Longevity Papers

Changes in the proteome and its dysregulation have long been known to be a hallmark of aging. We derived a proteomic aging trait using data on 1459 plasma proteins from 44,435 UK Biobank individuals measured using an antibody-based assay. This metric is strongly associated with four age-related disease outcomes, even after adjusting for chronological age. Survival analysis showed that one-year older proteomic age, relative to chronological age, increases all-cause mortality hazard by 13 percent. We performed a genome-wide association analysis of proteomic age acceleration (proteomic aging trait minus chronological age) to identify its biological determinants. Proteomic age acceleration showed modest genetic correlations with four epigenetic clocks (R

Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS) triggered by the replacement of D-glucose by D-galactose in ESC media. Enhanced OXPHOS in turn activates NAD + -dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, which results in a robustly enhanced ESC phenotype. This exploitation of a NAD + /NADH coenzyme coupled to OXPHOS as a means of programming lineage-specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.

Aging induces significant alterations in the immune system, with immunosenescence contributing to age-related diseases. Peripheral blood mononuclear cells (PBMCs) offer a convenient and comprehensive snapshot of the body's immune status. In this study, we performed an integrated analysis of PBMCs using both bulk-cell and single-cell RNA-seq data, spanning from children to frail elderlies, to investigate age-related changes. We observed dynamic changes in the PBMC transcriptome during healthy aging, including dramatic shifts in inflammation, myeloid cells, and lymphocyte features during early life, followed by relative stability in later stages. Conversely, frail elderly individuals exhibited notable disruptions in peripheral immune cells, including an increased senescent phenotype in monocytes with elevated inflammatory cytokine expression, heightened effector activation in regulatory T cells, and functional impairment of cytotoxic lymphocytes. Overall, this study provides valuable insights into the complex dynamics of immunosenescence, elucidating the mechanisms driving abnormal inflammation and immunosuppression in frailty.

Skeletal muscle plays a crucial role in maintaining motor function and metabolic homeostasis, with its loss or atrophy leading to significant health consequences. Long non-coding RNAs (lncRNAs) have emerged as key regulators in muscle biology; however, their precise roles in muscle function and pathology remain to be fully elucidated. This study demonstrates that lncRNA maternally expressed gene 3 (MEG3) is preferentially expressed in slow-twitch muscle fibers and dynamically regulated during muscle development, aging, and in the context of Duchenne muscular dystrophy (DMD). Using both loss- and gain-of-function mice models, this study shows that lncRNA-MEG3 is critical for preserving muscle mass and function. Its depletion leads to muscle atrophy, mitochondrial dysfunction, and impaired regenerative capacity, while overexpression enhances muscle mass, increases oxidative muscle fiber content, and improves endurance. Notably, lncRNA-MEG3 overexpression in MDX mice significantly alleviates muscle wasting and adipose tissue infiltration. Mechanistically, this study uncovers a novel interaction between lncRNA-MEG3 and the polycomb repressive complex 2 (PRC2), where lncRNA-MEG3 binds to SUZ12 polycomb repressive complex 2 subunit (Suz12), stabilizes PRC2, facilitates SUZ12 liquid-liquid phase separation (LLPS), and regulates the epigenetic modulation of four and a half lim domains 3 (Fhl3) and ring finger protein 128 (Rnf128). These findings not only highlight the crucial role of lncRNA-MEG3 in muscle homeostasis but also provide new insights into lncRNA-based therapeutic strategies for muscle-related diseases.

The mitochondrial translocator protein (TSPO) is a biomarker of inflammation associated with neurodegenerative diseases, widely regarded to be upregulated in the aging brain. Here we investigated the interaction between aging and TSPO immunomodulatory function in the mouse hippocampus, a region severely affected in Alzheimer's Disease (AD). Surprisingly, we found that TSPO levels were decreased in brain innate immune populations in aging. Aging resulted in a reversal of TSPO knockout transcriptional signatures following inflammatory insult. TSPO deletion drastically exacerbated inflammatory transcriptional responses in the aging hippocampus, while dampening inflammation in the young hippocampus. This age-dependent effect of TSPO was linked to NF-kβ and interferon regulatory transcriptional networks. Drugs that disrupt the cell cycle and induce DNA damage, such as heat shock protein and topoisomerase inhibitors, were identified to mimic the inflammatory transcriptional signature characterizing aging in TSPO knockout mice most closely. These findings indicate that TSPO plays a protective role in brain aging. This TSPO-aging interaction is an important consideration in the interpretation of TSPO-targeted biomarker and therapeutic studies, as well as in vitro studies that cannot model the aging brain.

Presbycusis or age-related hearing loss (ARHL) affects millions of people worldwide, increasing their risk of cognitive decline and poor quality of life. However, ARHL remains an irreversible condition due to our inability to induce inner-ear hair cell regeneration. Nevertheless, multisession epidural stimulation of the auditory cortex (AC) at the onset of ARHL prevents hearing threshold elevation in naturally aging Wistar rats. Accordingly, we hypothesized that anodal direct current (DC) stimulation of the AC may also compensate for age-related maladaptive, activity-dependent changes. Here, we examined immunocytochemical markers in the AC, including early genes (c-fos and Arc), AMPA receptors (GluR2/3), parvalbumin (PV), and GAD67, along with auditory-evoked potentials (CAEPs) recorded in both auditory and visual (VC) cortices. When comparing 6 and 18.13-month-old rats without AC simulation, we observed loss of c-fos and Arc-positive neurons and decreased GluR2/3 expression, confirming altered AC neuronal network plasticity and activation. In addition, we noted changes in PV and decreased GAD67 immunoreactivity suggesting disrupted inhibition and significantly increased wave amplitudes in CAEPs, altered AC latencies, and decreased VC responses. By contrast, electrically stimulated rats showed no significant variations in early gene markers, GluR2/3, PV, or GAD67 with age, and the amplitudes and latencies of CAEPs recorded in their AC and VC resembled those of young rat. These findings indicate that anodal DC stimulation at the onset of ARHL delays AC aging by minimizing the loss of inhibition and preventing increases in cortical excitability in Wistar rats.

Exercise and diet are direct physical contributors to human health, wellness, resilience, and performance [1-5]. Endurance and resistance training are known to improve healthspan through various biological processes such as mitochondrial function [6-8], telomere maintenance [9], and inflammaging [10]. Although several training prescriptions have been defined with specific merits [1,10-20], the long-term effects of these in terms of their molecular alterations have not yet been well explored. In this study, we focus on two combined endurance and resistance training programs: (1) traditional moderate-intensity continuous endurance and resistance exercise (TRAD) and (2) a variation of high-intensity interval training (HIIT) we refer to as high intensity tactical training (HITT), to assess the dynamics of DNA methylation (DNAm) in blood and muscle derived from males (N=23) and females (N=31), over a 12-week period of training followed by a 4-week period of detraining, sampled at pre-exercise and acute time points, totaling 528 samples. Due to its rapid responsiveness to stimuli and its stability, DNAm has been known to facilitate regulatory cascades that significantly affect various physiological processes and pathways. We find that several thousand differentially methylated regions (DMRs) associated with acute exercise in blood, many of which are shared across males and females. This trend is reversed when comparing the baseline (pre-exercise) time points or post-exercise timepoints at the untrained state with those at the post-conditioned state. Here, muscle shows majority of DNAm changes, with most of those being unique. We also find several hundred memory DMRs in muscle that maintain the gain or loss of methylation after four weeks of inactivity. Comparing phenotypic measurements, we find specific DMRs that correlate significantly with mitochondrial function and myofiber switching. Using machine learning, we select a subset of DMRs that are most characteristic of training modalities, sex and timepoint. Most of the DMRs are enriched in pathways associated with immune function, cell differentiation, and exercise adaptation. These findings reveal mechanisms by which exercise- and training-induced epigenetic changes alter immune surveillance, mitochondrial function, and inflammatory response, and underscore the relevance of epigenetic plasticity to health monitoring and wellness.

Extracellular vesicles (EVs) are secreted by most cell types, transmitting crucial signaling molecules like proteins, small RNAs, and DNA. We previously demonstrated that EVs from murine and human mesenchymal stem cells (MSCs) functioned as senomorphics to suppress markers of senescence and the inflammatory senescence-associated secretory phenotype (SASP) in cell culture and in aged mice. Here we demonstrate that EVs from additional types of human adult stem cells and embryonic progenitor cells have a senomorphic activity. Based on their miRNA profiles showing prevalence in stem cell EVs versus nonstem cell EVs and the number of age-related genes targeted, we identified eight miRNAs as potential senomorphic miRNAs. Analysis of these miRNAs by transfection into etoposide-induced senescent IMR90 human fibroblasts revealed that each of the miRNAs alone regulated specific senescence and SASP markers, but none had complete senomorphic activity. Evaluation of ~300 combinations of miRNAs for senotherapeutic activity identified a senomorphic cocktail of miR-181a-5p, miR-92a-3p, miR-21-5p, and miR-186-5p that markedly reduced the expression of p16

Background: Sleep, physical activity, and nutrition (SPAN) are key determinants of both life expectancy (lifespan) and disease-free life expectancy (healthspan) yet are often studied and promoted in isolation. This study examined the joint association of these three behaviours with lifespan and healthspan. Methods: Prospective cohort analysis of 59,078 participants from the UK Biobank accelerometry sub-study (median age: 64.0 years; 45.4% male) who wore accelerometers for 7 days and self-reported dietary data. Moderate to vigorous physical activity (MVPA; mins/day) and sleep (hours/day) were calculated using a validated wearables-based algorithm. Diet quality was assessed using a 10-item diet quality score (DQS) based on the consumption of vegetables, fruits, whole grains and refined grains, unprocessed and processed meats, fish, dairy, vegetable oils, and sugary beverages (ranging 0-100, where higher values indicate a higher diet quality). Lifespan and healthspan (defined as years lived free of cardiovascular disease (CVD), cancer, type 2 diabetes (T2D), chronic obstructive pulmonary disease (COPD), and dementia) were estimated across 27 joint tertile combinations of SPAN behaviours and a continuous composite SPAN score using a life table approach. Mortality rates in the life table were adjusted using hazard ratios from a Cox proportional hazards model. The minimum meaningful dose was defined as the smallest combination of behavioural changes associated with a statistically significant gain in lifespan or healthspan. Results: During a median follow-up of 8.1 years, 2,458 deaths, 9,996 incident CVD, 7,681 cancers, 2,971 T2D, 1,540 COPD, and 508 dementia events occurred. Compared with participants in the least favourable tertiles for all SPAN behaviours, those in the optimal tertiles (7.2-8.0 hours/day of sleep; >42 mins/day of MVPA; a DQS of 57.5-72.5) had 9.35 additional years of lifespan (95% CI: 6.67, 11.63) and 9.45 additional years of healthspan (95% CI: 5.45, 13.61). When compared to the 5th percentile for all SPAN behaviours, a minimum combined improvement of 5 mins/day of sleep, 1.9 mins/day MVPA, an extra 5-point increase in DQS (e.g., an additional 1/2 serving of vegetables/day) was associated with 1 additional year of lifespan (95% CI: 0.77, 1.26). For healthspan, a combined improvement of 18.6 mins/day of sleep, 3.4 mins/day of MVPA, and a 21-point diet score increase (e.g. additional 1 cup of vegetables and two servings per week of fish) was associated with 4.0 additional disease-free years (95% CI: 0.27, 8.11). Conclusion: Small, concurrent improvements in sleep, physical activity, and diet quality were associated with substantial gains in lifespan and healthspan. These findings highlight a pragmatic and synergistic approach to improving population health through modest, combined behavioural changes.

The pace of life (POL) is shaped by a complex interplay between genetic and environmental factors, influencing growth, maturation, and lifespan across species. The Hippo signaling pathway, a key regulator of organ size and cellular homeostasis, has emerged as a central integrator of environmental cues that modulate POL traits. In this review, we explore how the Hippo pathway links environmental factors-such as temperature fluctuations and dietary energy availability-to molecular mechanisms governing metabolic balance, hormonal signaling, and reproductive timing. Specifically, we highlight the regulatory interactions between the Hippo pathway and metabolic sensors (AMPK, mTOR, SIRT1 and DLK1-Notch), as well as hormonal signals (IGF-1, kisspeptin, leptin, cortisol, thyroid and sex steroids), which together orchestrate key life-history traits, including growth rates, lifespan and sexual maturation, with a particular emphasis on their role in reproductive timing. Furthermore, we consider its role as a potential coordinator of POL-related molecular processes, such as telomere dynamics and epigenetic mechanisms, within a broader regulatory network. By integrating insights from molecular biology and eco-evolutionary perspectives, we propose future directions to dissect the Hippo pathway's role in POL regulation across taxa. Understanding these interactions will provide new perspectives on how organisms adaptively adjust life-history strategies in response to environmental variability.

Increasing longevity and the growing elderly population necessitate a deeper understanding of aging mechanisms to prolong productive life and improve treatments for age-related diseases linked with cellular senescence. Mesenchymal stem cells (MSCs) are crucial for maintaining tissue homeostasis, but their physiological changes during senescence are not well understood. Growth differentiation factor 11 (GDF11) has emerged as a potential rejuvenation factor, enhancing MSC viability, mobility, and angiogenic functions, which improves outcomes in ischemic models and cardiac repair. This study aims to identify transcriptomic changes in young and senescent MSCs influenced by GDF11, highlighting its potential in MSC-based therapies.

Biological aging is marked by a decline in resilience at the cellular and systemic levels, driving an exponential increase in mortality risk. Here, we evaluate several clinical and epigenetic clocks for their ability to predict mortality, demonstrating that clocks trained on survival and functional aging outperform those trained on chronological age. We present an enhanced clinical clock that predicts mortality more accurately and provides actionable insights for guiding personalized interventions. These findings highlight the potential of mortality-predicting clocks to inform clinical decision-making and promote strategies for healthy longevity.

Single-cell analysis is a transformative approach to understanding cellular heterogeneity in aging and cancer, interconnected processes driven by mechanisms like senescence and immune modulation. This review explores how aging influences cancer initiation, progression, and treatment resistance within the tumor microenvironment (TME). By examining recent studies using single-cell technologies, we reveal the nuanced roles of aging in tumorigenesis, immune interactions, and therapeutic outcomes. Aging is closely tied to cancer progression, with senescent cells demonstrating heightened proliferative, invasive, and metastatic capabilities. Emerging senolytic therapies targeting aging-related pathways hold promise for enhancing treatment efficacy. Advanced tools such as spatial transcriptomics, molecular probes, and artificial intelligence further refine our understanding of aging-related heterogeneity in the TME. By integrating single-cell analysis with these technologies, future research can clarify the intricate interactions between aging and cancer, advancing precision oncology and improving outcomes for aging cancer patients.

DNA methylation (DNAm) is a core gene regulatory mechanism that captures cellular responses to short- and long- term stimuli such as environmental exposures, aging, and cellular differentiation. Although DNAm has proven valuable as a baseline biomarker for aging by enabling robust characterization of disease-associated methylation shifts associated with age, its potential to reveal analogous shifts in the context of tissue remains underexplored. A major obstacle has been the absence of comprehensive, curated reference atlases spanning diverse normal human tissues, limiting most existing work to disease-subtype differentiation or localized tissue comparisons. To bridge this gap, we assemble the largest and most diverse atlas of exclusively healthy human tissue and cell samples profiled by 450K arrays, comprising of 16,959 samples across 86 tissues and cell types. Leveraging this resource, we introduce an ontology-aware classification framework that identifies robust CpG features associated with tissue and cell identity while integrating known anatomical and functional relationships (e.g., prefrontal cortex in the brain, leukocytes in blood). Our novel application of Minipatch learning distills a set of 190 CpG sites that can accurately support multi-label classification. We further validate our approach through an ontology-based label transfer task, demonstrating the effectiveness of ontology-informed learning to accurately predict relevant labels for 31 tissues and cell types not seen during training. These findings underscore the potential of our framework to enhance our understanding of healthy methylation landscapes and facilitate future applications in disease detection and personalized medicine.

To understand how aging affects functional decline and increases disease risk, it is necessary to develop accurate and reliable measures of how fast a person is aging. Epigenetic clocks measure aging but require DNA methylation data, which many studies lack. Using data from the Dunedin Study, we introduce an accurate and reliable measure for the rate of longitudinal aging derived from cross-sectional brain MRI: the Dunedin Pace of Aging Calculated from NeuroImaging or DunedinPACNI. Exporting this measure to the Alzheimer's Disease Neuroimaging Initiative and UK Biobank datasets revealed that faster DunedinPACNI predicted participants' cognitive impairment, accelerated brain atrophy, and conversion to diagnosed dementia. Underscoring close links between longitudinal aging of the body and brain, faster DunedinPACNI also predicted physical frailty, poor health, future chronic diseases, and mortality in older adults. Furthermore, DunedinPACNI followed an established socioeconomic health gradient with people of lower socioeconomic status showing faster DunedinPACNI. Associations between DunedinPACNI and cognitive impairment were replicated in BrainLat, a sample of Latin American patients with dementia. When compared to brain age gap, an existing MRI aging biomarker, DunedinPACNI was similarly or more strongly related to clinical outcomes. DunedinPACNI is a 'next generation' MRI measure that will be made publicly available to the research community to help accelerate aging research and evaluate the effectiveness of dementia prevention and anti-aging strategies.

Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechano-signaling but its role for mechanotransduction in stem cell aging has not been investigated yet. Here, we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell intrinsically activates RhoA. Interestingly, aged HSCs experience physiologically higher intrinsic NE tension, associated with increased NE P-cPLA2 and RhoA activity. Reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated to RhoA inhibition, which includes the restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons. Eventually, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSCs regenerative capacity and lympho/myeloid skewing in vivo. Overall, our data support that an intrinsic mechano-signaling axis dependent on RhoA can be pharmacologically targeted to rejuvenate stem cell function upon aging.

Background: Mechanisms underlying Doxorubicin (Doxo) chemotherapy-induced vascular endothelial dysfunction are incompletely understood. Objectives: Determine the role of cellular senescence in mediating Doxo-induced vascular endothelial dysfunction and the influence of senolytic therapy as a therapeutic strategy to mitigate endothelial dysfunction with Doxo. Methods: Endothelial function (carotid artery endothelium-dependent dilation [EDD] to increasing concentrations of acetylcholine) and associated mechanisms were assessed in young adult p16-3MR mice (which allow for genetic-based clearance of senescent cells with ganciclovir [GCV]) injected with Doxo and subsequently treated with GCV or ABT263 (senolytic). We also assessed the influence of Doxo and ABT263 ex vivo on EDD to increased flow in human arterioles. Results: Lower peak EDD with Doxo (75% vs. control, 93%; P<0.05) was prevented with GCV (94%; P<0.05) and ABT263 (95%; P<0.05) treatment, which was mediated by preserved nitric oxide bioavailability and prevention of excess mitochondrial oxidative stress. In human arterioles, ex vivo Doxo exposure impaired peak EDD (Doxo, 32% vs. Control, 94%; P<0.05) which was prevented with concomitant incubation of Doxo with ABT263 (82%; P<0.05 vs. Doxo alone; P=0.63 vs. Control). Conclusion: We provide translational evidence that cellular senescence contributes to Doxo-induced vascular endothelial dysfunction and that senolytics hold promise for preserving vascular endothelial function following Doxo exposure.

Aging has been identified as a leading risk factor for many diseases, including neurodegenerative disorders. While cellular senescence has been linked to age-related neurodegenerative conditions, its involvement in peripheral stress-associated brain disorders is just beginning to be explored. In this study, we investigated the impact of senescent cells on peripheral stress-induced neuroinflammation using orthopedic surgery as a model. Our results demonstrate an increased accumulation of senescent cells and neuroinflammation in the aged mouse hippocampus following surgery. Intermittent treatment of the mice with the senolytic drugs dasatinib and quercetin (D/Q) showed a significant reduction in surgery-induced senescent cell burden. This reduction in senescent cell accumulation was correlated with reduced surgery-induced neuroinflammation, as evidenced by decreased glial cell activity. Consistent with these observations, we also observed reduced levels of proinflammatory senescence-associated secretory phenotype factors in circulation, following fracture surgery, in mice treated with D/Q. Overall, our findings underscore the pivotal role of cellular senescence in surgery-induced neuroinflammation and highlight the therapeutic potential of eliminating senescent cells as a potential strategy to manage peripheral stress-induced neuroinflammatory conditions.

Skeletal muscle wasting results from numerous conditions, such as sarcopenia, glucocorticoid therapy or intensive care. It prevents independent living in the elderly, predisposes to secondary diseases, and ultimately reduces lifespan. There is no approved drug therapy and the major causative mechanisms are not fully understood. Dual specificity phosphatase 22 (DUSP22) is a pleiotropic signaling molecule that plays important roles in immunity and cancer. However, the role of DUSP22 in skeletal muscle wasting is unknown. In this study, DUSP22 was found to be upregulated in sarcopenia patients and models of skeletal muscle wasting. DUSP22 knockdown or treatment with BML-260 (a small molecule previously reported to target DUSP22) prevented multiple forms of muscle wasting. Mechanistically, targeting DUSP22 suppressed FOXO3a, a master regulator of skeletal muscle wasting, via downregulation of the stress-activated kinase JNK, which occurred independently of aberrant Akt activation. DUSP22 targeting was also effective in human skeletal muscle cells undergoing atrophy. In conclusion, phosphatase DUSP22 is a novel target for preventing skeletal muscle wasting and BML-260 treatment is therapeutically effective. The DUSP22-JNK-FOXO3a axis could be exploited to treat sarcopenia or related aging disorders.

Emerging evidence strongly supports a close relationship between age-related hearing loss and frailty, highlighting the importance of early detection and intervention. Recently, we invented a mitochondria-homing drug named mitochonic acid 5 (MA-5), that increases the adenosine triphosphate (ATP) levels, rescue mitochondrial function, and protect tissue damages. Currently, the phase I clinical trial has been finished in Japan (jRCT2031210495) and the phase 2 clinical trial has already been approved by PMDA. Here we show that MA-5 improved various types of hearing loss in mouse models. Structural chemical bioanalysis revealed that MA-5 is a mixture of equal amount of S- and R- enantiomer and both S- and R-enantiomer increase ATP by binding mitochondrial protein, mitofilin. However, S-enantiomer significantly increased the NAD+ levels by binding to the NAD+-producing key enzyme nicotinamide phosphoribosyltransferase (NAMPT). Moreover, the S-enantiomer increased the sirtuin 1 protein by suppressing polyubiquitination induced by tripartite motif containing 28 (TRIM28) phosphorylation which was triggered by DNA-dependent protein kinase (DNA-PK) activation in the absence of DNA damage. Transcriptomic signatures showed that the signature of MA-5 shows an inverse correlation with aging and mortality and is oriented in the same direction as the OSKM-related iPSCs, suggesting the modification of aging pathways. Oral administration of MA-5 to mitochondrial disease model mouse showed increased survival. Our findings suggest that, in addition to enhancing ATP levels, the coordinated regulation of NAD metabolism, SIRT protein expression, and DNA-PK activity-constituting a novel therapeutic triad may contribute to the amelioration of hearing impairment and mitochondrial dysfunction, thereby improving life prognosis.

Accurately identifying senescent cells is essential for studying their spatial and molecular features. We developed DeepScence, a method based on deep neural networks, to identify senescent cells in single-cell and spatial transcriptomics data. DeepScence is based on CoreScence, a senescence-associated gene set we curated that incorporates information from multiple published gene sets. We demonstrate that DeepScence can accurately identify senescent cells in single-cell gene expression data collected both in vitro and in vivo, as well as in spatial transcriptomics data generated by different platforms, substantially outperforming existing methods.

The ability of biomolecular condensates to reversibly dissolve and reform is crucial for maintaining cellular stability and functions. In metabolically active cells, stress granules can rapidly assemble and disassemble in response to environmental changes. However, as metabolic rates decline with aging, stress granules persist longer, disrupting mRNA translation and stress responses. Temperature, as a physical stimulus, plays a key role in controlling condensate formation, dissolution, and material properties. In this study, we explore how the reversibility of the liquid-to-solid transition of biomolecular condensates can be modulated by temperature change. Our findings reveal that aged condensates exhibit reduced responsiveness to external temperature stimuli. By using thermal cycling experiments to simulate repeated heat stress, we found that the time taken for irreversible fiber formation could be delayed up to 4.7-fold compared to condensates without thermal cycles. We also found the dissolution rate of condensates progressively slows as they age but remain more stable with thermal cycles. Importantly, our results indicate that continuous cycles of liquid-liquid phase separation and dissolution act as a reset mechanism, preserving the biomolecular condensates from further liquid-to-solid transition. These findings provide valuable insights into how aging impacts condensate behavior and highlight potential strategies to preserve cellular function through controlled phase transitions.

Epigenetic aging signatures provide insights into human aging, but traditional clocks rely on linear regression of DNA methylation levels, assuming linear trajectories. This study explores a non-parametric approach using 2D-kernel density estimation to determine epigenetic age. Our weighted model achieves similar predictive accuracy as conventional clocks and provides a variation score reflecting the inherent variability of age-related epigenetic changes within samples. This score is significantly increased in various diseases and associated with mortality risk in the Lothian Birth Cohort 1921. Thus, weighted 2D-kernel density estimation facilitates accurate epigenetic age predictions and offers an additional variable for biological age estimation.

To understand how early-life environmental exposures shape health and disease risk across the lifecourse, the TaRGET II Consortium exposed mice to diverse toxicants from pre-conception through weaning, and followed individual animals into adulthood, generating over 800 epigenomic and transcriptomic profiles. These profiles revealed that early-life exposures induced persistent epigenomic reprogramming and significantly disrupted the adult transcriptome. Notably, despite their diverse mechanisms of action, the exposure signatures of the xenoestrogen BPA, obesogen TBT, dioxin TCDD, and air pollutant PM2.5, were all largely comprised of genes normally differentially expressed during liver aging. Epigenetic histone modifications at enhancers - and, to a lesser extent, promoters - emerged as key targets for this reprogramming. Despite differing mechanisms of action, these four toxicants imparted similar \'fingerprints\' on the adult liver, characterized by direction- and cell type-specific polarization of the transcriptome. Hepatocyte genes that typically increase with age, particularly those in metabolic pathways, were downregulated, while conversely, non-parenchymal cell genes that typically decrease with age, such as those involved in extracellular matrix production, were upregulated. A similar signature of anti-correlation with programmed aging aging was also found in the transcriptome of patients with liver disease and hepatocellular carcinoma (HCC) and was effective at distinguishing healthy from diseased human livers. These findings demonstrate that the plasticity of epigenomic aging is vulnerable to early-life environmental exposures, which can reprogram the epigenome with lasting impacts on the transcriptome, and disease risk, later in life.

Ageing is characterised by persistent low-grade inflammation that is linked to impaired tissue homeostasis and functionality. However, the molecular mechanisms driving age-associated inflammation remain poorly understood. The mammalian skin is a clinically relevant target of age-driven inflammation associated with compromised barrier function, inefficient wound healing, elevated oxidative stress, and DNA damage accumulation. Here, we show that upon ageing a previously uncharacterised BMAL1-YAP transcriptional complex is hijacked from chromatin regions associated with homeostatic genes in adult epidermis and redirected to inflammation-related enhancers, amplifying the transcription of their target genes. Independently of its known role as a core circadian clock component, BMAL1 partners with the mechanosensitive transcriptional cofactor YAP at enhancer regions to regulate epidermal identity genes. In contrast, in aged skin, BMAL1-YAP complexes bind to enhancers of inflammation- related genes, co-regulated by NF-kB. Interestingly, aged pro-inflammatory signals from the IL- 17 pathway activate YAP in a Hippo-independent manner. These findings unveil a transcriptional mechanism underlying epidermal ageing, linking chromatin dynamics to inflammatory transcriptional programs through BMAL1-YAP-bound enhancer rewiring. By elucidating how ageing reprograms transcriptional networks, our work highlights potential strategies to counteract chronic inflammation and restore tissue homeostasis across age-related loss of functionality.

Aging is characterized by a gradual decline in physiological functions, with brain aging being a major risk factor for numerous neurodegenerative diseases. Given the brain's high energy demands, maintaining an adequate ATP supply is crucial for its proper function. However, with advancing age, mitochondria dysfunction and a deteriorating energy metabolism lead to reduced overall energy production and impaired mitochondrial quality control (MQC). As a result, promoting healthy aging has become a key focus in contemporary research. This review examines the relationship between energy metabolism and brain aging, highlighting the connection between MQC and energy metabolism, and proposes strategies to delay brain aging by targeting energy metabolism.

Cardiac aging is a multistep process that results in a loss of various structural and functional heart abilities, increasing the risk of heart disease. Since its remarkable discovery in the early 1800s, when limestone is heated, calcium's importance has been defined in numerous ways. It can help stiffen shells and bones, function as a reducing agent in chemical reactions, and play a central role in cellular signalling. The movement of calcium ions in and out of cells and between those is referred to as calcium signalling. It influences the binding of the ligand, enzyme activity, electrochemical gradients, and other cellular processes. Calcium signalling is critical for both contraction and relaxation under the sliding filament model of heart muscle. However, with age, the heart undergoes changes that lead to increases in cardiac dysfunction, such as myocardial fibrosis, decreased cardiomyocyte function, and noxious disturbances in calcium homeostasis. Additionally, when cardiac tissues age, cellular senescence, a state of irreversible cell cycle arrest, accumulates and begins to exacerbate tissue inflammation and fibrosis. This review explores the most recent discoveries regarding the role of senescent cell accumulation and calcium signalling perturbances in cardiac aging. Additionally, new treatment strategies are used to reduce aged-related heart dysfunction by targeting senescent cells and modulating calcium homeostasis.

There is a sex bias in the incidence and progression of many kidney diseases. To better understand such sexual dimorphism, we integrated data from six platforms, characterizing 76 kidney samples from 68 mice at six developmental and adult time points, creating a molecular atlas of the mouse kidney across the lifespan for both sexes. We show that proximal tubules have the most sex-biased differentially expressed genes emerging after 3 weeks of age and are associated with hormonal regulations. We reveal potential mechanisms involving both direct and indirect regulation by androgens and estrogens. Spatial profiling identifies distinct sex-biased spatial patterns in the cortex and outer stripe of the outer medulla. Additionally, older mice exhibit more aging-related gene alterations in loops of Henle, proximal tubules and collecting ducts in a sex-dependent manner. Our results enhance the understanding of spatially resolved gene expression and hormone regulation underlying kidney sexual dimorphism across the lifespan.

Episodic memory consolidation relies on the functional specialization of brain networks and sleep quality, both of which are affected by aging. Functional connectivity during wakefulness is crucial to support the integration of newly acquired information into memory networks. Additionally, the temporal dynamics of sleep spindles facilitates overnight memory consolidation by promoting hippocampal replay and integration of memories within neocortical structures. This study aimed at exploring how resting-state functional connectivity during wakefulness contributes to sleep-dependent memory consolidation in aging, and whether spindles clustered in trains modulates this relationship. Forty-two healthy older adults (68.82 ± 3.03 years), enrolled in the Age-Well clinical trial, were included. Sleep-dependent memory consolidation was assessed using a visuo-spatial memory task performed before and after a polysomnography night. Resting-state functional connectivity data were analyzed using graph theory applied to the whole brain, specific brain networks and the hippocampus. Lower limbic network integration and higher centrality of the anterior hippocampus were associated with better memory consolidation. Spindle trains modulated these effects, such that older participants with longer spindle trains exhibited a stronger negative association between limbic network integration and memory consolidation. These results indicate that lower functional specialization at rest is associated with weaker memory consolidation during sleep. This aligns with the dedifferentiation hypothesis, which posits that aging is associated with reduced brain specificity, leading to less efficient cognitive functioning. These findings reveal a novel mechanism linking daytime brain network organization and sleep-dependent memory consolidation, and suggest that targeting spindle dynamics could help preserve cognitive functioning in aging.

Human Werner syndrome (adult progeria, a well-established model of human aging) is caused by mutations in the Werner syndrome (WRN) gene. However, the expression patterns and functions of WRN in natural aging remain poorly understood. Despite the link between WRN deficiencies and progeria, our analyses of human colon tissues, mouse crypts, and Drosophila midguts revealed that WRN expression does not decrease but rather increases in intestinal stem cells (ISCs) with aging. Mechanistically, we found that the Drosophila WRN homologue (WRNexo) binds to Heat shock 70-kDa protein cognate 3 (Hsc70-3/Bip) to regulate the unfolded protein response of the endoplasmic reticulum (UPRER). Activation of the WRNexo-mediated UPRER in ISCs is required for ISC proliferation during injury repair. However, persistent DNA damage during aging leads to chronic upregulation of WRNexo in ISCs, where excessive WRNexo-induced ER stress drives age-associated gut hyperplasia in Drosophila. This study reveals how elevated WRNexo contributes to stem cell aging, providing new insights into organ aging and the pathogenesis of age-related diseases, such as colon cancer.

How genetic is human lifespan? Twin studies suggest genes explain 20-25% of lifespan variation, while some pedigree studies put it as low as 7% .However, these estimates do not distinguish between intrinsic and extrinsic mortality. We model genetic variation within two well-established mortality frameworks - the Saturating-Removal (SR) model and the Makeham-Gamma-Gompertz (MGG) model - and calibrate them using historical twin datasets from Sweden, Denmark, and the SATSA study - to show that extrinsic mortality underestimates heritability estimates by driving down measured lifespan correlations among twin pairs. In the SATSA cohort, heritability climbs across birth cohorts as extrinsic mortality falls, supporting our prediction. Computationally excluding extrinsic deaths and analysing survival from age 15 gives a broad-sense heritability of 0.54 -- on par with that of most complex traits. We thus challenge the consensus that genetics has only a minor effect on lifespan, showing that genetic variation explains about half of human lifespan differences. Our results support renewed efforts to uncover the molecular and genetic mechanisms of aging and translate them into clinical benefits.

The magnitude of telomere shortening per cell division in human somatic cells in vivo (MTSIV) is a fundamental but unquantified parameter. MTSIV is essential for understanding how telomere-length (TL)-dependent hematopoietic cell division influences age-related health and longevity. By leveraging sex differences in leukocyte TL and the differential dosage of DKC1, a telomerase-regulating gene, during early embryonic cell divisions, we estimate the MTSIV to be 28 base pairs per cell division (95% CI: 23 - 32). Using this estimate and leukocyte TL data from newborns and centenarians, we infer that hematopoietic stem cells (HSCs) undergo approximately 156 divisions (95% CI: 130 - 183) over a 100-year lifespan. Using longitudinal data on leukocyte telomere shortening in adults, we further estimate that HSCs divide about 0.97 times yearly (95% CI: 0.80 - 1.13) after age 20. These findings provide a quantitative framework for understanding TL-dependent hematopoiesis, the most proliferative process in the human soma. They also highlight that if telomere shortening affects age-related health and longevity, it acts primarily through its impact on hematopoiesis. Our results refine hematopoietic stem cell replicative history estimates and might guide treatments involving hematopoietic cell expansion, such as hematopoietic cell transplantation and immunotherapies.

The accumulation of dysfunctional giant mitochondria is a hallmark of aged cardiomyocytes. This study investigated the core mechanism underlying this phenomenon, focusing on the disruption of mitochondrial lipid metabolism and its effects on mitochondrial dynamics and autophagy, using both naturally aging mouse models and etoposide-induced cellular senescence models. In aged cardiomyocytes, a reduction in endoplasmic reticulum-mitochondrial (ER-Mito) contacts impairs lipid transport and leads to insufficient synthesis of mitochondrial phosphatidylethanolamine (PE). A deficiency in phosphatidylserine decarboxylase (PISD) further hinders the conversion of phosphatidylserine to PE within mitochondria, exacerbating the deficit of PE production. This PE shortage disrupts autophagosomal membrane formation, leading to impaired autophagic flux and the accumulation of damaged mitochondria. Modulating LACTB expression to enhance PISD activity and PE production helps maintain mitochondrial homeostasis and the integrity of aging cardiomyocytes. These findings highlight the disruption of mitochondrial lipid metabolism as a central mechanism driving the accumulation of dysfunctional giant mitochondria in aged cardiomyocytes and suggest that inhibiting LACTB expression could serve as a potential therapeutic strategy for mitigating cardiac aging and preserving mitochondrial function.

Sarcopenia, closely associated with other diseases such as diabetes, metabolic syndrome, and osteoporosis, significantly impacts aging populations. It is characterized by muscle atrophy, increased intramuscular adipose tissue, impaired myogenesis, chronic low-grade inflammation, and reduced muscle function. The mechanisms behind aging muscle remain incompletely understood. This study aims to elucidate the role of Sirt2 in the aging process of skeletal muscles and enhance our understanding of the underlying mechanisms. Sirt2 expression was reduced in aging muscle of male mice by 40%, compared to young muscle. Aged male Sirt2 knockout mice exhibit increased intramuscular adipose tissue infiltration by 8.5-fold changes. Furthermore, the deletion of Sirt2 exacerbated myogenesis impairment in aged muscle by decreasing the expression of Pax7 (50%) and NogoA (80%), compared to age- and sex- matched counterparts, emphasizing the role of Sirt2 in pathology of aging muscle. Additionally, long-term Sirt2 deletion affected other Sirtuin subfamily members, with decreased expressions of Sirt1 (65%), Sirt4 (94%), and Sirt5 (71%), and increased expressions of Sirt6 (4.6-fold) and Sirt7 (2.8-fold) in old male Sirt2 knockout mice, while there was no difference of these gene expression in young male mice. This study underscores the critical need for a deeper investigation into Sirt2, promising new insights that could lead to targeted therapies for sarcopenia, ultimately improving the quality of life in the elderly.

INTRODUCTION: Dual cognitive-motor impairment in aging is a strong predictor of dementia, yet its effects on vulnerable gray matter regions microstructure remain unexplored. METHODS: This study classified 582 individuals aged 36-90 into cognitive-motor impairment, isolated cognitive or motor impairment, and control groups. Microstructural differences in 27 temporal and motor-related gray matter regions and white matter tracts were assessed using DTI and mean apparent propagator (MAP-MRI), a technique well-suited for gray matter analysis. RESULTS: We found widespread microstructural alterations in gray and white matter among individuals with dual cognitive-motor impairment. These changes were not observed in isolated cognitive or motor impairment after multiple comparisons correction. DISCUSSION: Dual cognitive-motor impairment is associated with reduced cellular density in temporal gray matter, decreased fiber coherence, and potential demyelination in white matter tracts, suggesting widespread microstructural disruption. These findings could help understand brain aging and facilitate interventions to slow neurodegeneration and delay dementia onset.