Longevity Papers

Aging represents the gradual accumulation of alterations within an organism over time. The physical and chemical characteristics of our cells gradually change as we age, making it more difficult for our tissues and organs to self-regulate, regenerate, and maintain their structural and functional integrity. AMP- activated protein kinase (AMPK), a well-known sensor of cellular energy status acts as a central regulator of an integrated signalling network that control homeostasis, metabolism, stress resistance, cell survival and autophagy. Coniferaldehyde (CFA), a phenolic compound found in many edible plants, has multiple biological and pharmacological functions. Our findings demonstrated that 50 µM CFA could significantly activate autophagy and reduce oxidative stress, which enhanced the activity of antioxidant enzymes and increased resistance under oxidative stress. CFA treatment could efficiently decrease reactive oxygen species (ROS) levels and positively enhance the expression of antioxidant genes in Caenorhabditis elegans (C. elegans). On the other hand, CFA did not have any role in the lifespan extension of the several mutants linked to the AAK-2/AMPK pathway and it promotes SKN-1 (Skinhead-1) localization into the nucleus, which modulates downstream gene gst-4 (Glutathione S-transferase). In depth investigations revealed that CFA could lower oxidative stress and enhance the lifespan of C. elegans by activating the PAR-4/LKB-1-AAK-2/AMPK-SKN-1/NRF-2 pathway, with crucial involvement of bec-1 and lgg-1 genes for autophagy mediated lifespan extension. This study might contribute to understanding the interactions and mechanisms that allow natural compounds like CFA to treat age-related disorders among several species.

The complex mechanisms underlying the development of cardiovascular diseases remain not fully elucidated. Epigenetics, which modulates gene expression without DNA sequence changes, is shedding light on these mechanisms and their heritable effects. This review focus on epigenetic regulation in cardiovascular aging and diseases, detailing specific epigenetic enzymes such as DNA methyltransferases (DNMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs), which serve as writers or erasers that modify the epigenetic landscape. We also discuss the readers of these modifications, such as the 5-methylcytosine binding domain proteins, and the erasers ten-eleven translocation (TET) proteins. The emerging role of RNA methylation, particularly N6-methyladenosine (m

BackgroundCircular RNAs (circRNAs) are emerging as crucial regulators of biological processes and have been implicated in age-related diseases. Few studies have explored age-related circRNA expression in the human brain across the adult lifespan. This study aims to identify age-related differentially expressed circRNAs in human post-mortem dorsolateral prefrontal cortex (DLPFC) samples, a region critically involved in cognition that exhibits early signs of age-related changes. MethodsTotal RNA sequencing was conducted on a discovery cohort of 67 postmortem DLPFC samples, from individuals with no neurological disease diagnosis at the time of death (35-103 years). CircRNAs were identified using CIRCexplorer2, with 11,907 circRNAs available for analyses. Linear regression was used to analyse the relationships between circRNA expression and age at death. Replication of the results was performed in an independent neurologically healthy dataset from the CommonMind Consortium (n=321, age at death: 35-91 years). Co-expression network analysis was performed to identify modules of highly co-expressed circRNAs associated with age. Potential microRNA and RNA-binding protein target sites were predicted. ResultsIn the discovery dataset, 37 circRNAs were age-associated (FDR <0.05). Seven out of the 37 were successfully replicated. The host genes of replicated age-associated circRNAs are implicated in synapse regulation. Co-expression analysis revealed two circRNA modules significantly correlated with age. We identified 484 microRNA and 99 RNA-binding protein target sites on the replicated circRNAs. ConclusionSeven age-associated circRNAs were identified as important candidates for involvement in post-transcriptional regulatory networks in the DLPFC. Future studies should aim to elucidate their functional roles in brain ageing.

The etiology and mechanism causing Age-related hearing loss (ARHL) are not understood. This study aimed to investigate the molecular mechanism of interleukin 8 (IL-8) associated with ARHL. Sera content of IL-8 was significantly higher in patients with ARHL than normal volunteers and had a positive association with disease severity of ARHL. Human IL-8 (hIL-8) could exacerbate the progressive ARHL with time increase and promoted apoptosis of hair cells in cochlea. As the important component in maintaining the integrity of the blood-labyrinth barrier (BLB) and hearing function, cell viability of perivascular-resident macrophage-like melanocytes (PVM/Ms) was restrained while apoptosis of PVM/Ms was enhanced in the presence of hIL-8. Using a cell culture-based in vitro model, the permeability of the endothelial cells (ECs) monolayer increased markedly in the presence of IL-8-treated PVM/Ms or PVM/Ms-derived from LV5-hIL-8 mice as compared with the presence of PVM/Ms-derived from wild type (WT) mice or 12-months WT mice. Mechanistically, IL-8 exposure enhanced the expression of histone deacetylase 3 (HDAC3) in PVM/Ms and HDAC3 inhibitor significantly blocked the permeability of the ECs in the presence of IL-8-treated PVM/Ms. Besides, HDAC3 inhibitor had a protective effect on hIL-8-launched ARHL in mice. Collectively, the elevated of serum IL-8 in ARHL patients activated the activity of HDAC3 in PVM/Ms, subsequently increased the permeability of the ECs, resulting in the impairments of the BLB and hair cells in cochlea. Possibly, IL-8 could be used in the diagnosis of ARHL and these findings might help to identify the clinical therapeutic direction for ARHL.

Alzheimer's disease (AD) is an aging-related neurodegenerative disorder that results in progressively impaired memory and is often associated with amyloid plaques. Previous studies implicate the deacetylases SIRT1 and SIRT2 in regulating the processing of amyloid precursor protein (APP). Here, we investigated whether APP is regulated by the related deacetylase SIRT6, which shows aging-associated decreases in activity. We found that the abundance of SIRT6 was reduced in the cortex and hippocampus of aged and AD model mice and negatively correlated with that of APP. In mouse hippocampal neurons and transfected human cells, SIRT6 interacted with and deacetylated APP at three consecutive Lys residues (Lys

The female reproductive axis is one of the first organ systems to age, which has consequences for fertility and overall health. Here, we provide a comprehensive overview of the biological process of female reproductive aging across reproductive organs, tissues and cells based on research with widely used physiologic aging mouse models, and describe the mechanisms that underpin these phenotypes. Overall, aging is associated with dysregulation of the hypothalamic-pituitary-ovarian axis, perturbations of the ovarian stroma, reduced egg quantity and quality, and altered uterine morphology and function that contributes to reduced capacity for fertilization and impaired embryo development. Ultimately, these age-related phenotypes contribute to altered pregnancy outcomes and adverse consequences in offspring. Conserved mechanisms of aging, as well as those unique to the reproductive system, underlie these phenotypes. The knowledge of such mechanisms will lead to development of therapeutics to extend female reproductive longevity and support endocrine function and overall health.

BackgroundCalcific aortic valve disease (CAVD) is the pathological remodeling of valve leaflets. The initial steps in valve leaflet osteogenic reprogramming are not fully understood. As telomerase reverse transcriptase (TERT) overexpression primes mesenchymal stem cells to differentiate into osteoblasts, we investigated whether TERT contributes to the osteogenic reprogramming of valve interstitial cells (VICs). MethodsHuman control and CAVD aortic valve leaflets and patient-specific hVICs were used in in vivo and in vitro calcification assays. Loss of function experiments in hVICs and cells isolated from Tert-/-and Terc-/- mice were used for mechanistic studies. Calcification was assessed in Tert+/+ and Tert-/- mice ex vivo and in vivo. In silico modeling, proximity ligation and co-immunoprecipitation assays defined novel TERT interacting partners. Chromatin immunoprecipitation and CUT&TAG sequencing defined protein-DNA interactions. ResultsTERT protein was highly expressed in calcified valve leaflets without changes in telomere length, DNA damage, or senescence markers, and these features were retained in isolated primary hVICs. TERT expression increased with osteogenic or inflammatory stimuli, and knock-down or genetic deletion of TERT prevented calcification in vitro and in vivo. Mechanistically, TERT was upregulated via NF-{kappa}B and required to initiate osteogenic reprogramming, independent of its canonical reverse transcriptase activity and the lncRNA TERC. TERT exerts non-canonical osteogenic functions via binding with Signal Transducer and Activator of Transcription 5 (STAT5). Depletion or inhibition of STAT5 prevented calcification. STAT5 was found to bind the promoter region of Runt-Related Transcription Factor 2 (RUNX2), the master regulator of osteogenic reprogramming. Lastly, we demonstrate that TERT and STAT5 are upregulated and colocalized in CAVD tissue compared to control tissue. ConclusionsTERTs non-canonical activity is required to initiate calcification. TERT is upregulated via inflammatory signaling pathways and partners with STAT5 to bind the RUNX2 gene promoter. These data identify a novel mechanism and potential therapeutic target to decrease vascular calcification. Novelty and SignificanceWhat is known? Calcific aortic valve disease (CAVD) is the most prevalent form of aortic valve pathology. CAVD strongly correlates with age and leads to heart failure and a high risk of stroke. Currently, the only therapeutic option is valve replacement, which comes with significant healthcare costs and additional risks to patients. Runt-related transcription factor 2 (RUNX2) is the master transcription factor required for osteogenic differentiation of stem cells to osteoblasts and osteogenic reprogramming of cardiovascular cells. Yet, the early events driving its activity in aortic valve cells are poorly defined. In addition to its reverse transcriptase enzymatic activity, TERT exhibits non-canonical transcriptional regulatory functions and overexpression of TERT primes mesenchymal stem cells to differentiate down the osteoblast lineage. What new information does this article contribute? TERT protein levels in calcified aortic leaflets and valve interstitial cells, and its non-canonical osteogenic activity are independent of changes in telomere length and cell senescence. Genetic loss or depletion of TERT prevented calcification in valve interstitial cells, coronary smooth muscle cells, and mesenchymal stem cells in vitro and the vasculature in vivo. Early in the osteogenic reprogramming inflammatory signaling promotes TERT to co-localize with SMARCA4 and STAT5, and this TERT-tethered STAT5 binds to the RUNX2 gene promoter, the master regulator of osteogenic transcriptional programs. STAT5 depletion and pharmacological inhibition prevent calcification of human valve interstitial cells, coronary smooth muscle cells, and mesenchymal stem cells. What are the clinical implications? We have identified TERT-STAT5 as a novel signaling axis that orchestrates the early steps in the osteogenic reprogramming of aortic valve cells. Inhibiting TERT/STAT5 interaction or their activity may be leveraged for the development of therapeutic strategies to halt or prevent calcification in the aortic valve, bioprosthetic valves, and or perhaps other cardiovascular tissues. Invasive and expensive surgical procedures are currently the only treatment option for patients with CAVD. The discovery and defining of the early events driving vascular calcification identifies novel and druggable targets for developing non-surgical therapies.

Declining intrinsic capacity (IC) significantly impacts health outcomes in aging populations. While weak handgrip strength (HGS) is associated with IC impairment, the role of HGS asymmetry remains unclear, especially among older Chinese cohorts.

People today are choosing to have children later in life, often in their thirties and forties, when their fertility is in decline. We sought to identify and compile effective methods for improving either male or female fertility in this context of advanced reproductive age. We found few clinical studies with strong evidence for therapeutics that mitigate reproductive aging or extend fertility; however, this Perspective summarizes the range of emerging experimental strategies under development. Preclinical studies, in mouse models of aging, have identified pharmaceutical candidates that improve egg and sperm quality. Further, a diverse array of medically assisted reproduction methodologies, including those that stimulate rare ovarian follicles and rejuvenate egg quality using mitochondria, may have future utility for older patients. Finally, we highlight the many knowledge gaps and possible future directions in the field of therapeutics to extend the age of healthy human reproduction.

Substantial shifts in reproductive behaviors have recently taken place in many high-income countries including earlier age at menarche, advanced age at childbearing, rising childlessness and a lower number of children. As reproduction shifts to later ages, genetic factors may become increasingly important. Although monogenic genetic effects are known, the genetics underlying human reproductive traits are complex, with both causal effects and statistical bias often confounded by socioeconomic factors. Here, we review genome-wide association studies (GWASs) of 44 reproductive traits of both female and male individuals from 2007 to early 2024, examining reproductive behavior, reproductive lifespan and aging, infertility and hormonal concentration. Using the GWAS Catalog as a basis, from 159 relevant studies, we isolate 37 genes that harbor association signals for four or more reproductive traits, more than half of which are linked to rare Mendelian disorders, including ten genes linked to reproductive-related disorders: FSHB, MCM8, DNAH2, WNT4, ESR1, IGSF1, THRB, BRWD1, CYP19A1 and PTPRF. We also review the relationship of reproductive genetics to related health and behavioral traits, aging and longevity and the effect of parental age on offspring outcomes as well as reflecting on limitations, open questions and challenges in this fast-moving field.

Osteoarthritis (OA) is a joint disease closely related to aging and characterized by degeneration of articular cartilage. Robinin is a natural agent with various pharmacological properties. Recently, Robinin has been found to have the potential to improve the bone-related diseases. However, its effect on OA development remained unknown. Here, we discuss the specific role and underlying mechanisms of Robinin in interleukin-1beta (IL-1β)-treated chondrocytes and OA mouse model. Chondrocytes were isolated from the mouse to conduct in vitro assays. We evaluated cell viability and apoptosis using Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis, respectively. Western blotting assessed the levels of proteins related to apoptosis, extracellular matrix (ECM), and signaling pathways. Immunofluorescence staining was used to detect the expression of ECM and signaling markers. ELISA was conducted to assess the levels of inflammatory markers. The OA mice model was established using surgical destabilization of the medial meniscus (DMM), and then H&E staining and Safranin O staining were conducted to observe the histopathological changes in synovial tissues. TUNEL assay was used to detect cell apoptosis in vivo. Real-time RT-PCR was operated to measure mRNA level in vitro and in vivo. We discovered that Robinin reversed the IL-1β-induced decrease in chondrocyte viability. Robinin suppressed IL-1β-induced apoptosis of chondrocytes. The ECM destruction and inflammatory response induced by IL-1β were markedly reversed by Robinin incubation in the mouse chondrocytes. Besides, the upregulated cytokine mRNA levels in IL-1β-treated chondrocytes were reduced by Robinin treatment. The downregulation of COL2A1 level and upregulation of MMP13 and ADAMTS5 levels were counteracted by Robinin treatment. Robinin reduced the protein levels of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) but enhanced the level of phosphorylated p65 (p-p65) in IL-1β-stimulated chondrocytes and OA mice. Robinin mitigated inflammation, cell apoptosis and cartilage destruction in synovial tissues from the OA mice. In conclusion, Robinin alleviated OA development in vitro and in vivo via TLR2/TLR4/NF-κB signaling pathway.

Across diverse taxa, the composition of the microbiota is associated with lifelong host health. A mechanistic understanding of how microbial communities influence host physiology could lead to microbiota-based interventions for lifelong health. Here, we have developed a new host-microbiota model system utilising the model organism C. elegans combined with a defined natural microbiota (DefNatMta) consisting of 11 bacteria isolated from wild C. elegans, to study host-microbiota interactions in a more natural setting. We show that DefNatMta colonises the C. elegans gut, forming a stable and distinct gut microbiota. Using DefNatMta, we find a gut microbiota-muscle axis by which the microbiota affects age-related motility and muscular strength and protects against age-related decline in motor function. The gut microbiota-muscle axis acts by altering metabolism and mitochondrial network dynamics in muscle, and requires dynamin-related protein 1 DRP-1, a regulator of mitochondrial fission to protect against age-related motility decline. Our study demonstrates a gut microbiota-muscle axis and microbiota-mitochondria communication affecting age-related muscle function.

Traumatic brain injury (TBI) and stroke pose major health challenges, impacting millions of individuals globally. Once considered solely acute events, these neurological conditions are now recognized as enduring pathological processes with long-term consequences, including an increased susceptibility to neurodegeneration. However, effective strategies to counteract their devastating consequences are still lacking. Cellular senescence, marked by irreversible cell-cycle arrest, is emerging as a crucial factor in various neurodegenerative diseases. Recent research further reveals that cellular senescence may be a potential driver for secondary neurodegeneration following brain injury. Herein, we synthesize emerging evidence that TBI and stroke drive the accumulation of senescent cells in the brain. The rationale for targeting senescent cells as a therapeutic approach to combat neurodegeneration following TBI/stroke is outlined. From a translational perspective, we emphasize current knowledge and future directions of senolytic therapy for these neurological conditions.

Biological age, which reflects the physiological state of an individual, offers a better predictive value than chronological age for age-related diseases and mortality. Nonetheless, determining accurate functional features of biological age remains challenging due to the multifactorial nature of aging. Here, we established a unique mouse cohort comprising 1576 male and female outbred SWISS mice subjected or not to high-fat, high-sucrose diet to investigate multiorgan/system biological aging throughout adulthood. Comprehensive functional and biological phenotyping at ages of 6, 12, 18, and 24 months revealed notable sex-specific disparities in longitudinal locomotion patterns and multifunctional aging parameters. Topological data analysis enabled the identification of functionally similar mouse clusters irrespective of chronological age. Moreover, our study pinpointed critical functional markers of biological aging such as muscle function, anxiety characteristics, urinary patterns, reticulocyte maturation, cardiac remodeling and function, and metabolic alterations, underscoring muscle function as an early indicator of biological age in male mice.

TREX1 mutations underlie a variety of human diseases, including retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S), a catastrophic adult-onset vasculopathy that is often confused with multiple sclerosis, systemic vasculitis, or systemic lupus erythematosus. Patients with RVCL develop brain, retinal, liver, and kidney disease around age 35-55, leading to premature death in 100% of patients expressing an autosomal dominant C-terminally truncated form of TREX1. We previously demonstrated that RVCL is characterized by high levels of DNA damage, premature cellular senescence, and risk of early-onset breast cancer before age 45. Here, we report human TREX1 mosaicism causing organ-limited RVCL in the retina, as well as a gene therapy to synthetically create TREX1 mosaicism as a potential treatment for RVCL. In our patient with organ-limited disease, the mosaic TREX1 mutant allele underwent germline transmission to 3 children, who developed severe multi-organ disease at ~ age 40, unlike their mosaic parent, who has organ-limited disease at age 74. Additionally, we describe our TREX1 prime editor gene therapy that corrects the most common RVCL-causing TREX1 variant in cell culture and in mice. Thus, TREX1 mosaicism causes organ-limited RVCL with a normal lifespan, suggesting that a gene therapy to create TREX1 mosaicism in adults may someday become useful as a treatment for patients with RVCL.

Declines in lysosomal acidification and function with aging are observed in organisms ranging from yeast to humans. V-ATPases play a central role in organelle acidification and V- ATPase activity is regulated by reversible disassembly in many different settings. Using the yeast Saccharomyces cerevisiae as a replicative aging model, we demonstrate that V-ATPases disassemble into their V1 and V0 subcomplexes in aging cells, with release of V1 subunit C (Vma5) from the lysosome-like vacuole into the cytosol. Disassembly is observed after >5 cell divisions and results in overall vacuole alkalinization. Caloric restriction, an established mechanism for reversing many age-related outcomes, prevents V-ATPase disassembly in older cells and preserves vacuolar pH homeostasis. Reversible disassembly is controlled in part by the activity of two opposing and conserved factors, the RAVE complex and Oxr1. The RAVE complex promotes V-ATPase assembly and a rav1{Delta} mutant shortens replicative lifespan; Oxr1 promotes disassembly and an oxr1{Delta} mutation extends lifespan. Importantly, the level of Rav2, a subunit of the RAVE complex, declines in aged cells, and Rav2 overexpression delays V-ATPase disassembly with age. These data indicate that reduced V-ATPase assembly contributes to the loss of lysosome acidification with age, which affects replicative lifespan.

Single nucleotide mutations in the mitochondrial genome are linked to aging in humans, primates, and rodents and cause neuromuscular diseases in humans. Load of mitochondrial variants in healthy tissues, however, is little known. Employing an unbiased detection method with no prior enzymatic amplification, we observed that the mitochondrial genome of embryonic, adult, and aged mouse brain from two different strains contains a diversity of single nucleotide variants with no age-related increase in abundance. We also observed de novo variants in single oocytes and adult liver arising at 5x10

Age-related macular degeneration (AMD) is a representative age-related ophthalmic disease, and the pathogenesis of AMD remains unclear. This research intended to determine whether epigallocatechin gallate (EGCG) could alleviate the progression of AMD and the possible mechanism. We constructed three groups of mice (young, aged, and EGCG), and HE and TUNEL staining of retinal tissues was performed to observe the structural changes in the retinal pigment epithelial (RPE) layer and the level of apoptosis, respectively. Through RNA-Sequencing analysis of retinal tissues and by RT-qPCR, GO, KEGG, and literature analyses, we identified cytoplasmic fragile X mental retardation 1-interacting protein 2 (CYFIP2) as a possible effector gene for EGCG action and validated its role by immunofluorescent and western blotting experiments. The CCK-8 and Hoechst 33342 apoptosis assays, and western blotting and qRT-PCR assays showed that EGCG reduced hydrogen peroxide (H

It has long been assumed that cognitive aging is a universal phenomenon. However, increasing evidence substantiates the importance of individual differences in cognitive aging. How do experiential factors related to culture shape developmental trajectories of cognition? We propose a new model examining how age and culture influence cognitive processes, building on past models and expanding upon them to incorporate a lifespan developmental perspective. The current model posits that how age and culture interact to influence cognition depends on (a) the extent to which the cognitive task relies on top-down or bottom-up processes, and (b) for more top-down processes, the level of cognitive resources required to perform the task. To assess the validity of the model, we review literature not only from adulthood but also childhood, making this the first model to adopt a lifespan perspective in the study of culture and cognition. The current work advances understanding of cognitive aging by delineating the combined effects of biological aging processes, assumed to apply across cultures, and culture-dependent experiential aging processes, which reflect unique cultural experiences throughout one's lifespan. This approach enables understanding of comprehensive potential mechanisms that underlie the influence of culture on cognitive development across life stages.

A key driver that leads to age-associated decline and chronic disease is mitochondrial dysfunction. Our previous work revealed strong community interest in the concept of mitochondrial fitness, which led to the development of a video-based science communication intervention to prompt behavior change in adults aged 50 years and older.

Organellar homeostasis and crosstalks within a cell have emerged as essential regulatory and determining factors for the survival and functions of cells. In response to various stimuli, cells can activate the organellar quality control systems (QCS) to maintain homeostasis. Numerous studies have demonstrated that dysfunction of QCS can lead to various aging-related diseases such as neurodegenerative, pulmonary, cardiometabolic diseases and cancers. However, the interplay between QCS and their potential role in these diseases are poorly understood. In this review, we present an overview of the current findings of QCS and their crosstalk, encompassing mitochondria, endoplasmic reticulum, Golgi apparatus, ribosomes, peroxisomes, lipid droplets, and lysosomes as well as the aberrant interplays among these organelles that contributes to the onset and progression of aging-related disorders. Furthermore, potential therapeutic approaches based on these quality control interactions are discussed. Our perspectives can enhance insights into the regulatory networks underlying QCS and the pathology of aging and aging-related diseases, which may pave the way for the development of novel therapeutic targets.

During mesenchymal stem cell (MSCs) aging, a decrease in its proliferation and regenerative capacity occurs, which is implicated in human aging. The MSCs aging process is regulated by genetics, metabolism, the external environment, and various complex pathways.

Currently, there is no specific treatment for diabetes-induced osteoporosis (DOP). Our study identified diabetes-induced cellular senescence, marked by elevated activity of senescence-associated β-galactosidase. Targeting senescent cells holds promise for osteoporosis treatment. We demonstrated that scutellarin (SCU) effectively mitigated bone loss in DOP mice, and co-treatment with SCU significantly reduced diabetes-induced senescence in LepR+MSCs. Furthermore, our research highlighted the role of Nrf2 in SCU's anti-senescence effects on bone. The deletion of Nrf2 impaired SCU's ability to alleviate DOP. Mechanistically, SCU enhances Ezh2 expression and increases H3K27me3 activity at the Keap1 promoter region, leading to Keap1 repression and enhanced Nrf2-ARE signalling. Additionally, SCU notably inhibited cellular senescence and diabetes-related osteoporosis, these effects were significantly reduced in Ezh2

This study aims to investigate the association between metabolomic aging acceleration and body mass index (BMI) phenotypes with mortality and obesity-related morbidities (ORMs). 85,458 participants were included from the UK Biobank. Metabolomic age was determined using 168 metabolites. The Chronological Age-Adjusted Gap was used to define metabolomically younger (MY) or older (MO) status. BMI categories were defined as normal weight, overweight, and obese. Participants were categorized into MY normal weight (MY-NW, reference), MY overweight (MY-OW), MY obesity (MY-OB), MO normal weight (MO-NW), MO overweight (MO-OW), and MO obesity (MO-OB). Mortality and 43 ORMs were identified through death registries and hospitalization records. Compared with MY-NW phenotype, MO-OB phenotype yielded increased risk of mortality and 32 ORMs, followed by MO-OW with mortality and 27 ORMs, MY-OB with mortality and 26 ORMs, MY-OW with 21 ORMs, and MO-NW with mortality and 14 ORMs. Consistently, MO-OB phenotype showed the highest risk of developing obesity-related multimorbidities, followed by MY-OB phenotype, MO-OW phenotype, MY-OW phenotype, and MO-NW phenotype. Additive interactions were found between metabolomic aging acceleration and obesity on CVD-specific mortality and 10 ORMs. Additionally, individuals with metabolomic aging acceleration had higher mortality and cardiovascular risk, even within the same BMI category. These findings suggest that metabolomic aging acceleration could help stratify mortality and ORMs risk across different BMI categories. Weight management should also be extended to individuals with overweight or obesity even in the absence of accelerated metabolomic aging, as they face increased healthy risk compared with MY-NW individuals. Additionally, delaying metabolic aging acceleration is needed for all metabolomically older groups, including those with normal weight.

Many aspects of inflammation increase with aging in mice and humans. Transcriptomic analysis revealed that many murine anti-aging interventions produce lower levels of pro-inflammatory proteins. Here, we explore the hypothesis that different longevity interventions diminish NF-κB levels, potentially mediating some of the anti-inflammatory benefits of lifespan-extending interventions. We found that the NF-κB protein p65 is significantly downregulated in the liver of several kinds of slow-aging mice. These included both sexes of GHRKO and Snell Dwarf mutant mice, and in females only of PAPPA KO mice. P65 is also lower in both sexes of mice treated with rapamycin, canagliflozin, meclizine, or acarbose, and in mice undergoing caloric restriction. Two drugs that extend lifespan of male mice, i.e. 17α-estradiol and astaxanthin, however, did not produce lower levels of p65. We also measured other canonical NF-κB signaling regulators, including the activators IKKα and IKKβ and the inhibitor IκB-α. We found that those regulators do not consistently change in a direction that would lead to of NF-κB inhibition. In contrast, we found that NCoR1, an HDAC3 cofactor and a transcription co-repressor that regulates p65 activity, was also downregulated in many of these mouse models. Finally, we report downregulation of three p65 target proteins that regulate the metabolic and inflammatory states of the liver (HNF4α, IL-1β, and CRP) in multiple slow-aging mouse models. Together, these data suggest that NF-κB signaling, might be inhibited in liver of multiple varieties of slow aging mice. This establishes p65 as a potential target for novel longevity interventions.

Mitochondria, cellular powerhouses, harbor DNA (mtDNA) inherited from the mothers. MtDNA mutations can cause diseases, yet whether they increase with age in human germline cells-oocytes-remains understudied. Here, using highly accurate duplex sequencing of full-length mtDNA, we detected

The aging process is characterized by cellular functional decline and increased susceptibility to infections. Understanding the association between virus infection and aging is crucial for developing effective strategies against viral infections in older individuals. However, the relationship between Kaposi's sarcoma-associated herpesvirus (KSHV) infection, a cause of Kaposi's sarcoma prevalent among the elderly without HIV infection, and cellular senescence remains enigmatic. This study uncovers a fascinating link between cellular senescence and enhanced KSHV infectivity in human endothelial cells. Through a comprehensive proteomic analysis, we identified caveolin-1 and CD109 as novel host factors significantly upregulated in senescent cells that promote KSHV infection. Remarkably, CRISPR-Cas9-mediated knockout of these factors reduced KSHV binding and entry, leading to decreased viral infectivity. Furthermore, surface plasmon resonance analysis and confocal microscopy revealed a direct interaction between KSHV virions and CD109 on the cell surface during entry, with recombinant CD109 protein exhibiting an intriguing ability to inhibit infection by blocking virion binding. These findings uncover a previously unrecognized role of cellular senescence in enhancing KSHV infection through upregulation of specific host factors and provide novel insights into the complex interplay between aging and viral pathogenesis.

Biliary epithelial senescence is involved in the pathogenesis of primary biliary cholangitis (PBC). We hypothesized that a unique subtype of programmed death-ligand 1 (PD-L1)-positive senescent biliary epithelial cells (BECs) may be related to the pathogenesis of PBC in association with cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) pathway.

Biological age (BA), an integrated measure of physiological aging, has a clear link to stroke. There is a paucity of long-term longitudinal studies about the association between accelerated biological age and stroke prognosis in patients with previous strokes, and the differences in the predictive ability of various BA indicators calculated from clinical biochemistry biomarkers for future stroke outcomes are still unknown. To evaluate the role of three accelerated BA indicators for short- and long-term prognosis of patients with ischemic stroke or transient ischemic attack (TIA), and to identify the most appropriate predictor.

Aging is a complex biological process. Several animal models, including nematodes, Drosophila, and rodents, have been used in research on aging mechanisms and the extension of healthy life expectancy. The present study investigated the physiological and anatomical changes associated with aging in two sub-strains of aged C57BL/6 mice used in aging research: C57Bl/6NCrSlc (B6N) and C57BL/6J (B6J). The survival rate before 24 mo was higher in B6J mice than in B6N mice; however, after 24 mo, it was markedly lower in the former than in the latter. Body weight increased in male C57BL/6 mice until 15-18 mo and in females until 21-24 mo and then began to decrease. Body temperature was lower in B6N mice than in B6J mice until 24 mo. Food and water intakes increased from 18 mo in both strains. The incidence of alopecia was higher in female C57BL/6J mice from 3 mo. Necropsy findings showed a high rate of spontaneous tumors in both sub-strains. The incidence of cutaneous ulcerative infections and hepatic pathologies was significantly higher in the B6N strain. A high incidence of renal lesions was also observed in B6J mice, particularly in males. These results provide insights into the characteristics of these sub-strains and the phenotypic changes associated with aging, which will facilitate the use of aged mice as a quality resource for geriatric and gerontological research.

The aging process leads to negative changes in various bodily systems, including the neuromuscular system. Strength training, is considered the best strategy to counteract these neuromuscular changes, preventing sarcopenia and frailty in older adults.

Present theories on adult development and aging offer insights into how aging is characterized by gains and losses across different domains (e.g., social, emotional, physical, and cognitive). Such gains and losses are related to changes in behaviors and experiences across various facets of daily life. However, much of the literature has focused on overall quantity of experiences rather than how such experiences are spread across different types. In this article, we propose that experiential diversity, conceptualized as rich and balanced experiences, is an important component of healthy and resilient aging. A conceptual framework demonstrates the theoretical underpinnings associating person-environment interactions with differences in experiential diversity and linking experiential diversity with aging-related outcomes. Experiential diversity is also discussed in the context of ontogenetic and sociohistorical change processes. Advances in empirical studies of experiential diversity across three representative domains of daily experiences (activities, stressors, and emotions) demonstrate how diversity of experiences declines with age. We further provide methodological (e.g., quantification, measurement, and timescales) and theoretical (e.g., moderators and cross-domain considerations) considerations for future studies on experiential diversity beyond the daily domains. Experiential diversity theory provides a theoretical leap, taking advantage of rich categorical data measured in studies of psychology and aging, and allowing for more nuanced consideration of the role of diverse experiences for healthy aging. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Ribosomal DNA (rDNA) genes encode the structural RNAs of the ribosome and are present in hundreds of copies in mammalian genomes. Age-linked DNA hypermethylation throughout the rDNA constitutes a robust "methylation clock" that accurately reports age, yet the consequences of hypermethylation on rDNA function are unknown. We confirmed that pervasive hypermethylation of rDNA occurs during mammalian aging and senescence while rDNA copy number remains stable. We found that DNA methylation is exclusively found on the promoters and gene bodies of inactive rDNA. To model the effects of age-linked methylation on rDNA function, we directed de novo DNA methylation to the rDNA promoter or gene body with a nuclease-dead Cas9 (dCas9)-DNA methyltransferase fusion enzyme in human cells. Hypermethylation at each target site had no detectable effect on rRNA transcription, nucleolar morphology, or cellular growth rate. Instead, human UBF and Pol I remain bound to rDNA promoters in the presence of increased DNA methylation. These data suggest that promoter methylation is not sufficient to impair transcription of the human rDNA and imply that the human rDNA transcription machinery may be resilient to age-linked rDNA hypermethylation.

Telomeres, repetitive DNA sequences at chromosome ends, shorten with cell division, countered by telomerase. Short telomeres are linked to cardiovascular disease (CVD), alongside its risk factors like aging, hypertension, diabetes, obesity, inactivity, and smoking. Many studies have claimed the implication of TL in cardiac diseases. This study examines telomere length's (TL) impact on heart conditions using quantitative fluorescence in situ hybridization (Q-FISH) technology.

As the global population ages, the incidence of age-related musculoskeletal diseases continues to increase, driven by numerous complex and poorly understood factors. WNT-1 inducible secreted protein 1 (WISP-1), a secreted matrix protein, plays a critical role in the growth and development of the musculoskeletal system, including chondrogenesis, osteogenesis, and myogenesis. Numerous in vivo and in vitro studies have demonstrated that WISP-1 is significantly upregulated in age-related musculoskeletal conditions, such as osteoarthritis, osteoporosis, and sarcopenia, suggesting its involvement in the pathogenesis of these diseases. Regulating WISP-1 expression holds promise as a therapeutic strategy for improving musculoskeletal function, potentially offering new avenues for treating age-related musculoskeletal diseases in clinical practice. This review highlights the signaling pathways associated with WISP-1, its physiological roles within the musculoskeletal system, and its therapeutic potential in treating age-related musculoskeletal disorders.

Longevity medicine is an emerging and iterative healthcare discipline focusing on early detection, preventive measures, and personalized approaches that aim to extend healthy lifespan and promote healthy aging. This comprehensive review introduces the innovative concept of the "

Aging-associated cardiac hypertrophy (AACH) increases susceptibility to heart failure in the elderly. Chromatin remodeling contributes to the gene reprogramming in AACH; however, the intrinsic regulations remain elusive. We performed a transcriptome analysis for AACH in comparison with pressure-overload-induced pathological cardiac hypertrophy in mice and identified myeloid leukemia factor 1 (MLF1) as an aging-sensitive factor whose expression was reduced during aging but could be reversed by anti-aging administrations. In human AC16 cardiomyocytes, silencing MLF1 suppressed H2O2-induced cell senescence while the phenotype was exacerbated by MLF1 overexpression. RNA-seq analysis revealed that MLF1 functioned as a transcription activator, regulating genomic-clustered genes that mainly involved in inflammation and development. ATAC-seq analysis showed a prominent reduction in chromatin accessibility at the promoter regions of senescence effectors, like IL1B and p21, after MLF1 knockdown. Despite a potential interaction of MLF1 with the histone methyltransferase PRC2, its inhibition failed to reverse the impact of MLF1 knockdown. Instead, MLF1-mediated regulation was blunted by inhibiting the acetyltransferase EP300. CUT&Tag analysis showed that MLF1 bound to target promoters and recruited EP300 to promote H3K27ac deposition. Collectively, we identify MLF1 as a pro-aging epigenetic orchestrator that recruits EP300 to facilitate opening of the condensed chromatin encompassing senescence effectors.

Nicotinamide mononucleotide (NMN), a key precursor of NAD

Cellular senescence is an aging mechanism characterized by cell cycle arrest and a senescence-associated secretory phenotype (SASP). Preclinical studies demonstrate that senolytic drugs, which target survival pathways in senescent cells, can counteract age-associated conditions that span several organs. The comparative efficacy of distinct senolytic drugs for modifying aging and senescence biomarkers in vivo has not been demonstrated. Here, we established aging- and senescence-related plasma proteins and tissue transcripts that changed in old versus young female and male mice. We investigated responsivity to acute treatment with venetoclax, navitoclax, fisetin or luteolin versus transgenic senescent cell clearance in aged p16-InkAttac mice. We discovered that age-dependent changes in plasma proteins, including IL-23R, CCL5 and CA13, were reversed by senotherapeutics, which corresponded to expression differences in tissues, particularly in the kidney. In plasma from humans across the lifespan, IL-23R increased with age. Our results reveal circulating factors as candidate mediators of senescence-associated interorgan signal transduction and translationally impactful biomarkers of systemic senescent cell burden.

Intracellular lipid binding proteins (iLBPs) play crucial roles in lipid transport and cellular metabolism across the animal kingdom. Recently, a fat-to-neuron axis was described in Caenorhabditis elegans, in which lysosomal activity in the fat liberates polyunsaturated fatty acids (PUFAs) that signal to neurons and extend lifespan with durable fecundity. In this study, we investigate the structure and binding mechanisms of a lifespan-extending lipid chaperone, lipid binding protein-3 (LBP-3), which shuttles dihomo-γ-linolenic (DGLA) acid from intestinal fat to neurons. We present the first high-resolution crystal structure of LBP-3, which reveals a classic iLBP fold with an unexpected and unique homodimeric arrangement via interstrand interactions that is incompatible with ligand binding. We identify key ionic interactions that mediate DGLA binding within the lipid binding pocket. Molecular dynamics simulations further elucidate LBP-3's preferential binding to DGLA due to its rotational freedom and access to favorable binding conformations compared to other 20-carbon PUFAs. We also propose that LBP-3 dimerization may be a unique regulatory mechanism for lipid chaperones.

People with HIV (PWH) experience a higher burden of aging-associated comorbidities, the underlying mechanisms of which remain to be fully elucidated. We aimed to identify profiles based on immune, inflammatory, and aging biomarkers in blood from PWH and controls, and explore their association with total comorbidities over time.

The current narrative review was planned to elucidate the interplay between acupuncture, a cornerstone of Traditional Chinese Medicine, and the modulation of cellular mechanisms via Forkhead box O transcription factors, focussing on autophagy and cellular senescence. Autophagy, essential for cellular health, and cellular senescence, associated with aging and age-related diseases, are both significantly influenced by Forkhead box O transcription factors among other regulatory factors and pathways. These factors, known to diminish with age, play a pivotal role in promoting longevity. The current review analysed experimental models demonstrating acupuncture's capacity to activate Forkhead box O transcription factors, thereby inducing autophagy and reducing cellular senescence. Evidence from studies on human fibroblasts, ageing animal models, obesity-induced insulin resistance, and osteoporosis corroborates the beneficial effects of acupuncture. Despite these promising findings, the complexities of Forkhead box O transcription factors' activation by acupuncture and their precise impact on cellular processes warrant further investigation with a particular focus on the distinct roles of Forkhead box O isoforms.

The incidence of perioperative stroke, a rare but severe complication, is increasing in aging populations. Although anesthetics such as sevoflurane may provide protective preconditioning against ischemic injury, clinical outcomes have been inconsistent. In this study, we demonstrated that sevoflurane-induced neuroprotection is associated with the upregulation of genes involved in the mitochondrial unfolded protein response (UPRmt) and mitochondrial bioenergetic metabolism. Our findings emphasize the critical role of ATF5, a key transcription factor, in mediating these protective effects. Specifically, we observed that sevoflurane preconditioning significantly upregulates ATF5 and its downstream target GDF15 - a regulator of mitochondrial function - in the cerebral cortex. Notably, we found that this mechanistic pathway was not activated in the brain of aged mice, suggesting that age-specific strategies may be necessary for reducing the risk of perioperative stroke. Considering the steadily increasing age of patients, therapeutic approaches that enhance mitochondrial function in the aged brain may provide additional protection against perioperative stroke.

To evaluate the association between cardiorespiratory fitness (CRF) and cognition in a large sample of older adults, and to examine clinical and demographic factors that might moderate these associations.

Renal interstitial fibrosis, a condition prevalent in aging humans and animals, is closely linked to the eventual development of renal failure. Establishing an animal model that exactly replicates the pathogenesis of renal interstitial fibrosis induced by natural aging in humans is crucial for advancing mechanistic studies and testing antifibrotic therapies. Implanted allogeneic or xenogeneic cells are cleared by the immune system when stem cell therapy is applied in nonimmunodeficient animal fibrosis models, affecting the effect of the intervention and making it difficult to demonstrate the survival, proliferation, differentiation, or secretion of the delivered autologous human-derived cells. This study effectively developed a model of spontaneous renal interstitial fibrosis linked to natural aging in 43-week-old NOD/SCID mice. Compared with those of 12- and 32-week-old mice, the kidneys of the model mice exhibited prominent fibrosis characteristics, accompanied by numerous fibrous septa and collagen deposition, increased COL1A1 expression, and decreased MMP9 expression. SA-β-gal activity and P21 gene expression levels increased, confirming renal cell senescence in the model mice. Additionally, an increase in α-SMA staining indicated an increase in epithelial-mesenchymal transition. More importantly, we observed TGF-β-SMAD3 pathway activation, mitochondrial dysfunction, decreased antioxidant capacity, oxidative stress, and an enhanced inflammatory response in the model group, consistent with renal interstitial fibrosis in elderly individuals. In this comprehensive investigation, we successfully developed a spontaneous mouse model of renal interstitial fibrosis and revealed the molecular pathways contributing to increased susceptibility to kidney injury and renal fibrosis in elderly individuals.

To gain insight into how researchers of aging perceive the process they study, we conducted a survey among experts in the field. While highlighting some common features of aging, the survey exposed broad disagreement on the foundational issues. What is aging? What causes it? When does it begin? What constitutes rejuvenation? Not only was there no consensus on these and other core questions, but none of the questions received a majority opinion-even regarding the need for consensus itself. Despite many researchers believing they understand aging, their understanding diverges considerably. Importantly, as different processes are labeled as "aging" by researchers, different experimental approaches are prioritized. The survey shed light on the need to better define which aging processes this field should target and what its goals are. It also allowed us to categorize contemporary views on aging and rejuvenation, revealing critical, yet largely unanswered, questions that appear disconnected from the current research focus. Finally, we discuss ways to address the disagreement, which we hope will ultimately aid progress in the field.

Interoception, the perception and response to internal bodily states, significantly influences physical and mental wellbeing. While ageing is associated with interoceptive decline, research has primarily examined selective dimensions of interoception. Understanding these changes is vital as the global population ages, addressing age-related health issues and sustaining psychological wellbeing. This systematic review synthesised findings from 22 studies on age-related interoceptive changes and their impact on psychophysiological processes. Results showed age-related declines (48.4 %), no age differences (32.3 %), an age-related increase (16.13 %), and an inverted U-shaped curvilinear relationship (3.23 %) in interoceptive sensitivity across age groups and interoceptive dimensions. Three patterns emerged regarding psychophysiological processes in older adults: altered mind-body connections with age were associated with reduced high-arousal and increased positive emotional experiences, cognitive protective effects, and improved body representation that correlated with better interoceptive sensitivity. These patterns indicate the complex relationships between interoceptive ageing and psychophysiological processes, showing both, aspects of decline and compensatory mechanisms. We propose future research avenues to elucidate the functional significance of different interoceptive dimensions across the lifespan for optimised psychological wellbeing and health behaviours in older adults.

Age-dependent changes in adipose tissue are thought to play a role in development of insulin resistance. A major age-dependent change in adipose tissue is the downregulation of key proteins involved in carbohydrate metabolism. In the current study, we investigate the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) a key governor of the rate of glycolysis in adipocytes via the synthesis of fructose-2,6-bisphosphate that was significantly downregulated in aged mice. We employed an adipocyte-specific PFKFB3 mouse line to investigate the role of PFKFB3 on adipocyte function. In both aged mice and PFKFB3-knockout mice, we observed an increase in O-glcNAcylated proteins consistent with a shift in glucose metabolism toward the hexosamine biosynthetic pathway. Under chow-fed conditions, PFKFB3 knockout resulted in significantly smaller adipocyte area, but no difference in total fat mass. While glucose tolerance was unchanged under chow conditions, when mice were challenged with a 4 weeks high-fat feeding, PFKFB3 deletion led to a greater decrease in glucose tolerance as well as a significant increase in macrophage infiltration. These results indicate that perturbation of the glycolytic pathway in adipose tissue has multiple effects of adipocyte biology and may play a significant role in metabolic changes associated with aging. Results of this student support the notion that changes in glucose metabolism in adipose tissue impact whole-body metabolism.

Millions of people worldwide die from malignant tumors every year, and the current clinical treatment is still based on radiotherapy and chemotherapy. Immunotherapy-adjuvant chemotherapy is widely applied, yet resistance to various factors persists in the management of advanced malignancies. Recently researchers have gradually discovered that the integrity of primary cilia is closely related to many diseases. The phenotypic changes in primary cilia are found in some cases of progeria, tumorigenesis, and drug resistance. Primary cilia seem to mediate signaling during these diseases. Hedgehog inhibitors have emerged in recent years to treat tumors by controlling signaling proteins on primary cilia. There is evidence for the use of anti-tumor drugs to treat senescence-related disease. Considering the close relationship between aging and obesity, as well as the obesity is the phenotype of many ciliopathies. Therefore, we speculate that some anti-tumor or anti-aging drugs can treat ciliopathies. Additionally, there is evidence suggesting that anti-aging drugs for tumor treatment, in which the process may be mediated by cilia. This review elucidates for the first time that cilia may be involved in the regulation of senescence, metabolic, tumorigenesis, and tumor resistance and hypothesizes that cilia can be regulated to treat these diseases in the future.

Fibroblast growth factor 21 (FGF21) is a key regulator of metabolism and cardiovascular health. However, its upregulation in aging and age-related disorders suggests the presence of FGF21 resistance. This study aimed to elucidate the mechanisms underlying senescence-associated FGF21 resistance in human umbilical vein endothelial cells (HUVECs) and to explore potential therapeutic interventions. Transcriptomic analysis revealed a significant reduction in the number of FGF21-regulated genes in senescent HUVECs compared to young cells, indicating the onset of FGF21 resistance. In young HUVECs, FGF21 inhibited inflammatory cytokines and upregulated mitochondrial ribosomal protein genes. Conversely, senescent HUVECs showed a downregulation of β-klotho, an essential co-receptor for FGF21, at the cell membrane, concomitant with an upregulation of ADAM10, a protease involved in β-klotho degradation. These changes were also observed in aged mouse aortas. ADAM10 was shown to bind directly to β-klotho and promote its degradation, contributing to FGF21 resistance. Inhibition of ADAM10 or overexpression of β-klotho restored FGF21 responsiveness in senescent HUVECs. Moreover, pharmacologically high concentrations of FGF21 were effective in overcoming resistance and restoring its regulatory effects on senescent cells. These findings suggest that ADAM10-mediated degradation of β-klotho is a central mechanism in the development of FGF21 resistance, and that targeting the ADAM10/β-klotho axis could represent a novel therapeutic approach to restore FGF21 sensitivity. Pharmacological administration of FGF21 may hold promise in treating vascular aging and its associated cardiovascular pathologies.

Carotenoids are naturally occurring pigments found in plants and certain microorganisms. Some carotenoids act as precursors to vitamin A, which is essential for various health aspects, including vision, immune function, and skin health. Carotenoids, including α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein and zeaxanthin, are known to reduce the risk of age-related diseases and promote healthy aging. This study examines the relationship between dietary carotenoid levels and biological age. This study utilized data from the National Health and Nutrition Examination Survey (NHANES) from 2009 to 2018, and 19,280 participants were included. The Phenotypic Age (PhenoAge) was used to measure biological age, and the Klemera-Doubal Method (KDM) was employed in sensitivity analyses. Biological age acceleration was determined by calculating the residuals of PhenoAge or KDM after regressing them against chronological age. Weighted multivariate linear and logistic regressions were conducted to examine the relationship between carotenoids and biological age acceleration. Additionally, restricted cubic spline regression, subgroup analysis, interaction analysis, and sensitivity analyses were employed for further examination. Both linear regression and logistic regression analyses indicated that participants with higher carotenoid intake exhibited lower rates of phenotypic age acceleration, with α-carotene, β-carotene, β-cryptoxanthin, lutein and zeaxanthin, and lycopene all demonstrating protective effects. Restricted cubic spline regression indicates non-linear associations between carotenoid levels and phenotypic age acceleration. Subgroup analyses revealed that younger participants, females, and individuals with hypertension or diabetes benefited more from higher carotenoid intake. Sensitivity analyses further confirmed the robustness of inverse relationship. The WQS analysis identifies β-carotene and β-cryptoxanthin as the most influential compounds. Higher dietary intake of carotenoids is associated with reduced biological age acceleration, underscoring their protective role against aging. Further longitudinal studies are needed to establish causal relationships and explore the underlying mechanisms of carotenoid benefits on aging.

Glutathione (GSH) is a crucial redox scavenger, essential for maintaining cellular redox balance. This study explores the long-term effects of chronic GSH deficiency on lifespan, motor function, cognitive performance, redox status and inflammation. GCLM

The choroid plexus (ChP) is critical to the glymphatic system of the human brain through its primary function as the source of cerebrospinal fluid (CSF) production, which plays an important role in brain waste clearance. Developing noninvasive imaging techniques to assess ChP is crucial for studying its function and age-related neurofluid dynamics. In this study, we developed a relaxation-selective intravoxel incoherent motion (IVIM) technique to assess tissue and fluid compartments in the ChP of 83 middle-aged to elderly participants (age: 61.5 ± 17.1 years) and 15 young controls (age: 30.7 ± 2.9 years). Using a 3-T MRI scanner, we implemented T1- and T2-selective IVIM approaches, including Fluid-Attenuated Inversion Recovery IVIM (FLAIR-IVIM), LongTE-IVIM, and Vascular Space Occupancy-LongTE-IVIM (VASO-LongTE-IVIM), to measure diffusivity and volume fractions of fluid compartments in ChP. Our results showed that FLAIR-IVIM identified an additional interstitial fluid (ISF) compartment with free-water-like diffusivity in ChP. We then evaluated the aging effects on microvascular perfusion and ISF in ChP. Compared to younger adults, older adults exhibited increased ChP volume, reduced perfusion, decreased ISF volume fraction, and lower tissue diffusivity. Relaxation-selective IVIM may offer enhanced specificity for characterizing age-related changes in ChP structure and fluid dynamics.

Dietary restriction (DR) has long been recognized as a powerful intervention for extending lifespan and improving metabolic health across species. In laboratory animals, DR-typically a 30%-40% reduction in caloric intake-delays aging and enhances mitochondrial function, oxidative defense, and anti-inflammatory pathways. In humans, findings from the CALERIE™ trial confirm DR's potential benefits, with a 25% caloric reduction over 2 years resulting in reduced visceral fat, improved cardiometabolic health, and favorable gene expression changes linked to proteostasis, DNA repair, and inflammation. However, recent research in genetically diverse mouse populations reveals that the impact of DR on lifespan is substantially modulated by genetic background, underscoring the importance of individual variability. Additionally, emerging evidence challenges previous assumptions that lower body temperature universally benefits lifespan extension, with data indicating complex relationships between thermoregulation, sex, and longevity. These findings underscore the need for nuanced approaches to DR in both research and potential therapeutic applications, with considerations for genetic and sex-specific factors to maximize healthspan and lifespan outcomes.

Oral antibiotic use is both widespread and frequent in older adults and has been linked to dysbiosis of the gut microbiota, enteric infection, and chronic diseases. Diet and nutrients, particularly prebiotics, may modify the susceptibility of the gut microbiome to antibiotic-induced dysbiosis. We fed 12-month-old mice a high glycemic (HG) or low glycemic (LG) diet with or without antibiotics (ampicillin and neomycin) for an additional 11 months. The glycemic index was modulated by the ratio of rapidly digested amylopectin starch to slowly digested amylose, a type-2-resistant starch. We observed a significant decrease in survival of mice fed a HG diet containing antibiotics (HGAbx) relative to those fed a LG diet containing antibiotics (LGAbx). HGAbx mice died with an enlarged and hemorrhagic cecum, which is associated with colonic hyperplasia and goblet cell depletion. Gut microbiome analysis revealed a pronounced expansion of Proteobacteria and a near-complete loss of Bacteroidota and Firmicutes commensal bacteria in HGAbx, whereas the LGAbx group maintained a population of Bacteroides and more closely resembled the LG microbiome. The predicted functional capacity for bile salt hydrolase activity was lost in HGAbx mice but retained in LGAbx mice. An LG diet containing amylose may therefore be a potential therapeutic to prevent antibiotic-induced dysbiosis and morbidity.

Sarcopenia and AD are both classic degenerative diseases, and there is growing epidemiological evidence of their comorbidity with aging; however, the mechanisms underlying the biology of their commonality have not yet been thoroughly investigated. APP is a membrane protein that is expressed in tissues and is expressed not only in the nervous system but also in the NMJ and muscle. Deposition of its proteolytic cleavage product, Aβ, has been described as a central component of AD pathogenesis. Recent studies have shown that excessive accumulation and aberrant expression of APP in muscle lead to pathological muscle lesions, but the pathogenic mechanism by which APP and its proteolytic cleavage products act in skeletal muscle is less well understood. By summarizing and analyzing the literature concerning the role, pathogenicity and pathological mechanisms of APP and its cleavage products in the nervous system and muscles, we aimed to explore the intrinsic pathological mechanisms of myocerebral comorbidities and to provide new perspectives and theoretical foundations for the prevention and treatment of AD and sarcopenia comorbidities.

The study of split-belt treadmill adaptation provides insight into the priorities determining how we adapt to novel conditions during walking. During split-belt adaptation, young adults reduce their metabolic cost and positive leg work in part by learning to take longer steps on the fast belt, thus adopting a positive step length asymmetry. However, aging may lead to a shift in the work performed by distal versus proximal joints, so it is unknown if older adults can similarly reduce the work performed by the legs during split-belt walking. Therefore, we quantified the relationship between joint work rate and step length asymmetry when fourteen older adults walked on a split-belt treadmill. We hypothesized that total positive joint work would decrease at more positive step length asymmetries and that more positive asymmetries would be associated with a reduction in positive ankle joint work on the fast belt. We found that step length asymmetry was negatively correlated with total positive work (p = 0.01) and that changes in positive joint work were primarily driven by positive ankle work on the fast belt (p = 0.01). Since ankle musculature is hypothesized to be a major contributor to metabolic cost during gait, reductions in ankle joint work likely contribute to the reduction in metabolic cost observed in other studies of split-belt walking. These results demonstrate that healthy aging still allows individuals to take advantage of the work performed by the treadmill to reduce the mechanical energy cost of walking.

Photoaged skin features an appearance of premature aging induced by external factors, mainly ultraviolet (UV) irradiation. Visible aging signs and increased susceptibility to skin-related diseases triggered by UV irradiation have raised widespread concern. As a critical component of human skin, the extracellular matrix (ECM) provides essential structural, mechanical, and functional support to the tissue. Consequently, UV-induced ECM deterioration is a major contributor to photoaging. This review begins by analyzing the structural and functional changes between healthy and photoaged skin in prominent ECM components, including collagens, glycosaminoglycans (GAGs), proteoglycans, basement membrane proteins, and elastic fibers. Furthermore, we explore the key mechanisms driving ECM deterioration in response to UV irradiation, focusing on mitogen-activated protein kinase/matrix metalloproteinase and transforming growth factor-β/Smad signaling pathways, as well as the synthesis and degradation of GAGs. A comprehensive understanding of these changes and underlying mechanisms is crucial for elucidating the biological influence of UV on the ECM, ultimately providing more reliable evidence for the prevention and treatment of skin photoaging.

Various metabolic abnormalities including obesity, insulin resistance, hypertension, dyslipidemia, hyperthyroidism, and low vitamin D levels have been linked to both osteopenia and sarcopenia. Osteo-sarcopenia is also commonly observed due to aging that notably include postmenopausal women. GLP-1, a labile incretin secreted from the intestinal L-cells stimulates insulin secretion and sensitivity, making it an effective anti-diabetic medication. GLP-1 binds to its receptor, the GLP-1 receptor, a G-protein-coupled receptor, and leads to the stimulation of adenylate cyclase, increasing the levels of cyclic AMP (cAMP). Elevated cAMP then activates protein kinase A and other downstream signaling pathways. These signaling cascades result in various cellular responses, such as enhanced insulin secretion from pancreatic beta cells, improved insulin sensitivity, and modulation of appetite and gastric emptying. Additionally, GLP-1 signaling can promote cell growth and survival, contributing to its effects on muscle and bone health. Its role as an anti-diabetic medication has been enhanced through various modifications to extend its half-life, thereby improving its effectiveness and druggability. GLP-1 analogs, initially developed for diabetes management, have also been harnessed for obesity treatment due to the effect of GLP-1 to induce satiety and slow gastric emptying. Beyond their well-known anti-diabetic and anti-obesity effects, GLP-1 agonists can enhance muscle mass and bone density, making them valuable in addressing conditions like sarcopenia and osteoporosis. This review focuses on the effects of GLP-1 analogs on musculoskeletal health, by critically assessing the underlying signaling mechanisms in order to understand their translational potential for the treatment of osteo-sarcopenia.

Autophagy is a naturally conserved mechanism crucial for degrading and recycling damaged organelles and proteins to support cell survival. This process slows biological ageing and age-related disease in preclinical models. However, there has been little translation of autophagy to the clinic, and we have identified a lack of measurement tools for physiological human autophagy as a barrier. To address this, we have previously developed a direct measurement tool for autophagy in pooled human peripheral blood mononuclear cells (PBMCs) in the context of whole blood. In order to better understand how autophagy behaves and changes in humans, we measured human autophagic flux using flow cytometry in 19 cell sub-populations in whole blood to retain physiological flux. Autophagic flux was different between different cell types, being highest in B lymphocytes and lowest in T lymphocytes and monocytes. Autophagic flux also varied with sex, being higher in monocytes in females compared with males. In keeping with previous observations in humans, autophagy also increased with ageing at sub-population levels. Importantly, we found that only monocytes - specifically, non-classical monocytes - displayed increased autophagic flux following amino acid withdrawal, underscoring the importance of population selection for measurement of autophagic flux during nutrient restriction studies in humans. Collectively, these data show PBMC population level analysis improves sensitivity of human autophagic flux measurement.

Parkinson's disease (PD) is an age-related neurodegenerative disorder. The pathological feature of PD is abnormal α-synuclein (α-syn) formation and transmission. Recent evidence demonstrates that α-syn preformed fibrils (α-syn PFFs) can be detected in the serum of patients with PD. The peripheral blood α-syn PFF can cross the blood-brain barrier (BBB) and aggravate neuronal damage, but the mechanism remains to be elucidated. We constructed the PD mouse models of different severity: the mild pathology (A53T ONLY) and the severe pathology (A53T + Brain FIB); this was followed by α-syn PFFs intravenous injection. Then, we used endothelium-specific Lag3 knockout mice (Lag3-ECs-CKO) to decrease the blood α-syn PFFs spreading. We observed that intravenous transmission of α-syn PFFs significantly aggravated motor deficits, dopaminergic neuron loss, neuroinflammation, and pathologic α-syn deposition in A53T ONLY, but not in A53T + Brain FIB. Blocking endothelial Lag3 endocytosis by Lag3-ECs-CKO decreased the blood α-syn PFFs spreading and improved the symptoms and pathogenesis of PD mice. Our findings reveal the role of peripheral blood α-syn PFFs transmission in the mild pathology or early-stage PD and the mechanism of endothelial Lag3 endocytosis in the pathology of α-syn transmission. Targeting endothelial Lag3 to prevent α-syn from spreading from the blood to the brain may be a disease-modifying therapy in early-stage PD.

The rapid aging of the global population necessitates addressing age-related conditions through innovative strategies. Nutritional supplements have emerged as potential interventions for preventing or slowing age-related changes, with betaine being a promising candidate. This systematic review aims to provide a comprehensive analysis of current literature on the impact of betaine on the aging process. Specifically, we summarize the mechanisms through which betaine is proposed to affect aging, we integrate existing findings, we identify gaps in the literature, and we discuss practical implications for promoting healthy aging. Evidence suggests that betaine may counteract aging-related changes in methylation potential by increasing concentration of S-adenosylmethionine, a key methyl donor. Additionally, betaine reduces homocysteine concentrations, potentially mitigating vascular, neurodegenerative, and oxidative damage. Betaine has also been shown to enhance mitochondrial function, to reduce oxidative stress, and to attenuate inflammation. It may serve as a preventive agent against sarcopenia by promoting anabolic signaling pathways and improving muscle strength in younger adults. Betaine may also exert an effect on bone remodeling and adipose tissue metabolism, with animal studies indicating enhanced fat oxidation and reduced fat synthesis. Although certain limited studies have suggested betaine's potential in mitigating age-related neurodegenerative diseases, the currently available evidence does not establish a clear link between dietary betaine intake and the incidence of cardiovascular diseases or type-2 diabetes. In conclusion, emerging evidence highlights the potential of betaine in attenuating age-related changes. However, further research is required to elucidate the efficacy and safety of betaine supplementation in older populations.

Aging naturally involves a decline in biological functions, often triggering a disequilibrium of physiological processes. A common outcome is the altered response exerted by the immune system to counteract infections, known as immunosenescence, which has been recognized as a primary cause, among others, of the so-called long-COVID syndrome. Moreover, the uncontrolled immunoreaction leads to a state of subacute, chronic inflammatory state known as inflammaging, responsible in turn for the chronicization of concomitant pathologies in a self-sustaining process. Anti-inflammatory and immunosuppressant drugs are the current choice for the therapy of inflammaging in post-COVID complications, with contrasting results. The increasing knowledge of the biochemical pathways of inflammaging led to disclose new small molecules-based therapies directed toward different biological targets involved in inflammation, immunological response, and oxidative stress. Herein, paying particular attention to recent clinical data and preclinical literature, we focus on the role of endocannabinoid system in inflammaging, and the promising therapeutic option represented by the CB2R agonists, the role of novel ligands of the formyl peptide receptor 2 and ultimately the potential of newly discovered monoamine oxidase (MAO) inhibitors with neuroprotective activity in the treatment of immunosenescence.

Progenitor cell dedifferentiation is important for stem cell maintenance during tissue repair and age-related stem cell decline. Here, we use the

Age-related cerebromicrovascular endothelial dysfunction underlies the initiation and progression of cognitive dysfunction and dementia, thus increasing the susceptibility of older adults to such conditions. Normal brain function requires dynamic adjustment of cerebral blood flow to meet the energetic demands of active neurons, which is achieved the homeostatic mechanism neurovascular coupling (NVC). In this context, therapeutical strategies aimed at rescuing or preserving NVC responses can delay the incidence or mitigate the severity of age-related cognitive dysfunction, and time-restricted eating (TRE) is a potential candidate for such a strategy. Studies have reported that TRE can improve cardiometabolic risk factors in older adults. However, the effect of TRE on cerebrovascular endothelial function remains unexplored. Thus, this protocol outlines the study procedures to test our hypothesis that a 6-month TRE regimen of 10-h eating window will improve NVC responses and endothelial function in community-dwelling older adults. This is a single-arm, open-label interventional trial. We aim to recruit 32 adults aged 55-80 years. Participants are instructed to maintain a TRE regimen of 10 h of free eating followed by 14 h of fasting for 6 months. Before and after fasting, participants are assessed for cognitive performance, peripheral micro- and macrovascular endothelial function, and NVC responses, as well as for several confounding factors, including body composition, dietary, and physical activity data. We expect that 6 months of TRE will improve NVC response and endothelial function in older adults compared with baseline, and that these improvements will be accompanied by improvements in cognitive performance. The study proposed herein will provide critical insight into a new potential therapeutical strategy for targeting age-related cognitive dysfunction. Ultimately, slowing down or alleviating cognitive decline will translate into improved quality of life and longer healthspan for aging adults. This study was prospectively registered at ClinicalTrials.gov (NCT06019195) on August 24, 2023.