. Here, we assessed the 24 h muscle metabolome by serial muscle sampling performed under 24 h real-life conditions in young, healthy (YH) men versus older, metabolically compromised (OMC) men. We find that metabolites associated with the initial steps of glycolysis and hexosamine biosynthesis are higher in OMC men around the clock, whereas metabolites associated with glutamine-alpha-ketoglutarate, ketone, and redox metabolism are lower in OMC men. The night period shows the largest number of differently expressed metabolites. Both groups demonstrate 24 h rhythmicity in half of the metabolome, but rhythmic metabolites only partially overlap. Specific metabolites are only rhythmic in YH men (adenosine), phase shifted in OMC men (cis -aconitate, flavin adenine dinucleotide [FAD], and uridine diphosphate [UDP]), or have a reduced 24 h amplitude in OMC men (hydroxybutyrate and hippuric acid). Our data highlight the plasticity of the skeletal muscle metabolome over 24 h and large divergence across the metabolic health spectrum. [Display omitted] • The skeletal muscle metabolome vastly changes over 24 h • Most muscle metabolites are less abundant in older, metabolically compromised men • 24 h rhythms differ between young, healthy men versus older, metabolically compromised men • The largest differences between groups are identified during the night Harmsen et al. examine the skeletal muscle metabolome over 24 h comparing serial tissue samples from young, healthy men versus older, metabolically compromised men. Different abundance levels of most metabolites around the clock, as well as different temporal dynamics, are evident between groups. The night period demonstrates the largest disparity. [ABSTRACT FROM AUTHOR]

To ensure proper transmission of genetic information, cells need to preserve and faithfully replicate their genome, and failure to do so leads to genome instability, a hallmark of both cancer and aging. Defects in genes involved in guarding genome stability cause several human progeroid syndromes, and an age‐dependent accumulation of mutations has been observed in different organisms, from yeast to mammals. However, it is unclear whether the spontaneous mutation rate changes during aging and whether specific pathways are important for genome maintenance in old cells. We developed a high‐throughput replica‐pinning approach to screen for genes important to suppress the accumulation of spontaneous mutations during yeast replicative aging. We found 13 known mutation suppression genes, and 31 genes that had no previous link to spontaneous mutagenesis, and all acted independently of age. Importantly, we identified PEX19, encoding an evolutionarily conserved peroxisome biogenesis factor, as an age‐specific mutation suppression gene. While wild‐type and pex19Δ young cells have similar spontaneous mutation rates, aged cells lacking PEX19 display an elevated mutation rate. This finding suggests that functional peroxisomes may be important to preserve genome integrity specifically in old cells. [ABSTRACT FROM AUTHOR]

Reversing or slowing the aging process brings great promise to treat or prevent age‐related disease, and targeting the hallmarks of aging is a strategy to achieve this. Epigenetics affects several if not all of the hallmarks of aging and has therefore emerged as a central target for intervention. One component of epigenetic regulation involves histone deacetylases (HDAC), which include the "classical" histone deacetylases (of class I, II, and IV) and sirtuin deacetylases (of class III). While targeting sirtuins for healthy aging has been extensively reviewed elsewhere, this review focuses on pharmacologically inhibiting the classical HDACs to promote health and longevity. We describe the theories of how classical HDAC inhibitors may operate to increase lifespan, supported by studies in model organisms. Furthermore, we explore potential mechanisms of how HDAC inhibitors may have such a strong grasp on health and longevity, summarizing their links to other hallmarks of aging. Finally, we show the wide range of age‐related preclinical disease models, ranging from neurodegeneration to heart disease, diabetes to sarcopenia, which show improvement upon HDAC inhibition. [ABSTRACT FROM AUTHOR]

The ability to perceive and respond to harmful conditions is crucial for the survival of any organism. The transcription factor DAF-16/FOXO is central to these responses, relaying distress signals into the expression of stress resistance and longevity promoting genes. However, its sufficiency in fulfilling this complex task has remained unclear. Using C. elegans, we show that DAF-16 does not function alone but as part of a transcriptional regulatory module, together with the transcription factor HLH-30/TFEB. Under harmful conditions, both transcription factors translocate into the nucleus, where they often form a complex, co-occupy target promoters, and co-regulate many target genes. Interestingly though, their synergy is stimulus-dependent: They rely on each other, functioning in the same pathway, to promote longevity or resistance to oxidative stress, but they elicit heat stress responses independently, and they even oppose each other during dauer formation. We propose that this module of DAF-16 and HLH-30 acts by combinatorial gene regulation to relay distress signals into the expression of specific target gene sets, ensuring optimal survival under each given threat. The transcription factor DAF-16/FOXO is a downstream effector of insulin/insulin-like growth factor signaling and plays an important role in stress resistance and longevity. Here, the authors show that DAF-16/FOXO can form a complex with HLH-30/TFEB to synergistically regulate transcription of target genes in response to certain stress stimuli. [ABSTRACT FROM AUTHOR]