Longevity Papers

Activation of hepatic stellate cells (HSCs) represents a central pathological event in liver fibrogenesis, and targeted clearance of activated HSCs is considered to be a promising therapeutic strategy. However, our understanding of the underlying molecular mechanisms is limited. Here, we report that Oroxylin A (OA) inhibited the activation of HSCs by inhibiting the dual roles of Sirtuin 7 (SIRT7). Single-cell transcriptome sequencing analysis and bioinformatics analysis were employed to identify critical pathways, followed by validation through molecular assays including Western blotting, immunofluorescence, and co-immunoprecipitation. In human samples, animal models, and primary cultures, the translational relevance of molecular discoveries was heightened. OA binds to the Gln299 and Asp305 residues of SIRT7, triggering a dual regulatory program in hepatic fibrosis. OA suppresses SIRT7, triggering succinylation-dependent proteasomal degradation of protein arginine methyltransferase 5 (PRMT5). This cascade attenuated symmetric dimethylation of cyclic GMP-AMP synthase (cGAS), thereby activating the cGAS-stimulator of interferon genes (STING) signaling and promoting HSC senescence. Concurrently, OA-elicited SIRT7 inhibition promotes externalized calreticulin (ecto-CRT) expression, thereby enhancing natural killer (NK) cell recognition and targeted elimination of activated HSCs. However, enzymatically dead mutant SIRT7 (H187Y) also suppressed ecto-CRT expression promoted by OA, showing that it is independent of its desuccinylase activity. Our findings reveal a dual regulatory mechanism whereby SIRT7 inhibition by OA coordinates PRMT5 degradation-mediated cellular senescence and ecto-CRT-dependent NK cell immune clearance of HSCs. This work establishes SIRT7 as a pivotal therapeutic target and provides mechanistic insights for developing antifibrotic strategies.

Microdefects, including microcracks and resorption trenches, may be important contributors to bone fragility. 3D microdefect morphology was imaged using synchrotron micro-CT to develop a classification system for investigating the relationship with bone mechanics and hip-fractures. Femoral heads from ageing hip-fracture patients (n = 5, 74-82 years) were compared to ageing non-fracture controls (n = 5, 72-84 years). Two trabecular cores were prepared from the chiasma; one was imaged using synchrotron micro-CT to measure microdefects and one was mechanically tested to measure tensile strength. Morphological and mechanical data were compared and correlated using Mann Whitney U test and Pearson's rank correlation. All the procedures performed were in accordance with the ethical standards of the Imperial College Tissue Bank (R13004) and the 1984 Declaration of Helsinki. Microdefects varied and were classified into four categories based on shape and measurable parameters. Hip-fracture donors exhibited significantly higher density of all microdefects (p < 0.05). Microdefect volume was strongly negatively correlated with ultimate tensile strength (p < 0.05) and stiffness (p < 0.05). Microdefects might contribute to loss of bone strength and fragility fracture via runaway resorption. Microcracks could promote focussed osteoclastic resorption and the formation of resorption pits which create stress risers leading to the re-formation of microcracks under continued load. CT-based classification methods should be used to explore the complex interaction between microdefects, metabolism, and bone fracture mechanics.

To sustain the essential biological functions required for life, eukaryotic cells rely on complex interactions between different intracellular compartments. Membrane contact sites (MCS), regions where organelles come into close proximity, have recently emerged as major hubs for cellular communication, mediating a broad range of physiological processes, including calcium signalling, lipid synthesis and bioenergetics. MCS are particularly abundant and indispensable in polarized and long-lived cells, such as neurons, where they support both structural and functional integrity. In this review, we explore the functional diversity, molecular composition, and dynamic regulation of key mammalian MCS: endoplasmic reticulum (ER)-plasma membrane, ER-mitochondria and contact sites involving lipid droplets. We highlight their central role in neuronal health and discuss how MCS dysfunction has increasingly been recognized as a hallmark of brain aging and various neurodegenerative diseases, most notably Alzheimer's disease, where altered MCS dynamics contribute to pathogenesis. Finally, we emphasize the therapeutic potential of targeting MCS and outline key unanswered questions to guide future research.

In this paper, we advance the network theory of aging and mortality by developing a causal mathematical model for the mortality rate. First, we show that in large networks, where health deficits accumulate at nodes representing health indicators, the modelling of network evolution with Poisson processes is universal and can be derived from fundamental principles. Second, with the help of two simplifying approximations, which we refer to as mean-field assumption and homogeneity assumption, we provide an analytical derivation of Gompertz law under generic and biologically relevant conditions. Third, we identify for which network parameters Gompertz law is accurate, express the parameters in Gompertz law as a function of the network parameters, and illustrate our computations with simulations and analytic approximations. Our paper is the first to offer a full mathematical explanation of Gompertz law and its limitations based on network theory.

Aging increases the risk of developing fibrotic diseases by hampering tissue regeneration after injury. Using longitudinal single-cell RNA-seq and spatial transcriptomics, here we compare the transcriptome of bleomycin (BLM) -induced fibrotic lungs of young and aged male mice, at 3 time points corresponding to the peak of fibrosis, regeneration, and resolution. We find that lung injury shifts the transcriptomic profiles of three pulmonary capillary endothelial cells (PCEC) subpopulations. The associated signatures are linked to pro-angiogenic signaling with strong Lrg1 expression and do not progress similarly throughout the resolution process between young and old animals. Moreover, part of this set of resolution-associated markers is also detected in PCEC from samples of patients with idiopathic pulmonary fibrosis. Finally, we find that aging also alters the transcriptome of PCEC, which displays typical pro-fibrotic and pro-inflammatory features. We propose that age-associated alterations in specific PCEC subpopulations may interfere with the process of lung progenitor differentiation, thus contributing to the persistent fibrotic process typical of human pathology.

A randomized, placebo-controlled citizen science-based dietary intervention was conducted among 147 healthy adults to evaluate the effects of 8-week high dietary fiber (HDF) and high fermented food (HFF) diets on gut microbiota, immune function, gut transit time, well-being, and sleep quality. The HDF group significantly increased fiber intake ({Delta}10.3 g/1000 kcal/day) following high dietary fiber recipes with addition of dried chicory root, while the HFF group increased fermented food consumption (+6.3 portions/day), including a fermentation-derived liquid supplement. At the 21-week follow-up, modest improvements in fiber and fermented intake were sustained, compared to baseline. Microbial diversity significantly increased within the HFF and control groups, especially in HFF participants over 50 (p = 0.04). Compared to CG, HFF showed no difference in microbial diversity, whereas the HDF group showed a significant decrease. The HDF intervention enhanced butyrogenic potential by increasing Anaerostipes, Faecalibacterium, and Bifidobacterium spp., and significantly reduced gastrointestinal transit time (p = 0.01). The intake of high fiber improved and sustained sleep quality (p = 0.03). The HFF intervention significantly increased blood immune markers including CD5, CD6 and CD8A (T-cell activation), IL-18R1 (inflammatory signaling) and SIRT2, a longevity-associated deacetylase (Q < 0.05), and induced a modest shift in the gut microbiota of participants over 50 years toward a composition characteristic of younger participants. These findings highlight distinct biological pathways through which dietary fibers and fermented foods modulate host physiology. This is the first randomized controlled nutritional intervention using a citizen science approach that demonstrates the feasibility and scientific value of engaging participants in healthier food choices.

Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells. Chronic inflammation contributes to a variety of age-related diseases, such as neurodegenerative disease, cancer, infectious disease, and autoimmune diseases. Although not fully understood, recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels. Immunosenescence is associated with dysregulated signaling pathways (e.g., overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway) and abnormal immune cell responses with functional alterations and phenotypic shifts. These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases. Some anti-immunosenescence treatments have already shown promising results in clinical trials. In this review, we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases. Potential interventions to mitigate immunosenescence, including reshaping immune organs, targeting different immune cells or signaling pathways, and nutritional and lifestyle interventions, are summarized. Some treatment strategies have already launched into clinical trials. This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence, thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.

Older individuals are typically more susceptible to stroke, and age-related differences in brain plasticity significantly affect recovery and treatment responses following cerebral ischemia and traumatic brain injury. Extracellular vesicles (EVs) have emerged as promising diagnostic and therapeutic tools due to their role in intercellular communication and ability to cross the blood-brain barrier. While EVs hold potential in promoting brain repair, their efficacy is influenced by donor age-those derived from young stem cells exhibit more regenerative profiles, whereas aged donor EVs may carry senescence-related signals that impede recovery. Emerging therapies, including senolytics, exosome-based approaches, and immune modulation, aim to enhance post-stroke repair, yet a substantial translational gap persists, especially in adapting these strategies to the aged brain. Differences in immune responses, neurovascular integrity, and repair mechanisms between young and aged individuals further complicate therapeutic development. Incorporating aged animal models in preclinical research is thus essential for ensuring the relevance and safety of interventions in elderly patients. These findings underscore the need for age-tailored strategies that reflect the unique biological landscape of aging, paving the way for more effective treatments for stroke and related neurological conditions in older adults.

The desire to increase life expectancy, coupled with the decline in biological functions that occurs as we age, represents one of the most significant challenges facing our society. Age-related declines in biological functions contribute to frailty and morbidity, demanding innovative strategies to promote healthy aging. The circadian clock, which controls daily physiological processes, is intricately linked to aging and overall health. Circadian disruptions can lead to metabolic dysfunction, impaired immune responses, increased DNA damage, and elevated disease susceptibility. On the other hand, maintaining robust circadian rhythms through interventions such as regular sleep-wake patterns, time-restricted feeding, and physical activity may extend health span and longevity. The circadian clock affects various molecular pathways associated with aging, including the insulin/IGF, mTOR, and sirtuin signaling pathways. Enhancing circadian rhythms presents a promising avenue for mitigating age-related disorders and promoting healthy aging. This review highlights the potential of circadian clock-based interventions as a transformative strategy to improve the quality of life and extend the healthspan of aging individuals.

Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigenetic clocks. Leveraging data from over 200 perturbation experiments across multiple tissues, EnsembleAge integrates predictions from multiple penalized models. Empirical evaluations demonstrate that EnsembleAge outperforms existing clocks in detecting both pro-aging and rejuvenating interventions. Furthermore, we introduce EnsembleAge HumanMouse, an extension that enables cross-species analyses, facilitating translational research between mouse models and human studies. Together, these advances underscore the potential of EnsembleAge as a robust tool for identifying and validating interventions that modulate biological aging.

This perspective critically examines the paradigm-shifting findings regarding cellular senescence's dual role in tissue biology, particularly focusing on its unexpected regenerative potential in hair growth. While cellular senescence has traditionally been viewed as a detrimental process associated with aging and tissue dysfunction, research has revealed its surprising beneficial effects on tissue regeneration. We analyze the groundbreaking discovery that senescent melanocytes can stimulate hair follicle stem cells through the osteopontin-CD44 signaling pathway, challenging the conventional understanding of senescence. This perspective also evaluates the implications of this finding for both basic research and therapeutic applications, suggesting that cellular senescence represents a complex, context-dependent phenomenon rather than a uniformly detrimental process. We discuss how this new perspective necessitates a more nuanced approach to senescence-targeted therapies and opens novel therapeutic possibilities for hair loss treatment. This analysis underscores the importance of understanding senescent cell heterogeneity and their diverse functions in tissue homeostasis, which could lead to more precise therapeutic strategies in regenerative medicine.

Mitochondria, cellular powerhouses, harbor DNA [mitochondrial DNA (mtDNA)] inherited from the mothers. mtDNA mutations can cause diseases, yet whether they increase with age in human oocytes remains understudied. Here, using highly accurate duplex sequencing, we detected de novo mutations in single oocytes, blood, and saliva in women 20 to 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies were less prevalent in coding than noncoding regions, whereas mutations with low allele frequencies were more uniformly distributed along the mtDNA, suggesting frequency-dependent purifying selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations with aging and having functional consequences. These findings are particularly timely as humans tend to reproduce later in life.

Meiotic segregation errors in human oocytes are the leading cause of miscarriages and trisomic pregnancies and their frequency increases exponentially for women in their thirties. One factor that contributes to increased segregation errors in aging oocytes is premature loss of sister chromatid cohesion. However, the mechanisms underlying age-dependent deterioration of cohesion are not well-defined. Autophagy, a cellular degradation process critical for cellular homeostasis, is known to decline with age in various organisms and cell types. Here we quantify basal autophagy in Drosophila oocytes and use GAL4/UAS inducible knockdown to ask whether disruption of autophagy in prophase oocytes impacts the fidelity of chromosome segregation. We find that individual knockdown of autophagy proteins in Drosophila oocytes during meiotic prophase causes a significant increase in segregation errors. In addition, Atg8a knockdown in prophase oocytes leads to premature loss of arm cohesion and missegregation of recombinant homologs during meiosis I. Using an oocyte aging paradigm that we have previously described, we show that basal autophagy decreases significantly when Drosophila oocytes undergo aging. Our data support the model that a decline in autophagy during oocyte aging contributes to premature loss of meiotic cohesion and segregation errors.

The accumulation of senescent cells contributes to morbidity and mortality; however, common mechanisms underpinning this age-associated phenomenon remain elusive. Hematopoietic loss of the Y chromosome (LOY) is the most frequently acquired somatic mutation in males, and this condition has been associated with various age-associated diseases and reduced lifespan. Therefore, we investigated the role of hematopoietic LOY in promoting cellular senescence, focusing on kidney disease because of its well-documented connection with aging and senescence. Herein, a prospective cohort study revealed that LOY in blood is associated with an increased incidence of kidney diseases. Analyses of transcriptional signatures in human kidneys found that immune cell LOY is enriched in patients with kidney disease and associated with greater amounts of cellular senescence. In male mice reconstituted with bone marrow lacking the Y chromosome, renal dysfunction was accompanied by senescent cell accumulation in models of kidney injury and advanced age. Treatment with a senolytic agent promoted senolysis and preferentially inhibited the progression of renal dysfunction in LOY mice. Hematopoietic LOY led to up-regulation of multiple immune inhibitory receptors, and treatment with the combination of antibodies targeting PD-1 (programmed cell death protein 1) and SIRPα (signal regulatory protein α) reduced senescent cell accumulation and rescued the renal pathology conferred by hematopoietic LOY in the kidney injury model. Collectively, these data indicate that hematopoietic LOY contributes to pathological conditions by impairing the clearance of senescent cells through up-regulation of immune checkpoint proteins.

Circulating extracellular vesicles (EVs) play a crucial role in mediating communication between different cell populations and organs, significantly influencing inflammation and vascular diseases. To evaluate the role of EVs in regulating senescence, small EVs isolated from umbilical cord plasma (young sEVs, Y-sEVs) are compared with those from the plasma of elderly individuals (old sEVs, O-sEVs, >70 years old) to identify key cargo components. To investigate their effects on senescence, Y-sEVs or O-sEVs are administered to aged mice using transdermal microneedle patches, enabling sustained EV release into the circulation. Doxorubicin is administered to induce enhanced endothelial senescence in aged mice (22-24 months old). Single-cell RNA sequencing revealed that Y-sEV treatment downregulated senescence-related genes in endothelial cells decreased the proportion of activated fibroblasts in the heart, and reduced disease-associated microglia in the brain. Delivery of Y-sEVs via microneedle patches preserved endothelial cell function, and mitigated inflammation and senescence, whereas O-sEVs exacerbated endothelial dysfunction.

Premature senescence is essential for tissue remodeling. Myocardial infarction (MI) induces pathological cardiac remodeling through fibroblast-driven extracellular matrix (ECM) production. The role of senescence in MI-induced remodeling process remains elusive. Here we identify a gradual increment number of senescent cells within the ischemic heart, peaking at day 7 post- MI, in both wild-type and p16Ink4a-CreERT2-mT/mG senescence reporter mice. Lineage tracing shows that senescent cells transition to non-senescent state within 4 weeks after MI. We perform single-nucleus (sn) Multiome and fluorescence-based spatial transcriptomics analyses to profile senescent cells. We next generate a reference (query dataset) based on SPiDER- {beta}Gal/p16-EGFP positivity and map it back to the snMultiome dataset. We then deconvolute senescent cells in the integrated dataset using multiple computational algorisms. Through these approaches, we reveal that fibroblasts and its subpopulation-late myofibroblasts (MF)-constitute a major proportion of senescent cells, which functionally reduce ECM production. Importantly, ischemia-induced senescent MF show less soluble collagen production compared to TGF-{beta}1- induced non-senescent MF in vitro. At the functional level, depletion of senescent cells in vivo augments fibrosis and worsens cardiac myopathy post-MI. Our findings highlight the transient nature of senescent cells in the heart and underscore the importance of dynamic regulation of senescent cells post-MI.

Loss of function mutations of NDUFS4 resulted in Leigh syndrome, which is a progressive neurodegenerative disease and characterized by mitochondrial oxidative stress, inflammation and aberrant mitochondrial dynamics. However, there is currently no effective treatment. Here, we demonstrate that pioglitazone significantly mitigates mitochondrial reactive oxygen species (ROS) generation, lowers cyclooxygenase-2 (COX-2) mRNA levels, and rescues aberrant mitochondrial dynamics in vitro (increasing Opa-1 expression while decreasing Drp-1 expression). Furthermore, similar effects were observed with the selective Drp-1 inhibitor mdivi-1, suggesting that inhibiting mitochondrial fission mediates the therapeutic effects of pioglitazone. Pioglitazone administration activated AMPK phosphorylation, but these effects, along with pioglitazone's ability to reverse oxidative stress, inflammation, and mitochondrial fission, were abolished by the AMPK inhibitor compound C. In vivo, pioglitazone alleviated motor dysfunction, prolonged lifespan, and promoted weight gain in Ndufs4 KO mice. This was accompanied by enhanced mitochondrial fusion and increased levels of mitochondrial complex subunits. Consistently, pioglitazone attenuated neuroinflammation and oxidative stress in vivo. Collectively, our findings indicate that pioglitazone alleviates mitochondrial oxidative stress and inflammation through an AMPK-dependent inhibition of Drp-1-mediated mitochondrial fission. Therefore, suppression of mitochondrial fission may represent a novel therapeutic strategy for Leigh syndrome (LS).

Multi-organ biological aging clocks derived from clinical phenotypes and neuroimaging data have emerged as valuable tools for studying human aging and disease. Plasma proteomics provides an additional molecular dimension to enrich these clocks. In this study, I developed 11 multi-organ proteome-based biological age gaps (ProtBAGs) using 2,448 plasma proteins from 43,498 participants in the UK Biobank. Here I highlight methodological and clinical considerations for developing and using these clocks, including correction for age bias, organ specificity of proteins, sample size and underlying pathologies in the training data, which can affect model generalizability and clinical interpretability. In addition, I integrated 11 ProtBAGs with previously developed nine multi-organ phenotype-based biological age gaps to investigate genetic overlap and causal associations with disease endpoints. Finally, I show that incorporating features across organs improves predictions for systemic disease categories and all-cause mortality. These analyses provide methodological and clinical insights for developing and interpreting these clocks and highlight future avenues toward a multi-organ, multi-omics biological aging clock framework.

Arterial biomechanical indicators have long been recognized as fundamental contributors to the physiology and pathology of cardiovascular systems. Probing multiple biomechanical parameters of arteries simultaneously throughout the cardiac cycle is highly important but remains challenging. Here, we report a method to quantify arterial anisotropic stiffness, arterial wall stresses, and local blood pressure in a single measurement. With programmed ultrasound excitation and imaging, arterial axial and circumferential guided waves were simultaneously induced and measured in the longitudinal view. Then, a mechanical model was proposed to quantitatively predict the correlation of arterial guided waves with arterial biomechanical parameters. Our experimental design and biomechanical model enable an elastography method to assess temporal variations in blood pressure, bidirectional stiffness, and mechanical stresses in arterial walls. In vivo experiments were performed on healthy young, normotensive older, and hypertensive older volunteers. The results demonstrate that our method can find applications in understanding aging of cardiovascular system and diagnosis of cardiovascular diseases.

Aging is a process of gradual decline in physical and cognitive function and is a major risk factor for mortality. Despite the increasing number of relevant studies, the mechanisms regulating the aging process have not been fully elucidated. Genetic factors have long been recognized as key factors in controlling the rate of aging. Testes-specific protease 50 (TSP50) has been shown to be involved in the regulation of embryonic development and intestinal homeostasis, but its role in the regulation of aging remains unclear. Here, we showed that TSP50 expression was reduced in the hippocampus of both aged humans and mice. TSP50 deficiency in neural stem cells (NSCs) drove accelerated aging in mice, characterized by exacerbated age-related cognitive impairments and significantly elevated neuroinflammation. Notably, aged mice with NSCs-specific knockout of TSP50 exhibited impaired intestinal mucosal barriers, dysbiosis of gut microbiota, and a marked reduction in the production of short-chain fatty acids (SCFAs). Restoring gut microbial ecology using fecal microbiota transplantation (FMT) and overexpressing TSP50 successfully alleviated aging-associated cognitive decline and neuroinflammation. Taken together, our study suggests that TSP50 plays a critical role in the aging process and identifies gut microbiota as a pivotal mediator of TSP50's influence on age-related cognitive decline and neuroinflammation. These findings highlight the potential therapeutic value of targeting TSP50 and gut microbiota for aging, offering insights into aging mechanisms and interventions for aging-related neurodegenerative diseases.

Older adults are the primary population for cell-based therapies for age-related diseases, but the efficacy of administering autologous mesenchymal stem cells (MSCs) is impaired due to biological aging. In the present study, we cultured aging adipose (AD)-derived MSCs from > 65-year-old donors on extracellular matrix (ECM) synthesized by human amniotic fluid-derived pluripotent stem cells (ECM Plus) versus tissue culture plastic (TCP) and hypothesized that ECM Plus provided an ideal "young" microenvironment for reactivating and preserving early-stage progenitor cells within aging AD-MSCs. To test our hypothesis, we serially sub-cultured aging AD-MSCs on ECM Plus or TCP and characterized the cells both phenotypically and functionally, and then analyzed the cells at the single-cell transcriptomic level for the mechanisms that control cell fate. The results showed that the maintenance of aging AD-MSCs on ECM Plus significantly restored their quantity and quality. The mechanisms responsible for these effects were associated with a remarkable up-regulation of intracellular CD74 when cells were maintained on ECM Plus compared to TCP, which triggered activation of the phosphoinositide-3-kinase (PI3K) pathway as a key modulator of cell survival (anti-apoptosis) and suppression of cellular senescence. Moreover, AD-MSCs maintained on ECM Plus increased their expression of HLA-DR and stimulated T cell activity. These findings challenge the "immune privilege" of allogeneic MSCs as a universal source for MSC-based therapies. The present study leads to a new paradigm for treating age-related diseases: serial administration of rejuvenated autologous MSCs, which may not only replace aged MSCs but also gradually reverse the aged microenvironment.

A physically active lifestyle benefits cellular aging, however the mechanisms linking physical activity (PA) with longevity remain unclear. PA is associated with longer telomere length (TL), while shorter TL has been associated with increased cellular aging. Some research suggests increased levels of inflammatory markers, such as C-reactive protein (CRP), are associated with telomere dysfunction. We tested the hypothesis that CRP levels mediate the association between PA and TL. Using data from the UK Biobank, we analyzed adjusted leukocyte T/S ratio (relative telomere to single gene copy), serum CRP, and moderate-to-vigorous physical activity (MVPA) data via device-measured actigraphy. We applied general linear regressions and a causal mediation analysis with 10,000 bootstraps while controlling for a range of covariates (age, BMI, smoking status, sex, ethnicity, time between data collection, time wearing the accelerometer, and the Townsend Deprivation Index). Variables of interest were transformed to approximate normality. A total of 79,873 participants were included in the final analytic sample. MVPA and CRP were both significant predictors of TL (β

Cellular senescence, often referred to simply as "senescence", is a complex intracellular process with diverse biological, physiological, and pathological roles. Biologically, it is essential for embryogenesis and development. Physiologically, senescence acts as a safeguard against tumorigenesis by preventing the proliferation of damaged or defective cells. However, persistent activation of senescence can contribute to various pathological conditions, particularly those associated with aging, cancer, and other chronic diseases such as liver and pulmonary diseases. Growing evidence links aging to heightened activation of cellular senescence, leading to the accumulation of senescent cells. Here in this perspective, we aim to decipher the latest molecular mechanisms and regulatory pathways of cellular senescence in the context of aging and aging-related diseases. Additionally, we discuss emerging research directions, highlighting current limitations and gaps in the field. Addressing these challenges may not only advance our understanding of senescence but also uncover new therapeutic opportunities.

Ageing is a process characterized by a wide array of cellular and systemic changes that together increase the risk of developing cancer. While cell-autonomous mutations within incipient tumour cells are important, age-related changes in the microenvironment are critical partners in the transformation process and response to therapy. However, aspects of ageing that are important and the degree to which they contribute to cancer remain obscure. One of the factors that impacts ageing is increased cellular senescence but it is important to note that ageing and cellular senescence are not synonymous. We highlight open questions, including if senescent cells have phenotypically distinct impacts in aged versus young tissue, or if it is the cell type that dictates the impact of senescence on tissue homeostasis and disease. Finally, it is probable that our current definition of cellular senescence encompasses more than one mechanistically distinct cellular state; thus, we highlight phenotypic differences that have been noted across cell types and tissues of origin. This Review focuses on the role that senescent stromal cells have in cancer, with a particular emphasis on fibroblasts given the amount of work that has focused on them.

Ribosome-associated quality control (RQC) is a pivotal biological process that governs the fidelity of messenger RNA (mRNA) homeostasis and protein synthesis. Defects in RQC are implicated in cellular dysfunction and proteotoxicity, but their impact on aging remains elusive. Here, we show that Pelota, the ribosome rescue factor, promotes longevity and protects against age-related pathological phenotypes in multiple metazoan species. By performing a targeted genetic screen, we find that Pelota is indispensable for longevity in the nematode

The degradation of cellular components through autophagy is essential for longevity and healthy aging. However, autophagy function decreases with aging, contributing to age-related diseases. In this study, we characterized a small-molecule activator of autophagy called

RNA modifications are key epigenetic alterations that play regulatory functions in RNA biology, including RNA stability and translation. Emerging evidence indicates that RNA modification is crucial for various physiological and pathological processes, including aging. This review describes functions of key RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), 2'-O-methylation (Nm), N1-methyladenosine (m1A), adenosine-to-inosine (A-to-I) RNA editing, pseudouridylation (ψ), and N4-acetylcytidine (ac4C), highlighting their roles in aging and age-associated diseases. We also discuss dynamics of RNA modifications and associated protein factors during aging. This review provides important information on molecular mechanisms underlying aging regulation, focusing on effects of RNA modifications, which can help us understand healthy longevity in humans.

The olm (Proteus anguinus), with a predicted maximum lifespan of more than 100 years, is the longest-lived amphibian, which in addition possesses a range of unique adaptations to its dark, subterranean cave habitat. To assess the underlying molecular signatures, we present the first comprehensive transcriptome of the olm. Our study provides gene expression data across six organs and comparative genomics analyses, accessible via an interactive web server: http://comp-pheno.de/olm . The data uncover significant organ-specific gene expression, with the brain showing the highest number of organ-specific expressed genes. Our findings reveal significantly more genes under strong negative selection than positive selection, particularly in brain-specific expressed genes. Processes under positive selection in the olm resemble those in other long-lived species.