Few studies have focused on the correlation between leukocyte telomere length (LTL) and cancer-related mortality or identified potential factors that mediate the relationship between LTL and mortality among chronic kidney disease (CKD) patients. Our study aimed to explore the associations between LTL and all-cause and cause-specific mortality and to identify the underlying mediators.

CKD patients were obtained from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Cox regression analysis and restricted cubic spline analysis were used to explore the associations between LTL and all-cause or specific-cause mortality and their nonlinear connections. Stratified analyses were executed to assess the relationships among the different subgroups. The latent mediated factors were confirmed using mediation analysis. Sensitivity analyses were used to evaluate the robustness of our findings.

Longer LTL associated with the lower risk of all-cause mortality, cardiovascular disease (CVD) and cancer-related mortality, and U-shaped relationships were detected. Patients younger than 65 years with greater LTL or who had hypertension had better prognoses. Age and history of hypertension were associated with LTL and overall mortality. In addition, estimated glomerular filtration rate (eGFR), albumin, and total bilirubin mediated the association, and the proportions of indirect effects were 7.81%, 3.77%, and 2.50%, respectively. Six sensitivity analyses confirmed the robustness of our findings.

This study revealed that LTL was a protective factor for survival among patients with CKD and emphasized the mediating roles of oxidative stress and kidney function.

Age-related diseases imposed heavy burdens to the healthcare systems globally, while cell senescence served as one fundamental molecular/cellular basis for these diseases. How to tackle the senescence-relevant problems is a hotspot for biomedical research. In this review article, the hallmarks and molecular pathways of cell senescence were firstly discussed, followed by the introduction of the current anti-senescence strategies, including senolytics and senomorphics. With suitable physical or chemical properties, multiple types of nanomaterials were used successfully in senescence therapeutics, as well as senescence detection. Based on the accumulating knowledges for senescence, the rules of how to use these nanoplatforms more efficiently against senescence were also summarized, including but not limited to surface modification, material-cargo interactions, factor responsiveness etc. The comparison of these "senescence-selective" nanoplatforms to other treatment options (prodrugs, ADCs, PROTACs, CART etc.) was also given. Learning from the past, nanotechnology can add more choice for treating age-related diseases, and provide more (diagnostic) information to further our understanding of senescence process.

Pulmonary fibrosis (PF) is a fatal disease associated with ageing. The senescence of alveolar epithelial type II cells (AECIIs) can drive PF. Therefore, reducing AECII senescence is a promising treatment to prevent PF. Mai-wei-yang-fei decoction (MWYF) has shown significant clinical efficacy in the treatment of patients with PF. However, its mechanism of action remains unclear.

To investigate the role and underlying mechanism of MWYF in protecting against PF.

The main chemical components of MWYF were identified using UPLC-MS. The mouse and in vitro cell models of PF were established using BLM. Micro-CT, H&E, and Masson staining were used to observe the protective effect of MWYF on mice with PF. Immunohistochemistry, β-galactosidase staining, and IF-FISH were used to observe the inhibitory effect of MWYF on senescence and telomere shortening in mouse lung tissue or A549 cells. The Transwell assay and cell co-culture method were used to observe the effect of MWYF on the migration and activation of lung fibroblasts by inhibiting AECII senescence. Finally, lentiviral vector was used to overexpress FBW7 gene in A549 cells in vitro to observe the mechanism pathway of MWYF inhibiting AECII senescence and telomere shortening.

MWYF was effective in protecting against bleomycin (BLM)-induced PF. Furthermore, MWYF alleviated cellular senescence by reducing the DNA damage response (DDR) and shortening of the telomere in AECⅡs in mouse lung tissues. Mechanistically, genes related to telomere disorders were detected in BLM-induced PF mouse models using q-PCR. MWYF mainly inhibited telomere shortening by regulating FBW7 and reducing the degradation of TPP1. In vitro, MWYF reduced BLM-induced senescence in A549 cells, as well as proliferation and migration of MRC5 cells, by inhibiting DDR and telomere shortening via regulation of the FBW7/TPP1 axis.

MWYF is a potential therapeutic agent against PF, as it inhibits telomere shortening and reduces AECII senescence by regulating FBW7/TPP1.

Senescence is a complex cellular state that can be considered as a stress response phenotype. A decade ago, we suggested the intricate connections between unfolded protein response (UPR) signaling and the development of the senescent phenotype. Over the past ten years, significant advances have been made in understanding the multifaceted role of the UPR in regulating cellular senescence, highlighting its contribution to biological processes such as oxidative stress and autophagy. In this updated review, we expand these interconnections with the benefit of new insights, and we suggest that targeting specific components of the UPR could provide novel therapeutic strategies to mitigate the deleterious effects of senescence, with significant implications for age-related pathologies and geroscience.

Aging and heavy metal pollution are global challenges, and cadmium (Cd) may negatively affect aging. However, effective interventions for Cd toxicity among populations remain insufficient. Selenium (Se) is recognized for its protective effects against heavy metal toxicity and aging. This study utilized data from the National Health and Nutrition Examination Survey (2015-2018) to explore the individual and joint effects of Cd and Se on biological aging acceleration, measured by Klemera-Doubal method biological age acceleration (KDM-BA-Accel) (n = 7119) and Phenotypic age acceleration (PhenoAge-Accel) (n = 7433). Results showed that Cd was positively associated with KDM-BA-Accel (β = 0.57) and PhenoAge-Accel (β = 0.77), while Se had negative associations with both (β values were -4.01 and -5.30, respectively). Nonlinear analyses revealed J-shaped associations for Cd and L-shaped for Se with aging indicators. Moreover, inflammation significantly mediated the Cd-aging and Se-aging relationships. Most importantly, a significant negative interaction between Cd and Se on PhenoAge-Accel (β for interaction = -1.29) suggested an antagonistic effect, particularly among never smokers. Increasing Se content can mitigate the harmful effects of Cd on PhenoAge-Accel were demonstrated through three methods. Specifically, ⅰ) compared to "Cd (-) & Se (-)" group, "Cd (+) & Se (-)" group had β = 0.87, while "Cd (+) & Se (+)" group was non-significant; ⅱ) higher Se content was associated with a lower increase in PhenoAge-Accel as Cd content rose; ⅲ) there were no significant associations between Cd & Se mixture and aging indicators (both p > 0.310). These findings highlight Se supplementation as a potential strategy to counteract Cd-induced aging, offering a new direction for public health interventions in polluted populations.

Telomeres, the protective ends of chromosome, are key to tissue repair and regeneration. Telomere shortening is linked to aging and age-related disorders, while excessive telomerase activity may support tissue regeneration or transformation. Some of the functions of telomeres and telomerase may be mediated by its important role in the process of stemness. Active telomerase, and subsequent telomerase-dependent telomere extension, supports stem-cells self-renewal and pluripotency - essential for tissue healing. During cellular reprogramming, differentiated cells are converted into induced pluripotent stem cells (iPSCs), which resemble embryonic stem cells. During iPSC derivation, telomere length is reset, enhancing iPSCs' regenerative potential. During this process, incomplete telomerase activation and telomere extension can lead to genomic instability and/or haltered cell functionality. Understanding the intricate relation of telomeres, telomerase and stemness may be critical when designing novel cell-based therapies targeting degenerative diseases or to unlock strategies to delay aging. Here, we explore the recent bibliography linking these areas, raising awareness of their important when designing novel breakthroughs in health and longevity.

The prolyl-isomerase Pin1 is a unique enzyme that catalyzes cis-trans isomerization of phosphorylated Ser/Thr-Pro motifs. These motifs are present in many proteins, where isomerization of the typically rigid prolyl-peptide bond can lead to conformational changes, and subsequently regulate activity, stability, or localization. The specificity of Pin1 for phosphorylated motifs allows it to serve as a master regulator of proteins after phosphorylation, adding an additional layer of regulation to intricately control cellular signaling. As such, Pin1 plays an expansive role in numerous cancer and age-related signaling pathways, and is recognized as a major driver of cancer and promising therapeutic target. In this review, we discuss the role of Pin1 in regulation of age-related cancer signaling pathways, and we highlight the early development and current landscape of Pin1 inhibitors, and the prospect of Pin1 inhibition for cancer therapy.

The three stereoisomers of a previously reported dinuclear ruthenium(II) complex have been quantitatively separated using cation-exchange chromatography and the individual crystal structures of the racemic pair are reported. Cell-based studies on the three stereoisomers disclosed differences in the rate of uptake of the two chiral forms of the rac diastereoisomer with the ΛΛ-enantiomer being taken up noticeably more rapidly than the ΔΔ-form. Cell viability studies reveal that the three cations show identical cytotoxicity over 24 hours, but over more extended exposure periods, the meso-ΔΛ stereoisomer becomes slightly less active. More significantly, microscopy studies revealed that although both isomers display a near infra-red "light-switch" effect associated with binding to duplex DNA on binding to chromatin in live MCF7 and L5178-R cells, only the ΛΛ enantiomer displays a distinctive, blue-shifted component associated with binding to quadruplex DNA. An analysis of the ratio of "quadruplex emission" compared to "duplex emission" for the ΛΛ-enantiomer indicated that there was a decrease in the average quadruplex DNA content within live primary cells as they undergo multiple cell divisions.

Replicative senescence occurs in response to shortened telomeres and is triggered by ATM and TP53-mediated DNA damage signaling that blocks replication. hTERT lengthens telomeres, which is thought to block damage signaling and the onset of senescence. We find that normal diploid fibroblasts expressing hTERT mutants unable to maintain telomere length do not initiate DNA damage signaling and continue to replicate, despite having telomeres shorter than senescent cells. The TRF1 and TRF2 DNA binding proteins of the shelterin complex stabilize telomeres, and we find that expression of different mutant hTERT proteins decreases levels of the Siah1 E3 ubiquitin ligase that targets TRF2 to the proteasome, by increasing levels of the CDC20 and FBXO5 E3 ligases that target Siah1. This restores the TRF2:TRF1 ratio to block the activation of ATM and subsequent activation of TP53 that is usually associated with DNA damage-induced senescence signaling. All hTERT variants reduce DNA damage signaling, and this occurs concomitantly with telomeres assuming a more compact, denser conformation than senescent cells as measured by super-resolution microscopy. This indicates that hTERT variants induce TRF2-mediated telomere compaction that is independent of telomere length, and it plays a dominant role in regulating the DNA damage signaling that induces senescence and blocks replication of human fibroblasts. These observations support the idea that very short telomeres often seen in cancer cells may fail to induce senescence due to selective stabilization of components of the shelterin complex, increasing telomere density, rather than maintaining telomere length via the reverse transcriptase activity of hTERT.

The maintenance of telomere length by telomerase plays an essential role in senescence, aging, and cancer. Mutations in the TERT promoter, a telomerase subunit, are frequent in human cancers. In hepatocellular carcinoma (HCC), telomere shortening contributes to preneoplastic conditions such as cirrhosis. Telomerase activation during cirrhosis may reduce chromosomal instability, while its suppression in early dysplastic nodules may prevent hepatocarcinogenesis. Evidence suggests that bioactive food compounds (BFCs) can reduce the incidence and/or delay the onset of HCC by modulating telomerase activity. A systematic review was conducted on the role of BFCs in telomerase activity during hepatocarcinogenesis. BFCs were analyzed in isolated form or as part of extracts and categorized into fatty acids, isoprenoids, isothiocyanates, and phenolic compounds. Despite structural diversity, BFCs modulate telomerase through common mechanisms, including inhibition of activating proteins at the TERT promoter, activation of nuclear receptors, or histone H3 hyperacetylation. Indirectly, telomerase can also be modulated via activation of antioxidant defense pathways. Understanding telomerase reactivation and its modulation by BFCs is key to establishing effective HCC chemoprevention strategies targeting telomerase.

Telomere shortening during eukaryotic cell division can lead to severe problems such as inactivation of neighboring genes and aberrant chromosomal fusion. To protect chromosome ends from the replicative errors, most eukaryotes have evolved an enzymatic defense mechanism called telomerase, in which telomerase reverse transcriptase (TERT) plays a central role. This enzymatic activity is highly elevated in consecutively dividing somatic cells of regenerating and probably asexually reproducing, platyhelminths. Therefore, flatworms can be powerful models to investigate the biological implications of TERT in these non-embryonic developments. Current information on the protein is largely limited to a handful of representative species within the phylum Platyhelminthes. This study characterizes the structural features of TERT proteins and their encoding genes in flatworms, aiming to expand our knowledge of the telomere-protecting protein in this lower animal taxon. The platyhelminth genes exhibited exon-intron architectures that were highly divergent from their orthologs in the other lophotrochozoans, and their protein products lacked some TERT-specific domains such as the telomerase essential N-terminal and repeat addition processivity domains. Nevertheless, the unique gene and protein structures were tightly conserved among the flatworm homologs. Analysis of the tert transcripts showed that use of alternative splice acceptors or donors in a minor AT-AC intron, as well as intron retention and exon exclusion, contribute to the generation of aberrant mRNAs. The present findings demonstrate that the tert gene has undergone structural changes soon after the emergence of the platyhelminth lineage, which might have been coordinated with those of its functional counterpart, the telomerase RNA molecule.

Repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. Repeat-associated non-AUG (RAN) translation generates neurotoxic dipeptide repeat proteins (DPRs). To study endogenous DPRs, we inserted the minimal HiBiT luciferase reporter downstream of sense repeat derived DPRs polyGA or polyGP in C9orf72 patient iPSCs. We show these "DPReporter" lines sensitively and rapidly report DPR levels in lysed and live cells and optimize screening in iPSC neurons. Small-molecule screening showed the ERK1/2 activator periplocin dose dependently increases DPR levels. Consistent with this, ERK1/2 inhibition reduced DPR levels and prolonged survival in C9orf72 repeat expansion flies. CRISPR knockout screening of all human helicases revealed telomere-associated helicases modulate DPR expression, suggesting common regulation of telomeric and C9orf72 repeats. These DPReporter lines allow investigation of DPRs in their endogenous context and provide a template for studying endogenous RAN-translated proteins, at scale, in other repeat expansion disorders.

The integrity of plant genomes is intricately safeguarded by telomeres, the protective caps located at the ends of the chromosome. This review provides a comprehensive analysis of the molecular mechanisms governing the structure, maintenance, and dynamics of plant telomeres, highlighting their genetic and epigenetic regulation and their pivotal roles in plant development, longevity, stress adaptation, and disease resistance. Recent advancements, such as next-generation sequencing and single-molecule imaging, have revolutionized our understanding of telomere biology, unveiling new insights into telomerase activity and telomere-associated genetic variants. Additionally, the review also discusses the challenges and future directions of telomere research, including the potential applications of telomere biology in plant breeding and genetic engineering.

Aging is the greatest risk factor for a multitude of age-related diseases including sarcopenia-the loss of skeletal muscle mass and strength-which occurs at remarkable rates each year. There is an unmet need not only to understand the mechanisms that drive sarcopenia but also to identify novel therapeutic strategies. Given the ease and affordability of husbandry, along with advances in genomics, genome editing technologies, and imaging capabilities, teleost models are increasingly used for aging and sarcopenia research. Here, we explain how teleost species such as zebrafish, African turquoise killifish, and medaka recapitulate many of the classical hallmarks of sarcopenia, and discuss the various dietary, pharmacological, and genetic approaches that have been used in teleosts to understand the mechanistic basis of sarcopenia.

Saccharomyces cerevisiae, a model organism in telomere biology, has been instrumental in pioneering a comprehensive understanding of the molecular processes that occur in the absence of telomerase across eukaryotes. This exploration spans investigations into telomere dynamics, intracellular signaling cascades, and organelle-mediated responses, elucidating their impact on proliferative capacity, genome stability, and cellular variability. Through the lens of budding yeast, numerous sources of cellular heterogeneity have been identified, dissected, and modeled, shedding light on the risks associated with telomeric state transitions, including the evasion of senescence. Moreover, the unraveling of the intricate interplay between the nucleus and other organelles upon telomerase inactivation has provided insights into eukaryotic evolution and cellular communication networks. These contributions, akin to milestones achieved using budding yeast, such as the discovery of the cell cycle, DNA damage checkpoint mechanisms, and DNA replication and repair processes, have been of paramount significance for the telomere field. Particularly, these insights extend to understanding replicative senescence as an anticancer mechanism in humans and enhancing our understanding of eukaryotes' evolution.

Telomerase reactivation allows cancer cells to maintain telomere length and evade senescence, making it an appealing therapeutic target. Imetelstat, an antisense oligonucleotide, is the first clinically effective telomerase inhibitor approved by the FDA and the European Commission for treating anemia in transfusion-dependent low-risk myelodysplastic syndromes (MDS).

Sources for this review were identified through searches of PubMed, ClinicalTrials.gov, and conference abstracts. This review highlights the pharmacology, efficacy, and ongoing trials of imetelstat in treating MDS, myelofibrosis, essential thrombocythemia, and other malignancies. In the IMerge trial, imetelstat induced durable transfusion independence in heavily transfused LR-MDS patients. Pilot trials in myelofibrosis suggest imetelstat's potential disease-modifying properties and survival benefit, warranting further studies of imetelstat as a monotherapy or in combination therapies. Imetelstat can cause thrombocytopenia, leukopenia, elevated liver enzymes, and infusion reactions, which are mostly reversible but may rarely lead to fatal events.

Future clinical trials in LR-MDS should focus on optimal sequencing and combination strategies for imetelstat with other agents, and identifying biomarkers that can predict response. Monitoring real-world outcomes will offer valuable insights into imetelstat's safety and efficacy in patient populations underrepresented in clinical trials. Imetelstat's role in other malignancies, especially myelofibrosis, is being explored.

Aging is the primary risk factor for the development of many chronic diseases, including dementias, cardiovascular disease, and diabetes. There is significant interest in identifying novel "geroprotective" agents, including by repurposing existing drugs, but such treatments may affect organ systems differently. One current example is the nucleoside reverse transcriptase inhibitor 3TC, which has been increasingly studied as a potential gerotherapeutic. Recent data suggest that 3TC may reduce inflammation and improve cognitive function in older mice; however, the effects of 3TC on other tissues in aged animals are less well characterized. Here, we use transcriptomics (RNA-seq) and targeted metabolomics to investigate the influence of 3TC supplementation on skeletal muscle in older mice. We show that 3TC 1) does not overtly affect muscle mass or functional/health markers, 2) largely reverses age-related changes in gene expression and metabolite signatures, and 3) is potentially beneficial for mitochondrial function in old animals via increases in antioxidant enzymes and decreases in mitochondrial reactive oxygen species. Collectively, our results suggest that, in addition to its protective effects in other tissues, 3TC supplementation does not have adverse effects in aged muscle and may even protect muscle/mitochondrial health in this context.NEW & NOTEWORTHY Recent studies suggest that the nucleoside reverse transcriptase inhibitor 3TC may improve brain health and cognitive function in old mice, but its effects on other aging tissues have not been comprehensively studied. This is the first study to use a multiomics approach to investigate the effects of 3TC treatment on skeletal muscle of old mice. The results suggest that 3TC reverses age-related transcriptomic and metabolite signatures and is potentially beneficial for mitochondrial function in aged muscle.

A significant increase in life expectancy worldwide has resulted in a growing aging population, accompanied by a rise in aging-related diseases that pose substantial societal, economic, and medical challenges. This trend has prompted extensive efforts within many scientific and medical communities to develop and enhance therapies aimed at delaying aging processes, mitigating aging-related functional decline, and addressing aging-associated diseases to extend health span. Research in aging biology has focused on unraveling various biochemical and genetic pathways contributing to aging-related changes, including genomic instability, telomere shortening, and cellular senescence. The advent of induced pluripotent stem cells (iPSCs), derived through reprogramming human somatic cells, has revolutionized disease modeling and understanding in humans by addressing the limitations of conventional animal models and primary human cells. iPSCs offer significant advantages over other pluripotent stem cells, such as embryonic stem cells, as they can be obtained without the need for embryo destruction and are not restricted by the availability of healthy donors or patients. These attributes position iPSC technology as a promising avenue for modeling and deciphering mechanisms that underlie aging and associated diseases, as well as for studying drug effects. Moreover, iPSCs exhibit remarkable versatility in differentiating into diverse cell types, making them a promising tool for personalized regenerative therapies aimed at replacing aged or damaged cells with healthy, functional equivalents. This review explores the breadth of research in iPSC-based regenerative therapies and their potential applications in addressing a spectrum of aging-related conditions.

Background: Aplastic anemia (AA) is a rare bone marrow failure syndrome characterized by notably short telomere length, which is associated with treatment responses. In this study, we measured telomere lengths in Korean pediatric AA patients using flow-fluorescence in situ hybridization (Flow-FISH) and explored their shortening in relation to disease characteristics, genetic conditions and patient outcomes. Methods: We analyzed peripheral blood samples from 75 AA patients and 101 healthy controls. Telomere lengths were measured using Flow-FISH, and relative telomere length (RTL) and delta RTL assessments were conducted. Genetic evaluations included karyotyping, chromosome breakage tests and clinical exome sequencing (CES) to identify inherited bone marrow failure syndrome (IBMFS)-associated genetic variants. Results: Telomere lengths in AA patients were significantly lower than those of age-adjusted healthy controls. Patients receiving immunosuppressive therapy tended to have long telomeres, as indicated by high delta RTL values. Patients with genetic abnormalities, including karyotype abnormalities (n = 2) and genetic variants (n = 11) such as carrier genes of IBMFS or variants of unclear significance, showed significantly short telomere lengths. Conclusions: This study reinforces the importance of telomere length as a biomarker in acquired AA. Utilizing Flow-FISH, we were able to accurately measure telomere lengths and establish confidence in this method as an appropriate laboratory test. We found significant reduction in telomere lengths in AA patients, and importantly, longer telomeres were correlated with better outcomes in immunosuppressive therapy. Additionally, our genetic analysis underscored the relevance of variants in IBMFS-associated genes to the pathophysiology of short telomeres.

Skeletal muscle aging, characterized by progressive declines in muscle mass and strength, correlates with reduced quality of life and increased mortality. Resistance exercise is known to be critical for maintaining skeletal muscle health. This study investigated the effects of aging and resistance exercise on muscle strength, physiological properties, longevity proteins, and telomere length in mice. Twenty-eight-week-old senescence-accelerated mouse prone 8 (SAMP8) mice were used as a model for muscle aging, with senescence-accelerated mouse resistant 1 (SAMR1) mice serving as healthy controls. The mice underwent a 12-week regimen of ladder-climbing training, a form of resistance exercise, performed three days per week. After the training, muscle strength and muscle weight were measured. Levels of the longevity proteins adenosine monophosphate-activated kinase (AMPK), mammalian target of rapamycin (mTOR), and sirtuin 1 (SIRT1) were assessed via western blotting, and telomere length was evaluated by qPCR. SAMP8 mice exhibited significantly lower muscle mass and strength than SAMR1 mice, while resistance exercise attenuated these deficits in SAMP8 mice. SAMP8 mice showed elevated AMPK phosphorylation and SIRT1 levels compared to SAMR1 mice; resistance exercise normalized AMPK phosphorylation levels to approximate those of SAMR1 mice. mTOR activity was significantly reduced in SAMP8 mice but tended to be restored by resistance exercise. Telomere length remained unchanged in SAMP8 mice after resistance exercise compared to their sedentary controls. In conclusion, aging reduces muscle function and disrupts levels of longevity proteins. Resistance exercise mitigates these effects by improving muscle function and restoring molecular balance.

To determine the association between telomere length (TL) and age-related macular degeneration (AMD) and examine the potential variations with sex and ethnicity.

Population-based, cross-sectional study. A total of 52,083 participants from the UK Biobank were included. Leucocyte TL, measured using quantitative polymerase chain reaction assay, was presented as the ratio of telomere repeat copy number relative to that of a single copy gene, and then log-transformed and Z-standardised. AMD cases were identified based on a combination of in-patient, self-reported and primary care data, and furtherly classified as early, intermediate and late AMD using the Beckmann classification system (based on more severe eye).

Among the 52,083 participants aged 60.2 ± 5.4 years, 725 were any-AMD cases. AMD patients had shorter TL than those without AMD (-0.22 ± 0.95 vs. -0.10 ± 0.99, P = 0.001). In multivariable model, shorter TL (per standard deviation) was significantly associated with higher odds of AMD in Whites (OR:1.09; 95% CI: 1.01-1.18; P = 0.036). When stratified by sex and ethnicity, this association was only significant in White women (OR:1.14; 95%CI: 1.02, 1.27; P = 0.018), but not in men and nonwhite populations (all P ≥ 0.335). Among white women, the association was more pronounced (OR:1.47; 95%CI:1.23-1.77; P < 0.001) for intermediate/late AMD but not for early AMD (P = 0.789).

Shorter TL was associated with any AMD in white women but not in men and other ethnicities. Our findings highlight the potential role of telomere length in the pathogenesis of AMD and the importance of considering sex and ethnicity variation in this research area.

Early life telomere length is thought to influence and predict an individual's fitness. It has been shown to vary significantly in early life compared to adulthood. Investigating the factors influencing telomere length in young individuals is therefore of particular interest, especially as the relative importance of heredity compared to post-natal conditions remains largely uncertain. Adélie penguins are eco-indicators of the Antarctic ecosystem and their population are currently undergoing variable trajectories due to climate change. Here, we conducted a correlative study to investigate how telomere length was influenced by external and internal factors in Adélie penguin chicks. We found that most of the parameters we tested, including sex, body mass, brood size and hatching order as well as parental foraging trip duration, did not significantly influence chick telomere length at 32 days. However, siblings had similar telomere length, suggesting that hereditary factors play a stronger role in determining telomere length at this stage compared to the post-natal environment. In addition, telomere length and oxidative damage did not directly correlate but did interact in a complex way mediated by chick mass. High levels of oxidative damage were associated with longer telomeres in heavy chicks, whereas they were associated with shorter telomeres in light chicks. Although this mass-dependent relationship between telomere length and oxidative damage needs to be confirmed in future studies, it could reflect two different scenarios: (1) short telomeres may mimic the cost of poor nutritional conditions and oxidative damage in light chicks; (2) long telomeres may be maintained despite high oxidative damage in heavy chicks thanks to optimal nutritional conditions.

Telomeres protect the ends of chromosomes but shorten following cell division in the absence of telomerase activity. When telomeres become critically short or damaged, a DNA damage response is activated. Telomeres then become dysfunctional and trigger cellular senescence or death. Telomere shortening occurs with ageing and may contribute to associated maladies such as infertility, neurodegeneration, cancer, lung dysfunction and haematopoiesis disorders. Telomere dysfunction (sometimes without shortening) is associated with various diseases, known as telomere biology disorders (also known as telomeropathies). Telomere biology disorders include dyskeratosis congenita, Høyeraal-Hreidarsson syndrome, Coats plus syndrome and Revesz syndrome. Although mouse models have been invaluable in advancing telomere research, full recapitulation of human telomere-related diseases in mice has been challenging, owing to key differences between the species. In this Review, we discuss telomere protection, maintenance and damage. We highlight the differences between human and mouse telomere biology that may contribute to discrepancies between human diseases and mouse models. Finally, we discuss recent efforts to generate new 'humanized' mouse models to better model human telomere biology. A better understanding of the limitations of mouse telomere models will pave the road for more human-like models and further our understanding of telomere biology disorders, which will contribute towards the development of new therapies.

While previous research has demonstrated the therapeutic efficacy of telomerase reverse transcriptase (TERT) overexpression using adeno-associated virus and cytomegalovirus vectors to combat aging, the broader implications of TERT germline gene editing on the mammalian genome, proteomic composition, phenotypes, lifespan extension, and damage repair remain largely unexplored. In this study, we elucidate the functional properties of transgenic mice carrying the Tert transgene, guided by precise gene targeting into the Rosa26 locus via embryonic stem (ES) cells under the control of the elongation factor 1α (EF1α) promoter. The Tert knock-in (TertKI) mice harboring the EF1α-Tert gene displayed elevated telomerase activity, elongated telomeres, and extended lifespan, with no spontaneous genotoxicity or carcinogenicity. The TertKI mice showed also enhanced wound healing, characterized by significantly increased expression of Fgf7, Vegf, and collagen. Additionally, TertKI mice exhibited robust resistance to the progression of colitis induced by dextran sodium sulfate (DSS), accompanied by reduced expression of disease-deteriorating genes. These findings foreshadow the potential of TertKI as an extraordinary rejuvenation force, promising not only longevity but also rejuvenation in skin and intestinal aging.

Aging is the leading risk factor for Alzheimer's Disease (AD). Understanding the intricate interplay between biological aging and the AD pathophysiology may help to discover innovative treatments. The relationship between aging and core pathways of AD pathogenesis (amyloidopathy and tauopathy) have been extensively studied in preclinical models. However, the potential discordance between preclinical models and human pathology could represent a limitation in the identification of new therapeutic targets. This narrative review aims to gather the evidence currently available on the associations of β-Amyloid and Tau pathology with the hallmarks of aging in human studies. Briefly, our review suggests that while several hallmarks exhibit a robust association with AD pathogenesis (e.g., epigenetic alterations, chronic inflammation, dysbiosis), others (e.g., telomere attrition, cellular senescence, stem cell exhaustion) demonstrate either no relationship or weak associations. This is often due to limitations such as small sample sizes and study designs, being either cross-sectional or with short follow-up intervals, limiting the generalizability of the findings. Distinct hallmarks play varying roles in different stages of AD pathology, emphasizing the need for longitudinal studies with longer follow-up periods. Considering the intricate interconnections across the hallmarks of aging, future research on AD pathology should focus on multiple hallmarks simultaneously.

The reactivation of telomerase enables cancer cells to maintain the telomere length, bypassing replicative senescence and achieving cellular immortality. In addition to its canonical role in telomere maintenance, accumulating evidence highlights telomere-length-independent functions of TERT, the catalytic subunit of telomerase. These extratelomeric functions involve the regulation of signaling pathways and transcriptional networks, creating feed-forward loops that promote cancer cell proliferation, resistance to apoptosis, and disease progression. This review explores the complex mechanisms by which TERT modulates key signaling pathways, such as NF-κB, AKT, and MYC, highlighting its role in driving autonomous cancer cell growth and resistance to therapy in B-cell malignancies. Furthermore, we discuss the therapeutic potential of targeting TERT's extratelomeric functions. Unlike telomere-directed approaches, which may require prolonged treatment to achieve effective telomere erosion, inhibiting TERT's extratelomeric functions offers the prospect of rapid tumor-specific effects. This strategy could complement existing chemotherapeutic regimens, providing an innovative and effective approach to managing B-cell malignancies.

Given the growing challenges posed by an ageing population, particularly in Western countries, we aimed to investigate the potential geroprotective effects of resveratrol and melatonin in ageing rats.

The animals were treated with these two compounds starting at 3 months of age and continuing until 1 year or 2 years of age. Using a multibiomarker approach, we assessed DNA damage, telomere length, and the oxidative status in their urine, liver, and kidneys.

Despite employing this experimental approach, our results did not provide conclusive evidence of geroprotective effects across the evaluated organs. However, we observed sex-dependent differences in response to treatment.

Given the high potency of these two compounds, further research is warranted to explore their incorporation into daily routines as a strategy to mitigate ageing-related effects.

Human telomere length is tightly regulated and associated with diseases at either extreme, but how these bounds are established remains incompletely understood. Here, we developed a rapid cell-based telomere synthesis assay and found that nucleoside salvage bidirectionally constrains human telomere length. Metabolism of deoxyguanosine (dG) or guanosine via purine nucleoside phosphorylase (PNP) and hypoxanthine-guanine phosphoribosyltransferase to form guanine ribonucleotides strongly inhibited telomerase and shortened telomeres. Conversely, salvage of dG to its nucleotide forms via deoxycytidine kinase drove potent telomerase activation, the extent of which was controlled by the dNTPase SAMHD1. Circumventing limits on salvage by expressing Drosophila melanogaster deoxynucleoside kinase or augmenting dG metabolism using the PNP inhibitor ulodesine robustly lengthened telomeres in human cells, including those from patients with lethal telomere diseases. Our results provide an updated paradigm for telomere length control, wherein telomerase reverse transcriptase activity is actively and bidirectionally constrained by the availability of its dNTP substrates, in a manner that may be therapeutically actionable.

The rising intake of ultra-processed foods (UPFs) has been linked to adverse health outcomes, yet its impact on aging acceleration remains unclear.

This study aimed to examine the association between the percentage of total daily calories (%Kcal) and grams (%Gram) from UPFs and phenotypic age acceleration (PhenoAgeAccel).

Data from 12,079 adults in the NHANES 2005-2010 cycles were analyzed. The relationship between UPFs intake and PhenoAgeAccel was assessed using multivariable linear regression and restricted cubic splines, with adjustments for relevant covariates. The mediating role of body mass index (BMI) was also explored.

A significant positive linear association was observed between UPFs intake (%Gram) and PhenoAgeAccel, with the highest quartile showing an increase of 0.60 (95% CI: 0.15, 1.05; p for trend = 0.039), but no association was found between UPFs intake (%Kcal) and PhenoAgeAccel. Mediation analysis indicated that BMI mediated 27.5% of the association between UPFs intake (%Gram) and PhenoAgeAccel. Sensitivity analyses confirmed the robustness of the results.

Higher intake of UPFs intake (%Gram) is positively associated with PhenoAgeAccel, with BMI playing a significant mediating role.

Few studies have investigated the associations between perchlorate, nitrate, and thiocyanate (PNT) and biological aging. This study aimed to assess the association between PNT and biological aging among U.S. adults.

Utilizing multivariable linear regression and restricted cubic splines (RCS), we analyzed urinary PNT levels' impact on phenotypic age and biological age. Subgroup and sensitivity analyses were also conducted. Weighted Quantile Sum (WQS) and Bayesian Kernel Machine Regression (BKMR) models examined PNT mixtures.

8,368 participants were analyzed. Mean phenotypic age was 43.05 ± 0.48 years, mean biological age was 47.08 ± 0.4 years. Multivariable linear regression showed significant negative associations between higher PNT levels and phenotypic age (perchlorate β = -0.6, 95% CI: -0.93 to -0.27; nitrate β = -0.81, 95% CI: -1.19 to -0.42; thiocyanate β = -0.56, 95% CI: -0.77 to -0.34) after covariates adjusted. RCS demonstrated negative nonlinear relationships between PNT exposure and phenotypic age (nonlinear p values: 0.002, <0.001, and <0.001), with stable results in sensitivity analyses. Nitrate exposure showed a significant negative association with biological age (β = -0.78, 95% CI: -1.13 to -0.44), indicating a consistent negative linear relationship observed through RCS and remaining stable across sensitivity analyses. WQS regression revealed a negative association between the mixture and phenotypic age in both positive and negative directions, with a significant negative association with biological age in the negative direction. BKMR analysis revealed a negative association between PNT mixtures and phenotypic age, with nitrate and thiocyanate identified as the primary predictors of phenotypic age. No association found between PNT mixture and biological age.

Individual or combined PNT are negatively associated with phenotypic age. High nitrate is associated with reduced biological age, showcasing consistent outcomes.

Mitochondrial DNA (mtDNA) release into the cytosol is a critical event in innate immune activation, often acting as a damage-associated molecular pattern (DAMP) that triggers inflammasome assembly. Here, we demonstrate that NLRP3 plays a direct role in cleaving and facilitating the release of D-loop mtDNA into the cytosol. We further show that NLRP3 interacts with NLRP10. NLRP10-mediated ox-DNA cleavage involves a Schiff base intermediate and is inhibited by small molecules known to inhibit glycosylases. These findings support a model where NLRP10 interaction with oxidized DNA may contribute to long-term senescence secretory phenotype and modulate inflammasome activation. Our study highlights a novel mechanism by which NLRP10 can respond to mitochondrial stress signals to influence innate immunity and suggests therapeutic potential for targeting these interactions in inflammatory diseases.

Skin aging represents a multifactorial process influenced by both intrinsic and extrinsic factors, collectively known as the skin exposome. Cellular senescence, characterized by stable cell cycle arrest and secretion of pro-inflammatory molecules, has been implicated as a key driver of physiological and pathological skin aging. Increasing evidence points towards the role of senescence in a variety of dermatological diseases, where the accumulation of senescent cells in the epidermis and dermis exacerbates disease progression. Emerging therapeutic strategies such as senolytics and senomorphics offer promising avenues to target senescent cells and mitigate their deleterious effects, providing potential treatments for both skin aging and senescence-associated skin diseases. This review explores the molecular mechanisms of cellular senescence and its role in promoting age-related skin changes and pathologies, while compiling the observed effects of senotherapeutics in the skin and discussing the translational relevance.

The constant exposure of the skin to internal and external stimuli drives towards skin aging and lost in skin hydration and elasticity. Chronic low-grade inflammation, called inflammaging, and oxidative stress are the leading causes of this phenomenon. Fatty acid coacervation is a preparation method for Solid Lipid Nanoparticles (SLNs), which does not employ solvents, and is associated to low energy consumption. Of note, Green SLNs by coacervation may be obtained from natural soaps. Within this concern, in this experimental work, Mango and Shea SLNs, prepared by coacervation from the corresponding vegetal soaps, were loaded with an UV-filter, 2-ethylhexyl 4-(dimethylamino)benzoate, and two anti-age ingredients, α-Tocopherol and Tocopheryl nicotinate, and characterized by a physico-chemical standpoint. Such Green cosmetic SLNs were monitored for stability after storage at 4, 25, 40 °C for 28 days. Moreover, an anti-age serum and hydrogel were prepared, based upon Green cosmetic SLNs. Stability studies were performed on sera and hydrogels, including physico-chemical stability studies (rheology, pH, centrifugation) and evaluation of organoleptic characteristics (appearance, odour, colour) after storage at 4, 25, 40 °C up to 1 year, with the best results obtained for Mango SLNs-based serum. Therefore, Franz cells studies with pig-ear skin were carried out on Mango SLNs and Mango SLNs-based serum, showing that loading in SLNs enhances the permeation of compounds. A challenge test and a patch test assessed the safety of such serum for human usage, and an efficacy study on human volunteers demonstrated its capability to increase skin hydration and elasticity.

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.

The threats to chemical warfare-associated agents (CWA), including nitrogen mustard, are increasing, and no direct antidote is currently available to mitigate the deleterious cutaneous and systemic responses to prevent mortality. Though most of these agents act as alkylating agents, a significant knowledge gap exists in the molecular mechanisms of how these vesicants cause toxic effects. Studies, including ours, have shown that exposure to reactive oxygen species (ROS)-generating stimuli, including alkylating chemotherapeutic agents, and thermal burn injuries with ethanol produce the potent family of lipid mediators, Platelet-activating factor (PAF) agonists that induce local inflammation, and multi-system organ dysfunction (MOD). Notably, nano-sized microvesicle particles (MVPs), released from cells in response to stimuli, carry PAF-agonists and act as potent signaling agents to induce the local (cutaneous) and systemic responses. The current review highlights mechanistic insights and applicable approaches to mitigate CWA-induced local and systemic toxic responses with implications in cellular senescence and aging.

The aim of this study was to explore the systemic inflammation response in relation to mortality in Helicobacter pylori (H. pylori) infection, and whether this relationship was mediated by accelerated biological aging.

This cross-sectional study encompassed U.S. participants from National Health and Nutrition Examination Survey (NHANES) in 1999-2000. Kaplan-Meier survival curve, Cox regression analysis, K-means clustering, mediation analysis and restricted cubic spline (RCS) were used to explore the relationships between inflammatory markers, biological aging, H. pylori infection and all-cause mortality.

A total of 3509 U.S. participants enrolled form NHANES 1999-2000. Compared with H. pylori seronegative participants, H. pylori seropositive participants had significantly higher all-cause mortality (P < 0.001). Among these H. pylori seropositive participants, both phenotypic age acceleration (PhenoAgeAccel) and all-cause mortality were positively associated with the increased levels of inflammation (P < 0.001). A significant indirect effect of inflammatory markers (neutrophil count and systemic inflammatory response index (SIRI)) with H. pylori infection on all-cause mortality through PhenoageAccel was found, and the proportions mediated were 50.0% and 49.1%, respectively.

The elevation of blood inflammatory markers is positively associated with an increased risk of all-cause mortality in H. pylori infection among U.S. population, and accelerated biological aging might be one of its biological mechanisms.

Fission yeast is the ideal model organism for studying telomere maintenance in higher eukaryotes. Telomere length has been directly correlated with life expectancy and the onset of aging-related diseases in mammals. In this study, we developed a novel simple, and reproducible method to measure the telomere length, by investigating the effect of caffeine and cisplatin on the telomere length in fission yeast. Hydroxyurea-synchronized fission yeast cells were exposed to 62 µM cisplatin and 8.67 mM caffeine treatments for 2 h, then their telomere lengths were evaluated with two different methods. First, the quantitative polymerase chain reaction (qPCR) assay was used as a confirmative method, where telomere length was determined relative to a single-copy gene in the genome. Second, the newly developed method standard polymerase chain reaction (PCR)/ImageJ assay assessed the telomere length based on the amplified PCR band intensity using a set of telomere primers, reflecting telomeric sequence availability in the genome. Both methods show a significant decrease and a notable telomere lengthening in response to cisplatin and caffeine treatments, respectively. The finding supports the accuracy and productivity of the standard PCR/ImageJ assay as it can serve as a quick screening tool to study the effect of suspected chemotherapeutic and antiaging drugs on telomere length in fission yeast.

Virus-induced senescence (VIS) is a significant biological phenomenon, which is associated with declining immune function, accelerating aging process and causing aging-related diseases. A variety of common viruses, including RNA viruses (such as SARS-CoV-2), DNA viruses (such as herpesviruses and hepatitis B virus), and prions can cause VIS in host cells. The primary mechanisms include abnormal activation of the cGAS-STING signaling pathway, DNA damage response, and potential correlations with the integrated stress response due to intracellular phase separation. Viral infection and cellular senescence influence each other: cellular senescence serves as a defense to restrict viral replication and transmission, while some viruses exploit cellular senescence to enhance their infectivity and replication. Understanding the mechanisms of VIS is conducive to the development of therapeutic strategies for viral infections and promotion of healthy aging. However, there is lack of research on therapeutic targets and drug development in this field so far. Although senolytics may be effective for anti-senescent cells therapy, their efficacy for VIS needs evidence from further clinical trials. This article reviews the research progress on the connection between viral infection and cellular senescence, to provide insights for the prevention and treatment of aging related diseases.

Biogenesis of human telomerase requires its RNA subunit (hTR) to fold into a multi-domain architecture that includes the template-pseudoknot (t/PK) and the three-way junction (CR4/5). These hTR domains bind the telomerase reverse transcriptase (hTERT) protein and are essential for telomerase activity. Here, we probe hTR structure in living cells using dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) and ensemble deconvolution analysis. Approximately 15% of the steady state population of hTR has a CR4/5 conformation lacking features required for hTERT binding. The proportion of hTR CR4/5 folded into the primary functional conformation is independent of hTERT expression levels. Mutations that stabilize the alternative CR4/5 conformation are detrimental to telomerase assembly and activity. Moreover, the alternative CR4/5 conformation is not found in purified telomerase RNP complexes, supporting the hypothesis that only the primary CR4/5 conformer is active. We propose that this misfolded portion of the cellular hTR pool is either slowly refolded or degraded, suggesting that kinetic RNA folding traps studied in vitro may also hinder ribonucleoprotein assembly in vivo.