Longevity Papers

cTAGE5/MEA6 plays a pivotal role in COPII complex assembly, ER-to-Golgi trafficking, and secretion. However, whether cTAGE5/MEA6 is involved in other cellular functions remains unclear. Here, we show that conditional cTAGE5 knockout results in embryonic lethality during development and premature aging in adult mice. cTAGE5 deficiency leads to abnormal nuclear structure and disturbed cell proliferation in MEF cells. Further mechanistic studies reveal that cTAGE5 localizes not only to the ER exit sites but also to other ER structures, where it interacts with the lamin B receptor (LBR). Loss of cTAGE5 disrupts LBR's localization to the inner nuclear membrane, leading to its retention in the ER and instability. This results in abnormal nuclear (envelope) morphology and cellular senescence, likely driven by activation of the P53/P21 senescence pathway. Thus, our study uncovers cTAGE5's role in maintaining nuclear envelope integrity and highlights its function and potential mechanism in preventing cellular senescence and animal aging.

Idiopathic pulmonary fibrosis (IPF) is a prevalent and deadly age-related disease characterized by chronic, progressive, and irreversible fibrosis. A key effector cell population in the fibroproliferative response is the fibroblasts. Fibroblast cell senescence gradually worsens during aging, and the acquisition of a senescence-associated secretory phenotype (SASP) turns senescent fibroblasts into pro-inflammatory cells. However, the mechanism promoting senescence in IPF, especially at the post-transcriptional level, is poorly understood. We recently discovered that Nudix Hydrolase 21 (NUDT21, also named CFIm25), an RNA-binding protein, plays a critical role in regulating the expression of SASP factors through alternative polyadenylation (APA). APA allows adding poly(A) tail at different sites of 3' UTR and generates transcript isoforms with different 3' UTR lengths. We found that NUDT21 was downregulated in aging and fibrotic lungs, particularly at the fibrotic foci of IPF lungs known to have abundant senescent myofibroblasts and collagens. NUDT21 knockdown in normal lung fibroblasts promoted the 3' UTR shortening of several STAT3 signaling components and enhanced STAT3 phosphorylation and the expression of several SASPs, including interleukins, collagens, and matrix metalloproteinases (MMPs). Moreover, NUDT21 downregulation may be associated with increased fibroblast senescence and abnormal mitochondrial function. Importantly, mice with Nudt21 deletion in Col1a1 expressing cells aggravated bleomycin-induced pulmonary fibrosis. Taking together, our study demonstrated an important role of NUDT21-mediated APA in regulating SASP expression and fibroblast senescence that could contribute to the pathogenesis of IPF.

Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson's disease, but the mechanistic link between pUb elevation and neurodegeneration remains unclear. Here, we demonstrate that pUb elevation is a common feature under neurodegenerative conditions, including Alzheimer's disease, aging, and ischemic injury. We show that impaired proteasomal activity leads to the accumulation of sPINK1, the cytosolic form of PINK1 that is normally proteasome-degraded rapidly. This accumulation increases ubiquitin phosphorylation, which then inhibits ubiquitin-dependent proteasomal activity by interfering with both ubiquitin chain elongation and proteasome-substrate interactions. Specific expression of sPINK1 in mouse hippocampal neurons induced progressive pUb accumulation, accompanied by protein aggregation, proteostasis disruption, neuronal injury, neuroinflammation, and cognitive decline. Conversely, Pink1 knockout mitigated protein aggregation in both mouse brains and HEK293 cells. Furthermore, the detrimental effects of sPINK1 could be counteracted by co-expressing Ub/S65A phospho-null mutant but exacerbated by over-expressing Ub/S65E phospho-mimic mutant. Together, these findings reveal that pUb elevation, triggered by reduced proteasomal activity, inhibits proteasomal activity and forms a feedforward loop that drives progressive neurodegeneration.

Retinal degenerative diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa, and glaucoma, have been linked to mitochondrial dysfunction. However, the impact of mitochondrial DNA (mtDNA) mutation accumulation in the context of these retinopathies has yet to be thoroughly explored. Our previous studies focused on the retinal phenotype observed in the PolgD257A mutator mice (D257A), revealing the effects of aging and mtDNA mutation accumulation in the retina. We have reported that this model exhibited significant morphological and functional deficits in the retina by 6 months of age, with notable alterations in the retinal pigment epithelium (RPE) occurring as early as 3 months, including changes in the cristae density and reduction in length of mitochondria. This study investigated how mtDNA mutations affect the metabolic interaction between the retina and RPE in young (3 months) and old (12 months) wild-type (WT) and D257A mice. We assessed cellular energy production using freshly dissected retina samples from both groups through Seahorse analysis, immunofluorescence, and Western blot experiments. The analysis of aged D257A retina punches revealed significantly reduced basal and maximal mitochondrial respiration, along with increased mitochondrial reserve capacity compared to WT. However, glycolytic flux, measured as a function of extracellular acidification rate (ECAR), did not differ between WT and D257A mice. Both D257A retina and RPE exhibited decreased expression of essential electron transport proteins involved in oxidative phosphorylation. Additionally, we observed a reduction in the expression of glucose transporter 1 (GLUT-1) and lactate transporter (MCT1) at the apical surface of the RPE. Enzymes associated with glycolysis, including hexokinase II and lactate dehydrogenase A, were significantly lower in the aged D257A retina, while hexokinase I and pyruvate kinase 2 were upregulated in the RPE. These findings indicate that the accumulation of mtDNA mutations leads to impaired metabolism in both the retina and RPE. Furthermore, it suggests that glucose from the choroidal blood supply is being utilized by the RPE rather than transported to the neural retina. Mitochondrial dysfunction in RPE promotes a glycolytic state in these cells, leading to reduced availability of metabolites and, consequently, diminished overall retinal function. These results are essential for advancing our understanding of the mechanisms underlying retinal degeneration and provide a new perspective on the role of mtDNA mutations in these diseases.

Cellular senescence, marked by irreversible cell cycle arrest and senescence-associated secretory phenotype, contributes to aging and cancer recurrence. While chemotherapy can induce senescence in cancer cells, these therapy-induced senescent cells often resist apoptosis and promote tumor recurrence. The nuclear interaction between FOXO4 and p53 is crucial for senescent cell survival. Using NMR spectroscopy, we identified that hydrophobic interactions in the p53 transactivation domain play a key role in FOXO4 forkhead domain binding. Based on this structural information, we designed an optimized peptide inhibitor with reduced negative charges and incorporated a cationic cell-penetrating peptide for enhanced cellular delivery (CPP-CAND). CPP-CAND exhibited high selectivity for senescent cells, effectively disrupting nuclear FOXO4-p53 foci and inducing caspase-dependent apoptosis. Notably, it showed cytotoxicity against senescent cancer cells induced by different chemotherapeutic agents including doxorubicin and cisplatin. With its enhanced selectivity, l-amino acid composition, and shorter length, CPP-CAND represents a promising therapeutic candidate for targeting therapy-induced senescent cancer cells.

Mosaic loss of Y chromosome (mLOY) in blood cells is an age-related somatic mutation, but its relationship with pulmonary health remains undercharacterized. Leveraging mLOY assessment in over 12,000 men, including 5,097 from the COPDGene Study and 7,235 from six additional cohorts in Trans-Omics for Precision Medicine program, we investigated its association with respiratory outcomes and epigenetic aging. Cross-sectionally, mLOY was associated with airflow obstruction with prevalence increasing with age, particularly in men with a former smoking history. Longitudinally, mLOY associated with lung function decline. Notably, mLOY was also associated with greater CT-quantified lung emphysema and faster pace epigenetic aging. Prospectively, in participants with normal lung function at baseline, mLOY was associated with lower future lung function and faster pace of epigenetic aging. These associations remained robust after adjusting for clonal hematopoiesis and telomere length. Collectively, these findings position mLOY as a potential biomarker of respiratory aging and obstructive lung disease.

Cytomegalovirus (CMV) drives immunosenescence, while its reactivation is associated with inflammation and oxidative stress. This study investigates the interplay between CMV, oxidative stress and inflammation in a cohort of 2065 age-stratified individuals randomly recruited from the general population (RASIG), as part of the MARK-AGE study, to better understand the role of CMV in immunosenescence and its potential impact on age-related diseases. CMV IgG titers were associated with oxidative stress, antioxidant, and inflammatory biomarkers. Stepwise-linear regression identified positive associations with age, BMI, apolipoprotein J (ApoJ/Clu), ceruloplasmin, α-2-macroglobulin, proteasome peptidase activity, and malondialdehyde, and negative associations with α-tocopherol, selenium, and vitamin D. Notably, the associations with ApoJ/Clu and proteasome peptidase activity represent novel findings that point to a potential involvement of proteostasis dysregulation and cellular stress responses in CMV-related immune alterations. Quartile-based analyses revealed significantly lower antioxidant levels (α-tocopherol, selenium, ascorbic acid and vitamin D) and higher oxidative stress markers (plasma 8-isoprostanes, malondialdehyde) in the highest quartile (Q4) compared to lower quartiles. Inflammatory markers (homocysteine, ceruloplasmin and α-2-macroglobulin) ApoJ/Clu and proteasome peptidase activity were elevated in Q4. This group also exhibited a higher prevalence of cardiovascular diseases, hypertension, and diabetes. This study highlights a link between CMV IgG titers, oxidative stress, inflammation, and the prevalence of cardiovascular and metabolic diseases. Our findings suggest that CMV may contribute to immunosenescence through mechanisms involving redox imbalance and dysregulation of protein degradation pathways. Further research is needed to explore the role of CMV reactivation in aging, and its impact on age-related metabolic and cardiovascular diseases.

Health behaviors affect life expectancy, but whether disease is present can greatly impact both the individual and society. How health behavior is reflected in the utilization of health care services is yet to be investigated to support the impact of prevention efforts. Based on data from 57,053 middle-aged individuals from the Danish Diet, Cancer and Health cohort, a health score including baseline smoking status, sport activity, alcohol consumption, diet, and waist circumference was constructed as a simple measure of general health behavior. During 20 years of follow-up, healthy life expectancy among men and women aged 65 years at baseline, was 0.83 [0.74 to 0.92] and 0.86 [0.77 to 0.94] years longer on average, respectively, per one point increment in the health score. Life expectancy with disease was shorter among men (-0.18 [-0.26 to -0.09]) and women (-0.37 [-0.45 to -0.29]) with higher health scores. Among individuals with the highest scores, major chronic disease diagnosis was postponed for more than 7 years. There were fewer disability years, especially with multimorbidity, (men: -1.6 years; women: -3.3 years), and there was a clear inverse association between health score and days of hospitalization looking 20 years ahead.

Mosaic loss of chromosome Y (mLOY) is the most common somatic mutation in hematopoietic cells of aging men and is linked to cancer risk and mortality. However, its relationship with treatment modalities remains unclear. In 348 prostate cancer patients at Juntendo University Hospital, local radiotherapy was associated with a higher prevalence of mLOY (OR = 2.55, 95% CI: 1.08-6.50, P = 0.04), whereas surgery and endocrine therapy were not. We then examined BioBank Japan data from over 30,000 patients with prostate, lung, colorectal, and gastric cancers. Fixed-effect meta-analysis across these sites showed a significant association between radiotherapy and mLOY (OR = 1.48, 95% CI: 1.11-1.98, P = 0.01). No significant effect heterogeneity was observed across cancer types (Q = 0.36, I² = 0%, P = 0.95). Our findings suggest that radiotherapy may exacerbate genomic instability, indicating a potential vulnerability in certain cancer patients to DNA damage induced by radiation therapy.

The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on organ aging. Here, we demonstrate that both transgenic Alzheimer's disease (AD) mice and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits. Senescent BMAds acquire a secretory phenotype, markedly increasing secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAds in vivo and promotes insoluble amyloid formation from soluble amyloid-β (Aβ) peptides in in vitro and ex vivo three-dimensional (3D) BMAd-based cultures. Combined SAP/PTX2 and Aβ treatment promotes osteoclastogenesis but inhibits osteoblastogenesis. Transplanting senescent BMAds into the bone marrow cavity of young mice induces bone loss, which is reversed by senolytic treatment. Finally, depleting SAP/PTX2 in aged mice abolishes marrow amyloid deposition and rescues low bone mass. Thus, senescent BMAds drive age-related skeletal amyloidosis and bone deficits via SAP/PTX2.

Biomolecular condensates are dynamic cellular compartments that concentrate proteins and enzymes to regulate biochemical reactions in time and space. While these condensates can enhance enzyme activity, how this function changes as condensates age remains poorly understood. Here, we design synthetic catalytic condensates that selectively recruit enzymes to investigate this temporal evolution. We show that catalytic condensates exhibit time-dependent activity: they initially accelerate enzymatic reactions but gradually lose efficiency due to the transition from liquid-like to solid-like states. This aging process, characterized by protein aggregation and loss of selective barriers, impairs enzyme function both in vitro and living cells. We further demonstrate that small molecules which influence aging dynamics can modulate catalytic efficiency of condensates. Our findings show that condensate aging as a key regulator of enzymatic activity and provide crucial insights for designing functional synthetic condensates.

Retinal fundus images offer a non-invasive window into systemic aging. Here, we fine-tuned a foundation model (RETFound) to predict chronological age from color fundus images in 71,343 participants from the UK Biobank, achieving a mean absolute error of 2.85 years. The resulting retinal age gap (RAG), i.e., the difference between predicted and chronological age, was associated with cardiometabolic traits, inflammation, cognitive performance, mortality, dementia, cancer, and incident cardiovascular disease. Genome-wide analyses identified genes related to longevity, metabolism, neurodegeneration, and age-related eye diseases. Sex-stratified models revealed consistent performance but divergent biological signatures: males had younger-appearing retinas and stronger links to metabolic syndrome, while in females, both model attention and genetic associations pointed to a greater involvement of retinal vasculature. Our study positions retinal aging as a biologically meaningful and sex-sensitive biomarker that can support more personalized approaches to risk assessment and aging-related healthcare.

The need to monitor the aging process as a risk factor for disease and mortality beyond chronological age (CA) has led to numerous investigations into the estimation of the biological age (BA) of individuals. However, the accuracy of BA estimation tools is often judged by their ability to approximate CA, questioning their value in capturing the variance in health status and thus correctly estimating BA. Their biological relevance is often assessed in relation to health outcomes or mortality, underexploiting their potential for real-time monitoring of BA. Furthermore, their complexity may limit their clinical translation to large populations. Here, we describe the gene expression-based age monitoring Clock (GamC), a simple biomarker of aging (BOA), and characterize its biological relevance with synchronous cardiovascular (CV) health-related functional data. GamC is calculated from the expression levels of three genes consistently dysregulated with age in blood (ABLIM1, CCR7, and LEF1). GamC shows moderate but reliable association with CA in three independent cohorts, supported by transcriptome-wide changes. It demonstrates specialized biological meaning, as it specifically describes current physical activity levels, but poorly correlates with autonomic nervous system function, both age-related factors associated with CV health. Finally, it expresses BA monitoring capacity by modestly responding to an effective exercise-based intervention in centenarians. In conclusion, GamC is proposed as a simple and affordable candidate BOA for reporting the individuals' current CV health-related BA, thus promoting its broad translation and application into measures aimed at promoting healthy aging in relation to CV health, the leading cause of death worldwide.

The escalating global trend of aging populations has brought attention to the rising prevalence of late-onset amyloid disorders. Among them, amyloid transthyretin (ATTR) amyloidosis presents a growing area of unmet medical needs. While current treatment modalities have demonstrated efficacy in preventing or delaying amyloid generation, methodology to selectively modify and neutralize existing amyloid burdens remains inadequately addressed, leaving the fundamental irreversibility and hence the fatality of these conditions, a long-standing medical challenge. Here, we report the first demonstration of therapeutic efficacy in ATTR amyloidosis via dynamic control of ATTR aggregation and toxicity, enabled by small-molecule organophotocatalysis. Selective incorporation of hydrophilic oxygen atoms into the hydrophobic amyloid core reshapes the aggregation landscape, neutralizing proteotoxicity, and mitigating cellular damage. Additionally, this targeted covalent modification significantly reduces in vivo ROS levels, correlating with the observed therapeutic effects in

Cognitive impairment is a major medical problem in the aging population. The risk of developing cognitive impairment is higher in several systemic conditions like hypertension, diabetes, and obesity. While a vascular contribution to cognitive impairment in these pathologies is well established, the underlying mechanisms are not fully understood. Endothelial dysfunction, which frequently accompanies the abovementioned conditions and increases with age, might be a key causal and mechanistic factor in cognitive deficits associated with systemic conditions. In this study, we demonstrate that the inducible deletion of the Gq/11 signaling pathway in brain endothelial cells leads to an impaired reactivity of the brain vasculature to vasodilating stimuli such as neuronal activity, representing an isolated cerebral endothelial dysfunction. These mice develop mild cognitive impairment with aging that could be explained by increased tau phosphorylation, decreased myelination, and capillary rarefaction, suggesting that endothelial cell-driven processes protect cognition in aging and providing a mechanistic explanation for how endothelial dysfunction can lead to cognitive impairment in cerebral small vessel disease.

Blood perfusion delivers oxygen and nutrients to all cells, making it a fundamental feature of brain organization. How cerebral blood perfusion maps onto micro-, meso- and macro-scale brain structure and function is therefore a key question in neuroscience. Here we analyze pseudo-continuous arterial spin labeling (ASL) data from [Formula: see text] healthy individuals in the HCP Lifespan studies (5-22 and 36-100 years) to reconstruct a high-resolution normative cerebral blood perfusion map. At the cellular and molecular level, cerebral blood perfusion co-localizes with granular layer IV, biological pathways for maintenance of cellular relaxation potential and mitochondrial organization, and with neurotransmitter and neuropeptide receptors involved in vasomodulation. At the regional level, blood perfusion aligns with cortical arealization and is greatest in regions with high metabolic demand and resting-state functional hubs. Looking across individuals, blood perfusion is dynamic throughout the lifespan, follows micro-architectural changes in development, and maps onto individual differences in physiological changes in aging. In addition, we find that cortical atrophy in multiple neurodegenerative diseases (late-onset Alzheimer's disease, TDP-43C, and dementia with Lewy bodies) is most pronounced in regions with lower perfusion, highlighting the utility of perfusion topography as an indicator of transdiagnostic vulnerability. Finally, we show that ASL-derived perfusion can be used to delineate arterial territories in a data-driven manner, providing insights into how the vascular system is linked to human brain function. Collectively, this work highlights how cerebral blood perfusion is central to, and interlinked with, multiple structural and functional systems in the brain.

As the global population trends toward aging, the number of individuals suffering from age-related debilitating diseases is increasing. With advancing age, skeletal muscle undergoes progressive oxidative stress infiltration, coupled with detrimental factors such as impaired protein synthesis and mitochondrial DNA (mtDNA) mutations, culminating in mitochondrial dysfunction. Muscle stem cells (MuSCs), essential for skeletal muscle regeneration, also experience functional decline during this process, leading to irreversible damage to muscle integrity in older adults. A critical contributing factor is the loss of mitochondrial metabolism and function in MuSCs within skeletal muscle. The mitochondrial quality control system plays a pivotal role as a modulator, counteracting aging-associated abnormalities in energy metabolism and redox imbalance. Mitochondria meet functional demands through processes such as fission, fusion, and mitophagy. The significance of mitochondrial morphology and dynamics in the mechanisms of muscle regeneration has been consistently emphasized. In this review, we provide a comprehensive summary of recent advances in understanding the mechanisms of aging-related mitochondrial dysfunction and its role in hindering skeletal muscle regeneration. Additionally, we present novel insights into therapeutic approaches for treating aging-related myopathies.

Strategies to slow the aging process or mitigate its consequences on health rely on the validation of minimally-invasive biomarkers of aging that can be used to track aging and test the effectiveness of antiaging interventions. Study of aging in a nonhuman primate species offers a robust translational approach to achieving these aims, avoiding wide differences in genetics and environmental exposures that confound human aging studies. As epigenetic age appears to predict biological aging, biomarkers linked to epigenetic aging should be especially valuable in identifying individual differences in aging progression and documenting the impact of antiaging strategies. Proteins are the final effectors in most signaling pathways, indicating that alteration in levels of circulating proteins potentially offers an informative and valuable quantitative index of aging. Accordingly, a proteomic analysis was conducted on matching CSF and plasma samples collected from a large group of African green monkeys, with epigenetic ages ranging from young to old as determined by differential methylation of blood DNA. In addition to analyzing the data with linear statistical models, a gradient boosting machine learning technique was employed to identify not only individual CSF and plasma proteins that correlated with aging progression but also groups of proteins that could be used as predictors of global aging and of specialized aspects of aging such as inflammation. Overall, this study identified new CSF and plasma protein targets for understanding aging biology, together with identifying biomarkers to track changes in the rate of biological aging in a translationally relevant nonhuman primate model.

Specialized ribosomes help determine which proteins are synthesized, however, the influence of age on ribosome heterogeneity and whether dysregulation of this process drives organismal aging is unknown. Here we examined the role of ribosomal RNA (rRNA) methylation in maintaining appropriate translation as organisms age. In a directed RNAi screen, we identified 18S rRNA N6'-dimethyl adenosine (m

Aging is associated with increased susceptibility to metabolic stress and chronic liver disease, yet the interactions between age and metabolic stressors and the potential for ameliorating interventions remain incompletely understood. Here, we examined the hepatic response of young (7-month-old) and old (25-month-old) C57BL/6 male mice to a 9-week high-fat diet (HFD) and assessed whether rapamycin, a well-established pro-longevity intervention, could mitigate age-exacerbated effects. While both age groups developed metabolic-associated steatohepatitis (MASH), older mice displayed more severe hepatic steatosis, inflammation, and transcriptional dysregulation. Transcriptomic profiling of whole livers and purified hepatocytes revealed that aging amplifies HFD-induced inflammatory and metabolic gene expression changes, including activation of immune pathways and suppression of metabolic pathways. Notably, treatment of aging mice with rapamycin reversed the majority of HFD-driven transcriptional alterations, including upregulation of pro-inflammatory regulators such as Stat1, and dysregulation of metabolic gene networks. Rapamycin also reduced hepatosteatosis, total body weight, and a tumorigenic transcriptomic signature associated with hepatocellular carcinoma risk. These findings demonstrate that aging intensifies hepatic sensitivity to metabolic stress and identify rapamycin as a promising therapeutic to counteract age-related liver dysfunction and MAFLD progression.

The effects of nicotine on aging-related motor and cognitive decline remain controversial due to limited empirical evidence. Here, mice are permitted to orally consume nicotine over a 22-month period and observed attenuated motor decline without pathological alterations in major metabolism-related peripheral organs or immune system dysfunction. Multi-organ metabolomic profiling and network analysis of aged mice (24 months old) identified nicotine-responsive pathways related to glycolipid metabolism and energy homeostasis. Dynamic gut microbiota profiling via series expression miner-based longitudinal analysis reveals that nicotine consumption preserved microbiota composition and altered microbial-derived metabolites associated with the sphingolipid pathway, known to regulate age-related muscle dysfunction and sarcopenia. Assays in aged mice and C2C12 cells confirmed that nicotine regulates sphingolipid turnover, particularly via sphingomyelin synthases and neutral sphingomyelinases, to enhance nicotinamide adenine dinucleotide availability and energy metabolism. These metabolic adaptations correlated with reduced ceramide accumulation and improved motor function. Behavior-Metabolome Age (BMAge) score confirmed a biologically younger phenotype in the nicotine-treated mice. Together, these findings suggest that life-long oral nicotine consumption reprograms aging-associated metabolism through regulation of systemic sphingolipid homeostasis, conferring resilience against age-related motor decline.