Longevity Papers

The transcription factor CCAAT/enhancer binding protein alpha (C/EBP) regulates cell differentiation, proliferation, and function in various tissues, including the liver, adipose tissue, skin, lung, and hematopoietic system. Studies in rats, mice, humans, and chickens have shown that CEBPA mRNA undergoes alternative translation initiation, producing three C/EBP protein isoforms. Two of these isoforms act as full-length transcription factors with N-terminal transactivation domains and a C-terminal dimerization and DNA-binding domains. The third isoform is an N-terminally truncated variant, translated from a downstream AUG codon. It competes with full-length isoforms for DNA binding, thereby antagonizing their activity. Expression of the truncated C/EBP isoform depends on the initial translation of a short upstream open reading frame (uORF) in CEBPA mRNA and subsequent re-initiation at a downstream AUG codon, a process stimulated by mTORC1 signaling. We investigated whether the ortholog of the CEBPA gene in the evolutionarily distant, short-lived African turquoise killifish (Nothobranchius furzeri) is regulated by similar mechanisms. Our findings reveal that the uORF-mediated regulation of C/EBP isoform expression is conserved in killifish. Disruption of the uORF selectively eliminates the truncated isoform, leading to unrestrained activity of the full-length C/EBP isoforms. This genetic modification significantly extended both the median and maximal lifespan and improved the healthspan of male N. furzeri. These results highlight a conserved mechanism of CEBPA gene regulation across species and its potential role in modulating the lifespan and aging phenotypes.

Pulmonary Fibrosis (PF) is a life-threatening illness that is characterized by progressive scarring in the lung interstitium. There is an urgent need for new PF therapies because current treatments only slow down the progression of fibrosis and the median life expectancy post-diagnosis is only 4 to 6 years. Since PF patients frequently exhibit telomere attrition, overexpressing telomerase, the enzyme responsible for synthesizing telomeres represents a compelling therapeutic option. In this study, we in vitro transcribed human telomerase reverse transcriptase (hTERT) mRNA using modified nucleosides (modRNA). ModRNA hTERT treatment led to transient activation of telomerase activity in a dose-dependent manner in MRC-5 cells and, importantly, in primary human alveolar type II pneumocytes (ATII cells). Consequently, the proliferative capacity was increased, concomitant with reduced DNA damage and elongated telomere length. Notably, induction of cellular immune response was only detectable at the highest modRNA concentration, and returned to normal levels within 48 hours. Next, we demonstrated that circularized, exonuclease-resistant modRNA hTERT extended the transient expression profile which may be clinically advantageous. Finally, we provided therapeutic proof of concept in organotypic 3D ex vivo human precision-cut lung slices derived from end-stage PF patients. Intriguingly, a single modRNA hTERT treatment inhibited senescence as indicated by significantly lower levels of senescence-associated {beta}-galactosidase, and pro-inflammatory IL6 and IL8. Concurrently, the key fibrosis mediators TGF{beta} and COL1A1 were markedly reduced. In conclusion, the data presented herein provide initial evidence for the potential of RNA-based hTERT therapy for treating human lung fibrosis.

Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract, and is usually accompanied by dysbiosis in the gut microbiome, a factor that contributes to disease progression. Excessive production of reactive oxygen species (ROS) because of gut microbiome dysbiosis-one of the hallmark features of IBD-promotes chronic inflammation and facilitates the transformation of normal cells into senescent cells. Cellular senescence is associated with the development of various chronic and age-related diseases. We hypothesise that senolytic agents, specifically dasatinib (D) and quercetin (Q), could have a beneficial effect on both the gut microbiome and intestinal cells in IBD. The modulatory effects of a combination of D + Q was assessed in the M-SHIME model with faecal microbiota sourced from Crohn's disease patients. D + Q significantly modulated butyrate and lactate levels in the samples from specific patients. In addition, metabolomic analysis showed that D + Q positively impacted the abundance of anti-inflammatory bacteria while also significantly reducing the several species of pathogenic bacteria. Findings from a Caco-2 cell/THP1 co-culture model of IBD demonstrated that D + Q exerted strong immunomodulatory effects on the gut epithelium, evidenced by reduced NF-kB activity, and lower levels of the pro-inflammatory markers TNF-α, CXCL-10, and MCP-1. Furthermore, D + Q induced the secretion of anti-inflammatory cytokines, including IL-6 and IL-10. However, it should be noted that D + Q also led to the secretion of the pro-inflammatory cytokines IL-8. These findings suggest that D + Q could offer a novel therapeutic approach for advanced IBD management by modulating both the gut microbiome and inflammatory pathways. The results support the potential repurposing of senotherapeutic agents as a strategy for addressing the chronic inflammation central to IBD pathogenesis.

Age-related macular degeneration (AMD) is a complex, multifactorial retinal degenerative disease that is influenced by both genetic and environmental factors. However, the strongest risk factor for AMD is advanced age. Several physiological processes are observed in aging tissues including a low level of chronic inflammation (inflammaging), changed lipid and energy metabolism, and senescence. Nevertheless, whereas everyone ages, only a subset of the population develops AMD. The purpose of this review is to delineate the differences on a cellular and molecular level between natural aging changes and those observed in AMD. We provide a unique perspective on how genetic and environmental components modulate aging in the eye, as well as the specific role of the aging RPE and retina in the pathogenesis of AMD. Topics discussed include the mechanism of aging and its relation to the mechanism of AMD, current animal models that can be used to recapitulate some aspects of the pathology, and potential interventions that shift the balance towards healthy aging and therefore attenuate, prevent or delay the initiation of the disease.

The telomerase RNA-protein enzyme is critical for most eukaryotes to complete genome copying by extending chromosome ends, thus solving the end-replication problem and postponing senescence. Despite the importance of the fission yeast Schizosaccharomyces pombe to biomedical research, very little is known about the structure of its 1212 nt telomerase RNA. We have determined the secondary structure of this large RNA, TER1, based on phylogenetics and bioinformatic modeling, as well as genetic and biochemical analyses. We find that several conserved regions of the rapidly evolving TER1 RNA are important for the ability of telomerase to maintain telomeres, based on testing truncation mutants in vivo, whereas, overall, many other large regions are dispensable. This is similar to budding yeast telomerase RNA, TLC1, and consistent with functioning as a flexible scaffold for the RNP. We tested if the essential three-way junction works from other locations in TER1, finding that indeed it can, supporting that it is flexibly scaffolded. Furthermore, we find that a half-sized Mini-TER1 allele, built from the catalytic core and the three-way junction, reconstitutes catalytic activity with TERT in vitro. Overall, we provide a secondary structure model for the large fission-yeast telomerase lncRNA based on phylogenetics and molecular-genetic testing in cells and insight into the RNP\'s physical and functional organization.

The longitudinal cellular interactions that drive pulmonary fibrosis are not well understood. To investigate the disease underpinnings associated with fibrosis onset and progression, we generated a scRNA-seq atlas of lungs from young and aged mouse models of multiple subtypes of Hermansky-Pudlak syndrome (HPS), a collection of rare autosomal recessive diseases associated with albinism, platelet dysfunction, and pulmonary fibrosis. We have identified an age-dependent increase in SAA3

Treating modifiable risk factors for dementia may serve to prevent maladaptive brain ageing. These include, and are not limited to, obesity, hypertension, and other metabolic disorders. Nearly two-thirds of affected individuals are females, and emerging research has pointed to potential sex-specific factors, like reproductive aging, as potent modifiers of dementia risk. Here, we leverage neuroimaging to characterize sex differences in the neural signatures of modifiable dementia risk factors, examining their relationship with brain anatomy, and integrate female-specific factors related to menopause history in a sex-specific analysis. Using cross-sectional data from the UK Biobank, we selected a cohort of 31,711 (age 44-82, 55.2% female/44.8% male) participants without diagnosed neurological conditions and collated behavioural data previously determined as modifiable risk factors. Using Partial Least Squares Analysis (PLS), we examined latent signatures that represent linear combinations that maximize covariance between patterns of brain (mean cortical thickness from 64 regions) and risk factor variables. To examine sex differences, we performed PLS analysis using the entire sample. We performed linear models to explore age-by-sex interactions with the PLS-derived brain scores and the risk factor pattern scores. To examine sex-specific relationships, we performed separate PLS analyses for the males and females and integrated menopause-related variables into the latter analysis. Our study found sex-dependent and menopause-dependent relationships between lifestyle risk factors and cortical thickness, highlighting stronger impacts of cardiometabolic factors on males and social and obesity-related factors on females in preserving brain health. The inclusion of menopause-related variables did not change the relationships to lifestyle risk factors, and strict age-matching dampened the strength of the findings. Our findings suggest that lifestyles and the female-specific endocrine environment influence sex differences in cortical anatomy during brain aging.

Ageing is a degenerative process characterised by a decline in physiological functioning of the organism. One of the core regulators of cellular ageing are telomeres, repetitive DNA sequences of TTAGGG that cap the ends of chromosomes and are maintained by the ribonucleoprotein complex, telomerase. Age-dependent progressive loss of the telomere ends eventually induces cell cycle arrest for the induction of either replicative senescence or apoptosis. It was previously established that overexpression of the 37 kDa/ 67 kDa laminin receptor (LRP/LR) increased telomerase activity and telomere length while concomitantly reducing senescence markers in aged normal cells in vitro. Therefore, it was hypothesized that elevating LRP/LR in vivo may increase telomerase activity and hinder the ageing process on an organism scale. To this end, aged C57BL/6J mice were treated/transfected to induce an overexpression of LRP::FLAG. Various physiological tests and histological analyses were performed to assess overall organism fitness as well as to discern the treatments' ability at reducing tissue degeneration and atrophy. It was found that mice overexpressing LRP::FLAG displayed improved physiological characteristics and markedly less tissue degeneration and atrophy when compared to control and non-treated mice. Alongside these improvements, certain organs displayed increased telomerase activity with a corresponding elongation in average telomere length. In addition the overexpression of LRP::FLAG significantly improved various proliferative and anti-ageing associated proteins while causing a concomitant decrease in senescence associated proteins. These findings are therefore indicative of a novel function of LRP/LR delaying the onset of senescence, while also promoting healthier ageing through elevating TERT and telomerase activity.

Therapy-induced senescence (TIS) alters calcium (Ca²⁺) flux and Mitochondria-ER Contact Sites (MERCS), revealing critical vulnerabilities in senescent cells. In this study, TIS was induced using Doxorubicin and Etoposide, resulting in an increased MERCS contact surface but a significant reduction in ER-mitochondria Ca²⁺ flux. Mechanistically, TIS cells exhibit decreased expression of IP3R isoforms and reduced interaction between type 1 IP3R and VDAC1, impairing Ca²⁺ transfer. This flux is crucial for maintaining the viability of senescent cells, highlighting its potential as a therapeutic target. Inhibition of ER-mitochondria Ca²⁺ flux demonstrates senolytic effects both in vitro and in vivo, offering a novel strategy for targeting senescent cells.

The accumulation of senescent cells within tissues promotes the aging process by remodelling the functions of the immune system. For many years, it has been known that senescent cells secrete pro-inflammatory cytokines and chemokines, a phenotype called the senescence-associated secretory phenotype (SASP). Chemokines and colony-stimulating factors stimulate myelopoiesis and recruit myeloid cells into aging tissues. Interestingly, recent studies have demonstrated that senescent cells are not only secretory but they also express an increased level of ligand proteins for many inhibitory immune checkpoint receptors. These ligands represent "don't eat me" markers in senescent cells and moreover, they are able to induce an exhaustion of many immune cells, such as surveying natural killer (NK) cells, cytotoxic CD8

Aging increases brain susceptibility to neurodegenerative diseases, but the mechanisms are not clear. Vocal behavior provides an accessible, reliable, and sensitive biomarker to address this because voice changes in middle age can be early indicators of neurodegenerative diseases. The adult male zebra finch is an excellent model organism for these studies due to well-characterized vocal brain circuitry and strong homology to human brain centers. We performed RNA sequencing of song-dedicated basal ganglia nucleus Area X followed by weighted gene co-expression network analyses to examine changes in gene patterns across younger adult, middle, and older ages. Song-correlated gene networks degrade with age, with modules losing their coherence and migrating to different sets of genes, and changes in connection strength particularly for hub genes including those associated with human speech, Parkinson's, and Alzheimer's diseases. Gene pathway enrichment analyses reveal a lack of ongoing metabolic and biogenic processes in older finches. Our findings provide a robust platform for targeting network hubs in the treatment of neurologically driven human vocal disorders.

Age-related hearing loss is characterized by senescent inner ear hair cells (HCs) and reduced autophagy. Despite the improved understanding of these processes, detailed molecular mechanisms underlying cochlear HC senescence remain unclear. Transcription Factor EB (TFEB), a key regulator of genes associated with autophagy and lysosomes, crucially affects aging-related illnesses. However, intricate regulatory networks that influence TFEB activity remain to be thoroughly elucidated. The findings revealed that RONIN (THAP11), through its interaction with host cell factor C1 (HCF1/HCFC1), modulated the transcriptional activity of Tfeb, thus contributing to the mitigation (D-galatactose [D-gal]) senescent HC loss. Specifically, RONIN overexpression improved autophagy levels and lysosomal activity and attenuated changes associated with the senescence of HCs triggered by D-gal. These findings highlight the possibility of using RONIN as a viable therapeutic target to ameliorate presbycusis by enhancing the TFEB function.

Bis-octanoyl-(R)-1,3-butanediol (BO-BD) is a novel ketone ester (KE) ingredient which increases blood beta-hydroxybutyrate (BHB) concentration rapidly after ingestion. KE is hypothesized to improve function in older adults. Whilst many studies have investigated KE in young adults, they have not been studied in healthy older adults (HOA), for whom age-related differences in metabolism may alter the effects. This randomized, observational, open-label study in HOA (n = 30, 50% male, age = 76.5y) aimed to elucidate tolerance, blood BHB and glucose concentrations for 4h following consumption of either 12.5 or 25 g of BO-BD formulated in ready-to-drink beverage (n = 30), and re-constituted powder (n = 21) with a meal. All study interventions were well tolerated, and increased blood BHB, inducing nutritional ketosis (≥0.5 mM) until the end of the study. Peak BHB concentration (C

Astronauts experience weightlessness-induced bone loss (WIBL) due to an imbalanced bone remodeling process involving bone mesenchymal stem cells (BMSCs), osteoblasts, and osteoclasts. Senescence is an important factor contributes to WIBL. In the current study, the effects of Alda-1 on senescence and WIBL were evaluated.

Frailty transition is common, and increased physical activity can prevent it. An objective assessment of physical activity could eliminate bias and provide more precise information on the association between frailty transitions and physical activity.

Endurance training is strongly recommended for older adults to maintain cognitive and motor function. The respective effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on improving behavioural function and cerebral plasticity remain unknown. The purpose of this study was to determine the relative effects of 4 weeks of MICT and HIIT training on endurance, sensorimotor, and cognitive performance, as well as on the expression of neurotrophic markers in the hippocampus and cerebral cortex in aged rats. Twenty-two old male Wistar rats were assigned to one of the following groups: MICT (n = 7), HIIT (n = 6), and Control (n = 9). Incremental treadmill exercise tests, the forelimb grip strength test, the adhesive removal test, and the novel object recognition test were performed. Cerebral cortex and hippocampus were then removed for ELISA and Western blot measurements. The results showed similar benefits of MICT and HIIT on sensorimotor and cognitive functions, and a greater benefit of HIIT on endurance performance. HIIT and MICT differentially promoted cortical and hippocampal neurotrophic markers, demonstrating their complementarity. However, MICT was found to be more effective in promoting a broader range of markers, suggesting its potential as an initial training strategy for older adults.

With the exacerbation of the aging population trend, a series of neurodegenerative diseases caused by brain aging have become increasingly common, significantly impacting the daily lives of the elderly and imposing heavier burdens on nations and societies. Brain aging is a complex process involving multiple mechanisms, including oxidative stress, apoptosis of damaged neuronal cells, chronic inflammation, and mitochondrial dysfunction, and research into new therapeutic strategies to delay brain aging has gradually become a research focus in recent years. Mesenchymal stem cells (MSCs) have been widely used in cell therapy due to their functions such as antioxidative stress, anti-inflammation, and tissue regeneration. However, accompanying safety issues such as immune rejection, tumor development, and pulmonary embolism cannot be avoided. Studies have shown that using exosome derived from mesenchymal stem cells (MSC-Exo) for the treatment of neurodegenerative diseases is a safe and effective method. It not only has the therapeutic effects of stem cells but also avoids the risks associated with cell therapy. Therefore, exploring new therapeutic strategies to delay normal brain aging from the mechanism of MSC-Exo in the treatment of neurodegenerative diseases is feasible. This review summarizes the characteristics of MSC-Exo and their clinical progress in the treatment of neurodegenerative diseases, aiming to explore the possibility and potential mechanisms of MSC-Exo in reversing brain aging.

Ageing is associated with cognitive decline, which is a significant factor in the development of dementia. Vitamin B12 (VB12) is crucial for maintaining proper nervous system function, as well as for protein, fat, and carbohydrate metabolism, and DNA synthesis. Moreover, it helps prevent serious health conditions such as pernicious anemia, neurodegenerative diseases, and Alzheimer's disease. VB12 deficiency is common among the elderly population. We found that serum VB12 levels were significantly elevated in centenarians. Interestingly, VB12 supplementation delayed aging but also improved learning and memory in nematodes. Our results suggest that increasing VB12 activates ptp-3 and helps maintain good cognitive function in centenarians. Furthermore, aging is the gradual decline in bodily functions that impacts nearly all living organisms, with significant effects on salivary glands. Salivary gland degeneration may contribute to VB12 deficiency in the elderly, underscoring the crucial role of salivary regulation in VB12 absorption for centenarians.

The present study aimed to assess whether Time-Restricted Feeding (TRF) modulates inflammation and hepatic Notch1 signalling in C57BL/6J-aged mice.

Oxidative stress plays a key role in aging and related diseases, including neurodegeneration, cancer, and organ failure. Copper (Cu), a redox-active metal ion, generates reactive oxygen species (ROS), and its dysregulation contributes to aging. Here, we develop activity-based imaging probes for the sensitive detection of Cu(I) and show that labile hepatic Cu activity increases with age, paralleling a decline in ALDH1A1 activity, a protective hepatic enzyme. We also observe an age-related decrease in hepatic glutathione (GSH) activity through noninvasive photoacoustic imaging. Using these probes, we perform longitudinal studies in aged mice treated with ATN-224, a Cu chelator, and demonstrate that this treatment improves Cu homeostasis and preserves ALDH1A1 activity. Our findings uncover a direct link between Cu dysregulation and aging, providing insights into its role and offering a therapeutic strategy to mitigate its effects.

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Studies have often equated the effects of knocking down one synthase with broader SAM-dependent outcomes such as histone methylation or phosphatidylcholine (PC) production. Humans and many other organisms express multiple SAM synthases. Evidence in Caenorhabditis elegans, which possesses four SAM synthase genes, suggest that the enzymatic source of SAM impacts its function. For instance, loss of sams-1 leads to enhanced heat shock survival and increased lifespan, whereas reducing sams-4 adversely affects heat stress survival. Here, we show that SAMS-1 contributes to a variety of intermediary metabolic pathways, whereas SAMS-4 is more important to generate SAM for methylation reactions. We demonstrate that loss of sams-1 exerts age-dependent effects on nuclear-encoded mitochondrial gene expression, mitochondrial metabolites, and may induce mitophagy. We propose a mechanistic model where reduced SAM from SAMS-1 acts through PC to impact mitochondria, thereby enhancing survival during heat stress.

Ionizing radiation causes three divergent effects in the human body: On one side, tissue death (= deterministic effects) sets on, on the other side, mutations and cancer growth (= stochastic effects) can occur. In recent years, the additional phenomenon of accelerated aging has come to light. In the following, we argue that these seemingly contradictory radiation responses namely: (i) increased cancer growth, (ii) ablation of cancer tissue or (iii) deterministic senescence, share an underlying cause from damage at the lamin A C-terminus. In other words, besides the typically described genomic radiation impact, we propose an additional destabilization pathway via oxidation at the nuclear envelope. We propose five concrete hypotheses that draw a direct mechanistic model from radiation damage and cellular oxidative stress, to micronuclei and clinical symptoms. In conjunction with lamin B compensation, we might be able to explain why deterministic or stochastic responses dominate. If our model holds true, a novel target for radiotherapeutics and radiooncology arises, and a rationale to closer connect laminopathy and radioprotection research.

Aging changes the protein activity status to affect the body's functions. However, how aging regulates protein posttranslational modifications (PTMs) to modulate the antiviral defense ability of the body remains unclear. Here, we found that aging promotes STAT1 β-hydroxybutyrylation (Kbhb) at Lys592, which inhibits the interaction between STAT1 and type-I interferon (IFN-I) receptor 2 (IFNAR2), thereby attenuating IFN-I-mediated antiviral defense activity. Additionally, we discovered that a small molecule from a plant source, hydroxy camptothecine, can effectively reduce the level of STAT1 Kbhb, thus increasing antiviral defense ability in vivo. Further studies revealed that STAT1 O-GlcNAc modifications at Thr699 block CBP-induced STAT1 Kbhb. Importantly, fructose can improve IFN-I antiviral defense activity by orchestrating STAT1 O-GlcNAc and Kbhb modifications. This study reveals the significance of the switch between STAT1 Kbhb and O-GlcNAc modifications in regulating IFN-I antiviral immunity during aging and provides potential strategies to improve the body's antiviral defense ability in elderly individuals.

The association between dietary diversity and increased mortality risk is well-documented. However, it remains unclear whether and to what extent dietary diversity affects mortality through appendicular skeletal muscle mass (ASM). Therefore, we assessed whether ASM mediated the association between dietary diversity and mortality.

Background: Bones and muscles are connected anatomically, and functionally. Preliminary evidence has shown the gut microbiome influences the aging process of bone and muscle in animal studies. However, such evidence in humans is still scarce. This study aimed to assess the microbiome-bone and microbiome-muscle associations in two cohorts of community-dwelling older adults. Methods: We leveraged information from two large population-based cohorts, i.e., the Rotterdam Study (mean age 62.7 (SD:5.6) years; n=1,249) and the Framingham Heart Study (mean age 55.2, (SD: 9.1) years; n=1,227). For individuals included in this study, gut microbiome 16S rRNA sequencing, musculoskeletal phenotyping derived from DXA images, lifestyle and socioeconomic data, and medication records were available. Per cohort, the 16S rRNA sequencing data, derived from stool, were processed with the DADA2 pipeline and taxonomies were assigned using the SILVA reference database. In addition, the microbiome functional potential was obtained with PICRUSt2. Further, we investigated the association between the human gut microbiome (alpha diversity, genera and predicted functional pathways) and appendicular lean mass (ALM), femoral neck bone mineral density (FN-BMD) and trabecular bone score (TBS) using multilinear regression models controlling for multiple confounders, and performed a joint analysis from both cohorts. Sex-stratified analyses were also conducted. Results: The gut microbiome alpha diversity was not associated with either tested phenotype after accounting for multiple-testing (P>1.67e-02). In the joint analysis, lower abundance of Oscillibacter (beta= -0.51, 95%CI [-0.74, -0.29]), Anaerotruncus (beta=-0.41, 95%CI [-0.61, -0.21]), Eisenbergiella (beta=-0.39, 95%CI [-0.59, -0.19]) and higher abundance of Agathobacter (beta=0.40, 95%CI [0.20, 0.60]) were associated with higher ALM (P<2.0e-04). Lower abundance of Anaerotruncus (beta=-0.32, 95%CI [-0.45, -0.19]), Hungatella (beta=-0.26, 95%CI [-0.38, -0.15]) and Clostridiales bacterium DTU089 (beta=-0.37, 95%CI [-0.55, -0.19]) was associated with higher ALM only in females (P< 2.0e-04). Moreover, the biotin biosynthesis II pathway was positively associated with ALM (beta=0.44, 95% CI [0.24, 0.64]) (P<1.90e-04) in females while no associations were observed in males. We did not observe any robust association of bone traits with gut microbiome features. Conclusion: Our results indicate that specific genera are associated with ALM in middle-aged and older adults and these associations can present in a sex-specific manner. Overall, our study suggests that the gut microbiome is linked to muscle aging in middle-aged and older adults. However, larger sample sizes are still needed to underpin the specific microbiome features involved.

With the global aging population, an increasing number of researchers are interested in the intertemporal choice issues faced by older adults. Previous studies have examined how age-related differences in time perception affect intertemporal choices. However, the impact of time perception strategy on intertemporal decision-making among older adults remains unclear. This study was designed to examine how timing perception strategy influence decision-making among older adults while also exploring the possible mechanisms. We manipulated timing perception strategy preferences through priming in two experiments (Experiment 1,

Both environmental exposures and genetics are known to play important roles in shaping human aging. Here we aimed to quantify the relative contributions of environment (referred to as the exposome) and genetics to aging and premature mortality. To systematically identify environmental exposures associated with aging in the UK Biobank, we first conducted an exposome-wide analysis of all-cause mortality (n = 492,567) and then assessed the associations of these exposures with a proteomic age clock (n = 45,441), identifying 25 independent exposures associated with mortality and proteomic aging. These exposures were also associated with incident age-related multimorbidity, aging biomarkers and major disease risk factors. Compared with information on age and sex, polygenic risk scores for 22 major diseases explained less than 2 percentage points of additional mortality variation, whereas the exposome explained an additional 17 percentage points. Polygenic risk explained a greater proportion of variation (10.3-26.2%) compared with the exposome for incidence of dementias and breast, prostate and colorectal cancers, whereas the exposome explained a greater proportion of variation (5.5-49.4%) compared with polygenic risk for incidence of diseases of the lung, heart and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and incidence of common age-related diseases, suggesting that the exposome shapes distinct patterns of disease and mortality risk, irrespective of polygenic disease risk.

Aging populations worldwide face an increasing burden of age-related chronic conditions, necessitating a deeper understanding of the underlying mechanisms. Purine metabolism has emerged as a crucial player in the pathophysiology of aging, affecting various tissues and organs. Dysregulation of purine metabolism, particularly alterations in extracellular adenosine levels and adenosine receptor signaling, contributes to age-related musculoskeletal problems, cardiovascular diseases, inflammation, and impaired immune responses. Changes in purine metabolism are associated with diminished tissue repair and regeneration, altered bone density, and impaired muscle regeneration. Mechanistically, age-related alterations in purine metabolism involve reductions in extracellular adenosine production, impaired autocrine signaling, and dysregulated expression of CD73 and CD39. Targeting adenosine receptors, such as A

Changes in DNA methylation patterns exhibit a high correlation with chronological age. Epigenetic clocks, developed through statistical models that estimate epigenetic age using the methylation levels of cytosine-guanine dinucleotide (CpG) sites, have emerged as powerful tools in understanding aging and age-related diseases. Despite their popularity, the generalizability of these clocks across diverse populations remains a challenge. We find that some of the widely used epigenetic clocks, such as Horvath clock (Horvath, 2013) and PedBE clock (McEwen et al., 2020) do not perform well in our target cohort. This lack of representativeness raises concerns about applying these clocks to quantify biological age in distinct demographic and ethnic groups. In addition, the feature space between existing clocks and our target data is different: most existing clocks are trained with data from older platforms, such as the Illumina HumanMethylation450 BeadChip (450K). In contrast, our target data are profiled with a more recent Illumina HumanMethylationEPIC BeadChip (EPIC) array. To address these gaps, we propose a transfer learning framework to adapt existing epigenetic clocks to underrepresented populations, using shared knowledge from diverse datasets. Furthermore, we develop imputation- and DNN-based methods for feature adaptation between existing clocks and our target data. Using data collected from 593 blood samples from a cohort of children and adolescents in the ELEMENT study, we find that our proposed transfer learning methods greatly improve the prediction performance compared to applying existing clocks directly. Performance is further enhanced by using the CpG sites profiled on the EPIC array. Our methodology showcases the potential to bridge the gap between different DNAm datasets and different profiling platforms, thus improving the applicability of epigenetic clocks in diverse population groups and contributing to more accurate aging research.

Microvascular endothelial dysfunction, characterized by impaired neurovascular coupling, reduced glucose uptake, blood-brain barrier disruption, and microvascular rarefaction, plays a critical role in the pathogenesis of age-related vascular cognitive impairment (VCI). Emerging evidence points to non-cell autonomous mechanisms mediated by adverse circulating milieu (an increased ratio of pro-geronic to anti-geronic circulating factors) in the pathogenesis of endothelial dysfunction leading to impaired cerebral blood flow and cognitive decline in the aging population. In particular, age-related adipose dysfunction contributes, at least in part, to an unfavorable systemic milieu characterized by chronic hyperglycemia, hyperinsulinemia, dyslipidemia, and altered adipokine profile, which together contribute to microvascular endothelial dysfunction. Hence, in the present study, we aimed to test whether thermogenic stimulation, an intervention known to improve adipose and systemic metabolism by increasing cellular energy expenditure, could mitigate brain endothelial dysfunction and improve cognition in the aging population. Eighteen-month-old C57BL/6J mice were treated with saline or β3-adrenergic agonist (CL 316, 243, CL) for 6 weeks followed by functional analysis to assess endothelial function and cognition. CL treatment improved neurovascular coupling responses and rescued brain glucose uptake in aged animals. In addition, CL treatment also attenuated blood-brain barrier leakage and associated neuroinflammation in the cortex and increased microvascular density in the hippocampus of aged mice. More importantly, these beneficial changes in microvascular function translated to improved cognitive performance in aged mice. Our results suggest that β3-adrenergic agonist treatment improves multiple aspects of cerebromicrovascular function and can be potentially repurposed for treating age-associated cognitive decline.

Age-related thymic involution precedes aging of all other organs in vertebrates and initiates the process of declining T cell diversity, which leads to eventual immune dysfunction. Whether FGF21, a liver-derived pro-longevity hormone that is also produced in thymic stroma, including by adipocytes, controls the mechanism of thymic demise is incompletely understood. Here, we demonstrate that elevation of FGF21 in thymic epithelial cells (TECs) and in adipocytes protects against thymic aging, whereas conditional hepatic overexpression did not impact thymic biology in aged mice. Notably, elevation of thymic FGF21 increased naïve CD8 T cells in aged animals and extended healthspan. Mechanistically, thymic FGF21 overexpression elevated TECs and reduced fibroadipogenic cells. Ablation of β-klotho, the obligatory co-receptor for FGF21 in Foxn1

Lysosomes catabolize lipids and other biological molecules, a function essential for cellular and organismal homeostasis. Key to lipid catabolism in the lysosome is bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles and a stimulator of lipid-degrading enzymes. BMP levels are altered in a broad spectrum of human conditions, including neurodegenerative diseases. While a lysosomal BMP synthase was recently discovered, the enzymes that mediate BMP turnover has remained elusive. Here we show that the lysosomal phospholipase PLA2G15 is a physiological BMP hydrolase. We further demonstrate that BMP resistance to hydrolysis in the lysosome is conferred by the combination of its unique sn2, sn2 esterification position and stereochemistry, as neither feature alone is sufficient to provide this resistance. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes under acidic conditions. Furthermore, PLA2G15 catalytic activity against synthesized BMP stereoisomers with primary esters was comparable to its canonical substrates challenging the long-held thought that BMP unique stereochemistry is sufficient to confer resistance to acid phospholipases. Conversely, BMP with secondary esters and S,S stereoconfiguration is intrinsically stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient cells and tissues accumulate multiple BMP species, a phenotype reversible by supplementing wildtype PLA2G15 but not its catalytically dead mutant. In addition, targeting PLA2G15 to increase BMP reverses the cholesterol phenotype in Niemann Pick Disease Type C (NPC1) patient fibroblasts and significantly ameliorates disease pathologies in NPC1-deficient mice leading to extended lifespan. Our findings establish the rules that govern the stability of BMP in the lysosome and identify PLA2G15 as a lysosomal BMP hydrolase and a potential target for therapeutic intervention in neurodegenerative diseases.

Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.

Understanding the evolving dynamics of the brain throughout life is pivotal for anticipating and evaluating individual health. While previous research has described age effects on spectral properties of neural signals, it remains unclear which ones are most indicative of age-related processes. This study addresses this gap by analyzing resting-state data obtained from magnetoencephalography (MEG) in 350 adults (18 to 88 y). We employed advanced time-series analysis at the brain region level and machine learning to predict age. While traditional spectral features achieved low to moderate accuracy, over a hundred time-series features proved superior. Notably, temporal autocorrelation (AC) emerged as the most robust predictor of age. Distinct patterns of AC within the visual and temporal cortex were most informative, offering a versatile measure of age-related signal changes for comprehensive health assessments based on brain activity.

Chemotherapy-induced cognitive impairment (CICI), commonly referred to as "chemobrain," is a frequent and debilitating side effect experienced by cancer survivors treated with paclitaxel (PTX). Preclinical models have shown that PTX promotes cerebromicrovascular endothelial cell senescence, leading to chronic blood-brain barrier (BBB) disruption and neuroinflammation. Conversely, the elimination of senescent cells through senolytic therapies has been shown to restore BBB integrity, reduce neuroinflammation, and alleviate PTX-induced cognitive impairment. In this study, we tested the hypothesis that PTX-induced endothelial senescence alters gene expression patterns associated with BBB integrity. To investigate this, we analyzed a scRNA-seq dataset from the brains of mice treated with a clinically relevant PTX regimen alongside vehicle-treated control mice. We identified capillary endothelial cells by their distinct transcriptomic profiles and matched these profiles to known transcriptomic markers of cellular senescence. Our analysis confirmed that PTX induces senescence in capillary endothelial cells and revealed significant transcriptional alterations linked to impaired BBB function. In senescent endothelial cells, gene set enrichment analysis (GSEA) highlighted downregulated pathways associated with cell junction assembly and upregulated pathways involved in extracellular matrix remodeling and inflammatory signaling, including Vitronectin (VTN) and Pleiotrophin (PTN) pathways. Additionally, cell-cell communication analysis revealed reduced Junctional Adhesion Molecule (JAM) signaling, further implicating senescence in BBB disruption. These findings highlight endothelial senescence as a driver of BBB dysfunction through transcriptional changes and altered intercellular signaling. The enrichment of VTN and PTN pathways in the senescent state indicates a shift toward vascular remodeling and inflammation, exacerbating microvascular fragility and BBB disruption. Supported by prior experimental findings, this study suggests that targeting endothelial senescence and its downstream effects could mitigate PTX-induced BBB dysfunction and associated cognitive impairments. These results advance our understanding of CICI pathogenesis and provide a foundation for developing therapeutic strategies aimed at preserving vascular integrity.

Mosaic loss of the Y chromosome (mLOY) in circulating leukocytes is the most frequently detected age-related chromosomal mosaic event in men. Current mLOY detection approaches use genotyping arrays and employ a phase-based approach that identifies B allele frequency (BAF) deviations in the pseudo-autosomal region (PAR) shared between the X and Y chromosome. As some widely used genotyping arrays lack sufficient probe coverage of the PAR, methods for accurately measuring mLOY utilizing the median log

Ovarian aging occurs earlier than the aging of many other organs and has a lasting impact on women's overall health and well-being. However, effective interventions to slow ovarian aging remain limited, primarily due to an incomplete understanding of the underlying molecular mechanisms and drug targets. Recent advances in omics data resources, combined with innovative computational tools, are offering deeper insight into the molecular complexities of ovarian aging, paving the way for new opportunities in drug discovery and development.

Haemodialysis (HD) is often required for patients with end-stage renal disease. Arteriovenous fistulas (AVFs), a surgical procedure connecting an artery to a vein, are the preferred vascular access for HD due to their durability and lower complication rates. The aim of AVFs is to promote vein remodelling to accommodate increased blood flow needed for dialysis. However, many AVFs fail to mature properly, making them unsuitable for dialysis. Successful maturation requires remodelling, resulting in an increased luminal diameter and thickened walls to support the increased blood flow. After AVF creation, haemodynamic changes due to increased blood flow on the venous side of the AVF initiate a cascade of events that, when successful, lead to the proper maturation of the AVF, making it suitable for cannulation. In this process, endothelial cells play a crucial role since they are in direct contact with the frictional forces exerted by the blood, known as shear stress. Patients requiring HD often have other conditions that increase the burden of senescent cells, such as ageing, diabetes and hypertension. These senescent cells are characterized by irreversible growth arrest and the secretion of pro-inflammatory and pro-thrombotic factors, collectively known as the senescence-associated secretory phenotype (SASP). This accumulation can impair vascular function by promoting inflammation, reducing vasodilatation, and increasing thrombosis risk, thus hindering proper AVF maturation and function. This review explores the contribution of senescent endothelial cells to AVF maturation and explores potential therapeutic strategies to alleviate the effects of senescent cell accumulation, aiming to improve AVF maturation rates.

Stroke remains a leading cause of mortality and long-term disability worldwide, underscoring the urgent need to identify novel therapeutic targets to enhance brain circuitry repair and functional recovery. This study explores the concept of longevity assurance genes, which primarily function within genetic pathways responsible for repair and maintenance. These pathways encompass molecular and metabolic processes as well as organ- and system-level functions. To investigate this, we employed comparative transcriptomics to analyze gene expression patterns across three age groups with progressively decreasing brain plasticity: native postnatal day seven brains, and young and old naïve and lesioned rat male brains. Analysis revealed a highly symmetrical distribution of upregulated and downregulated genes in postnatal day 7 brains. In contrast, the gene expression profiles of post-stroke brains exhibited significant asymmetry, with a disproportionate increase in upregulated genes compared to downregulated ones in both young and old post-ischemic brains. Gene variance in juvenile brains predominantly reflected processes associated with brain plasticity (e.g., Dcx, Tubb2b, Dok4, Dpysl5) and cell proliferation (e.g., Bex4). Conversely, gene expression variance in young and aged post-stroke brains was largely linked to inflammatory pathways, driven by cytokine and chemokine signaling. Notably, several genes specifically upregulated in aged brains were identified, including Ehd4, Fut7, Lilrb4, Plek, Slfn13, Slc14a1, and Smpdl3a. Immune genes that facilitate synaptic plasticity during early postnatal brain development-through processes such as pruning and sprouting to establish new connections in response to external stimuli-also contribute to post-stroke damage, confirming the concept of antagonistic pleiotropy. Our results suggest that targeting age-related immune responses could be an effective therapeutic strategy for stroke recovery.

Aging is a significant risk factor for male fertility and can lead to severe developmental disorders in offspring. It disrupts testicular function and spermatogenesis, resulting in sperm abnormalities and DNA fragmentation. Male aging alters the genome and epigenome of germ cells due to persistent oxidative stress caused by the cumulative effects of environmental factors over a lifetime. At the molecular level, DNA damage occurs and is poorly repaired due to impaired DNA repair pathways, leading to unrepaired lesions and de novo mutations. Aging also creates distinct epigenetic landscapes that modify gene expression in germ cells, affect the DNA damage response, and generate de novo DNA and epigenetic mutations that are transmitted to the sperm and inherited by the offspring. This review discusses current knowledge on the age-associated effects on male germ cells and the genomic and epigenomic mechanisms contributing to altered male reproductive health and outcomes in progeny. We propose a male reproductive aging threshold, where cumulative exposure to risk factors leads to oxidative stress, impaired spermatogenesis, and altered reproductive outcomes. Finally, we discuss novel interventions to prevent premature testicular aging and emphasize the need for public health policies and counseling guidelines for men seeking paternity.

Exosomes are small vesicles with diameters ranging from 30 to 150 nm. They originate from cellular endocytic systems. These vesicles contain a rich payload of biomolecules, including proteins, nucleic acids, lipids, and metabolic products. Exosomes mediate intercellular communication and are key regulators of a diverse array of biological processes, such as oxidative stress and chronic inflammation. Furthermore, exosomes have been implicated in the pathogenesis of infectious diseases, autoimmune disorders, and cancer. Aging is closely associated with the onset and progression of numerous diseases and is significantly influenced by exosomes. Recent studies have consistently highlighted the important functions of exosomes in the regulation of cellular senescence. Additionally, research has explored their potential to delay aging, such as the alleviatory effects of stem cell-derived exosomes on the aging process, which offers broad potential for the development and application of exosomes as anti-aging therapeutic strategies. This review aims to comprehensively investigate the multifaceted impact of exosomes while concurrently evaluating their potential applications and underscoring their strategic significance in advancing anti-aging strategies.

The blood-brain barrier (BBB) is a specialized vascular structure that protects the brain microenvironment from toxins and pathogens in the blood. At the same time, the BBB presents a significant challenge for drug development, as it restricts the entry of most therapeutics into the brain. In this review, we first examine recent findings on the molecular and cellular architecture of the BBB, emphasizing the diverse mechanisms that facilitate the transport and exchange of molecules between the blood and the brain. We discuss current knowledge on the heterogeneity of the BBB along the arteriovenous axis and across different brain regions. Then, we explore the molecular and functional changes in the BBB that occur during normal aging, neurodegeneration, and acute brain injuries and how prolonged BBB impairment affects transport mechanisms and disease progression. Additionally, we discuss novel developments in drug delivery strategies to transport small molecules, biologicals or cellular therapeutics across the BBB. Finally, we examine therapeutic opportunities to restore the BBB and discuss future directions in the field.

Brain-derived neurotrophic factor (BDNF) is a growth factor with a range of neurological, cardioprotective, and metabolic health benefits. While passive heat stress has been observed to increase circulating BDNF, the BDNF response to a given stressor may be attenuated with increasing age. To investigate the influence of age on the BDNF response to heat stress, we compared BDNF responses to daylong (9-hours) exposure to hot ambient conditions (40°C, 9% relative humidity) between 19 young (range: 19-31 years; 9 female) and 37 older adults (61-78 years; 12 female). We also explored whether cumulative thermal strain (area under the curve of rectal and mean body temperatures) impacted comparisons. Serum BDNF concentrations were assessed at pre- and end-exposure using enzyme-linked immunosorbent assays. Circulating BDNF concentrations increased from baseline in both groups (P<0.001), but end-exposure concentrations were 2594 [1555, 3633] pg/mL lower in older than young adults (P<0.001). This age-related difference persisted, albeit to a lesser magnitude, after accounting for the lower pre-exposure BDNF levels in older adults (baseline-adjusted between-group difference: 1648 [667, 2630] pg/mL; P<0.001). Additionally, the BDNF response was not related to indices of thermal strain (P≥0.562), and baseline-adjusted between-group differences were not appreciably altered by adjusting for area under the curve of rectal (1769 [714, 2825] pg/mL; P=0.002) or mean body temperatures (1745 [727, 2763] pg/mL; P=0.001). Our study is the first to demonstrate an age-related reduction in the BDNF response to prolonged passive heat exposure, which informs our wider understanding of how environmental stressors influence BDNF responses in older adults.

Aims: Cardiovascular disease is the leading cause of death in the European Union and aging is one of its major risk factors resulting in the progressive deterioration of the cardiac structures and function. Here, we have combined single-nucleus-RNA-sequencing, imaging, and molecular and cell biology approaches to explore the maladaptive signals that drive cardiac ageing. Methods and results: Single-nucleus-RNA-sequencing analysis of young (3 months) and old (18 months) murine hearts revealed that the expression of decorin, a secreted proteoglycan expressed in the extracellular matrix of endothelial cells, is induced by ageing. Decorin treatment via osmotic mini-pump induced diastolic dysfunction and a pro-inflammatory environment in the myocardium characterized by increased infiltration of immune cells, increased expression of IL-1{beta} in endothelial cells and microvascular leakage in 3 months old mice. In vitro, decorin treatment induces cardiomyocyte hypertrophy, the expression of different pro-inflammatory cytokines like IL1B in endothelial cells, and compromises the endothelial barrier function. Conclusions: Together, our results identify decorin as a novel player contributing to cardiac aging and disease. Decorin contributes to the age-related structural and functional dysfunction of the heart by inducing a pro-inflammatory environment in the myocardial microvasculature, a hallmark of cardiac ageing. Translational perspective: Ageing is a major risk factor of cardiovascular disease and the molecular and cellular mechanisms that drive this process have not been completely described. The data presented here identifies decorin as a novel player contributing to systemic inflammation and microvascular dysfunction, two hallmarks of ageing. Although, because of its role regulating TGF-{beta} signalling, decorin has been proposed for anti-fibrotic therapies, the pro-inflammatory effects observed on the cardiac microvasculature should be taken into account for the employment of decorin as an antifibrotic agent to treat disease associated cardiac fibrosis.

We tested whether homocysteine (Hcy) was linked to longitudinal change in plasma neurofilament light chain (NfL) overall and differentially across sex and race in a sample of middle-aged urban adults. We used data from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study [n = 690, Age at visit 1 (v

The persistent accumulation of senescence cells is one of the characteristics of radiation-induced skin injury (RISI), leading to fibrosis and impaired healing. However, the reasons why these senescence cells are resistant to clearance remain unclear.

Assessing impact on the hallmarks of aging has emerged as a novel method for prioritizing dual-purpose longevity therapeutic targets and developing drugs simultaneously targeting aging and disease. Cellular senescence, a central hallmark of aging, progressively induces cellular growth arrest and accelerates the production of a pro-inflammatory senescence-associated secretory phenotype (SASP). TGF-β signaling is situated at the center of multiple senescence-associated and aging-associated signaling pathways, and its inhibition may be favorable for aging-related disorders. A recently developed Traf2- and Nck-interacting kinase (TNIK) inhibitor, INS018_055, was identified as a potent, novel anti-fibrotic agent affecting multiple hallmarks of aging across fibrotic diseases. Thus, we hypothesized that TNIK is a potential senescence modulator and INS018_055 could attenuate senescent cell accumulation to treat specific age-related pathological processes. Using a fully automated robotics laboratory designed for automated, highly parallel, and iterative phenotypic and multi-omic analyses, we determined that pharmacological or siRNA-mediated TNIK inhibition decreased cellular senescence in multiple experimental senescence models. INS018_055 mechanistically demonstrated senomorphic activity through its reduction of SASP. Furthermore, transcriptomics analysis revealed that INS018_055 treatment reduced aging signatures and extracellular matrix fibronectin through TGF-β signaling. These findings reveal TNIK's previously unappreciated role in cellular senescence and INS018_055's senomorphic potential in mitigating processes well-established as driving organismal aging. Thus, TNIK inhibition as a novel senomorphic strategy may inform future therapeutic approaches for diverse aging-related diseases.

Dynamic changes in cell size are associated with development and pathological conditions, including aging. Although cell enlargement is a prominent morphological feature of cellular senescence, its functional implications are unknown; moreover, how senescent cells maintain their enlargement state is less understood. Here we show that an extensive remodeling of actin cytoskeleton is necessary for establishing senescence-associated cell enlargement and pro-inflammatory senescence-associated secretory phenotype (SASP). This remodeling is attributed to a balancing act between the SASP regulator GATA4 and the mechanosensor YAP on the expression of the Rho family of GTPase RHOU. Genetic or pharmacological interventions that reduce cell enlargement attenuate SASP with minimal effect on senescence growth arrest. Mechanistically, actin cytoskeleton remodeling couples cell enlargement to the nuclear localization of GATA4 and NF-κB via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. RhoU protein accumulates in mouse adipose tissue under senescence-inducing conditions. Furthermore, RHOU expression correlates with SASP expression in adipose tissue during human aging. Thus, our study highlights an unexpected instructive role of cell enlargement in modulating the SASP and reveals a mechanical branch in the senescence regulatory network.

Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention. Mitochondrial malate dehydrogenase (MDH2), an enzyme in the TCA cycle, was identified as an anti-aging target through activity-based protein profiling in present study. The expression level of MDH2 was positively correlated with the cellular senescence in Mdh2 knockdown or overexpression fibroblasts. Glibenclamide (Gli), a classic anti-glycemic drug, was found to inhibit the activity of MDH2 and relieve fibroblast senescence in an MDH2-dependent manner. The anti-aging effects of Gli were also further validated in vivo, as it extended the lifespan and reduced the frailty index of naturally aged mice. Liver specific Mdh2 knockdown eliminated Gli's beneficial effects in naturally aged mice, reducing p16

The Drosophila melanogaster (fruit fly) misexpression suppressor of Ras 4 (MESR4) gene encodes a potential transcription factor and plays critical roles in various biological processes, including embryonic development, lipid metabolism, eye-antennal development, and germline stem cell differentiation. However, whether it is involved in modulating intestinal homeostasis remains elusive. In this study, we provide compelling evidence demonstrating that MESR4 is a bona fide regulator in preventing age-onset intestinal leakage and dysbiosis in adult flies. Mechanistically, MESR4 is predominantly located at the nucleus of intestinal cells and controls the expression of bag-of-marbles (bam), thereby restricting the excessive activation of immune deficiency signaling during aging. The silencing of Relish (Rel), which encodes a key transcription factor of the immune deficiency signaling pathway, reverses the beneficial effects of MESR4 in mediating intestinal barrier function and fly lifespan. Collectively, our studies uncover an undescribed function of Drosophila MESR4 in the maintenance of intestinal homeostasis and overall organismal fitness.

The importance of vitamin D for a well-functioning immune system is becoming increasingly evident. Nevertheless, the other fat-soluble vitamins A, E and K also seem to play a central role regarding the adequate function of immune cells and to counteract excessive immune reactions and inflammatory processes. However, recognizing hidden hunger, particularly micronutrient deficiencies in vulnerable groups like the elderly, is crucial because older adults often lack sufficient micronutrients for various reasons. This review summarizes the latest findings on the immune modulating functions of fat-soluble vitamins in a physiological and pathophysiological context, provides a graphical comparison of the Recommended Daily Allowances between Deutschland, Austria, Confoederatio Helvetica (D-A-CH; eng. GSA, Germany, Switzerland, Austria), Deutsche Gesellschaft für Ernährung (DGE; eng. German Nutrition Society) and National Institutes of Health (NIH) across all age groups and, in particular, addresses the question regarding the benefits of supplementation of the respective micronutrients for the aging population of industrialized nations to strengthen the immune system. The following review highlights the importance of fat-soluble vitamins A, D, E and K which play critical roles in maintaining immune system function and, in some cases, in preventing excessive immune activation. Therefore, a better understanding of the relevance of adequate blood levels and consequently potential supplementation strategies may contribute to the prevention and management of infectious diseases as well as better overall health of the elderly.

Aging is marked by a progressive decrease in physiological function and reserve capacity, which results in increased susceptibility to diseases. Understanding the mechanisms of driving aging is crucial for extending health span and promoting human longevity. Hypoxia, marked by reduced oxygen availability, has emerged as a promising area of study within aging research. This review explores recent findings on the potential of oxygen restriction to promote healthy aging and extend lifespan. While the role of hypoxia-inducible factor 1 (HIF-1) in cellular responses to hypoxia is well-established, its impact on lifespan remains complex and context-dependent. Investigations in invertebrate models suggest a role for HIF-1 in longevity, while evidence in mammalian models is limited. Hypoxia extends the lifespan independent of dietary restriction (DR), a known intervention underlying longevity. However, both hypoxia and DR converge on common downstream effectors, such as forkhead box O (FOXO) and flavin-containing monooxygenase (FMOs) to modulate the lifespan. Further work is required to elucidate the molecular mechanisms underlying hypoxia-induced longevity and optimize clinical applications. Understanding the crosstalk between HIF-1 and other longevity-associated pathways is crucial for developing interventions to enhance lifespan and healthspan. Future studies may uncover novel therapeutic strategies to promote healthy aging and longevity in human populations.

As the only gateway governing nucleocytoplasmic transport, the nuclear pore complex (NPC) maintains fundamental cellular processes and deteriorates with age. However, the study of age-related roles of single NPC components remains challenging owing to the complexity of NPC composition. Here we demonstrate that the master energy sensor, AMPK, post-translationally regulates the abundance of the nucleoporin NPP-16/NUP50 in response to nutrient availability and energetic stress. In turn, NPP-16/NUP50 promotes transcriptomic activation of lipid catabolism to extend the lifespan of Caenorhabditis elegans independently of its role in nuclear transport. Rather, the intrinsically disordered region (IDR) of NPP-16/NUP50, through direct interaction with the transcriptional machinery, transactivates the promoters of catabolic genes. Remarkably, elevated NPP-16/NUP50 levels are sufficient to promote longevity and metabolic stress defenses. AMPK-NUP50 signaling is conserved to human, indicating that bridging energy sensing to metabolic adaptation is an ancient role of this signaling axis.

Progeria syndromes are very rare, incurable premature aging conditions recapitulating most aging features. Here, we report a whole genome, multiparametric CRISPR screen, identifying 43 genes that can rescue multiple cellular phenotypes associated with progeria. We implement the screen in fibroblasts from Néstor-Guillermo Progeria Syndrome male patients, carrying a homozygous A12T mutation in BAF. The hits are enriched for genes involved in protein synthesis, protein and RNA transport and osteoclast formation and are validated in a whole-organism Caenorhabditis elegans model. We further confirm that BAF A12T can disrupt protein synthesis rate and fidelity, which could contribute to premature aging in patients. This work highlights the power of multiparametric genome-wide suppressor screens to identify genes enhancing cellular resilience in premature aging and provide insights into the biology underlying progeria-associated cellular dysfunction.

As the global population continues to age, the prevalence of age-related diseases is increasing, significantly influencing social and economic development, the stability of social security systems, and progress in medical technology. Ferroptosis, a recently discovered form of programmed cell death driven by iron-dependent lipid peroxidation, has emerged as a key area of research. Studies have revealed a strong association between ferroptosis and senescence. In this article, we systematically summarize the molecular mechanisms and associated signaling pathways underlying ferroptosis, emphasizing its pivotal role in the onset and progression of age-related diseases. By providing new perspectives, we aim to advance understanding of the pathogenesis of age-related diseases and guide the development of effective intervention strategies.

Microglia depletion, followed by repopulation, improves cognitive functions in the aged mouse brain. However, even temporal ablation of microglia puts the brain at a high risk of infection. Hence, in the present work, we studied if the partial reduction of microglia with PLX3397 (pexidartinib), an inhibitor of the colony-stimulating factor 1 receptor (CSF1R), could bring similar benefits as reported for microglia ablation. Aged (two-years-old) mice were treated with PLX3397 for a total of 6 weeks, which reduced microglia numbers in the hippocampus and retrosplenial cortex (RSC) to the levels seen in young mice and resulted in layer-specific ablation in the expression of microglial complement protein C1q mediating synaptic remodeling. This treatment boosted long-term potentiation in the CA1 region and improved performance in the hippocampus-dependent novel object location recognition task. Although PLX3397 treatment did not alter the number or total intensity of Wisteria floribunda agglutinin-positive perineuronal nets (PNNs) in the CA1 region of the hippocampus, it changed the fine structure of PNNs. It also elevated the expression of perisynaptic proteoglycan brevican, presynaptic vGluT1 at excitatory synapses, and vGAT in inhibitory ones in the CA1 stratum radiatum. Thus, targeting the CSF1R may provide a safe and efficient strategy to boost synaptic and cognitive functions in the aged brain.

The mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1/2) are crucial for various physiological functions. Although the role of mTORC1 in retinal pigmented epithelium (RPE) homeostasis and age-related macular degeneration (AMD) pathogenesis is established, the function of mTORC2 remains unclear. We investigated both complexes in RPE health and disease. Therefore, in this study, we have attempted to demonstrate that the specific overexpression of mammalian lethal with Sec13 protein 8 (mLST8) in the mouse RPE activates both mTORC1 and mTORC2, inducing epithelial-mesenchymal transition (EMT)-like changes and subretinal/RPE deposits resembling early AMD-like pathogenesis. Aging in these mice leads to RPE degeneration, causing retinal damage, impaired debris clearance, and metabolic and mitochondrial dysfunction. Inhibition of mTOR with TORIN1 in vitro or βA3/A1-crystallin in vivo normalized mTORC1/2 activity and restored function, revealing a novel role for the mTOR complexes in regulating RPE function, impacting retinal health and disease.

If fertilization does not occur in a timely manner after ovulation, then that can lead to aging and a decline in relation to oocyte quality, which have detrimental effects on subsequent embryo development and offspring. Reactive oxygen species (ROS) induced oxidative stress is the main factor in the deterioration of oocyte aging. Herein, ceria nanoparticles (NPs) have been developed as ROS scavengers to improve the quality of aging oocytes. We found that ceria NPs could effectively inhibit senescence-induced morphological changes and lower ROS accumulation in the oocytes. In addition, ceria NPs reduced the abnormal spindle distribution and improved mitochondrial function. Ceria NPs also reduced oxidative stress in aging oocytes by increasing ROS scavenging capacity rather than inhibiting ROS generation capacity. Furthermore, ceria NPs increased the rate of blastocyst formation in aging oocytes. We conclude that ceria NPs can enhance the quality and development potential of aging oocytes by reducing the level of oxidative stress.

Sarcopenia and physical frailty are age-related syndromes characterized by progressive loss of muscle mass and function, significantly impacting mortality and quality of life in older adults. This systematic review evaluated the effectiveness of protein supplementation interventions for these conditions.

Leisure activity and sleep time are key factors in cognitive impairment, but the impact of their long-term trajectories on incident cognitive impairment remains unclear.

Nowadays, novel biomaterials are under intense research because they are part of promising therapies for the treatment of age-related diseases such as osteoporosis and bone defects. In the presented study, composites of poly(ε-caprolactone) (PCL), micro and nano hydroxyapatite (µ-HAp and n-HAp) and carbon nanofibers (CNFs) were prepared. The influence of additives on polymeric matrix was analyzed using scanning electron microscopy (SEM), Raman micro-spectroscopy, Raman mapping, and two-dimensional correlation spectroscopy (2D-COS). The bioactivity in vitro was evaluated by a 21-day incubation of prepared membranes in simulated body fluid (SBF). It was concluded that additives can behave as crystallization nuclei of PCL, but they are also located across the entire surface of PCL spherulites, not only in the center. With an increasing content of HAp additives, polymeric spherulites become smaller. The type of HAp (µ-HAp or n-HAp) influences the PCL matrix differently, as confirmed by 2D-COS. The component whose addition leads to most significant changes in the polymer is CNFs; polymeric spherulites are small to the extent that they are not distinguishable, and the overall amorphousness of the polymer is the highest among all tested materials, as is its hydrophobicity. The bioactivity test indicated that the membrane with the greatest potential for use as a biomaterial in bone tissue engineering is one consisting of n-HAp (15 wt%) and CNFs, as very uniform coverage of the produced apatite was observed on the surface of this membrane after incubation in SBF.

When faced with a choice between exploring an unknown option vs exploiting an option they know well, older adults explore less and exploit more than younger adults. Recent work has suggested that one cause of this age difference in exploration is a reduction in the extent to which older adults use "random exploration" - exploration driven by behavioral variability. Here we investigate potential mechanisms for this age-related difference in random exploration through the lens of a drift diffusion model (DDM) of the explore-exploit choice. In this model, random exploration can be modulated by two mechanisms - the fidelity with which information about the choice is represented in the brain, the "signal-to-noise ratio" (SNR), and the amount of information required to make a decision, the "decision threshold." Reduced random exploration in aging could be caused either by an increase in signal-to-noise ratio or an increase in decision threshold in older adults. By fitting the DDM to choices and response times in a sample of healthy younger and older adults, we found that older adults had a lower SNR and a higher threshold than younger adults. This suggests that reduced random exploration in aging is driven by higher response thresholds in older adults, which may compensate for the reduced signal-to-noise ratio with which decision information is represented in the brain.