Longevity Papers

Clonal hematopoiesis (CH) is characterized by expanding blood cell clones carrying somatic mutations in healthy aged individuals and is associated with various age-related diseases and all-cause mortality. While CH mutations affect diverse genes associated with myeloid malignancies, their mechanisms of expansion and disease associations remain poorly understood. We investigate the relationship between clonal fitness and clinical outcomes by integrating data from three longitudinal aging cohorts (n=713, observations=2,341). We demonstrate pathway-specific fitness advantage and clonal composition influence clonal dynamics. Further, the timing of mutation acquisition is necessary to determine the extent of clonal expansion reached during the host individual\'s lifetime. We introduce MACS120, a metric combining mutation context, timing, and variant fitness to predict future clonal growth, outperforming traditional variant allele frequency measurements in predicting clinical outcomes. Our unified analytical framework enables standardized clonal dynamics inference across cohorts, advancing our ability to predict and potentially intervene in CH-related pathologies.

Aging is the primary risk factor for most neurodegenerative diseases, yet the cell-type-specific progression of brain aging remains poorly understood. Here, we developed human cell-type-specific transcriptomic aging clocks using high-quality single-nucleus RNA sequencing data from post mortem human prefrontal cortex tissue of 31 donors aged 18-94 years, encompassing 73,941 high-quality nuclei. We observed distinct transcriptomic changes across major cell types, including upregulation of inflammatory response genes in microglia from older samples. Aging clocks trained on each major cell type accurately predicted chronological age and remained robust in independent single-nucleus RNA-sequencing datasets, underscoring their broad applicability. These findings demonstrate the feasibility of cell-type-specific transcriptomic clocks to measure biological aging in the human brain and highlight potential mechanisms of selective vulnerability in neurodegenerative diseases. We anticipate these clocks will serve as a basis for further studies in other brain regions and more diverse populations, ultimately advancing our understanding of age-related neurodegenerative processes at the single-cell level.

Recent evidence indicates that the organization of the human neocortex is underpinned by smooth spatial gradients of functional connectivity (FC). These gradients provide crucial insight into the relationship between the brain's topographic organization and the texture of human cognition. However, no studies to date have charted how intrinsic FC gradient architecture develops across the entire human lifespan. In this work, we model developmental trajectories of the three primary gradients of FC using a large, high-quality, and temporally-dense functional MRI dataset spanning from birth to 100 years of age. The gradient axes, denoted as sensorimotor-association (SA), visual-somatosensory (VS), and modulation-representation (MR), encode crucial hierarchical organizing principles of the brain in development and aging. By tracking their development throughout the human lifespan, we provide the first ever comprehensive low-dimensional normative reference of global FC hierarchical architecture. We observe significant age-related changes in global network features, with global markers of hierarchical organization increasing from birth to early adulthood and decreasing thereafter. During infancy and early childhood, FC organization is shaped by primary sensory processing, dense short-range connectivity, and immature association and control hierarchies. Functional differentiation of transmodal systems supported by long-range coupling drives a convergence toward adult-like FC organization during late childhood, while adolescence and early adulthood are marked by the expansion and refinement of SA and MR hierarchies. While gradient topographies remain stable during late adulthood and aging, we observe decreases in global gradient measures of FC differentiation and complexity from 30 to 100 years. Examining cortical microstructure gradients alongside our functional gradients, we observed that structure-function gradient coupling undergoes differential lifespan trajectories across multiple gradient axes.

Alzheimer\'s disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid {beta}-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid {beta}-oxidation.

Our previous research suggested that mechanistic target of rapamycin (mTOR)/blood-testis barrier (BTB) mechanism is involved in the regulation of the rates of epigenetic aging of sperm, where increased activity of mTORC1 opens BTB and accelerates epigenetic aging and increased activity of mTORC2 produces opposite results - increases BTB integrity and rejuvenates sperm epigenome. In the present study, we use our newly developed epigenetic clock model to investigate whether the mTOR/BTB mechanism is involved in the epigenetic reprogramming of sperm in mice exposed to heat stress (HS) and cadmium (Cd). Our findings show that both mTOR-dependent BTB disruption caused by HS and mTOR-independent BTB disruption due to Cd exposure accelerate sperm epigenetic aging, resulting in similar changes to sperm DNA methylation patterns. These results suggest that the mTOR/BTB mechanism is a novel molecular pathway through which environmental stressors influence sperm epigenetic aging, and this pathway may be relevant to a broad range of factors, including environmental, lifestyle, dietary, and health influences.

Cellular morphology is intimately connected with function. While the link between morphology and functional states has been studied extensively, the role of subcellular transcript localization in cellular function remains unclear. Here we use microglia, the brain\'s resident macrophages, as a model to dissect the interaction of morphology, transcript localization, and function. Using multiplexed error-robust fluorescence in situ hybridization combined with fluorescent immunohistochemistry, we analyzed transcript distribution and morphology simultaneously in young and aged mouse brains. Our approach revealed how mRNA spatial organization varies across microglial states. We identified distinct transcript localization patterns within microglial processes and uncovered morphological heterogeneity within transcriptomically defined populations. Notably, we found a subpopulation of disease-associated microglia with a ramified morphology (displaying numerous processes), challenging the conventional assumption between morphology and microglial states. Finally, we found that aging not only alters the distribution of compartmentalized mRNAs but also reshapes their colocalization networks, shifting microglial functions from synaptic maintenance and phagocytic processes in younger brains to migration and catabolic pathways in older brains. Our findings highlight the role of subcellular transcript organization in shaping microglial morphology and function, offering new avenues for studying and modulating microglial states in health, disease, and aging.

Aging is a biological process along with systemic and multiple organ dysfunction. It is more and more recognized that aging is a systemic disease instead of a single-organ functional disorder. Systemic aging plays a profound role in multiple diseases including neurodegenerative diseases, cardiovascular diseases, and malignant diseases. Aged organs communicate with other organs and accelerate aging. Skeletal muscle, heart, bone marrow, skin, and liver communicate with each other through organ-organ crosstalk. The crosstalk can be mediated by metabolites including lipids, glucose, short-chain fatty acids (SCFA), inflammatory cytokines, and exosomes. Metabolic disorders including hyperglycemia, hyperinsulinemia, and hypercholesterolemia caused by chronic diseases accelerate hallmarks of aging. Systemic aging leads to the destruction of systemic hemostasis, causes the release of inflammatory cytokines, senescence-associated secretory phenotype (SASP), and the imbalance of microbiota composition. Released inflammatory factors further aggregate senescence, which promotes the aging of multiple solid organs. Targeting senescence or delaying aging is emerging as a critical health strategy for solving age-related diseases, especially in the old population. In the current review, we will delineate the mechanisms of organ crosstalk in systemic aging and age-related diseases to provide therapeutic targets for delaying aging.

The redox imbalance induced by excessive reactive oxygen species (ROS) contributes to senescent phenotypes of chondrocytes in osteoarthritis (OA). However, there is limited evidence regarding the involvement of NADPH oxidase-4 (NOX4)/NFE2-related factor 2 (Nrf2) redox imbalance in OA. Isoquercetin (IQ), a quercetin derivative, exhibits promising antioxidative and anti-aging properties. Here, we found that IQ promoted redox homeostasis by inhibiting NOX4 and activating Nrf2-mediated antioxidant responses, thereby ameliorating OA. Specifically, IQ significantly suppressed the expression of senescence-associated secretory phenotypes (SASPs) in senescent chondrocytes. RNA sequencing analysis revealed that cellular senescence and oxidative stress were involved in the mechanism of IQ's effect on senescent chondrocytes. IQ effectively reversed redox imbalance, as evidenced by reduced levels of ROS and endogenous oxidants, and increased mitochondrial membrane potential and, elevated levels of endogenous antioxidants. Mechanistically, the elevated expression of NOX4 observed in patients with severe OA confirms its role in OA pathogenesis. Molecular docking and NOX4 knockdown experiments suggested that IQ may interact with NOX4 and inhibit its expression. This study identifies a potential therapeutic target and provides a promising candidate for OA treatment.

The increased vulnerability of the aging human brain to hypertension-induced neurovascular impairments, including cerebral small vessel diseases (SVD), marked by MRI-visible white matter hyperintensities (WMH), is well recognized. We examined WMH burdens between stroke patients and stroke-free participants across three age groups and explored patterns of modifiable risk factors, specifically the modulating effects of hypertension on WMH burden, providing insights for potential therapeutic interventions. This study comprised one hospital-based cohort of 254 stroke patients and another community-based cohort of 254 stroke-free normative participants. Clinical variables were obtained consecutively, and MRI neuroimaging classified WMH as absent, mild, moderate, or severe. A step-by-step statistical analysis was performed to explore the said gaps. There were 508 participants (mean age 63.5 ± 8.9 years) with 285 males. A similar prevalence but different WMH burden was recorded between stroke and normative cohorts across different age groups. The modulating effect of hypertension on WMH severity varied across age groups and is greater in middle-aged adults; intriguingly, this effect diminished in elderly adults (b = -0.882, 95%CI [-1.591, -0.172], t = -2.442, p = 0.015). It was shown that, in a non-uniform fashion across different age groups, hypertension is a culprit risk factor for exacerbating WMH severity, and middle-aged adults are the most vulnerable. While the elevation of systolic blood pressure predisposes adults to brain white matter deterioration, the decline in diastolic blood pressure suggests a protective role. Recognizing hypertension as a modifiable risk factor and understanding the aging-related changes in blood pressure patterns open avenues for developing age-specific strategies for the mitigation and management of WMH progression.

The choroid plexus (CP) plays a critical role in maintaining central nervous system (CNS) homeostasis, producing cerebrospinal fluid, and regulating the entry of specific substances into the CNS from blood. CP dysfunction has been implicated in various neurological and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This study investigates the relationship between CP structural integrity and cognitive decline in normative aging, using structural and advanced magnetic resonance imaging techniques, including CP volume, diffusion tensor imaging indices (mean diffusivity, MD, and fractional anisotropy, FA) and relaxometry metrics (longitudinal, T1, and transverse, T2, relaxation times). Our results show that diminished CP microstructural integrity, as reflected by higher T1, T2, and MD values, or lower FA values, is associated with lower cognitive performance in processing speed and fluency. Notably, CP microstructural measures demonstrated greater sensitivity to cognitive decline than macrostructural measures, i.e. CP volume. Longitudinal analysis revealed that individuals with reduced CP structural integrity exhibit steeper cognitive decline over time. Furthermore, structural equation modeling revealed that a latent variable representing CP integrity predicts faster overall cognitive decline, with an effect size comparable to that of age. These findings highlight the importance of CP integrity in maintaining cognitive health and suggest that a holistic approach to assessing CP integrity could serve as a sensitive biomarker for early detection of cognitive decline. Further research is needed to elucidate the mechanisms underlying the relationship between CP structural integrity and cognitive decline and to explore the potential therapeutic implications of targeting CP function to prevent or treat age-related cognitive deficits.

Nicotinamide adenine dinucleotide (NAD) and glutathione are vital molecules that control redox-state, enzyme functions and metabolic flux in hundreds of cellular metabolic reactions. High NAD+ level occurs in fasting and has been associated with health outcomes in model systems, while low NAD+/NADH ratio occurs in specific diseases. Still, the normal, booster-treated or disease-related levels of NADs or glutathiones are not well known in humans. Here, we present a standardized technology for high-throughput quantitative measurement of NAD+, NADH, NADP+, NADPH, GSH, and GSSG from a single whole-blood sample. In healthy population (n=299;18-70 year-olds) redox metabolites follow normal distribution in blood and remain unchanged during aging. NAD-boosting increased 4-6 fold the blood NAD+ depending on individual, pointing to need of personalized dose adjustment in treatment trials. In patients with cancer, diabetes or neurodegeneration, NADs and glutathiones showed disease-dependent \'\'redox fingerprints\'\'. The evidence highlights the potential of redox profiling as an indicator of metabolic pathology and as a measure of treatment response.

Aging is a multifaceted process associated with a functional decline in cellular function over time, affecting all lifeforms. During the aging process, metabolism, a fundamental hallmark of life (1), is profoundly altered. In the context of hematopoiesis, the proper function of hematopoietic stem cells - at the apex of the blood system - is tightly linked to their energy metabolism, which in turn shapes hematopoietic output. Here, we review the latest developments in our understanding of the metabolic states and changes in aged hematopoietic stem cells, molecular players and pathways involved in aged hematopoietic stem cell metabolism, the consequences of perturbed metabolism on clonal hematopoiesis and leukemogenesis, and pharmacologic/ genetic strategies to reverse or rejuvenate altered metabolic phenotypes.

Endothelial cell senescence contributes to vascular remodeling in hypertension, a condition that lacks specific clinical treatments. While plant-derived nanovesicles have shown anti-inflammatory properties that reduce endothelial inflammation, their role in endothelial cell senescence is less understood. Here, we isolated and purified nanovesicles from Semen Sinapis albae (SDNVs), a traditional Chinese medicine with antihypertensive properties, and evaluated their therapeutic effects on vascular remodeling in spontaneously hypertensive rats (SHRs) compared to nifedipine, a standard antihypertensive drug. SDNVs were as effective as nifedipine in reducing blood pressure and exceeded nifedipine in mitigating vascular wall thickening, collagen fiber disarray, and in decreasing senescence markers in aortic tissues. In vitro, SDNVs inhibited angiotensin II-induced senescence in human umbilical vein endothelial cells (HUVECs). miRNA and mRNA sequencing revealed that SDNVs downregulate CD38 expression through miR393a delivery, mediating their anti-senescence effects. Our results suggest that SDNVs significantly alleviate hypertension-associated vascular remodeling by targeting CD38 via miR393a, thus reducing endothelial cell senescence. Compared to conventional drugs like nifedipine, SDNVs offer a potentially more effective approach to vascular remodeling. These insights may guide the development of novel therapeutics for hypertension-induced vascular remodeling.

Senescent endothelial cells (EC) are key players in the pathophysiology of cardiovascular diseases and are characterized by a reduced angiogenic and regenerative potential. Therefore, targeting these cells has been suggested as an effective therapeutic strategy to reduce vascular disease burden and potentially improve health and lifespan of humans. Here, we aimed to establish a pharmacological, partial reprogramming strategy to improve replicative senescent endothelial cell function in the context of angiogenesis. We demonstrate that our treatment improves tube formation and sprouting capacity but also increases proliferation and migration capacity in vitro. Further, inflammation and DNA damage were reduced in the replicative senescent cells. These processes were initiated by a short and timely-restricted overexpression of the Yamanaka-factors induced by our pharmacological strategy. The advantage of these compounds is that they are FDA approved in their respective concentrations which could pave the way for use in a clinical setting.

Falls remain a major public health problem and a significant cause of preventable injury. Maintaining strength and balance by staying active can prevent falls in older adults, and public health advocates support referral to community exercise programs. Given the growth in use and acceptance of technological interfaces, there remains an interest in understanding the role of a synchronous exercise program designed to improve strength, postural alignment, and balance specifically designed to be delivered in a digital environment with respect to usability and feasibility.

Extracellular vesicles (EVs) of different sizes are secreted by cells and may contain microRNAs (miRNAs) among its cargo. These miRNAs in EVs can induce changes in gene expression and function of recipient cells. In different cells EVs content can change with age and physiological state affecting tissue function. Based on this, the aim of this study was to characterize the miRNA content and role of small EVs (sEVs) from cyclic female mice in the modulation of liver transcriptome in estropausal mice. Two-month-old female mice were induced to estropause using 4-vinylcyclohexene diepoxide (VCD). At six months of age, VCD-treated mice were divided into placebo group (VCD) and sEVs treated group (VCD + sEVs), which received 10 injections at 3-day intervals of sEVs isolated from serum of donor cyclic female mice. A group of cyclic mice also received placebo injection and served as controls (CTL). sEVs injection in mice undergoing estropause had no effect on body mass, insulin sensitivity or organ weight. We observed ten miRNAs differentially regulated in serum sEVs of VCD compared to CTL mice. In the liver we observed 931 genes differentially expressed in VCD + sEVs compared to VCD mice. Interestingly, eight pathways were up-regulated in liver by VCD treatment and down-regulated by sEVs treatment, indicating that sEVs from cyclic mice can reverse changes promoted by estropause in liver. The expression of Cyp4a12a, which is male-specific, was elevated in VCD females but not normalized by sEVs treatment. Our findings indicate that miRNA content in sEVs is regulated by estropause in mice independent of age. Additionally, treatment of estropausal mice with sEVs from cyclic mice can partially reverse changes in the liver transcriptome.

During the aging process, melanogenesis is downregulated, leading to hair graying. Various agents, including α-melanocyte-stimulating hormone (α-MSH), have been evaluated for their potential to enhance melanogenesis. Among them, N-tert-Butylhydroxylamine (NtBHA) has been reported to reverse cellular aging, enhance mitochondrial function, and exhibit antioxidant properties. The effect of NtBHA on melanogenesis remains unclear. This study aimed to explore the impact of NtBHA on melanogenesis in B16F1 cells. In this study, NtBHA exhibited strong antioxidant activity, as demonstrated by antioxidant activity, lipid peroxidation assay, and hydroxyl radical assay. Importantly, NtBHA did not show any cytotoxic effects in the MTT assay. Additionally, in a melanin production experiment in the presence of H₂O₂, NtBHA increased melanin production in cells exposed to oxidative stress induced by H₂O₂. Additionally, NtBHA enhanced the expression of crucial proteins related to melanogenesis, such as MITF, TRP-2, and TYR. Therefore, NtBHA may promote melanogenesis in H₂O₂-stressed melanoma cells, which are aged, potentially supporting melanogenesis through the MITF signaling pathway. In addition to its potential role in restoring pigmentation, the robust antioxidant properties of NtBHA underscore its promise as a therapeutic agent for managing pigmentation disorders and mitigating oxidative stress-related skin aging. This study establishes a foundation for further research into the clinical application of NtBHA in anti-aging and dermatological treatments.

Female reproductive aging is accompanied by a dramatic rise in the incidence of egg aneuploidy. Premature loss of chromosome cohesion proteins and untimely separation of chromosomes is thought to underly high rates egg aneuploidy during maternal aging. However, because chromosome cohesion loss occurs gradually over female reproductive lifespan and cytoskeletal defects alone can predispose eggs to chromosomal abnormalities, the root causes of exponential rise in egg aneuploidy at advanced reproductive ages remain a mystery. Here, we applied high-resolution live imaging to visualize for the first time cohesion protein dynamics underpinning meiotic chromosome segregation. To discover proteins whose dysfunction accelerates aneuploidies associated with female reproductive aging, we innovated the first experimental system in which chemically induced cohesion reduction rapidly triggers aging-like chromosomal abnormalities in young eggs. By integrating this direct cohesion manipulation system with quantitative high-resolution microscopy and targeted protein degradation tools, we identified the centromeric protein CENP-A as a new factor whose aging-like depletion causes a dramatic rise in premature separation of sister chromatids. Our work illuminates cohesion loss-independent origins of age-related egg aneuploidy and provides new avenues to discover therapeutic targets for extending the female reproductive lifespan.

Aging and metabolic disorders share intricate molecular pathways, with the Forkhead box O (FOXO)- Sirtuin 1 (SIRT1) axis emerging as a pivotal regulator of cellular stress adaptation, metabolic homeostasis, and longevity. This axis integrates nutrient signaling with oxidative stress defence, modulating glucose and lipid metabolism, mitochondrial function, and autophagy to maintain cellular stability. FOXO transcription factors, regulated by SIRT1 deacetylation, enhance antioxidant defence mechanisms, activating genes such as superoxide dismutase (SOD) and catalase, thereby counteracting oxidative stress and metabolic dysregulation. Recent evidence highlights the dynamic role of reactive oxygen species (ROS) as secondary messengers in redox signaling, influencing FOXO-SIRT1 activity in metabolic adaptation. Additionally, key redox-sensitive regulators such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) interact with this pathway, orchestrating mitochondrial biogenesis and adaptive stress responses. Pharmacological interventions, including alpha-lipoic acid (ALA), resveratrol, curcumin and NAD

Cardiovascular diseases (CVDs) are experiencing a rapid surge and are widely recognized as the leading cause of mortality in the current aging society. Given the multifactorial etiology of CVDs, understanding the intricate molecular and cellular mechanisms is imperative. Over the past 2 decades, many scientists have focused on Sirtuins, a family of nicotinamide adenine dinucleotide-dependent deacylases. Sirtuins are highly conserved across species, from yeasts to primates, and play a crucial role in linking aging and diseases. Sirtuins participate in nearly all key physiological and pathological processes, ranging from embryogenic development to stress response and aging. Abnormal expression and activity of Sirtuins exist in many aging-related diseases, while their activation has shown efficacy in mitigating these diseases (eg, CVDs). In terms of research, this field has maintained fast, sustained growth in recent years, from fundamental studies to clinical trials. In this review, we present a comprehensive, up-to-date discussion on the biological functions of Sirtuins and their roles in regulating cardiovascular biology and CVDs. Furthermore, we highlight the latest advancements in utilizing Sirtuin-activating compounds and nicotinamide adenine dinucleotide boosters as potential pharmacological targets for preventing and treating CVDs. The key unresolved issues in the field-from the chemicobiological regulation of Sirtuins to Sirtuin-targeted CVD investigations-are also discussed. This timely review could be critical in understanding the updated knowledge of Sirtuin biology in CVDs and facilitating the clinical accessibility of Sirtuin-targeting interventions.

Exercise is one of the most potent interventions known that is able to prevent and even treat dozens of age-related dysfunctions and diseases. Despite this, much remains unknown about how its benefits are derived. Because exercise exerts such wide-ranging effects, and because a decline in protein homeostasis (proteostasis) with age has been connected to numerous age-related diseases, I hypothesized that exercise could increase the activity of proteostasis pathways like the proteasome and autophagy and that this could ameliorate age-related declines in function. I decided to use a Caenorhabditis elegans exercise paradigm to explore the effects exercise has on proteostasis because of its inherent advantages that make it an appealing model organism. Recent studies of involuntary thrashing (swimming) in C. elegans found that it was able to replicate numerous aspects of mammalian exercise, including increased mitochondrial function, increased muscle function, and gene expression profiles that resemble mammalian endurance exercise. I used this thrashing exercise paradigm to look at effects of acute exercise and the effects of multiple days of exercise on aging and proteostasis, including the autophagy-lysosome system, the proteasome, and toxic peptides. I found that exercise is able to increase proteasomal activity and autophagic flux in vivo, improved resistance to toxic peptides, and increased lifespan. One of the primary rationales for studying the mechanisms of exercise is to uncover potential mediators that can be repurposed to deliver the benefits of exercise to those unable to engage in physical activity. I hypothesized that exercise-elevated metabolite alpha-ketoglutarate, already demonstrated to improve age-related declines in flies and mice, would mimic the effects of exercise on proteostasis. Interestingly, treatment with alpha-ketoglutarate showed mixed results on measures of proteostasis, indicative of the challenges in recapitulating a complex phenomenon like exercise.

Trees are long-lived plants that develop complex, highly branched shoot systems as they grow. Their extended lifespan allows somatic mutations to accumulate along these branching structures, ultimately becoming fixed in reproductive and vegetative tissues such as leaves, flowers, and fruits. Mature trees can easily sustain tens of thousands of terminal branches, each potentially carrying mutated gametes. To avoid mutational meltdown and inbreeding depression, long-lived plants appear to have evolved mechanisms that slow mutation accumulation per unit time. How this is achieved remains unclear. Here, we show that branching architecture can limit mutation accumulation to the same extent as reducing the mutation rate itself. Tree structures that maximize branch path sharing during development constrain mutational diversity in the crown. These architectural factors can drive differences in mutation burden by orders of magnitude, even when mutation rates and terminal branch numbers are identical. Building on these insights, we show that current estimates of somatic mutation rates in trees are actually upward biased by a factor that scales with the topological characteristics of the tree. These results raise the deeper question whether somatic mutation rate differences, recently detected among tree species, reflect variation in branching strategies rather than variation in the rates themselves. It is possible that specific branching architectures have evolved not only to optimize resource allocation and structural stability but also to limit mutational load.

Centrosomes localize to perinuclear foci where they serve multifunctional roles, arranging the microtubule organizing center (MTOC) and anchoring ubiquitin proteasome system (UPS) machinery, as suggested by prior studies. In mature cardiomyocytes, centrosomal proteins redistribute into a specialized perinuclear cage-like structure, and a potential centrosomal-UPS interface has not been studied, despite established roles for UPS in cardiomyopathy. In addition, there have been no reports citing cardiomyocyte UPS dysfunction upon or after manipulation of centrosomal proteins. Taxilin-beta (Txlnb), a cardiomyocyte-enriched protein, belongs to a family of centrosome adapter proteins implicated in protein quality control. We hypothesize that Txlnb is part of the perinuclear centrosomal cage and regulates proteostasis in cardiomyocytes. Herein, we show that centrosome proteins, including Txlnb, have significantly broadly dysregulated RNA expressions in failing hearts; however, Txlnb protein levels appear to be unchanged. Reanalysis of Txlnb's interactome supports its involvement in cytoskeletal, microtubule, and UPS processes, particularly centrosome-related functions. Using gain and loss of function approaches, in cells and mice, we show that Txlnb is a novel regulator of cardiac proteostasis through its influence on UPS. Overexpressing Txlnb in cardiomyocytes reduces ubiquitinated protein accumulation and enhances proteasome activity during hypertrophy. Germline Txlnb knockout in mice increases ubiquitinated protein accumulation, decreases 26Sβ5 proteasome activity, and lowers cardiac mass with aging, indicating proteasomal insufficiency and altered cardiac growth. Loss of Txlnb worsens heart phenotypes in mouse models of cardiac proteotoxicity and pressure overload. Overall, our data implicate the centrosomal protein Txlnb as a novel regulator of cardiac proteostasis, highlighting the likely presence of an understudied and important centrosome-proteasome functional connection in cardiomyocytes.

Vascular aging contributes to the morbidity and mortality in older individuals, closely linked to an imbalance between energy consumption and production. Despite its importance, our understanding of how aging affects vascular metabolism and leads to vascular diseases remains limited. In this study, we explored the metabolomic characteristics of vascular aging by analyzing aortic tissues from young and old mice through untargeted metabolomic analysis using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). We identified 85 differential metabolites, with 37 up-regulated and 48 down-regulated, primarily consisting of lipids and lipid-like molecules, based on the criteria of variable importance in projection (VIP) > 1 and P < 0.05. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed significant involvement of these metabolites in six metabolic pathways (P < 0.05), particularly in glycerophospholipid metabolism. Receiver operating characteristic (ROC) curve analysis highlighted eight altered metabolites in glycerophospholipid metabolism, such as phosphatidylcholine (PC) (17:0/22:6) and lysophosphatidylcholine (LPC) (18:2), which demonstrated strong discriminatory ability for vascular aging with an area under the curve (AUC) exceeding 0.85. This study provides novel insights into metabolomic signature of vascular aging, offering important clues for future treatments of age-related vascular disorders.

Perivascular spaces (PVS) play a critical role in fluid transfer and waste clearance in the brain, but few studies have explored how alterations to perivascular fluid flow may impact brain maturation and behavior. This study aims to characterize age-related alterations to perivascular and parenchymal fluid flow characteristics across the lifespan in typically developing children (8-21 years) and aging adults (35-90 years) and assess their contribution to cognition. In this study, we employ multi-compartment diffusion models, neurite orientation dispersion and density imaging (NODDI) and tissue tensor imaging (TTI), to quantify free water diffusion characteristics within automatically defined perivascular spaces using enhanced PVS contrasts, the surrounding parenchyma, and at variable distances from the PVS. Our findings show free water diffusion characteristics within the PVS and surrounding parenchyma are associated with age and cognitive scores.

Aging and pregnancy both involve changes in many physiological systems. Some of these changes are similar, leading to suggestions that pregnancy may be a model for aging. Recent studies using DNA methylation clocks showed apparent aging during gestation which resolves postpartum. Since aging and pregnancy are complex, it is important to compare them in terms of many physiological parameters and at many time points. Here, we analyzed cross-sectional data on 62 lab tests at weekly resolution in 300,000 pregnancies and 1.4 million nonpregnant females aged 20-80. We trained a regression model to predict age from lab tests. Apparent age dropped by 8 years in early pregnancy, rose by 30 years towards delivery, and recovered postpartum. Certain systems exhibited \"rejuvenation,\" with opposite trends in pregnancy and aging, including renal, iron, and most liver tests. Others, such as coagulation, thyroid, muscle, and metabolic systems, showed apparent aging. Some systems displayed mixed trends. Notably, in the systems that showed apparent aging, the physiological mechanisms for the changes differed between pregnancy and aging. Pregnancy complications led to an additional apparent aging of 4-8 years. We conclude that pregnancy is a superficial model of aging that involves different mechanisms and rejuvenation or aging-like changes in different systems. Nevertheless, apparent age may be a convenient way to measure magnitude and direction of physiological perturbations.

The hypothalamus has been recognized as a regulator of whole-body aging. Neuropeptide Y (NPY), highly abundant in the central nervous system and produced by the hypothalamus, enhances autophagy in this brain region and mediates autophagy triggered by caloric restriction, suggesting a potential role as a caloric restriction mimetic and an aging regulator. Considering that hypothalamic NPY levels decline during aging, we investigated if reestablishment of NPY levels mitigate aging phenotype, using a mouse model of premature aging - Zmpste24

The association between aging-related hyperphosphatemia and sarcopenia has been documented, and evidence suggests that inflammaging is involved in the manifestation of sarcopenia. The present study investigates whether hyperphosphatemia triggers inflammation, thereby inducing the appearance of sarcopenia along with the cytokines involved in these processes.

Acyl CoA binding protein encoded by diazepam binding inhibitor (ACBP/DBI) is a tissue hormone that stimulates lipo-anabolic responses and inhibits autophagy, thus contributing to aging and age-related diseases. Protein expression profiling of ACBP/DBI was performed on mouse tissues to identify organs in which this major tissue hormone is expressed. Transcriptomic and proteomic data bases corroborated a high level of human-mouse interspecies conservation of ACBP/DBI expression in different organs. Single-cell RNA-seq data confirmed that ACBP/DBI was strongly expressed by parenchymatous cells from specific human and mouse organs (e.g., kidney, large intestine, liver, lung) as well as by myeloid or glial cells from other organs (e.g., adipose tissue, brain, eye) following a pattern that was conserved among the two species. We identified a panel of 44 mRNAs that are strongly co-expressed with ACBP/DBI mRNA in normal and malignant human and normal mouse tissues. Of note, 22 (50%) of these co-expressed mRNAs encode proteins localized at mitochondria, and mRNAs with metabolism-related functions are strongly overrepresented (66%). Systematic data mining was performed to identify transcription factors that regulate ACBP/DBI expression in human and mouse. Several transcription factors, including growth response 1 (EGR1), E2F Transcription Factor 1 (E2F1, which interacts with retinoblastoma, RB) and transformation-related protein 53 (TRP53, best known as p53), which are endowed with oncosuppressive effects, consistently repress ACBP/DBI expression as well as its co-expressed mRNAs across multiple datasets, suggesting a mechanistic basis for a coregulation network. Furthermore, we identified multiple transcription factors that transactivate ACBP/DBI gene expression together with its coregulation network. Altogether, this study indicates the existence of conserved mechanisms determining the expression of ACBP/DBI in specific cell types of the mammalian organism.

Skin tissue is susceptible to oxidative stress-induced senescence provoked by ultraviolet (UV) exposure in our daily lives, resulting in photoaging. Herein, we explore whether N-benzyl-N-methyldecan-1-amine (BMDA) derived from garlic ameliorates UVB-induced photoaging. To address this issue, HaCaT keratinocytes were exposed to UVB irradiation under BMDA treatment. The presence of BMDA substantially reduced UVB-induced ROS levels in a dose-dependent manner. BMDA administration counteracted UVB-induced senescence in the β-galactosidase assay. Treatment with BMDA also rescued UVB-exposed cells (S phase; from 18.3 to 25.8%) from cell cycle arrest, similar to the level observed in untreated normal cells. These findings might support our observation that elevated levels of γ-H2AX, a DNA damage marker, under UVB exposure were reduced following BMDA administration. Additionally, BMDA treatment indirectly reduced UVB-induced melanin synthesis in melanocytes since BMDA failed to inhibit tyrosinase activity, a crucial enzyme in melanin synthesis. The topical application of BMDA on the skin of SKH-1 hairless mice also diminished wrinkle formation, supported by recovered collagen levels and the thickness of the epidermis and dermis, compared to those of UVB-control mice. Finally, the BMDA treatment diminished the expression of inflammatory cytokine transcripts such as TNF-α, IL-1β, IL-4, and IL-6 in the UVB-exposed skin tissues. This finding is further supported by Immunofluorescence microscopy, which showed a decrease in the expression of TNF-α, and IL-1β during BMDA treatment. Altogether, as BMDA mitigates UVB-induced photoaging by reducing ROS production, protecting against DNA damage, and suppressing inflammatory cytokine production, it has been proposed as an effective anti-photoaging molecule.

One of the hallmarks of aging is a decline in the function of mitochondria, which is often accompanied by altered morphology and dynamics. In some cases, these changes may reflect macromolecular damage to mitochondria that occurs with aging and stress, while in other cases they may be part of a programmed, adaptive response. In this study, we report that mitochondria undergo dramatic morphological changes in chronologically aged yeast cells. These changes are characterized by a large, rounded morphology, decreased co-localization of outer membrane and matrix markers, and decreased mitochondrial membrane potential. Notably, these transitions are prevented by pharmacological or genetic interventions that perturb sphingolipid biosynthesis, indicating that sphingolipids are required for these mitochondrial transitions in aging cells. Consistent with these findings, we observe that overexpression of inositol phospholipid phospholipase (Isc1) prevents these alterations to mitochondria morphology in aging cells. We also report that mitochondria exhibit similar sphingolipid-dependent morphological transitions following acute exposure to oxidative stress. These findings suggest that sphingolipid metabolism contributes to mitochondrial remodeling in aging cells and during oxidative stress, perhaps as a result of damaged sphingolipids that localize to mitochondrial membranes. These findings underscore the complex relationship between mitochondria function and sphingolipid metabolism, particularly in the context of aging and stress.

Synapse dysfunction is tightly linked to cognitive changes during aging, but underlying mechanisms driving dysfunction are minimally understood. The extracellular matrix (ECM) can potently regulate synapse integrity and plasticity. Yet the status of the brain ECM during aging remains virtually unexplored. Using novel ECM-optimized proteomic workflows, we discovered striking regional differences in ECM composition and aging-induced ECM remodeling. ECM status was also aligned with preserved synapse protein abundance across key basal ganglia nuclei. Moreover, using novel reward-learning paradigms and confocal imaging in fixed tissue, we demonstrated that reduced ECM-synapse remodeling and microglial aging phenotypes, are both linked with deficits in goal-directed behavior in aging mice. Finally, using mouse models of microglia ablation and premature microglial aging, we identified microglial aging phenotypes that promote ECM deposition and synapse numbers. Together, these foundational observations implicate glial-ECM interactions in the regulation of synapse function and cognitive abilities across the lifespan.

Most adults experience age-related cognitive decline. However, "Positive-Agers" exhibit superior cognition compared to their age-matched peers. Distinguishing between those with superior cognitive performance and those with cognitive decline over time could better inform treatment therapies in older adults. We developed an algorithm called Optimal Cognitive Scoring (OptiCS) that accurately differentiates "Positive-Agers" from "Cognitive Decliners." This study draws on a cohort of 5797 participants longitudinally enrolled in the UK Biobank. Using a predictive pipeline, OptiCS could strongly differentiate Positive-Agers versus Cognitive Decliners (area under the curve, or AUC of 83%). The top diffusion MRI attributes highlighted tracts implicated in pathological aging, including the fornix from the hippocampus, the tapetum from the splenium of the corpus callosum, and other key tracts. This study provides three key insights: (I) The proposed algorithm offers a robust cognitive scoring system for subtle cognitive changes, (II) OptiCS can use diffusion MRI to accurately gauge cognitive performance, and (III) OptiCS provides a predictive framework for early detection of cognitive decline.

Temperature profoundly impacts all living organisms, influencing development, growth, longevity, and metabolism. Specifically, when adult flies are exposed to high temperatures, there is a notable reduction in their body fat content. We investigate the roles of the insulin signaling pathway in temperature-mediated fat storage. This pathway is not only highly conserved from insects to mammals but also crucial in regulating lipid metabolism, cell proliferation, and tissue growth. The Forkhead box O (FoxO) protein functions as a key downstream signaling molecule in this pathway, mediating the inhibitory effects of insulin signaling. At elevated temperatures, direct targets of FoxO, such as insulin receptor (InR), Thor (Drosophila eukaryotic initiation factor 4E binding protein), and FoxO itself, are significantly upregulated, which indicates an inhibition of insulin signaling. Interestingly, this inhibition seems to occur independently of Drosophila insulin-like peptide (Ilp) stimuli, as not all Ilp transcripts were reduced at elevated temperatures. Furthermore, when S2R + Drosophila cells are incubated at high temperatures, there is a marked decrease in Akt phosphorylation, directly supporting the notion that elevated temperatures can inhibit insulin signaling in a cell-autonomous manner, independent of Ilp levels. Subsequent experiments demonstrated that either constitutively active InR or knockdown of FoxO prevents the reduction of body fat at high temperatures. Together, these findings highlight the critical role of the insulin signaling-FoxO branch in regulating lipid homeostasis under heat stress conditions.

Decline in ovarian function with age not only affects fertility but is also linked to a higher risk of age-related diseases in women (e.g. osteoporosis, dementia). Intriguingly, earlier menopause is linked to shorter lifespan; however, the underlying molecular mechanisms of ovarian aging are not well understood. Recent evidence suggests the gut microbiota may influence ovarian health. In this study, we characterized ovarian aging associated microbial profiles in mice and investigated the effect of the gut microbiome from young and estropausal female mice on ovarian health through fecal microbiota transplantation. We demonstrate that the ovarian transcriptome can be broadly remodeled after heterochronic microbiota transplantation, with a reduction in inflammation-related gene expression and trends consistent with transcriptional rejuvenation. Consistently, these mice exhibited enhanced ovarian health and increased fertility. Using metagenomics-based causal mediation analyses and serum untargeted metabolomics, we identified candidate microbial species and metabolites that may contribute to the observed effects of fecal microbiota transplantation. Our findings reveal a direct link between the gut microbiota and ovarian health.

Introduction: The aging lung enters into a state of irreversible cellular growth arrest characterized by senescence. While senescence is beneficial in preventing oncogenic cell proliferation, it becomes detrimental when persistent, promoting chronic inflammation and fibrosis through the senescence-associated secretory phenotype (SASP). Such senescence-related pathophysiological processes play key roles in lung diseases like chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). However, few models accurately represent senescence in the human lung. Methods: To generate a human lung senescence in vitro model, we first generated a human induced pluripotent stem cell (hiPSC)-derived lung organoid (LO) system which was dissociated into monolayers and air-liquid interface (ALI) cultures to enhance visualization and allow uniform exposure to agents. Cellular senescence was induced using doxorubicin, a DNA-damaging agent. Senescence markers, such as {beta}-galactosidase ({beta}-gal) activity, SASP cytokine production and secretion, cell morphology, proliferative capacity, and barrier integrity were evaluated to validate the senescent phenotype. Results: The doxorubicin-induced senescent hiPSC-derived lung cells demonstrated the hallmark characteristics of cellular senescence, including increased {beta}-gal activity and increased production of the pro-inflammatory SASP cytokine IL-6 and increased secretion of TNF-. Senescent cells displayed enlarged morphology, decreased proliferation, and reduced wound repair capacity. Barrier integrity was impaired with decreased electrical resistance, and increased permeability, as well as expression of abnormal tight junction proteins and increased fibrosis, all consistent with the senescent lung. Conclusion: Our hiPSC-derived lung cell senescent model reproduces key aspects of human lung senescence and offer an in vitro tool for studying age-related lung disease mechanisms and therapeutic interventions. This model has potential applications in exploring the impact of environmental factors (e.g., toxins, infectious pathogens, etc.) on the senescent lung and assessing treatments that could mitigate pathologies associated with pulmonary aging including barrier impairment, inflammation and fibrosis.

The incidence of inflammatory bowel disease among the elderly has significantly risen in recent years, posing a growing socioeconomic burden to aging societies. Moreover, non-gastrointestinal diseases, also prevalent in this demographic, have been linked to intestinal barrier dysfunction, thus highlighting the importance of investigating aged-mediated changes within the human gut. While gastrointestinal pathology often involves an impaired gut barrier, the impact of aging on the human gastrointestinal barrier function remains unclear. To explore the effect of senescence, a key hallmark of aging, on gut barrier integrity, we established and evaluated an

Gestational epigenetic aging (GEA) is a novel approach for characterizing associations between prenatal exposures and postnatal risks. Psychosocial adversity in pregnancy may influence GEA, but the molecular mechanisms are not well understood. DNA methylation to glucocorticoid regulation and hypothalamic-pituitary-adrenal (HPA) axis genes are implicated but have not been fully examined in association with GEA. This study investigated whether a polyepigenetic glucocorticoid exposure score (PGES) and HPA axis gene (

Cellular senescence can be triggered by a wide range of stress-inducing factors, including environmental and internal damaging events, such as oxidative stress. Moreover, stressed and senescent cells exhibit modifications in their transcriptional expression profile, but little is known regarding the common genes and pathways regulating these processes. Here, we analyzed the effects of long-term culture as well as exogenous acute oxidative stress on the transcriptional program of Wharton's jelly mesenchymal stem cells (WJ-MSCs). We demonstrate that, exposure to H

Naringenin (NAR), a natural flavonoid, exerts anti-inflammatory and antioxidant pharmacology. However, the pharmacological mechanisms through which NAR prevents and treats intervertebral disc degeneration (IDD) remain unclear. We utilized bioinformatics, machine learning, and network pharmacology to identify shared targets among NAR, senescence, and IDD. Subsequently, molecular docking was conducted to evaluate NAR's binding affinity to common target. Additionally, we used IL-1β to induce senescence and degeneration in nucleus pulposus cells (NPCs) and conducted a series of cellular assays, including immunoblotting, immunofluorescence, β-galactosidase staining, cell proliferation, cell cycle analysis, and measurement of reactive oxygen species levels, to investigate NAR's impact on IL-1β-induced senescence and degeneration of NPCs. Our study revealed that Insulin-like growth factor binding protein 3 (IGFBP3) was the only common target. IGFBP3 exhibited significant differences between the IDD and healthy groups and proved to be an effective diagnostic marker for IDD. Molecular docking confirmed the binding between NAR and IGFBP3. In vitro experiments, we observed that Igfbp3 expression increased in the senescence and degeneration groups. Igfbp3 knockdown and NAR attenuated IL-1β-induced senescence and degenerative phenotypes in NPCs. In contrast, the effect of NAR was attenuated by recombinant IGFBP3 protein. In conclusion, our findings suggest that NAR plays a preventive and therapeutic role in IDD, likely achieved through the inhibition of Igfbp3 expression.

The impact of preventing hypertension and maintaining normal blood pressure (BP) on life expectancy and healthy life expectancy (HLE) among Black adults, who are disproportionately affected by hypertension, has not been quantified.

The effects of granulose cell (GC) senescence on premature ovarian insufficiency/premature ovarian failure have been extensively examined, the association between GC senescence and ovarian aging remains to be clarified.

Autophagy is a waste-disposal pathway that protects against age-related pathology. It is widely accepted that autophagy declines with age, yet the role that sex and diet-related obesity play during aging remain unknown. Here, we present the most comprehensive in vivo study of autophagic flux to date. We employed transgenic mice overexpressing tandem-florescent LC3B (RFP-GFP-LC3B) to measure autophagic flux in the blood (PBMCs), heart, and motor cortex neurons of aging mice that were fed regular chow or a high-fat diet for 6-, 12- or 18-months. In male mice, aging decreased autophagic flux in the heart, increased it in the blood, and had no effect in motor cortex neurons. Age-dependent changes autophagic flux were less pronounced in female mice. High-fat diet influenced autophagic flux in the blood and heart of male but not female mice. Overall, we uncovered sexual dimorphisms that underpin how autophagy changes with age across different tissues and in response to a high-fat diet.

Frontotemporal dementia (FTD) shows autosomal dominant transmission in up to a third of families, enabling the study of presymptomatic and prodromal phases. Despite self-reported well-being and normal daily cognitive functioning, brain structural changes are evident a decade or more before the expected onset of disease. This divergence between cognitive function and brain structure contrasts with the coupling of structural and functional decline after symptom onset. In healthy ageing, it has been shown that functional connectivity is a better predictor of cognitive function than volumetric structural imaging. We previously proposed that in the presymptomatic phase of genetic FTD, the maintenance of brain functional network integrity enables mutation carriers to sustain cognitive performance. However, prior work has focused on a small number of, often predefined, networks. This provides a limited and potentially biased characterisation of the substrates and moderators of brain network integration. Here, we test the hypothesis that brain-wide functional integration in FTD determines resilience to progressive pathology before symptom onset. We assess functional connectome integration in 289 presymptomatic FTD-mutation carriers using functional magnetic resonance imaging in relation to cognition and contrast with 271 family members without mutations. Because structural atrophy, functional integration and cognitive profiles are multivariate, we used canonical correlation models, supplemented by multiple linear regression models for each imaging modality. We confirmed progressive atrophy and normal cognitive function in presymptomatic carriers compared to non-carriers. Notably, functional integration was preserved in presymptomatic carriers across age, while it declined in familial non-carriers. The strongest effects were observed in cognitive control networks. The changes in functional integration in presymptomatic carriers were behaviourally relevant and independent of the severity of atrophy, suggesting a resilience mechanism in those at risk of dementia. To generate hypotheses about the genetic and neurometabolic basis of resilience, we assessed the spatial overlap between behaviourally-relevant functional integration maps and gene transcription profiles. These spatial correlations suggested resilience signatures to glial cell composition (astrocytes, microglia, oligodendrocytes), revealing cellular mechanisms inaccessible to standard neuroimaging. Our findings suggest that resilience to atrophy arises from enhanced functional integration, protecting against clinical conversion for many years in individuals at risk of dementia. This result has implications for the design of presymptomatic disease-modifying therapy trials and gives hope for therapeutic strategies aimed at enhancing resilience and ability to maintain function despite the presence of genetically determined neuropathology.

Aging is a multifaceted process influenced by intrinsic and extrinsic factors, with lipid alterations playing a critical role in brain aging and neurological disorders. This study introduces DoliClock, a lipid-based biological aging clock designed to predict the age of the prefrontal cortex using post-mortem lipidomic data. Significant age acceleration was observed in samples with autism, schizophrenia, and Down syndrome, with autism showing the most pronounced effects in aging-rate. An increase in entropy around age 40, suggests dysregulation of the mevalonate pathway and dolichol accumulation. Dolichol, a lipid integral to N-glycosylation and intracellular transport, emerged as a potential aging biomarker, with specific variants such as dolichol-19 and dolichol-20 showing unique age-related associations. These findings suggest that lipidomics can provide valuable insights into the molecular mechanisms of brain aging and neurological disorders. By linking dolichol levels and entropy changes to aging, this study highlights the potential of lipid-based biomarkers for understanding and predicting biological age, especially in conditions associated with premature aging.

Keloids are pathological scars exhibiting tumour-like aggressiveness and high recurrence rate. Here we find increased proportion of pro-inflammatory and mesenchymal fibroblast subpopulations and senescent fibroblasts, and enhanced expression of senescence-associated secretory phenotype genes using single-cell RNA sequencing analysis, as well as elevated p16 protein and more β-galactosidase-positive cells in keloids. The up-regulated p53-serine15 phosphorylation (p53-pS15) in keloids is identified by phosphospecific protein microarray and western blotting. We further demonstrate that a senolytic FOXO4-D-retro-inverso-isoform peptide (FOXO4-DRI) promotes apoptosis and decreases G0/G1 phase cells in pro-senescence models of keloid organ cultures and fibroblasts, accompanied with p53-pS15 nuclear exclusion. Our study indicates that upregulation of p53-pS15 and p16 maintains a persistent senescent microenvironment to promote cell cycle arrest and apoptosis resistance in keloid fibroblasts. FOXO4-DRI shows potential as a treatment targeting the senescence and apoptosis resistance, and holds promise as an approach to prevent the aggressiveness and relapse of keloids.

Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.

The experience of human parenthood is near ubiquitous and can profoundly alter one's body, mind, and environment. However, we know very little about the long-term neural effects of parenthood for parents themselves, or the implications of pregnancy and caregiving experience on the aging adult brain. Here, we investigate the link between the number of children parented and age on brain function in 19,964 females and 17,607 males from the UK Biobank. In both females and males, parenthood was positively correlated with functional connectivity, such that higher number of children parented was associated with higher connectivity, particularly within the somato/motor network. Critically, the spatial topography of parenthood-linked effects was inversely correlated with the impact of age on functional connectivity across the brain for both females and males, such that the connections that were positively correlated with number of children were negatively correlated with age. This result suggests that a higher number of children is associated with patterns of brain function in the opposite direction to age-related alterations. Overall, these results indicate that the changes accompanying parenthood may confer benefits to brain health across the lifespan, altering aging trajectories, consistent with animal models of parenthood and preliminary findings of "younger-looking" brain structure in human parents. Observing this effect in both females and males implicates the caregiving environment, rather than pregnancy alone, and highlights the importance of future work to disentangle the underlying mechanisms related to the direct impact of caregiving, the indirect impact of the environment, and the result of covarying sociodemographic factors.

Cellular senescence gene sets have been leveraged to overcome the inadequate sensitivity or specificity of single markers. However, growing evidence of heterogeneity among tissues in senescent cell phenotypes and gene expression profiles has highlighted the need for tissue-specific gene sets. SenSkin™ was curated by an expert review of literature on cellular senescence in the skin and characterized with pathway analysis. To validate SenSkin™, it was evaluated for enrichment with chronological aging in a bulk RNA-sequencing (RNA-seq) dataset and a pseudobulk RNA-seq dataset. Further, changes to SenSkin™ in different skin cell types with photoaging were evaluated in two single-cell RNA-seq datasets. SenSkin™ predominantly included genes related to the senescence-associated secretory phenotype (SASP), which were associated with metabolism and multiple aspects of immune responses. SenSkin™ was more enriched in chronologically aged skin than other commonly used cellular senescence and aging gene sets. In scRNA-seq, SenSkin™ displayed significant upregulation due to photoaging in ten skin cell types. In conclusion, SenSkin™ is a human skin-specific senescence gene set validated in chronological aging and photoaging, which may be more effective at detecting senescent cells in the skin than non-tissue-specific gene sets.

Stellate ganglia (SG) provide sympathetic innervation to the heart and may predispose the myocardial conducting system to arrhythmias. However, little is known about age-related changes in the electrophysiology of murine SG. We investigated alterations in the electrophysiological properties of SG with aging. The loose patch clamp technique was adapted to SG tissue to investigate the voltage-gated ionic currents in its neuronal cells. We compared SG and ventricular cells from young (4 months) and aged (13 months) C57BL/6J mice to explore age-related alterations in their voltage-gated ionic currents (n > 30 patches, eight mice in each group). We observed that the voltage-gated inward sodium current (peak I

We tested the hypothesis that environmental enrichment (EE) can attenuate early-onset cognitive decline in a stress-hyperresponsive rat strain. The novel genetic model, the Wistar Kyoto More Immobile (WMI) inbred rat strain demonstrates increased stress reactivity and enhanced depression-like behavior compared to its nearly isogenic control, the Wistar Kyoto Less Immobile strain (WLI). Middle-aged (12 months) WMI females exhibited diminished fear, and spatial memory in the contextual fear conditioning and Morris Water Maze paradigms, respectively, compared to young animals (6 months) of both strains and to middle-aged WLIs. Middle-aged WMI males showed a lesser age-induced deficit. EE from six to 12 months of age reversed these memory deficits in middle-aged WMI females and attenuated them in WMI males. Plasma levels of estradiol followed the same pattern as memory in WMI females following EE. RNA sequencing from female hippocampi revealed significant strain, age, and enrichment-induced differentially expressed genes. Among these, solute carrier family 35, member A4 (Slc35a4) and potassium inwardly rectifying channel, subfamily J, member 2 (Kcnj2) were confirmed to show hippocampal expression changes parallel to that of memory in the WMI. These genes have critical roles in the integrated stress response, cellular metabolism, and the effects of stress on neurovascular coupling, respectively. Pathway analyses revealed the involvement of oxidative phosphorylation and mitochondrial dysfunction in the hippocampal processes of aging and EE-induced reversal. These findings underscore the critical involvement of molecular stress responses in early-onset memory decline and suggest potential therapeutic targets for age-related cognitive impairment.

Heart failure is known as the leading cause of mortality and morbidity in adults, not only in USA but worldwide. Since the world's population is aging, the burden of cardiovascular disorders is increasing. Mesenchymal stem/stromal cells (MSCs) from a patient's bone marrow or other tissues have been widely used as the primary source of stem cells for cellular cardiomyoplasty. The incongruencies that exist between various cell-therapy approaches for cardiac diseases could be attributed to variations in cell processing methods, quality of the process, and cell donors. Off-the-shelf preparations of MSCs, enabled by batch processing of the cells and controlled cell processing factories in regulated facilities, may offer opportunities to overcome these problems. In this study, for the first time, we focused on the fetal membranes and childbirth byproducts as a promising source of cells for regenerative medicine. While many studies have described the advantages of cells derived from these organs, their advantage as a source of younger cells has not been sufficiently covered by the literature. Thus, herein, we highlight challenges that may arise from the impairment of the regenerative capacity of MSCs due to donor age and how allograft cells from fetal adnexa can be a promising substitute for the aged patients' stem cells for myocardial regeneration. Moreover, obstacles to the use of off-the-shelf cell-therapy preparations in regenerative medicine are briefly summarized here.

Alterations in the gut microbiome constitute a feature of aging and therefore represent a therapeutic target for aging-related diseases. In this study, we investigated the impact of ketogenic interventions on the microbiome of mice genetically predisposed to Alzheimer disease (AD). AD mice exhibited several microbial alterations, notably increased levels of Bifidobacterium and decreased levels of Bacteroidetes. Ketogenic interventions, either a medium-chain triglyceride-enriched diet (MCT) or carbohydrate-free high-fat diet (CFHF), administered for 1 month restored the levels of more than 50% of the bacteria altered in AD mice, including a strong reduction in Bifidobacterium levels. Ketogenic interventions induced a shift in the gut microbiome associated with increased levels of short-chain fatty acid-producing bacteria, such as Lachnospiraceae and Muribaculaceae. MCT and CFHF also triggered diet-specific microbial changes, which may contribute to the distinct physiological effects of these diets. In conclusion, ketogenic interventions may influence AD pathophysiology by modulating the gut microbiome.

While the vestibular system is crucial for balance, posture, and stable vision, emerging evidence connects vestibular loss in older adults to spatial cognitive deficits. However, the specific neural pathways remain unclear. This study examines morphometric changes in the entorhinal cortex (ERC) and trans-entorhinal cortex (TEC), key regions in the vestibular spatial cognitive network, with vestibular function.

Telomeres shorten with each cell division, acting as a chronometer of cell age. The enzyme telomerase, primarily active in stem cells, reverses telomere erosion. We have previously observed that transient transfection with human TERT mRNA extends telomeres and mitigates hallmarks of senescence in replicatively aged human cells or those affected by Hutchinson-Gilford progeroid syndrome (HGPS). However, due to its short half-life, mRNA requires frequent administration. In this study, we hypothesized that TERT circular (circ) RNA would extend the duration of telomerase expression and be more effective at reversing hallmarks of senescence in endothelial cells derived from HGPS patients. We observe that a single transfection of TERT circRNA is more effective than mRNA in the extension of telomere length, as determined by quantitative fluorescence in situ hybridization. Furthermore, TERT circRNA reduced the number of β-gal positive cells by three-fold and normalized nuclear morphology in HGPS endothelial cells (HGPS-ECs). Moreover, TERT circRNA substantially reduced senescent markers, inflammatory markers, and DNA damage markers, including Progerin, p16, p21, IL-1B, IL-6, IL-8, MCP1, and γH2AX. Additionally, it restored NO production, enhanced cell proliferation, promoted angiogenesis, improved LDL uptake, reduced mitochondrial ROS, and normalized mitochondrial membrane potential more effectively. Our data suggest that TERT circRNA is superior to linear TERT mRNA in reversing processes involved in senescence.

Bone marrow (BM) of postmenopausal osteoporosis has been found highly inflammatory, resulting from dysregulated immune cells induced by both estrogen efficiency and body aging. NETosis of neutrophils has been found aberrantly activated in age-related chronic inflammation, while their role in postmenopausal osteoporosis remains unclear. Here we found NETosis of BM neutrophils of OVX (ovariectomy) mice was significantly activated, and we verified NETs released by neutrophils induced M1 polarization and osteoclastogenesis of RAW264.7 macrophages. Further, we demonstrated effects of NETs on osteoclastogenesis was mediated by cGAS-STING/AKT2 pathway. Finally, we found in vivo NETs-clearance through GSK484 significantly inhibited osteoclastogenesis and attenuated osteoporosis of OVX mice. Our study highlights the role of neutrophil NETosis in activating osteoclastogenesis and bone resorption of postmenopausal osteoporosis, thereby providing novel targets for bone loss treatment.

As the world's population ages, more and more people are expected to suffer from age-related diseases. Biological aging markers derived from DNA methylation and brain structure show promise in predicting health outcomes. Understanding the relationship between these biomarkers can promote the development of effective health interventions. In a sample of 254 participants from the Netherlands Twin Register (20-84 years), we investigated associations between DNA methylation age acceleration based on five epigenetic biomarkers (Hannum, Horvath, PhenoAge, GrimAge, and DunedinPACE) and brain age acceleration based on neuroimaging (brainageR). Furthermore, we applied bivariate twin models to examine the contribution of genetic and environmental factors to the associations (cross-twin cross-trait correlations and within monozygotic-twin pair differences). We observed relationships with brain age acceleration for DNA methylation age acceleration based on the Hannum and GrimAge clocks that were supported by within MZ twin pair difference modelling. Cross-twin cross-trait modelling confirmed a non-shared environmental etiology. Twin analyses highlight the importance of the environment in accelerated aging, raising the possibility for interventions such as lifestyle modification.

As a member of the class II cysteine-based protein tyrosine phosphatases, low molecular weight protein tyrosine phosphatase (LMWPTP) plays a pivotal role in animal physiology, particularly in signaling transduction, but its specific function in lipid metabolism remains poorly understood. Herein, the structure and metabolic functions of LMWPTP were investigated using the Caenorhabditis elegans (C. elegans) as a convenient model. The nematode LMWPTP was found to be highly conserved in sequence, functional domains, and tertiary structure compared to its mammalian homologs. Through RNA interference (RNAi) targeting lmwptp, we observed a modest increase in lipid accumulation in nematodes, evidenced by higher triglyceride levels, enlarged lipid droplets, and an increase in total fatty acid content, despite no changes in body size. Mechanistically, lmwptp RNAi promoted adipogenesis by modulating the insulin-like growth factor 1 signaling pathway, facilitating the nuclear translocation of DAF-16, which in turn upregulated fat-7 expression. Furthermore, increased ROS levels were associated with enhanced lipogenesis. The knockdown of lmwptp also attenuated lipolysis and lipophagy via modulation of the AMPK pathway. Despite these alterations, key physiological functions related to energy metabolism were preserved, and lifespan was extended with delayed aging markers. These findings highlight LMWPTP's significant role in lipid regulation, offering new insights and potential therapeutic targets for human lipid metabolism disorders.

Association of both intrinsic and extrinsic risk factors leading to accelerated skin ageing is reflected in excessive ROS production and ir/reversible mitochondrial injury and burnout, as abundantly demonstrated by accumulating research data. Due to the critical role of mitochondrial stress in the pathophysiology of skin ageing and disorders, maintained (primary care) and restored (secondary care) mitochondrial health, rejuvenation and homoeostasis are considered the most effective holistic approach to advance dermatological treatments based on systemic health-supportive and stimulating measures. Per evidence, an effective skin anti-ageing protection, wound healing and scarring quality - all strongly depend on the sustainable mitochondrial functionality and well-balanced homoeostasis. The latter can be objectively measured and, if necessary, restored in a systemic manner by pre- and rehabilitation algorithms tailored to individualised patient profiles. The entire spectrum of corresponding innovations in the area includes natural and systemic skin rejuvenation, aesthetic and reconstructive medicine, sustainable skin protection and targeted treatments of skin disorders. Contextually, mitochondria-centric dermatology is instrumental for advanced 3PM-guided approach which makes a good use of predictive multi-level diagnostics and targeted protection of skin against both - the health-to-disease transition and progression of relevant disorders. Cost-effective targeted protection and new treatment avenues focused on sustainable mitochondrial health and physiologic homoeostasis are proposed in the article including in-depth analysis of patient cases and exemplified 3PM-guided care with detailed mechanisms and corresponding expert recommendations presented.

Sleep disorders may increase neurodegenerative diseases risks and alter gut microbiota composition. Saffron (Crocus sativus) supplementation has been linked to sleep improvements and gut microbiome changes, but its effect on sleep quality through gut microbiota-brain axis modulation remains unexplored. A randomised, placebo-controlled pilot study of saffron (30mg/day for 4-weeks) was conducted with 52 older adults (55-85 years) experiencing sleep complaints. Subjective and objective sleep quality were measured using validated questionnaires and electroencephalography-based sleep tracker respectively. A subgroup (n=26) underwent microbiome analysis. Saffron supplementation improved subjective sleep quality (p=0.02) and sleep efficiency (p=0.04). Objective measures showed reduced latency to persistent sleep (p=0.003) and sleep onset latency (p=0.03). Linear discriminant analysis effect size analysis of the microbiome revealed increases in Faecalibacterium (q=0.013), Lachnoclostridium (q=0.045), Prevotella (q=0.022), UBA1819 (q=0.020) and Oscillibacter (q=0.045), while decreasing Dialister (q=0.028). Univariate analysis further indicated increases in Lachnospiraceae-UGC-001 (p=0.020) and Roseburia (p=0.03), with a decrease in Turicibacter (p=0.045) in the saffron group. Oscillibacter and UBA1819 correlated with subjective measures of sleep efficiency (r=0.63, p=0.0007) and sleep latency (r=-0.39, p=0.04. Changes in Dialister, Turicibacter and UBA1819 were correlated with several measures of objective sleep quality including wake duration, latency to persistent sleep and wake-after-sleep-onset. Four-weeks saffron supplementation improved both subjective and objective sleep quality in older adults with sleep complaints, while increasing gut bacteria that produce short-chain fatty acids. These results pave the way for further randomised controlled trials exploring the links between sleep quality and gut health and may help devising new preventative strategies for age-related brain disorders.

Sport participation among older adults, is increasing, but many still fall short of meeting physical activity (PA) guidelines. Master athletes, who engage in PA through systematic training, and competition, offer unique insights into PA practices in later life. This study explored whether master athletes embody the principles of physical literacy and how their experiences could inform strategies to promote PA among older adults. An electronic survey completed by 35 master athletes (55-75 years, 20 female) and follow-up interviews with eight participants revealed that most were unfamiliar with the term "physical literacy," yet they intuitively practiced its principles. Master athletes identified parallels between their behaviors and physical literacy but viewed existing models as primarily youth-focused and less applicable to older adults. Additionally, lifelong sport participation was not universal; nine participants, predominantly women, began competitive sports later in life. A key finding was the importance of social connectedness, which emerged as a critical motivator and enabler for sustained PA among master athletes. This element, largely absent from current physical literacy frameworks, may be vital for engaging older adults in PA. Integrating social connection into physical literacy models could address barriers unique to this demographic, enhancing participation and promoting healthier aging.

The global population is ageing and the gap between lifespan (total years lived) and healthspan (years lived free of diseases) is increasing. Healthy Longevity Medicine (HLM) is an approach to optimise health and healthspan, and it has substantial public health implications. Despite those implications, the understanding of public perspectives on this field is lacking. The HEalthy LOngevity (HELO) framework was developed through a literature review guided by expert discussions across disciplines to include evidence-based concepts of health-related decision-making, ageing, and HLM. The framework organises concepts into three components. The first two components, awareness and knowledge, explore public perception and understanding of the healthy longevity field, respectively. The third component, motivations, reflects factors underlying motivations towards healthy longevity. These include personality, current behaviours, personal values and beliefs, and health-related perceptions. The framework outlines the theoretical foundation to explore public knowledge and interest in healthy longevity. The framework will be refined based on findings from qualitative focus groups in Singapore and then applied to quantitative population surveys globally. These HELO initiatives aim to inform strategies for integrating HLM into public healthcare, promoting health and healthspan.

Brain age (BA), distinct from chronological age (CA), can be estimated from MRIs to evaluate neuroanatomic aging in cognitively normal (CN) individuals. BA, however, is a cross-sectional measure that summarizes cumulative neuroanatomic aging since birth. Thus, it conveys poorly recent or contemporaneous aging trends, which can be better quantified by the (temporal) pace

Phloretin exhibits strong antioxidant and anti-aging properties by inhibiting mitochondrial oxidation of glutamate, succinic acid, and ascorbic acid. However, its clinical application is limited by poor aqueous solubility and low oral bioavailability. To enhance its bioavailability and efficacy, we incorporated phloretin into nano-micelles (phloretin-MM) using the thin film dispersion method. Characterization revealed that the optimal formulation had TPGS and Pluronic F68 in a 4:1 ratio as the excipients, which resulted in spherical micelles with an average particle size of 33.28 nm and an encapsulation efficiency of 71.2 ± 0.48%. The in vitro release profile showed that the phloretin-MM showed significantly higher cumulative release rates than free phloretin across various pH conditions, while the pharmaceutical analysis in rats indicated that phloretin-MM significantly improved the oral bioavailability of phloretin (about 5 folds) in circulation. Additionally, through the analysis of the staining of zebrafish under light microscopy and the average gray value, it can be concluded that phloretin has anti-aging drug effect, and phloretin-MM is better than free phloretin. These findings suggest that TPGS/Pluronic F68-modified phloretin-MM could serve as an excellent nano-drug carrier system, potentially enhancing the solubility, bioavailability, and anti-aging effects of phloretin for broader clinical applications.