Longevity Papers

Aging results in a loss of metabolic flexibility during fasting, characterized by the inability to acutely switch between metabolic substrates and reduced lipid mobilization. However, the drivers of these effects intracellularly remain unclear. Here, in Caenorhabditis elegans, we show that loss of coordinated inter-organelle dynamics causally initiates metabolic inflexibility with age. In young animals, peroxisomes emerge as the priming orchestrators of the fasting response, simultaneously governing lipid droplets (LDs) utilization and mitochondrial bioenergetics. With age, peroxisomal priming is lost, leading to mitochondrial fragmentation and impaired dynamic nutrient responses during fasting. Notably, dietary restriction (DR) exerts a rejuvenating effect on peroxisomal function, thereby preserving mitochondrial integrity and promoting longevity. Our study uncovers the expansive network of organelles enabling lipid mobilization during youth, providing critical context to the poorly understood role of peroxisomes in actively maintaining organelle homeodynamics and metabolic flexibility throughout the aging process.

Meibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and niche of Meibomian gland stem cells and the signals controlling their activity are poorly defined. Using snRNA-seq, in vivo lineage tracing, ex vivo live imaging, and genetic studies in mice, we identify markers for stem cell populations that maintain distinct regions of the gland and uncover Hedgehog (Hh) signaling as a key regulator of stem cell proliferation. Consistent with this, we show that human Meibomian gland carcinoma exhibits increased Hh signaling. Aged glands display decreased Hh and EGF signaling, deficient innervation, and loss of collagen I in niche fibroblasts, indicating that alterations in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These findings suggest new approaches to treat aging-associated Meibomian gland loss.

Visual function deteriorates throughout the natural course of aging. Age-related structural and functional adaptations are observed in the retina, the light-sensitive neuronal tissue of the eye where visual perception begins. Molecular mechanisms underlying retinal aging are still poorly understood, highlighting the need to identify biomarkers for better prognosis and alleviation of aging-associated vision impairment. Here, we investigate dynamics of transcriptional dysregulation in the retina and identify affected pathways within distinct retinal cell types. Using an optimized protocol for single-cell RNA sequencing of mouse retinas at 3, 12, 18, and 24 months, we detect a progressive increase in the number of differentially expressed genes across all retinal cell types. The extent and direction of expression changes varies, with photoreceptor, bipolar, and Müller cells showing the maximum number of differentially expressed genes at all age groups. Furthermore, our analyses uncover transcriptionally distinct, heterogeneous subpopulations of rod photoreceptors and bipolar cells, distributed across distinct areas of the retina. Our findings provide a plausible molecular explanation for enhanced susceptibility of rod cells to aging and correlate with the observed loss of scotopic sensitivity in elderly individuals.

The study of biomarkers in biofluids and tissues expanded our understanding of the biological processes that drive physiological and functional manifestations of aging. However, most of these studies were limited to examining one biological compartment, an approach that fails to recognize that aging pervasively affects the whole body. The simultaneous modeling of hundreds of metabolites and proteins across multiple compartments may provide a more detailed picture of healthy aging and point to differences between chronological and biological aging. Herein, we report proteomic analyses of plasma and urine collected in healthy men and women, age 22-92 years. Using these data, we developed a series of metabolomic and proteomic predictors of chronological age for plasma, urine, and skeletal muscle. We then defined a biological aging score, which measures the departure between an individual's predicted age and the expected predicted age for that individual based on the full cohort. We show that these predictors are significantly and independently related to clinical phenotypes important for aging, such as inflammation, iron deficiency anemia, muscle mass, and renal and hepatic functions. Despite a different set of selected biomarkers in each compartment, the different scores reflect a similar degree of deviation from healthy aging in single individuals, thus allowing identification of subjects with significant accelerated or decelerated biological aging.

A diverse naive CD8 T cell repertoire is essential to provide broad protection against infection and cancer. Aging diminishes naive T cells, reducing potential diversity and leading to lymph node contraction. Here, we revealed that this decline occurs earlier in males, resulting in significant sex differences in immunity during middle age. Earlier in life, naive CD8 T cells in males become virtual memory cells prone to premature senescence. Due to androgen-driven thymic atrophy in males, naive CD8 T cells are insufficiently replenished. Therapeutic thymus rejuvenation via testosterone ablation restored naive CD8 T cells in lymph nodes of middle-aged male mice, leading to enhanced tumor recognition. These findings show the crucial role of sex and age on lymph node T cell repertoires and suggest potential strategies to restore immune function in males during aging.

Exercise can improve health via skeletal muscle remodeling. Elucidating the underlying mechanism may lead to new therapeutics for aging-related loss of skeletal muscle mass. Here, we show that endurance exercise suppresses expression of YT521-B homology domain family (Ythdf1) in skeletal muscle, which recognizes the N6-methyladenosine (m6A). Ythdf1 deletion phenocopies endurance exercise-induced muscle hypertrophy in mice increases muscle mitochondria content and type I fiber specification. At the molecular level, Ythdf1 recognizes and promotes the translation of m6A-modified Mstn mRNA, which encodes a muscle growth inhibitor, Myostatin. Loss of Ythdf1 leads to hyperactivation of skeletal muscle stem cells (MuSCs), also called satellite cells (SCs), enhancing muscle growth and injury-induced regeneration. Our data reveal Ythdf1 as a key regulator of skeletal muscle homeostasis, provide insights into the mechanism by which endurance exercise promotes skeletal muscle remodeling and highlight potential strategies to prevent aging-related muscle degeneration.

Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that

Intracranial cardiac impulse propagation along penetrating arterioles is vital for both nutrient supply via blood circulation and waste clearance via CSF circulation. However, current neuroimaging methods are limited to simultaneously detecting impulse propagation at pial arteries, arterioles, and between them. We hypothesized that this propagation could be detected via paravascular CSF dynamics and that it may change with aging. Using dynamic diffusion-weighted imaging (dynDWI), we detected oscillatory CSF motion synchronized with the finger photoplethysmography in the subarachnoid space (SAS) and cerebral cortex, with a delay revealing an impulse propagation pathway from the SAS to the cortex, averaging 84 milliseconds. Data from 70 subjects aged 18 to 85 years showed a bimodal age-related change in the SAS-Cortex travel time: it initially increases with age, peaks around 45 years, then decreases. Computational biomechanical modeling of the cardiovascular system was performed and replicated this 84-millisecond delay. Sensitivity analysis suggests that age-related variations in travel time are primarily driven by changes in arteriolar compliance. These findings support the use of dynDWI for measuring intracranial impulse propagation and highlight its potential in assessing related vascular and waste clearance functions.

The aging brain experiences a significant decline in proteasome function. The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains, including in the hippocampus, this is driven by reduced functionality of aged proteasome. The decline in proteasome activity is matched by a decline in 20S proteasome assembly. In contrast, 26S proteasome assembly was found to increase with age, though 26S proteasome activity was still found to decline. Our data suggests that age-related declines in proteasome activity is driven predominantly by reduced functionality of proteasome rather than altered composition. By overexpressing the proteasome subunit PSMB5 in the neurons of mice to increase the proteasome content and thus enhance its functionality, we slowed age-related declines in spatial learning and memory. We then showed acute treatment with a proteasome activator to rescue spatial learning and memory deficits in aged mice. These findings highlight the potential of proteasome augmentation as a therapeutic strategy to mitigate age-related cognitive declines.

Senescent mandibular bone repair poses a formidable challenge without a completely satisfactory strategy. Endogenous cell recruitment and osteogenic differentiation are two sequential stages in bone regeneration, and disruptions in these two processes present significant obstacles to senescent bone repair. To address these issues, engineered extracellular vesicles (EV) with sequential stem cell recruitment and osteogenic functions were developed. This study demonstrated that Apt19s-engineered extracellular vesicles (Apt19s-EV) recognize and recruit bone marrow mesenchymal stem cells derived from old rats (O-BMSCs) specifically and effectively. MiR-376b-5p, identified by RNA sequencing and transfection, was significantly decreased in O-BMSCs, and it was selected to construct miR-376b-5p-engineered extracellular vesicles (376b-EV). 376b-EV could promote osteogenesis and alleviate senescence of O-BMSCs by targeting Camsap1. To combine the advantages of Apt19s and miR-376b-5p, dual engineered extracellular vesicles (Apt-376b-EV) comprising both Apt19s and miR-376b-5p modifications were constructed. To further validate its function, Gelatin methacryloyl (GelMA) hydrogel was used as a carrier to construct the Apt-376b-EV@GelMA delivery system. The in vitro results have demonstrated that Apt-376b-EV@GelMA could recruit O-BMSCs, alleviate senescence and promote osteogenic differentiation sequentially. Notably, the in vivo study also showed that Apt-376b-EV@GelMA could sequentially recruit endogenous stem cells and enhance new bone formation in senescent bone fracture and critical-sized defect models. In summary, the dual engineered extracellular vesicles, Apt-376b-EV, offer an appealing solution for recruiting endogenous stem cells and promoting bone repair sequentially in the senescent microenvironment, which may broaden the clinical applications of engineered EV and provide valuable strategies for treating senescent bone-related diseases in the future clinical work.

Age-associated thymic involution leads to a significant decline in thymic T cell output, a major contributor to immunosenescence in the elderly. Accurately measuring thymic output is therefore critical for understanding the mechanisms behind immune aging. Furthermore, robust quantification of thymic output is essential in various other clinical and research settings, including the diagnosis of immunodeficiencies and the monitoring of T cell reconstitution following therapeutic interventions like hematopoietic stem cell transplantation. Current methodologies for measuring thymic output include T cell receptor excision circle (TREC) quantification via quantitative polymerase chain reaction and the enumeration of recent thymic emigrants (RTEs) using flow cytometry. However, TREC-based assays are inherently insensitive to subtle changes in thymic output, limiting their applicability beyond neonatal immunodeficiency screening. Similarly, RTE enumeration presents challenges; while surface markers exist for CD4⁺ RTEs, validated markers for CD8⁺ cytotoxic T lymphocytes are lacking. This represents a significant knowledge gap, particularly as aging has been shown to disproportionally affect the CD8 T cell pool. Moreover, while flow cytometry effectively measures mature naïve T cells, these cells do not accurately represent real-time thymic output, as they can persist in peripheral circulation for extended periods. These limitations highlight the pressing need for more accurate and sensitive methods to assess thymic output. Improved measurement techniques would not only enhance our understanding of thymic involution in the context of aging but also enable large-scale investigations into thymic function and the mechanisms driving its decline in both health and disease. In this review, we examine current methodologies for measuring thymic output in humans, critically evaluate their limitations, and discuss emerging approaches to address these gaps in the field.

Maintenance of organismal function requires tightly regulated biomolecular communication. However, with aging, communication deteriorates, thereby disrupting effective information flow. Using information theory applied to skeletal muscle single cell RNA-seq data from young, middle-aged, and aged animals, we quantified the loss of communication efficiency over time. We considered communication channels between transcription factors (TF; input message) and corresponding target genes (TG; output message). Mutual information (MI), defined as the information effectively transmitted between TFs and TGs, declined with age. This decline was attributed to escalating biological noise and loss of precision with which TFs regulate TGs (i.e., channel capacity). When we ranked TF:TG pairs by MI, pairs associated with fatty acid oxidation displayed the greatest loss of communication with aging, while the system preserved communication between pairs related to RNA synthesis. These data suggest ineffective communication with aging against a backdrop of resource reallocation to support essential cellular functions.

Deep learning (DL) and explainable artificial intelligence (XAI) have emerged as powerful machine-learning tools to identify complex predictive data patterns in a spatial or temporal domain. Here, we consider the application of DL and XAI to large omic datasets, in order to study biological aging at the molecular level. We develop an advanced multi-view graph-level representation learning (MGRL) framework that integrates prior biological network information, to build molecular aging clocks at cell-type resolution, which we subsequently interpret using XAI. We apply this framework to one of the largest single-cell transcriptomic datasets encompassing over a million immune cells from 981 donors, revealing a ribosomal gene subnetwork, whose expression correlates with age independently of cell-type. Application of the same DL-XAI framework to DNA methylation data of sorted monocytes reveals an epigenetically deregulated inflammatory response pathway whose activity increases with age. We show that the ribosomal module and inflammatory pathways would not have been discovered had we used more standard machine-learning methods. In summary, the computational deep learning framework presented here illustrates how deep learning when combined with explainable AI tools, can reveal novel biological insights into the complex process of aging.

The ovary is one of the first organs in humans to exhibit age-related functional impairments. As an organ composed of diverse heterogeneous cell types, the ovary exhibits cell-type-specific changes during the aging process, ultimately leading to a decline in female fertility. Investigating the molecular mechanisms of ovarian aging is crucial for understanding age-related fertility dysfunction in females. In this study, we combine scRNA-seq and scATAC-seq from mouse young/aged ovaries to characterize molecular features during ovarian aging. Using the single-cell multi-omic data, we revealed the cell-type-specific transcriptional changes during the aging process in seven major ovarian cell types and identified the cis/trans-regulatory elements governing these transcriptional changes. Specifically, we uncovered the transcriptional alterations of TGF-beta signaling in mesenchymal cells and endoplasmic reticulum stress in granulosa cells of aged mouse ovaries and further identified the potential corresponding cis/trans-regulatory elements. These molecular alterations may contribute to aging-induced functional impairments in mouse ovaries. In summary, this work provides transcriptome and chromatin accessibility landscape of ovarian aging in mice, which serve as a resource for identifying the cell-type-specific molecular mechanisms underlying ovarian aging, aiding in the identification of potential diagnostic biomarkers and treatment strategies.

Microvascular aging, predominantly driven by endothelial cells (ECs) dysfunction, is a critical early event in cardiovascular diseases. However, the specific effects of aging on ECs across the microvascular network segments and the associated mechanisms are not fully understood. In this study, we detected a microvascular rarefaction and a decreased proportion of venular ECs in the subcutaneous adipose tissue of aged mice using light-sheet immunofluorescence microscopy and single-cell RNA sequencing. Moreover, aged ECs, especially in the venular subtype, exhibited a pseudotemporal transition to a terminal state characterized by diminished oxidative phosphorylation and strengthened cytokine signaling. Metabolic flux balance analysis predicted that among the 13 differentially expressed cytokines identified in aged EC subpopulations, Cxcl9 was strongly correlated with impaired oxidative phosphorylation in aged ECs. It was further validated using microvascular ECs treated with Cxcl9. Notably, the G protein-coupled receptor signaling pathway was subsequently suppressed, in which Aplnr suppression was also observed in aged ECs, contributing to their impaired energy metabolism and reduced angiogenesis. Based on these findings, we propose Cxcl9 as a biomarker for aging-related dysfunction of microvascular ECs, suggesting that targeting Cxcl9 signaling may help combat microvascular aging.

Global population aging is an escalating challenge in modern society, especially as it impairs the function of multiple organs and increases the burden of age-related diseases. The kidneys, in particular, experience function decline, reduced regenerative capacity and increased susceptibility to injury as they age. As a result, the prevalence of chronic kidney disease (CKD) rises with aging, further contributing to the growing health burden in older populations. One of the key factors in this process is the dysfunction of specialized renal endothelial cells (RECs), which are essential for maintaining kidney health by regulating blood flow, and supporting filtration, solute and water reabsorption, and vascular integrity. As the kidneys age, REC dysfunction drives vascular and microenvironmental changes, contributing to the overall decline in kidney function. In this review, we outline the structural and functional effects of aging on kidney's macrovascular and microvascular compartments and provide a phenotypic description of the aged endothelium. We particularly focus on the molecular and metabolic rewiring driving and sustaining growth-arrested EC senescence phenotype. We finally give an overview of senotherapies acting on ECs especially on those modulating metabolism. Given that the pathophysiological processes underlying kidney aging largely overlap with those observed in CKD, REC rejuvenation could also benefit CKD patients. Moreover, such interventions may hold promise in improving the outcomes of aged kidney transplants. Hence, advancing our understanding of REC and kidney aging will create opportunities for innovations that could improve outcomes for both elderly individuals and CKD patients.

Heart disease is the leading cause of death in the elderly population and the heart is a highly energy-consuming tissue. Aging-related heart failure is often driven by energy depletion in cardiomyocytes (CM), which rely on their abundant, cristae-dense mitochondria for ATP production. ATP synthase, localized along the cristae rims, plays a critical role in energy conversion, but the connection between its organization and function remains unclear. Here, we explored the spatiotemporal organization of ATP synthase in senescent CM at the level of individual complexes. Using single-molecule localization and tracking microscopy, we observed reduced enzyme mobility within the cristae, coinciding with decreased ATP synthase activity, despite a stable resting mitochondrial membrane potential. This reduction in activity was independent of changes in ATP synthase expression or dimerization. Electron tomography revealed an increased prevalence of curved inner membranes and fenestrated cristae in senescent CM, explaining the reduced enzyme mobility. Senescent CM displayed irregular autonomous and paced beating patterns. These abnormalities suggest that impaired cardiac function is directly driven by disrupted energy metabolism, rooted in the suboptimal organization and function of ATP synthase in altered cristae.

Robust 3D tissue culture models to activate aged fibroblasts for cell-based therapies and identify regulators of such activation are still missing. In our previous study, we showed that aged fibroblasts can be activated simply through applying compressive force, without the need for exogenous factors, leading to increased migration. In this study, we develop a pipeline to evaluate the role of specific pharmacological inhibitors for transcription factor inference and cell migration involved in aged fibroblast activation. By integrating RNA-seq data with bioinformatic tools (prize collecting Steiner tree method and iRegulon) we inferred 15 candidates. In addition, we used cell migration and heterochromatin content as readouts for validating these candidates. Furthermore, we identified three potential master regulators of fibroblast activation and rejuvenation: FOXO1, STAT3, and PDK1. These findings offer valuable insights for future drug discovery, disease modeling, and regenerative medicine.

The decline in oocytes quality and developmental potential with female reproductive aging is well recognized, yet the underlying mechanisms remain insufficiently investigated. In this study, through an integrative analysis of transcriptomes and morphologies of individual oocytes from young and aged mice, morphologically defective aged oocytes are identified with distinct transcriptomic features. Further analysis demonstrates that both apoptotic and ferroptotic pathways are activated in the defective aged oocytes, and simultaneously blocking both pathways reverses the defective morphology to the largest extent. The Plat gene, which encodes tissue-type plasminogen activator (tPA), is downregulated with oocyte aging, and Plat knockdown increases oocytes susceptibility to both apoptosis and ferroptosis. Mechanistically, tPA functions as an upstream signaling molecule for Erk1/2 activation by interacting with particular phosphorylation kinases such as Alk. Consequently, Plat loss downregulates Erk1/2 pathway activity in oocytes, leading to degeneration through programmed cell death. Supplementing exogenous tPA in in vitro oocyte maturation cultures reduces defect rate of aged oocytes, thereby improving oocyte quality and developmental potential. Collectively, Plat plays a pivotal role in protecting aged mouse oocytes from programmed cell death, and tPA supplementation may serve as a potential clinical strategy to enhance oocyte quality in females of advanced maternal age.

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

Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging-related diseases. It has long been speculated that "rejuvenation molecules" exist in their blood to promote extended lifespan. We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity from the elderly. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids. Mechanistically, we revealed that increased bisphosphoglycerate mutase (BPGM) and reduced MFSD2B protein levels in the erythrocytes of longevity individuals collaboratively work together to induce elevation of intracellular S1P, promote the release of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from membrane to the cytosol, and thereby orchestrate glucose metabolic reprogramming toward Rapoport-Luebering Shunt to induce the 2,3-BPG production and trigger oxygen delivery. Furthermore, increased glutamine and glutamate transporter expression coupled with the enhanced intracellular metabolism underlie the elevated GSH production and the higher anti-oxidative stress capacity in the erythrocytes of longevity individuals. As such, longevity individuals displayed less systemic hypoxia-related metabolites and more antioxidative and anti-inflammatory metabolites in the plasma, thereby healthier clinical outcomes including lower inflammation parameters as well as better glucose-lipid metabolism, and liver and kidney function. Overall, we identified that youthful erythrocyte function and metabolism enable longevity individuals to better counteract peripheral tissue hypoxia, inflammation, and oxidative stress, thus maintaining healthspan.

The impact of mid-late-life exercise on the aging heart remains unclear, particularly the effects of high-intensity interval training (HIIT) and continuous moderate-intensity training (CMIT). This study was the first to examine cardiac function, tissue characteristics, electrical remodeling, mitochondrial morphology and homeostasis in old mice subjected to CMIT or HIIT, compared to untrained controls. Our results showed that 8-week HIIT significantly improved the survival rate of old mice. HIIT presented advantages on cardiac function, deposition of collagen fibers, neovascularization, aging biomarkers and mitochondrial homeostasis. Only CMIT alleviated age-related cardiac hypertrophy. However, CMIT potentially exacerbated adverse cardiac electrical remodeling. Those findings suggested HIIT as a particularly appealing option for clinical application for aging populations.

Cardiotoxicity remains a major limiting factor in the clinical implementation of anthracycline chemotherapy. Though the etiology of doxorubicin-dependent heart damage has yet to be fully elucidated, the ability of doxorubicin to damage DNA and trigger oxidative stress have been heavily implicated in the pathogenesis of chemotherapy-associated cardiomyopathy. Here, we demonstrate that fibronectin type III domain-containing protein 5 (FNDC5), the precursor protein for myokine irisin, is depleted in the hearts of human cancer patients or mice exposed to chemotherapeutics. In cardiomyocytes, restoration of FNDC5 expression was sufficient to mitigate reactive oxygen species (ROS) accumulation and apoptosis following doxorubicin exposure, effects dependent on the irisin encoding domain of FNDC5 as well as signaling via the putative irisin integrin receptor. Intriguingly, we identified two parallel signaling cascades impacted by FNDC5 in cardiomyocytes: the ROS-driven intrinsic mitochondrial apoptosis pathway and the ROS-independent Ataxia Telangiectasia and Rad3-Related Protein (ATR)/Checkpoint Kinase 1 (Chk1) pathway. In fact, FNDC5 forms a co-precipitable complex with Chk1 alluding to possible intracellular actions for this canonically membrane-associated protein. Whereas FNDC5 overexpression in murine heart was cardioprotective, introduction of FNDC5-targeted shRNA into the myocardium was sufficient to trigger Bax up-regulation, ATR/Chk1 activation, oxidative stress, cardiac fibrosis, loss of ventricular function, and compromised animal survival. The detrimental impact of FNDC5 depletion on heart function could be mitigated via treatment with a Chk1 inhibitor identifying Chk1 hyperactivity as a causative factor in cardiac disease. Though our data point to the potential clinical utility of FNDC5/irisin-targeted agents in the treatment of chemotherapy-induced cardiotoxicity, we also found significant down regulation in FNDC5 expression in the hearts of aged mice that attenuated the cardioprotective impacts of FNDC5 overexpression following doxorubicin exposure. Together our data underscore the importance of FNDC5/irisin in maintenance of cardiac health over the lifespan.

Aging is associated with cognitive decline and memory impairment, but the underlying neural mechanisms remain unclear. Phase-amplitude coupling (PAC) between mid-frontal theta (5 Hz) and occipital gamma (>30 Hz) oscillations is a proposed marker for parallel storage of multiple items in working memory. However, research has mainly focused on young individuals and epilepsy patients, with only a few studies on aging populations. Moreover, these studies have relied on univariate PAC methods, which can be flawed by potential spurious or biased PAC estimates due to non-stationarity of EEG signals. Additionally, these methods typically assess PAC at the level of individual electrodes, potentially overlooking the broader functional significance of theta-gamma coupling in coordinating neural activity across distant brain regions. To address these gaps, we employed multivariate PAC (mPAC) through generalized eigendecomposition (GED) analysis, which avoids the pitfalls of non-sinusoidal oscillations. 113 young and 117 older healthy participants engaged in a sequence learning paradigm (6423 sequence repetitions, 55\'944 stimuli), in which they learned a fixed sequence of visual stimuli over repeated observations, allowing us to track the mPAC during the incremental process of learning. Behavioral results revealed that younger participants learned significantly faster than older participants. Neurophysiological data showed that mPAC increased over the course of learning in both age groups and could identify fast and slow learners. However, older participants exhibited lower mPAC compared to younger counterparts, which suggest compromised parallel storage of items in working memory in older age. Finally, stratification analysis revealed that mPAC effects persist across performance groups with similar mid-frontal theta levels, suggesting that theta alone does not account for these effects. These findings shed light on the age-related differences in memory formation processes and may guide interventions to enhance memory performance in older adults and slow learners.

Deterioration in nutritional condition with aging could reduce reproductive success but coincides with declines in residual reproductive potential, thus invoking opposing expectations for late-life reproduction. Yet, the mechanisms regulating energy accrual and allocation to reproduction and survival throughout the lifetime of long-lived, iteroparous animals have remained elusive owing to variation in energetic costs across their extended reproductive cycle (from conception to juvenile independence). Using 10 years of repeated measures of both nutrition (i.e., body fat and food availability) and reproductive allocation across the reproductive cycle of 232 free-ranging, adult, female mule deer, we revealed that nutrition is a critical piece in understanding patterns of reproductive senescence and terminal investment. From conception to weaning, age-related patterns of reproduction were influenced by both body fat and environmental conditions. Reproductive senescence was clear across the entire reproductive cycle, although allocation to offspring was partly mediated by nutrition. Terminal investment, however, was most evident towards the end of the annual reproductive cycle and unveiled only when considering nutritional condition and food availability; during years with poor resource availability, older mothers raised larger juveniles (i.e., 6-months old). Our work evokes nutrition as a lurking variable in end-of-life reproductive tactics for long-lived animals, while demonstrating the necessity of accounting for energy when considering patterns of reproductive senescence and terminal investment in wild animals.

Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes is significantly diminished in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1 and SCGB3A2. Furthermore, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-β signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.

Neuronal architecture established embryonically must persist lifelong to ensure normal brain function. However, little is understood about the mechanisms behind the long-term maintenance of neuronal organization. To uncover maintenance mechanisms, we performed a suppressor screen in sax-7/L1CAM mutants, which exhibit progressive disorganization with age. We identified the conserved extracellular matrix protein MIG-6/papilin as a key regulator of neuronal maintenance. Combining incisive molecular genetics, structural predictions, in vivo quantitative imaging, and cutting-edge Brillouin microscopy, we show that MIG-6/papilin remodels extracellular matrix collagen IV, working in concert with the secreted enzymes MIG-17/ADAMTS and PXN-2/peroxidasin. This remodeling impacts tissue biomechanics and ensures neuronal stability, even under increased mechanical stress. Our findings highlight an extracellular mechanism by which MIG-6/papilin supports the integrity of neuronal architecture throughout life. This work provides critical insights into the molecular basis of sustaining neuronal architecture and offers a foundation for understanding age-related and neurodegenerative disorders.

Several progeroid syndromes' causative mutations have been linked to epigenetic age acceleration as measured via several epigenetic clocks. At the same time, several protective variants have also been discovered that can reduce the risk of developing certain age-related disorders. However, the impact of these protective variants on epigenetic aging has not been well elucidated. Our research, which involved screening over 14,669 healthy individuals enrolled in the Qatar BioBank (QBB) and sequenced by the Qatar Genome Project (QGP), identified individuals carrying protective variants against age-related disorders, including Alzheimer's disease (AD), type 2 diabetes (T2D), and atherosclerosis. In this study, we measured methylation levels in blood DNA using the EPIC v2 arrays. In addition, epigenetic age was calculated using various epigenetic clocks. Our analysis revealed that the APOE*E2 protective variant reduces the rate of GrimAge epigenetic aging when compared to individuals with the APOE4 AD risk allele. Furthermore, our differential DNA methylation analysis discovered the association of the PCSK9 protective variant with specific biological processes related to immune function and the cardiovascular system. In conclusion, APOE*E2 protective variants have a positive impact on epigenetic aging, while PCSK9 protective variants have a significant effect on DNA methylation signatures. Further studies are needed to better understand the underlying mechanisms by which protective variants influence epigenetic aging, particularly the role of APOE*E2 protective variants in biological aging. Furthermore, additional research is required to fully uncover the processes that might enable specific targeted therapies to mimic the effects of beneficial mutations, such as LOF variants in PCSK9, in reducing the risk of geriatric disorders.