Longevity Papers

Diapause has long been proposed to play a significant role in the evolution of eusociality in Hymenoptera. Recent studies have shown that shifts in the diapause stage precede social evolution in wasps and bees; however, the genomic basis remains unknown. Given the overlap in molecular pathways that regulate diapause and lifespan, we hypothesized that the evolutionary loss of developmental diapause may lead to extended lifespan among adults, which is a prerequisite for the evolution of eusociality. To test whether the loss of prepupal diapause is followed by genomic changes associated with lifespan extension, we compared 27 bee genomes with or without prepupal diapause. Our results point to several potential mechanisms for lifespan extension in species lacking prepupal diapause, including the loss of the growth hormone PTTH and its receptor TORSO, along with convergent selection in genes known to regulate lifespan in animals. Specifically, we observed purifying selection of prolongevity genes and relaxed selection of antilongevity genes within the IIS/TOR pathway in species that have lost prepupal diapause. Changes in selection pressures on this pathway may lead to the evolution of new phenotypes, such as lifespan extension and altered responses to nutritional signals that are crucial for social evolution.

Diastolic dysfunction in aging mice is linked to mitochondrial abnormalities, including mitochondrial morphology disorders and decreases in membrane potential. Studies also show that aberrant mitochondrial lipid metabolism impairs mitochondrial function in aging cardiomyocytes. Our lipidomic analysis revealed that phosphatidylethanolamine (PE) levels were significantly decreased in aging myocardial mitochondria. Here, we investigated whether a reduction in PE levels in myocardial mitochondria contributes to mitochondrial injury as well as HFpEF pathogenesis and whether modulation of PE levels could ameliorate aging-induced HFpEF. Echocardiography was used to assess cardiac diastolic function in adult and aging mice treated with lysophosphatidylethanolamine (LPE) or saline. Mitochondrial morphologies from tissue samples were evaluated by transmission electron microscopy (TEM), while mitochondrial membrane potential and reactive oxygen species (ROS) levels were assessed using JC-1, MitoSOX, and DCFH-DA detection assays. We performed GO enrichment analysis between adult and aging mice and discovered significant enrichment in transcriptional programs associated with mitochondria and lipid metabolism. Also, mitochondrial PE levels were significantly decreased in aging cardiomyocytes. Treatment with LPE (200 μg/kg) significantly enhanced PE content in aging mice and improved the structure of mitochondria in cardiac cells. Also, LPE treatment protects against aging-induced deterioration of mitochondrial injury, as evidenced by increased mitochondrial membrane potential and decreased mitochondrial ROS. Furthermore, treatment with LPE alleviated severe diastolic dysfunction in aging mice. Taken together, our results suggest that LPE treatment enhances PE levels in mitochondria and ameliorates aging-induced diastolic dysfunction in mice through a mechanism involving improved mitochondrial structure and function.

Natural ovarian aging is one of the major causes for declining fertility in female animals, which has become an insurmountable issue in human reproduction clinics and assisted reproductive technology (ART) procedures. Nevertheless, the molecular basis of oocyte aging remains poorly understood, and feasible improvement strategies are unavailable. In the present study in vivo supplementation of pyrroloquinoline-quinone (PQQ) effectively elevated the fecundity of reproductively aged mice by balancing hormonal secretion, harmonizing the estrus cycle, and eliminating ovarian fibrosis. Moreover, oocyte quality also increased in aged mice after PQQ administration from various aspects, including nuclear and cytoplasmic maturation competency, fertilization capacity and pre-implantation embryonic development potential. Transcriptomic analysis identified target pathways that might mediate PQQ's effects in aged oocytes. Specifically, it was demonstrated that PQQ supplementation restored the mitochondrial dynamics and lysosomal function to remove excessive reactive oxygen species (ROS) and suppress apoptosis in aged oocytes. Jointly, these findings demonstrate PQQ administration is an efficacious method to restore the compromised ovary function and damaged oocyte quality in reproductively aged mice, which might be a potential clinical therapy for women of advanced maternal age with infertility.

Senescence in renal cells has attracted wide attention as the critical factor promoting renal fibrosis and chronic kidney disease. Establishing a reliable cellular model is essential to study mechanisms underlying renal cell senescence. Herein, we compared various inducers to define the most suitable senescence inducer for HK-2 proximal tubular cells. These inducers included hydrogen peroxide (H

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare genodermatosis characterized clinically by extensive inflammation, cutaneous destruction, and fibrosis that demonstrates properties similar to rapid skin aging. As tissue ages, it accumulates cellular damage and exhaustion leading to a state of senescence. Cellular senescence is an aging or disease-related phenomenon of stable exit from the cell cycle that leads to an increased inflammatory phenotype. RDEB and other EB subsets of patients need an adjunct to or alternate therapy that addresses the issues of inflammation, pain, and pruritus. Fisetin is a safe, naturally occurring compound proven to be effective at sensitizing senescent cells to cell death and ameliorating senescence-associated inflammation. In this paper, we demonstrate fisetins ability to increase survival and reduce senescent cell burden in a hypomorphic mouse model of RDEB.

Zuogui Pills (ZGP) is a classic traditional Chinese herbal formula originating from the Ming Dynasty. It has been widely used in the treatment of kidney deficiency-related diseases, including ovarian aging.

Senescence is a crucial hallmark of ageing and a significant contributor to the pathology of age-related disorders. As committee members of the young International Cell Senescence Association (yICSA), we aim to synthesise recent advancements in the identification, characterisation, and therapeutic targeting of senescence for clinical translation. We explore novel molecular techniques that have enhanced our understanding of senescent cell heterogeneity and their roles in tissue regeneration and pathology. Additionally, we delve into in vivo models of senescence, both non-mammalian and mammalian, to highlight tools available for advancing the contextual understanding of in vivo senescence. Furthermore, we discuss innovative diagnostic tools and senotherapeutic approaches, emphasising their potential for clinical application. Future directions of senescence research are explored, underscoring the need for precise, context-specific senescence classification and the integration of advanced technologies such as machine learning, long-read sequencing, and multifunctional senoprobes and senolytics. The dual role of senescence in promoting tissue homoeostasis and contributing to chronic diseases highlights the complexity of targeting these cells for improved clinical outcomes.

In aging, skeletal muscle regeneration declines due to alterations in both myogenic and non-myogenic cells and their interactions. This regenerative dysfunction is not understood comprehensively or with high spatiotemporal resolution. We collected an integrated atlas of 273,923 single-cell transcriptomes and high-resolution spatial transcriptomic maps from muscles of young, old and geriatric mice (~5, 20 and 26 months old) at multiple time points following myotoxin injury. We identified eight immune cell types that displayed accelerated or delayed dynamics by age. We observed muscle stem cell states and trajectories specific to old and geriatric muscles and evaluated their association with senescence by scoring experimentally derived and curated gene signatures in both single-cell and spatial transcriptomic data. This revealed an elevation of senescent-like muscle stem cell subsets within injury zones uniquely in aged muscles. This Resource provides a holistic portrait of the altered cellular states underlying muscle regenerative decline across mouse lifespan.

Dietary restriction (DR) extends lifespan in diverse species, from yeast to mammals. However, its underlying mechanisms are not well understood. In this study, through using the tractable model Caenorhabditis elegans, we show a role for the DEAD-box RNA helicase, DDX-23 (homologous to mammal DDX23) as a regulator of healthspan in response to dietary restriction. Meanwhile, DDX-23 is also required for heat and oxidative stress response in C. elegans. Intriguingly, DDX-23 functions in the germline during adult to regulate dietary restriction-induced longevity. We then find that PHA-4/FOXA acts downstream of DDX-23 to mediate the transcriptional response of SOD-related genes and consequently the lifespan of the animals. Furthermore, we find that the DEAD-box RNA helicase, DDX-23 negatively regulates the healthy lifespan extension by up-regulating the expression of miR-231, and resulting in suppressing the activation of FOXO transcription factor DAF-16. Our work shows a newly discovered for DEAD-box RNA helicase DDX-23 in the regulation of dietary restriction-mediated longevity in C. elegans and reveals the downstream transcriptional regulation mechanisms.

Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder to which genetic mutations and risk factors contribute. Evidence is increasing that environmental and lifestyle-related factors, such as exercise, nutrition, education, and exposure to (early-life) stress modify the onset, incidence, and progression of AD. Here, we discuss recent preclinical findings on putative substrates that can explain or contribute to the effects of stress early in life on the risk of developing AD. We focus in particular on stress hormones, neural networks, synapses, mitochondria, nutrient and lipid metabolism, adult neurogenesis, engram cell ensembles, and neuroinflammation. We discuss the idea that stress exposure early in life can alter these processes, either combined or in isolation, thereby reducing the capacity of the brain to resist deleterious consequences of, for example, amyloid-β accumulation, thereby accelerating cognitive decline and progression of Alzheimer-related changes in model systems of the disease. A better understanding of whether experiences early in life also modify trajectories of cognitive decline and pathology in AD and how the substrates discussed translate to humans may help develop novel preventive and/or therapeutic strategies to mitigate the consequences of stressors early in life and increase resilience to developing dementia.

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In solid cancers, the antitumor efficacy of HMAs involves the derepression of TEs, mimicking a state of viral infection. In this study, we demonstrate a significant disorganization of heterochromatin in CMML HSCs and progenitors (HSPCs) characterized by an increase in the repressive mark H3K9me2, mainly at the level of TEs, and a repression of immune and age-associated transcripts. Combining HMAs with G9A/GLP H3K9me2 methyltransferase inhibitors reactivates these pathways, selectively targeting mutated cells while preserving wild-type HSCs, thus offering new therapeutic avenues for this severe myeloid malignancy.

With increasing age, the optimal functioning of the choroid is essential for efficient removal of waste products formed from photoreceptor renewal. A decline in regulatory elements of the immune system, termed immunosenescence, and the failure of para-inflammation to restore tissue homeostasis can result in the progression of healthy aging to sight-threatening inflammation of the choroid. Macrophages are uniquely situated between the innate and adaptive immune systems, with a high capacity for phagocytosis, recognition of complement components, as well as antigen presentation. In this review, we provide an overview of macrophages and their properties in the healthy choroid and cover the impact of aging, immunosenescence and inflammaging on the function of choroidal macrophages. We will discuss the impact of age on macrophage phenotype and behaviour in the pathophysiology of age-related macular degeneration.

MicroRNAs (miRNAs) play crucial roles in regulating inflammation and cellular senescence. Among them, miR-146a has emerged as a key modulator of inflammation, but its role in obesity-induced senescence remains unexplored. This study investigates the involvement of miR-146a in high-fat diet (HFD)-induced hypothalamic senescence and in protective effects of elocalcitol (Elo), a non-hypercalcemic, fluorinated vitamin D analog on HFD-induced senescence.

Nuclear pore complexes (NPCs) are embedded in the nuclear envelope and facilitate the exchange of macromolecules between the nucleus and cytoplasm in eukaryotic cells. The dysfunction of the NPC and nuclear transport plays a significant role in aging and the pathogenesis of various neurodegenerative diseases. Common features among these neurodegenerative diseases, including Parkinson's disease (PD), encompass mitochondrial dysfunction, oxidative stress and the accumulation of insoluble protein aggregates in specific brain regions. The susceptibility of dopaminergic neurons to mitochondrial stress underscores the pivotal role of mitochondria in PD progression. Disruptions in mitochondrial-nuclear communication are exacerbated by aging and α-synuclein-induced oxidative stress in PD. The precise mechanisms underlying mitochondrial impairment-induced neurodegeneration in PD are still unclear. Evidence suggests that perturbations in dopaminergic neuronal nuclei are linked to PD-related neurodegeneration. These perturbations involve structural damage to the nuclear envelope and mislocalization of pivotal transcription factors, potentially driven by oxidative stress or α-synuclein pathology. The presence of protein aggregates, pathogenic mutations, and ongoing oxidative stress can exacerbate the dysfunction of NPCs, yet this mechanism remains understudied in the context of oxidative stress-induced PD. This review summarizes the link between mitochondrial dysfunction and dopaminergic neurodegeneration and outlines the current evidence for nuclear envelope and nuclear transport abnormalities in PD, particularly in oxidative stress. We highlight the potential role of nuclear pore and nucleocytoplasmic transport dysfunction in PD and stress the importance of systematically investigating NPC components in PD.

With aging, the risk of fractures and compromised healing increases. Angiogenesis plays a significant role in bone healing and is impaired with aging. We have previously shown the impact of megakaryocytes (MKs) in regulating bone healing. Notably, MKs produce factors known to promote angiogenesis. We examined the effects of conditioned media (CM) generated from MKs derived from young (3-4-month-old) and aged (22-24-month-old), male and female C57BL/6J mice on bone marrow endothelial cell (BMEC) growth and function. Female MK CM, regardless of age, caused a >65% increase in BMEC proliferation and improved vessel formation by >115%. Likewise, young male MK CM increased vessel formation by 160%. Although aged male MK CM resulted in >150% increases in the formation of vascular nodes and meshes, 62% fewer vessels formed compared to young male MK CM treatment. Aged female MK CM improved migration by over 2500%. However, aged female and male MK CM caused less wound closure. MK CM treatments also significantly altered the expression of several genes including PDGFRβ, CXCR4, and CD36 relative to controls and between ages. Further testing of mechanisms responsible for age-associated differences may allow for novel strategies to improve MK-mediated angiogenesis and bone healing, particularly within the aging population.

Many aging clocks have recently been developed to predict health outcomes and deconvolve heterogeneity in aging. However, existing clocks are limited by technical constraints, such as low spatial resolution, long processing time, sample destruction, and a bias towards specific aging phenotypes. Therefore, here we present a non-destructive, label-free and subcellular resolution approach for quantifying aging through optically resolving age-dependent changes to the biophysical properties of NAD(P)H in mitochondria through fluorescence lifetime imaging (FLIM) of endogenous NAD(P)H fluorescence. We uncover age-dependent changes to mitochondrial NAD(P)H across tissues in C. elegans that are associated with a decline in physiological function and construct non-destructive, label-free and cellular resolution models for prediction of age, which we refer to as "mito-NAD(P)H age clocks." Mito-NAD(P)H age clocks can resolve heterogeneity in the rate of aging across individuals and predict remaining lifespan. Moreover, we spatiotemporally resolve age-dependent changes to mitochondria across and within tissues, revealing multiple modes of asynchrony in aging and show that longevity is associated with a ubiquitous attenuation of these changes. Our data present a high-resolution view of mitochondrial NAD(P)H across aging, providing insights that broaden our understanding of how mitochondria change during aging and approaches which expand the toolkit to quantify aging.

The ability to accurately quantify biological age could help monitor and control healthy aging. Epigenetic clocks have emerged as promising tools for estimating biological age, yet they have been developed from heterogeneous bulk tissues, and are thus composites of two aging processes, one reflecting the change of cell-type composition with age and another reflecting the aging of individual cell-types. There is thus a need to dissect and quantify these two components of epigenetic clocks, and to develop epigenetic clocks that can yield biological age estimates at cell-type resolution. Here we demonstrate that in blood and brain, approximately 39% and 12% of an epigenetic clocks accuracy is driven by underlying shifts in lymphocyte and neuronal subsets, respectively. Using brain and liver tissue as prototypes, we build and validate neuron and hepatocyte specific DNA methylation clocks, and demonstrate that these cell-type specific clocks yield improved estimates of chronological age in the corresponding cell and tissue-types. We find that neuron and glia specific clocks display biological age acceleration in Alzheimers Disease with the effect being strongest for glia in the temporal lobe. Moreover, CpGs from these clocks display a small but significant overlap with the causal DamAge-clock, mapping to key genes implicated in neurodegeneration. The hepatocyte clock is found accelerated in liver under various pathological conditions. In contrast, non-cell-type specific clocks do not display biological age-acceleration, or only do so marginally. In summary, this work highlights the importance of dissecting epigenetic clocks and quantifying biological age at cell-type resolution.

At over 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth, reaching over 80,000 kg

Cellular growth and organismal development are remarkably complex processes that require the nutrient-responsive kinase mechanistic target of rapamycin complex 1 (mTORC1). Anticipating that important mTORC1 functions remained to be identified, we employed genetic and bioinformatic screening in C. elegans to uncover mechanisms of mTORC1 action. Here, we show that during larval growth, nutrients induce an extensive reprogramming of gene expression and alternative mRNA splicing by acting through mTORC1. mTORC1 regulates mRNA splicing and the production of protein-coding mRNA isoforms largely independently of its target p70 S6 kinase (S6K) by increasing the activity of the serine/arginine-rich (SR) protein RSP-6 (SRSF3/7) and other splicing factors. mTORC1-mediated mRNA splicing regulation is critical for growth; mediates nutrient control of mechanisms that include energy, nucleotide, amino acid, and other metabolic pathways; and may be conserved in humans. Although mTORC1 inhibition delays aging, mTORC1-induced mRNA splicing promotes longevity, suggesting that when mTORC1 is inhibited, enhancement of this splicing might provide additional anti-aging benefits.

Cellular senescence is a prominent accomplice of aging. The expression of gene p16ink4a has been established as a biomarker of cellular senescence in humans and animal models. However, it has not been extensively studied in clinical settings in the context of natural aging and the development of age-related diseases. Here, we report the results of a natural aging study that provided an assessment of cellular senescence and a battery of measures of clinical status, quality of life (QOL), and physical performance in 250 community-dwelling participants across age continuum. This report focused on analyzing predictive relationships between cellular senescence and different clinical assessments. Our results suggest that clinical labs and QOL assessments produce distinct groupings of participants, yet both have strong predictive associations with p16ink4a. Furthermore, the highest accuracy of p16ink4a prediction requires subsets of measurements representing diverse aspects of each assessment, pointing towards a system-level role of p16ink4a. Our analysis also led to an assessment-based composite indexes that strongly correlate with p16ink4a expression. Our study underscores p16ink4as association with both earlier signs of physiological decline (based on clinical labs) and the later onset of health issues limiting the quality of life.

Pentosidine (PEN), an advanced glycation end product (AGE), is associated with various age-related diseases and schizophrenia. This study aimed to identify the natural compounds that inhibit PEN synthesis from glucuronic acid using an in vitro system. A screening of 93 natural compounds revealed 47 that reduced PEN synthesis by > 50 %, with eight inhibiting it by > 80 %. The top five inhibitors were anthocyanins, with petunidin chloride showing the strongest effect, inhibiting PEN synthesis by approximately 90 %. These compounds directly inhibited PEN synthesis without degrading or capturing the synthesized PEN. Petunidin chloride had an IC

The mucociliary clearance (MC) system is a vital host defense against infection in the lung. MC system function is dependent on ciliary density, structure, and function and airway surface liquid (ASL) composition and hydration. Animal and human studies indicate that MC rate decreases with age which may contribute to the increased rates of pulmonary infection experienced by older people. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene encodes an anion channel on epithelial surfaces that plays a key role in maintaining ASL hydration. Failure or dysfunction of CFTR could result in the dehydration of airway mucus, depressing MC. Here we use two available databases including bulk (GTEx) and single-cell (CELLxGENE) sequencing data from the lung to determine if CFTR expression decreases with age. Bulk expression data and single-cell expression data from goblet, club, and respiratory basal cells all demonstrated patterns of decreasing CFTR expression with age. Ciliated airway cells did not. Secretory cells (including club and goblet cells) and basal cells are the largest source of CFTR expression in the airway. This indicates that changes in CFTR expression and ASL dehydration may contribute to the decreasing MC associated with aging.

In developed nations, women have increasingly deferred childbearing, leading to a rise in demand for infertility treatments and the widespread use of assisted reproductive technologies. However, despite advancements in in vitro fertilization (IVF), live birth rates among women over 40 remain suboptimal. Mitochondrial dysfunction is widely recognized as a key factor in the processes driving the age-related deterioration in both the quantity and quality of oocytes. We aim to summarize current insights into ovarian aging, with a particular focus on pathways that impair mitochondrial function, and explore directions for future research.

Intervertebral disc degeneration (IVDD), a disease associated with ageing, is characterised by a notable increase in senescent nucleus pulposus cells (NPCs) as IVDD progresses. However, the specific mechanisms that regulate the senescence of NPCs remain unknown. In this study, we observed impaired autophagy in IVDD-NPCs, which contributed to the upregulation of NPCs senescence and the senescence-associated secretory phenotype (SASP). The dysregulated SASP disrupted NPCs viability and initiated extracellular matrix degradation. Conversely, the restoration of autophagy reversed the senescence phenotype by inhibiting GATA binding protein 4 (GATA4). Moreover, we made the novel observation that a cross-talk between histone H3 lysine 4 trimethylation (H3K4me3) modification and N6-methyladenosine(m

Kidney is a classic organ undergoing senescence, and chronic inflammation has an important effect in cellular senescence. Mincle has been shown to be vital for maintaining the M1 phenotype of macrophages, but its role in regulating renal aging has yet to be explored. Young (2 months of age) and old (24 months of age) mice were used to analyze the changes of kidney damage during natural aging. Mice were subcutaneously injected with D-galactose (D-gal) to establish a renal aging model, and miR-6948-3p mimic and Mincle siRNA were administered via the tail vein every 3 days. Aged kidney and experimental aging kidney were characterized by decreased renal function and structural damage, and upregulated expression of senescence-related proteins and SPAP components. The ratio of M1 macrophages was increased in the aged kidney, and Mincle accumulated in the aged kidney macrophages. Administration of miR-6948-3p mimic or Mincle siRNA alleviated D-gal-induced renal senescence. LPS was used to induce M1 polarization of bone marrow-derived macrophages, and a coculture system of M1 macrophages and mouse renal tubular epithelial cells (TCMK-1) was established. Mincle was upregulated in LPS-induced M1 macrophages in vitro, and silencing Mincle in M1 macrophages attenuated M1 macrophage-induced TCMK-1 cell senescence. Mechanistically, Mincle was regulated by miR-6948-3p and maintained the M1 phenotype of macrophages through the Syk/NF-κB pathway. In conclusion, Mincle, posttranscriptionally suppressed by miR-6948-3p, modulated renal senescence by maintaining the phenotype of M1 macrophages through the Syk/NF-κB pathway.

Older adults struggle with tasks requiring selective attention amidst distractions. Experimental observations about age-related decline have relied on visual search designs using static displays. However, natural environments often embed dynamic structures that afford proactive anticipation of task-relevant information. We investigate the capacity to benefit from spatiotemporal predictions across the adult lifespan. Participants (N = 300, aged 20-80) searched for multiple targets that faded in and out of displays among distractors. Half of the targets appeared at a fixed time and approximate location, whereas others appeared unpredictably. Overall search performance was reduced with age. Nevertheless, prediction-led behaviour, reflected in a higher detection of predictable targets, remained resistant to aging. Predictions were most pronounced when targets appeared in quick succession. When evaluating response speed, predictions were also significant but reduced with progressing age. While our findings confirm an age-related decline, we identified clear indications for proactive attentional guidance throughout adulthood.

DNA methylation can give rise to robust biomarkers of aging, yet most studies profile it at the bulk tissue level, which masks cell type-specific alterations that may follow distinct aging trajectories. Long-read sequencing technology enables methylation profiling of extended DNA fragments, which allows mapping to their cell type of origin. In this study, we introduce a framework for evaluating cell type-specific aging using long-read sequencing data, without the need for cell sorting. Leveraging cell type-specific methylation patterns, we map long-read fragments to individual cell types and generate cell type-specific methylation profiles, which are used as input to a newly developed probabilistic aging model, LongReadAge, capable of predicting epigenetic age at the cell-type level. We apply LongReadAge to track aging of myeloid cells and lymphocytes from bulk leukocyte data as well as circulating cell-free DNA, demonstrating robust performance in predicting age despite limited shared features across samples. This approach provides a novel method for profiling the dynamics of epigenetic aging at cell-type resolution.

Understanding the genetics of kidney function decline, or trait change in general, is hampered by scarce longitudinal data for GWAS (longGWAS) and uncertainty about how to analyze such data. We use longitudinal UK Biobank data for creatinine-based estimated glomerular filtration rate from 348,275 individuals to search for genetic variants associated with eGFR-decline. This search was performed both among 595 variants previously associated with eGFR in cross-sectional GWAS and genome-wide. We use seven statistical approaches to analyze the UK Biobank data and simulated data, finding that a linear mixed model is a powerful approach with unbiased effect estimates which is viable for longGWAS. The linear mixed model identifies 13 independent genetic variants associated with eGFR-decline, including 6 novel variants, and links them to age-dependent eGFR-genetics. We demonstrate that age-dependent and age-independent eGFR-genetics exhibit a differential pattern regarding clinical progression traits and kidney-specific gene expression regulation. Overall, our results provide insights into kidney aging and linear mixed model-based longGWAS generally.

Single-ingredient dietary supplements have demonstrated some potential to extend lifespan and improve healthspan; however, the efficacy of defined multi-ingredient nutraceuticals remains underexplored. Senolytic interventions have been successful in reducing multi-morbidity, frailty, and cognitive decline in animal models and are seen as promising anti-ageing interventions in mammals. We compared the effects of a 12-ingredient nutraceutical on mice lifespan and healthspan markers with that of a high efficacy senolytic intervention consisting of a low dose of Navitoclax combined with the specific mitochondrial uncoupler BAM15. Both interventions were started at old age (20 months). The supplement was given daily until the end of the experiment (30 months of age), but the senolytic intervention consisted of two short (5 days each) rounds of treatment at 20 and 23 months of age. Despite late onset, both interventions increased median lifespan similarly by around 20% over controls. The senolytic intervention significantly reduced frailty progression and improved cognitive function after the second round of treatment, but without subsequent treatment, these effects appeared to wane at later ages. The multi-ingredient supplement tended to reduce frailty progression steadily with time, albeit not significant, and maintained cognitive function. Mechanistically, in vitro, there was no evidence of senolytic activity of the multi-ingredient nutraceutical as a whole nor of its individual ingredients. Continuous multi-ingredient dietary supplementation shows promise in achieving comparable anti-ageing efficacy as a senolytic intervention.

Although age-related deterioration of the cardiac function is a well-studied area of research, the interventions and their molecular pathways have not yet been fully identified. Since physical activity is a powerful preventive measure against cardiac aging, our study compared the effects of long-term voluntary and forced physical activity with a sedentary group, utilizing an aging rat model characterized by mitochondrial dysfunction that contributes to age-related cardiovascular diseases. Four experimental groups were created: (I) young controls (12-week-old); (II) 18-month-old aged sedentary rats; (III) aged group with free access to running wheels for 6 months; (IV) aged rats subjected to forced physical activity for 6 months. At the endpoint of the study, the aged animals were two years old. The aged sedentary rats exhibited increased Tei-index, LA/Ao and E/e' ratios as well as decreased e'/a' ratio and lengthened DecT and IVRT, higher perivascular fibrosis ratio and reduced myocardial PKG, STAT3 and Opa1 protein expression, along with decreased ATP synthase (ATPS) activity in comparison to the young controls. In terms of echocardiographic parameters and perivascular fibrosis, the forced running provided more substantial benefits than the voluntary activity demonstrated by decreased Tei-index, E/e' ratio, increased e'/a' ratio and reduced DecT and IVRT. Forced exercise was strongly associated with elevated myocardial expression of PKG, STAT3 and Opa1 proteins and, moreover, the ATPS activity was restored only in the forced running rats. In conclusion, forced but not voluntary exercise has significant protective effects on age-associated diastolic dysfunction by upregulating PKG-STAT3-Opa1 axis and thereby enhancing ATPS activity.

Prior studies have shown that interrupting the growth hormone/insulin-like growth factor-I (GH/IGF-I) signaling axis extends laboratory mouse lifespan, but confounding effects of additional gene or hormone deficiencies that exist in commonly used models of GH/IGF-I interruption obscure the specific effect of GH on longevity. We address this issue by using mice with a specific knockout of the GH gene and show that both males and females on a mixed genetic background display extended lifespans resulting from GH deficiency. Our physiological assessment of these mice revealed that in addition to weighing significantly less and displaying significantly greater body fat (as a percentage of body weight), GH deficient mice display significant impairments in glucose metabolism and preferential fat utilization. These data provide strong evidence that GH deficiency is directly responsible for the altered nutrient utilization and extended lifespan that is commonly observed in mouse models of GH/IGF-I interruption.

Earth's old animals are in decline. Despite this, emerging research is revealing the vital contributions of older individuals to cultural transmission, population dynamics, and ecosystem processes and services. Often the largest and most experienced, old individuals are most valued by humans and make important contributions to reproduction, information acquisition and cultural transmission, trophic dynamics, and resistance and resilience to natural and anthropogenic disturbance. These observations contrast with the senescence-focused paradigm of old age that has dominated the literature for over a century yet are consistent with findings from behavioral ecology and life-history theory. Here, we review why the global loss of old individuals can be particularly detrimental to long-lived animals with indeterminate growth, increasing reproductive output with age, and those dependent on migration, sociality and cultural transmission for survival. Longevity conservation is needed to protect the important ecological roles an ecosystem services provided by old animals.

Throughout the course of evolution, organisms and cells have evolved a suite of mechanisms to manage persistent stimuli, thereby preserving cellular and organismal homeostasis. Upon detecting stress signals, cells activate a transcriptional response termed the mitochondrial unfolded protein response (UPR

With an increasing aging population and Alzheimer's disease tsunami, it is critical to identify early antecedents of brain aging to target for intervention and prevention. Women and men develop and age differently, thus using a sex differences lens can contribute to identification of early risk biomarkers and resilience. There is growing evidence for fetal antecedents to adult memory impairments, potentially through disruption of maternal prenatal immune pathways. Here, we hypothesized that in utero exposure to maternal pro-inflammatory cytokines will have sex-dependent effects on specific brain circuitry regulating offspring's memory and immune function that will be retained across the lifespan. Using a unique prenatal cohort, we tested this in 204 adult offspring, equally divided by sex, who were exposed/unexposed to an adverse in utero maternal immune environment and followed into early midlife (~age 50). Functional magnetic resonance imaging results showed exposure to pro-inflammatory cytokines in utero (i.e., higher maternal IL-6 and TNF-α levels) was significantly associated with sex differences in brain activity and connectivity underlying memory circuitry and performance and with a hyperimmune state, 50 years later. In contrast, the anti-inflammatory cytokine, IL-10 alone, was not significantly associated with memory circuitry in midlife. Predictive validity of prenatal exposure was underscored by significant associations with age 7 academic achievement, also associated with age 50 memory performance. Results uniquely demonstrated that adverse levels of maternal in utero pro-inflammatory cytokines during a critical period of the sexual differentiation of the brain produced long-lasting effects on immune function and memory circuitry/function from childhood to midlife that were sex-dependent, brain region-specific, and, within women, reproductive stage-dependent.

Cells are subjected to dynamic mechanical environments which impart forces and induce cellular responses. In age-related conditions like pulmonary fibrosis, there is both an increase in tissue stiffness and an accumulation of senescent cells. While senescent cells produce a senescence-associated secretory phenotype (SASP), the impact of physical stimuli on both cellular senescence and the SASP is not well understood. Here, we show that mechanical tension, modeled using cell culture substrate rigidity, influences senescent cell markers like SA-{beta}-gal and secretory phenotypes. Comparing human primary pulmonary fibroblasts (IMR-90) cultured on physiological (2 kPa), fibrotic (50 kPa), and plastic (approximately 3 GPa) substrates, followed by senescence induction using doxorubicin, we identified unique high-stiffness-driven secretory protein profiles using mass spectrometry and transcriptomic signatures, both showing an enrichment in collagen proteins. Consistently, clusters of p21+ cells are seen in fibrotic regions of bleomycin induced pulmonary fibrosis in mice. Computational meta-analysis of single-cell RNA sequencing datasets from human interstitial lung disease confirmed these stiffness SASP genes are highly expressed in disease fibroblasts and strongly correlate with mechanotransduction and senescence-related pathways. Thus, mechanical forces shape cell senescence and their secretory phenotypes.

Telomeres are pivotal determinants of cell stemness, organismal aging, and lifespan. Herein, we examined similarities in telomeres of Arabidopsis thaliana, mice, and humans. We report the common traits, which include their composition in multimers of TTAGGG sequences and their protection by specialized proteins. Moreover, given the link between telomeres, on the one hand, and cell proliferation and stemness on the other, we discuss the counterintuitive convergence between plants and mammals in this regard, focusing on the impact of niches on cell stemness. Finally, we suggest that tackling the study of telomere function and cell stemness by taking into consideration both plants and mammals can aid in the understanding of interconnections and contribute to research focusing on aging and organismal lifespan determinants.

Muscular atrophy is among the systematic decline in organ functions in aging, while defective thermogenic fat functionality precedes these anomalies. The potential crosstalk between adipose tissue and muscle during aging is poorly understood. In this study, it is showed that UCP1 knockout (KO) mice characterized deteriorated brown adipose tissue (BAT) function in aging, yet their glucose homeostasis is sustained and energy expenditure is increased, possibly compensated by improved inguinal adipose tissue (iWAT) and muscle functionality compared to age-matched WT mice. To understand the potential crosstalk, RNA-seq and metabolomic analysis were performed on adipose tissue and muscle in aging mice and revealed that creatine levels are increased both in iWAT and muscle of UCP1 KO mice. Interestingly, molecular analysis and metabolite tracing revealed that creatine biosynthesis is increased in iWAT while creatine uptake is increased in muscle in UCP1 KO mice, suggesting creatine transportation from iWAT to muscle. Importantly, creatine analog β-GPA abolished the differences in muscle functions between aging WT and UCP1 KO mice, while UCP1 inhibitor α-CD improved muscle glycolytic function and glucose metabolism in aging mice. Overall, these results suggested that iWAT and skeletal muscle compensate for declined BAT function during aging via creatine metabolism to sustain metabolic homeostasis.

Aging is an inevitable biological process accompanied by various physiological changes, and researchers have long sought interventions to promote healthy aging. This article explores the effects of four natural compounds-Omega-3 fatty acids, Coenzyme Q10, Gingerol, and Curcumin-on the aging process. We delve into the scientific literature to examine the potential benefits and mechanisms behind these substances in mitigating age-related conditions. Omega-3's anti-inflammatory properties, Coenzyme Q10's cellular energy support, Gingerol's antioxidant effects, and Curcumin's anti-aging properties are all discussed. By shedding light on the impact of these compounds, this review aims to contribute to a better understanding of how natural substances may play a role in promoting longevity and enhancing the quality of life during the aging journey.

Falls in older adults increase the risk of mobility loss. Proper understanding of gait mechanisms related to falls may provide novel solutions for maintaining mobility in older adults.

Nutrition at midlife and beyond influences how an individual ages. Nutrition risk, the risk of poor nutritional health, is highly prevalent in community-dwelling adults in these age groups. As the factors associated with nutrition risk may vary between different age groups, research is needed on the differences in nutrition risk between age groups.

Aging in mammals, including humans, is marked by a multitude of molecular, cellular, and systemic changes that increase the risk of various diseases, including cancer. While the link between aging and increased cancer incidence is well documented, the precise biological mechanisms driving tumor initiation remain less clear. In a recent issue of Cancer Cell, Yan and colleagues have identified Midkine, a heparin-binding growth factor, as an age-related biomarker mediating both ageing related phenotypes and cancer development. Further exploration of these molecular dynamics, alongside the development of targeted drugs, holds great promise for reducing aging-related cancer incidence.

Hutchison-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by a mutation in LMNA, the gene encoding A-type lamins, leading to premature aging with severely reduced life span. HGPS is characterized by growth deficiency, subcutaneous fat and muscle issue, wrinkled skin, alopecia, and atherosclerosis. Patients also develop a bone phenotype with reduced bone mineral density, osteolysis and striking demineralization of long bones. To further clarify the tissue modifications in HGPS, we characterized bone mineralization in the Lmna

The health advantages of Ramadan fasting, a time-restricted eating from dawn to dusk, have garnered attention. Nevertheless, prior observational studies have found inconsistent findings because of challenges regulating variables such as sleep patterns, dietary habits, and physical activity. This study sought to investigate the impact of the Ramadan fasting model (RFM) on longevity and metabolic biomarkers in obese and non-obese rats. For 12 weeks, 48 male Wistar albino rats were separated into two groups and fed either a standard or a high-fat diet (HFD). During the final four weeks, rats in each group were separated into four subgroups to investigate the effect of RFM with/without training (on Treadmill) or glucose administration on the biomarkers of interest. The HFD groups subjected to RFM had significantly lower Insulin-like growth factor 1 (IGF-1) and mechanistic target of rapamycin (mTOR) serum, whereas AMPK, anti-inflammatory, and antioxidative stress serum levels were significantly higher. All groups reported decreased serum levels of Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) compared to the HFD control group. Furthermore, the Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) results indicated a significant elevation in the TP53 gene expression in groups subjected to RFM. The data indicate that RFM can improve longevity and metabolic biomarkers and reduce pro-inflammation and oxidative stress. Also, RFM improves anti-inflammatory and antioxidant markers in HFD-induced obese rats.

In humans, various pathologies have been associated with snoRNAs. Others have shown that the expression of a non-canonical snoRNA Jouvence is involved in lifespan determination in relation to gut homeostasis. As snoRNAs are evolutionary conserved, both structurally and functionally, a jouvence orthologue has been identified in humans. This study aimed to locate the Jouvence snoRNA in the horse genome. Using our previous snoRNA data in ageing equine cartilage along with equine genome data we identified a putative equine Jouvence snoRNA gene. ECABCGRLG0000000730 was the primary candidate horse Jouvence snoRNA. The expression of equine Jouvence snoRNA was increased in ageing equine cartilage.

Parkinsons disease (PD) is a neurodegenerative disorder characterized by the accumulation of alpha-synuclein aggregates and progressive neuronal loss in the substantia nigra, with aging being its primary risk factor. The current available models to study PD mechanisms are largely relying on genetic mutations to recapitulate PD typical hallmarks, such as increased alpha-synuclein aggregation. However, they do not model the aging features associated with the disease. Microgravity, a condition experience by astronauts during space missions, is known to induce ageing-like modifications on both systemic and cellular physiology. To replicate the aging-related stress observed in PD patients, we exposed SH-SY5Y and 3K-SNCA mutant cell lines to simulated microgravity. Our findings revealed that simulated microgravity enhanced PD alterations, with a significant increase in misfolded and phosphorylated a-syn. This was accompanied by heightened oxidative stress, as evidenced by increased levels of reactive oxygen species, without a sufficient antioxidant response. These results suggest that simulated microgravity effectively mimics and accelerate the stress associated with aging in PD cell models, regardless of the presence of PD mutation. This study highlights the potential of simulated microgravity as a tool for investigating aging processes in neurodegenerative diseases.

Alzheimer's disease (AD), commonly known as senile dementia, is a neurodegenerative disease with insidious onset and gradually worsening course. The brain is particularly sensitive to senescence, and neuronal senescence is an important risk factor for the occurrence of AD. However, the exact pathogenesis between neuronal senescence and AD has not been fully elucidated so far. Neuronal senescence is characterized by the permanent stagnation of the cell cycle, and the changes in its structure, function, and microenvironment are closely related to the pathogenesis and progression of AD. In recent years, studies such as the Aβ cascade hypothesis and Tau protein phosphorylation have provided new strategies for the therapy of AD, but due to the complexity of the etiology of AD, there are still no effective treatment measures. This article aims to deeply analyze the pathogenesis between AD and neuronal senescence, and sort out various existing therapeutic methods, to provide new ideas and references for the clinical treatment of AD.

Aging is characterized by a decline in various biological functions that is associated with changes in gene expression programs. Recent transcriptome-wide integrative studies in diverse organisms and tissues have revealed a gradual uncoupling between RNA and protein levels with aging, which highlights the importance of post-transcriptional regulatory processes. Here, we provide an overview of multi-omics analyses that show the progressive uncorrelation of transcriptomes and proteomes during the course of healthy aging. We then describe the molecular changes leading to global downregulation of protein synthesis with age and review recent work dissecting the mechanisms involved in gene-specific translational regulation in complementary model organisms. These mechanisms include the recognition of regulated mRNAs by trans-acting factors such as miRNA and RNA-binding proteins, the condensation of mRNAs into repressive cytoplasmic RNP granules, and the pausing of ribosomes at specific residues. Lastly, we mention future challenges of this emerging field, possible buffering functions as well as potential links with disease.

In Caenorhabditis elegans (C. elegans), there is a single FOXO transcription factor homolog, encoded by the gene, daf-16. As a central regulator for multiple pathways, DAF-16 integrates these signals to result in changes in longevity, development, fat storage, stress resistance, innate immunity, and reproduction. One of the main advantages of using C. elegans is the ability to study FOXO in the context of the whole animal. Therefore, manipulating the levels or the activity of daf-16 results in visible, scorable phenotypic changes. DAF-16 is the downstream target of the conserved insulin/IGF-1 signaling (IIS) pathway, a PI 3-kinase signaling cascade that ultimately controls its nuclear localization. Since the IIS pathway is a major regulator of lifespan, almost all studies of lifespan modulation examine the requirement of daf-16. More recently, lifespan analysis has been accompanied by healthspan analysis, referring to the time an animal is healthy. In this chapter, I will focus on the assays to assess lifespan and healthspan of C. elegans FOXO/daf-16, in the context of a whole animal.

Proteins are the major and most diverse biomolecules, directing all activities of a cell. For this reason, visualizing protein expression, localization, and dynamics is fundamental in biology. In most cases, protein visualization relies on the overexpression of fluorescently tagged proteins which may not recapitulate endogenous expression pattern and dynamics. Henceforth, tagging proteins in the endogenous locus is the most accurate way to recapitulate physiological gene expression. However, this method is not widely implemented for the FOXO gene family due to its technical inefficiency and difficulty. Here we describe the methodology followed to generate a knock-in reporter line for the Foxo1a transcription factor for the zebrafish model system. We describe insertion of an EGFP-polyA cassette in frame at the C-terminal of Foxo1a, generating a fusion protein. Foxo1a has been involved in the regulation of metabolism, stress response, longevity, and cell differentiation, and its functions are conserved from invertebrates to vertebrates. Using in vivo confocal live microscopy at early developmental stages, we validated the expression of Foxo1a in the cardiovascular network, central nervous system, olfactory epithelium, spinal cord, retina, skeletal muscle, and myocardium. This knock-in line opens the way for imaging studies aiming to characterize the expression and localization (cytoplasmic or nuclear) of this transcription factor in a tissue- and context-specific manner, as well as the dynamics of stress adaptation at a whole organism level. Moreover, the knock-in line can be used in combination with other modern techniques such as Cut&Run to determine the transcriptional targets of Foxo1a, with a GFP-directed proteomic to identify interacting partners, many of which remain largely unknown.

The world population is shifting sharply toward an older-age demographic. To navigate the escalating burden of physical and cognitive decline common to aging, and heightened risk of neurodegenerative and neuropsychiatric disease, we require advances in treatment and prevention interventions. These advances are predicated on attaining a deeper understanding of the molecular processes underlying brain aging. Here, we employed novel GWAS and cis-eQTL-based polygenic risk scores (GWASAGE-PRS and cis-eQTLAGE-PRS) indexing genetic risk for accelerated molecular brain aging, and examined their associations with cortical thickness and performance in age-sensitive cognitive domains in 31 384 participants (16 392 women, age 64.1{+/-}7.65) from the UK Biobank. While GWASAGE-PRS was nominally associated with lower cortical thickness in frontotemporal regions, cis-eQTLAGE-PRS displayed robust associations with greater cortical thickness in age-sensitive frontal, temporal, and parietal regions, including the left and right precentral (pFDR<0.0001, pFDR=0.05), left insula (pFDR=0.05), as well as the right supramarginal (pFDR=0.05) and precuneus (pFDR=0.05) regions. Similar pFDR trending associations occurred bilaterally in the caudal middle frontal (pFDR=0.052, pFDR=0.078) and right insula (pFDR=0.071). These structural findings co-occurred alongside increased executive function performance on the Trail Making Test B (pFDR=0.035), suggesting a potential neurostructural and cognitive reserve phenotype. This resilience profile may reflect previously uncharacterized pathways of brain reserve in age-related pathology, informing future translational research identifying novel treatment and prevention targets.

We investigated associations of childhood socioeconomic position and health with trajectories of grip strength from middle to older ages in two distinct populations.

Aging leads to progressive bone loss, which is associated with impaired bone and marrow perfusion. The purpose of this study was to determine whether chronic exercise training enhances blood flow to the femur at rest and during exercise, and elucidate whether putative changes in training-induced bone perfusion are associated with alterations in the intrinsic vasomotor properties of the femoral principal nutrient artery (PNA) in old age. Young (4-6 mo old) and old (20-22 mo old) male Fischer-344 rats were either treadmill exercise trained (ET) or remained sedentary (SED). Regional blood flow to the femur was assessed at rest and during treadmill exercise. Endothelium-dependent (acetylcholine, ACh) and -independent (Dea-NONOate) vasodilator, and vasoconstrictor (phenylephrine (PE), KCl and myogenic) responses of femoral PNAs were determined. Exercise training led to higher blood flow to distal metaphysis and epiphysis in old rats at rest, and old ET rats showed greater regional blood flow during exercise compared to old SED rats. The increased blood flow to the proximal and distal metaphysis and epiphysis were also higher in old ET rats than that in young ET rats. Exercise training enhanced the vasodilator response to ACh, corresponding to increased eNOS expression in femoral PNAs from both young and old rats. Aging did not alter PE- or KCl-induced vasoconstriction, whereas myogenic responses were impaired. Exercise training enhanced vasoconstrictor responses to PE in old rats but had no effect on KCl or myogenic responses in either group. These data demonstrate that exercise training enhances both regional bone and marrow blood flow and vasodilator responses, which are impaired in the femora of old SED rats.

The conserved transcription factor DAF-16/FOXO is a central hub in the regulation of stress responses and aging. It was first discovered as a protein activated by reduced insulin/IGF-like signaling (IIS) that would drive aging-preventive transcriptional outcomes. However, research from the last two decades has shown that its functions extend much further, with it responding to a broad spectrum of stress and deprivation-related stimuli and relaying them into optimal transcriptional outcomes that promote stress resistance, slow aging, and ultimately help the organism to survive each given threat. Evidence is mounting that DAF-16/FOXO is not self-sufficient in this important role but relies on numerous binding partners that help it achieve appropriate activity and target gene selectivity, with prominent examples being the chromatin remodeling complex SWI/SNF, the DAF-16-inhibitory protein HCF-1, or the transcription factor HLH-30/TFEB-just to mention a few. Here we present a protocol for the identification of such DAF-16/FOXO binding partners in Caenorhabditis elegans, comprising the large-scale growth and harvest of such animals, their lysis, and the eventual purification of DAF-16/FOXO, to yield samples that can be analyzed for co-purifying proteins und thus potential binding partners by tandem mass spectrometry.

In mammals, the FOXO protein family consists of four distinct isoforms: FOXO1, FOXO3, FOXO4, and FOXO6. These isoforms are key players in a wide spectrum of physiological and pathological processes, including context-specific tumor suppression. FOXO3, in particular, has emerged as a gene associated with extraordinary human longevity. While these four FOXO isoforms share common biological functions, the mechanisms underlying their overlapping and distinct roles remain less understood. It is believed that intrinsic properties and context-dependent factors contribute to isoform-specific and nonredundant FOXO functions. One promising avenue for unraveling the commonalities and specificities of these proteins involves characterizing their expression patterns in specific cell types and their activation in response to different stimuli. To facilitate this, we have developed immunocytochemistry methods capable of detecting FOXO isoforms in a highly specific manner within various human cancer cell types and fibroblasts. Importantly, this approach enables the visualization of endogenous FOXO proteins as they translocate into the cell nucleus in response to different stimuli. In this article, we present a comprehensive guide to these procedures, offering valuable insights into the distinct roles of FOXO isoforms in cellular function.

In this study, the ultraviolet B (UVB)-induced skin photoaging inhibitory activity of pomegranate peel extract with increased ellagic acid content through enzymatic hydrolysis was evaluated in HaCaT cells. Among various enzymes, Viscozyme with high tannase and β-glucosidase activities was used, and 1.0 % Viscozyme was added to hydrolyze pomegranate peel for 2 h at 40°C to establish the optimal reaction conditions for high ellagic acid content. Subsequently, when cells were treated with enzyme extracted pomegranate peels (40 μg/mL), the gene expression of matrix metalloproteinases (MMP)-2 and 13, which play key role in skin elasticity and moisture, and the protein expression of MMP13 were downregulated compared to the UVB-control group (UVB-C). In addition, the protein expression levels of tissue inhibitors, metalloproteinase-1 and 2, and collagen type I alpha 1 were upregulated, the gene expression of hyaluronic acid synthase-1, and filaggrin significantly increased, and interleukin-1β increased by photoaging was decreased. Furthermore, compared to the UVB-C, there was a significant increase in the gene expression of superoxide dismutase-1 and glutathione peroxidase, which resulted in a decrease in reactive oxygen species and malondialdehyde levels. These results were confirmed to be due to the inhibition of the mitogen-activated protein kinase pathway and downregulation of the protein expression of phosphorylated extracellular signal-regulated kinase, c-Jun N-terminal kinase, and P38. In conclusion, pomegranate peel, from which ellagic acid was extracted using Viscozyme, showed a reactive oxygen species inhibitory effect in UVB-irradiated HaCaT cells and thus may have a significant potential as a cosmetic ingredient with anti-aging effects.

Polyphenols from the phytoestrogen group, including pterostilbene (PTS), are known for their antioxidant, anti-inflammatory, and anti-cancer effects. In recent reports, phytoestrogens attenuate age-related diseases; however, their pro-longevity effects in healthy models in mammals remain unknown. As longevity research demonstrates age-related transcriptomic signatures in human blood, the current study hypothesizes that phytoestrogen-supplemented diet may induce changes in gene expression that ultimately confer pro-longevity benefits.

Little is known as to how rest-activity rhythms (RAR) are associated with frailty and how this relationship differs by sex. This study examined the relationship between RAR and frailty in a nationally representative sample of US older adults, focusing on the moderating role of sex.

Time-restricted eating (TRE) has been shown to extent lifespans in drosophila and mouse models by affecting metabolic and anti-inflammatory activities. However, the effect of TRE on the human immune system, especially on immunosenescence, intestinal microbiome, and metabolism remains unclear. We conducted a 30-day 16:8 TRE single-arm clinical trial with 49 participants. Participants consumed daily meals from 9 a.m. to 5 p.m., provided by a nutrition canteen with a balanced, calorie-appropriate nutrition, which is designed by clinical nutritionists (ChiCTR2200058137). We monitored weight changes and weight-related parameters and focused on changes in the frequency of CD4

Organismal aging is marked by decline in cellular function and anatomy, ultimately resulting in death. To inform our understanding of the mechanisms underlying this degeneration, we performed standard RNA sequencing (RNA-seq) and Oxford Nanopore Technologies direct RNA-seq over an adult time course in Caenorhabditis elegans. Long reads allowed for identification of hundreds of novel isoforms and age-associated differential isoform accumulation, resulting from alternative splicing and terminal exon choice. Genome-wide analysis reveals a decline in RNA processing fidelity. Finally, we identify thousands of inosine and hundreds of pseudouridine edits genome-wide. In this first map of pseudouridine modifications for C. elegans, we find that they largely reside in coding sequences and that the number of genes with this modification increases with age. Collectively, this analysis discovers transcriptomic signatures associated with age and is a valuable resource to understand the many processes that dictate altered gene expression patterns and post-transcriptional regulation in aging.

Ginkgo biloba extract is reported to have therapeutic effects on aging-related disorders. However, the specific component responsible for this biological function and its mechanism of action remain largely unknown. This study finds that Ginkgetin, an active ingredient of Ginkgo biloba extract, can alleviate cellular senescence and improve pathologies in multiple tissues of aging mice. To reveal the molecular mechanism of Ginkgetin's anti-aging effect, a graph convolutional network-based drug "on-target" pathway prediction algorithm for prediction is employed. The results indicate that the cGAS-STING pathway may be a potential target for Ginkgetin. Subsequent cell biological and biophysical data confirmed that Ginkgetin directly binds to the carboxy-terminal domain of STING protein, thereby inhibiting STING activation and signal transduction. Furthermore, in vivo pharmacodynamic data showed that Ginkgetin effectively alleviates systemic inflammation in Trex1

Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimers disease (AD) but much less is known on the key cell types and pathways driving mechanisms of senescence in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed whole transcriptomic data and utilized single-cell RNA seq integration techniques to unveil the convoluted cell-type-specific and sub-cell-type-state-specific senescence pathologies in AD using both ROSMAP and Sea-AD datasets. We identified that microglia are central components to AD associated senescence phenotypes in ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex of 239 AD and 188 non-AD) among non-neuron cell types. We identified that homeostatic, inflammatory, phagocytic, lipid processing and neuronal surveillance microglia states were associated with AD associated senescence in ROSMAP (152,459 microglia nuclei from six regions of brain tissue of 138 early AD, 79 late AD and 226 control subject) and in Sea-AD (82,486 microglia nuclei of 42 dementia, 42 no dementia and 5 reference subjects) via integrative analysis, which preserves the meaningful biological information of microglia cell states across the datasets. We assessed top senescence associated bioprocesses including mitochondrial, apoptosis, oxidative stress, ER stress, endosomes, and lysosomes systems. Specifically, we found that senescent microglia have altered cholesterol related bioprocesses and dysregulated cholesterol. We discovered three gene co-expression modules, which represent the specific cholesterol related senescence transcriptomic signatures in postmortem brains. To validate these findings, the activation of specific cholesterol associated senescence transcriptomic signatures was assessed using integrative analysis of snRNA-seq data from iMGs (microglia induced from iPSCs) exposed to myelin, Abeta, and synaptosomes (56,454 microglia across two replicates of untreated and four treated groups). In vivo cholesterol associated senescence transcriptomic signatures were preserved and altered after treatment with AD pathological substrates in iMGs. This study provides the first evidence that dysregulation of cholesterol metabolism in microglia is a major driver of senescence pathologies in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to slow down AD progression.

Bone homeostasis primarily stems from the balance between osteoblasts and osteoclasts, wherein an augmented number or heightened activity of osteoclasts is a prevalent etiological factor in the development of bone loss. Nuclear Dbf2-related kinase (NDR2), also known as STK38L, is a member of the Hippo family with serine/threonine kinase activity. We unveiled an upregulation of NDR2 expression during osteoclast differentiation. Manipulation of NDR2 levels through knockdown or overexpression facilitated or hindered osteoclast differentiation respectively, indicating a negative feedback role for NDR2 in the osteoclastogenesis. Myeloid NDR2-dificient mice (Lysm+NDR2f/f) showed lower bone mass and further exacerbated ovariectomy-induced or aging-related bone loss. Mechanically, NDR2 enhanced autophagy and mitophagy through mediating ULK1 instability. In addition, ULK1 inhibitor (ULK1-IN2) ameliorated NDR2 cKO-induced bone loss. Finally, we clarified a significant inverse association between NDR2 expression and the occurrence of osteoporosis in patients. In a word, NDR2-ULK1-mitophagy axis was a potential innovative therapeutic target for the prevention and management of bone loss.

Commensal bacteria and their derivatives hold significant promise as therapeutic interventions to delay aging. However, with the diverse nature of the soil microbiome and the long lifespan of mammalian models, the exploration of the influence of soil bacteria and bacteria-derived molecules on host aging remains limited. We conducted a lifespan screening in Caenorhabditis elegans using plant root bacterial collection. Our screening identified 8 genera of bacterial isolates capable of extending lifespan, with Mycobacterium sp. Root265 exhibits the most pronounced effect on lifespan extension. Biochemical analysis revealed two specific molecules derived from Root265, polysaccharides (PSs) and arabinogalactan peptidoglycan (AGP), responsible for lifespan extension via daf-16-dependent and -independent pathways, respectively. Notably, AGP exhibited a unique ability to enhance protein homeostasis effectively. Moreover, polar lipids originating from Root265 were found to extend lifespan while mitigating age-related BAS-1 decline in neurons. Intriguingly, even brief exposures to these bioactive compounds were sufficient to achieve the lifespan-promoting effects. We found diverse beneficial bacteria and anti-aging active compounds from soil bacteria. These findings highlight the potential of exploring bacterial derivatives as therapies targeting aging without the constraints associated with direct microbial interventions.

Low-load resistance training with blood flow restriction (LRT-BFR) has shown potential to improve muscle strength and mass in different populations; however, there remains limited evidence in sarcopenic people diagnosed with sarcopenia criteria. This study systematically compared the effectiveness of LRT-BFR and conventional high-intensity resistance training (CRT) on clinical muscle outcomes (muscle mass, strength and performance), cardiovascular disease (CVD) risk factors and sarcopenia-related biomarkers of older people with sarcopenia. Twenty-one older individuals (aged 65 years and older) diagnosed with sarcopenia were randomly assigned to the LRT-BFR (20%-30% one-repetition maximum (1RM), n = 10) or CRT (60%-70% 1RM, n = 11) group. Both groups underwent a supervised exercise program three times a week for 12 weeks. The primary outcome was knee extensor strength (KES), and the secondary outcomes included body composition (body mass, body mass index and body fat percentage), muscle mass [appendicular skeletal muscle mass index (ASMI)], handgrip strength, physical performance [short physical performance battery (SPPB) and 6-m walk], CVD risk factors [hemodynamic parameters (systolic and diastolic blood pressure and heart rate (SBP, DBP and HR)) and lipid parameters (total cholesterol, triglyceride (TG), high-density lipoprotein (HDL) and low-density lipoprotein)], sarcopenia-related blood biomarkers [inflammatory biomarkers, hormones (growth hormone (GH) and insulin-like growth factor 1) and growth factors (myostatin and follistatin)] and quality of life [Short Form 36 Health Survey (SF-36)]. Both interventions remarkably improved the body composition, KES, 6-m walk, SBP, HDL, TG, GH, FST and SF-36 scores. CRT significantly improved the ASMI (p < 0.05) and SPPB (p < 0.05). A significant improvement in HR was observed only after LRT-BFR. No significant between-group differences were found before and after the interventions. This study suggested that LRT-BFR and CRT are beneficial to the clinical muscle outcomes, CVD risk factors and certain sarcopenia-related biomarkers of older people with sarcopenia. By comparison, CRT seems more effective in improving muscle mass, while LRT-BFR may be more beneficial for improving cardiovascular health in this population. Therefore, LRT-BFR is a potential alternative to CRT for aging sarcopenia.

The paper illustrates the definition of a home adaptation design support tool for selecting interior finishes and partition systems based on multicriteria evaluations. In line with Universal Design principles, the selection criteria promote the creation of homes that respond to the changing needs of people over their life course, allowing for aging in place. Based on a literature review on the design of age-friendly living spaces, optimal requirements for safety, comfort, usability, management, environmental protection and integrability related to partitioning elements and interior finishes were identified. Then, through the multicriteria analysis technique of the Analytic Hierarchy Process, selection criteria were established, and weights were assigned to classify market-available products according to performance, thereby informing the choices of designers and end users.

It had long been considered that no new neurons are generated in the primate brain beyond birth, but recent studies have indicated that neurogenesis persists in various locations throughout the lifespan. The dentate gyrus of the hippocampus is of particular interest due to the postulated role played by neurogenesis in memory. However, studies investigating the presence of adult hippocampal neurogenesis (AHN) have reported contradictory findings, and no systematic review of the evidence has been conducted to date. We searched MEDLINE, Embase and PsycINFO on 27

Irisin, an exercise-induced myokine, is known to be able to regulate bone metabolism. However, the underlying mechanisms regarding the effects of irisin on senile osteoporosis have not been fully elucidated. Here, we demonstrated that irisin can inhibit bone mass loss and bone microarchitecture alteration in senile osteoporosis mouse model. In addition, irisin has effects on bone remodeling that is in favor of bone formation. Remarkably, irisin induced autophagy in osteocytes demonstrated by increased LC3-positive osteocytes, and increased autophagy-related genes and proteins.

Aging of the epidermis partially occurs as a consequence of epidermal cell senescence, a non-proliferative state in which cells remain metabolically active and acquire changes in their secretome. We previously reported that senescent normal human epidermal keratinocytes (NHEKs) have two opposite outcomes: either cell death by excess of autophagic activity or escape from senescence to give rise to post-senescence neoplastic emerging (PSNE) cells. In this study, we investigated the role of PTGS2, the inducible enzyme of the prostaglandin biosynthesis pathway, in the onset of NHEK senescence and in the switch from senescence to pre-transformation. We provide evidence that the PTGS2/PGE

Anti-ageing medicines are products intended to extend lifespan and healthspan in humans that have a good potential use in public health policies. In the European Union, their development, production and consumption are dependent on regulatory science performed by the European Medicines Agency and its associated epistemic policies. They impose, among other things, an unfavourable burden of proof, a strict standard of proof and meta-methodological constrictions related to some theoretical issues. This results in a distribution of errors that tends to reduce false positives while increasing false negatives, leading to a set of social consequences that are generally accepted when the focus is placed on conventional medicines. However, when the same epistemic policies are applied to anti-ageing medicines, the distribution of errors is imbalanced, and undesirable outcomes like research discouragement and waiting time extensions appear. Three possible strategies that policymakers could implement to unblock the situation are presented for future reflection: the consideration of ageing as a disease, the application of methodological asymmetry and the use of biomarkers during clinical research.

Cellular senescence is a state of permanent proliferative arrest that occurs in response to DNA damage-inducing endogenous and exogenous stresses, and is often accompanied by dynamic molecular changes such as a senescence-associated secretory phenotype (SASP). Accumulating evidence indicates that age-associated increases in the upstream and downstream signals of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, are closely related to the induction of cellular senescence and its phenotype. Furthermore, elevated levels of pro-inflammatory SASP factors with aging can be both a cause and consequence of several cell death modes, suggesting the reciprocal effects of cellular senescence and cells undergoing regulated cell death. Here, we review the critical molecular pathways of the regulated cell death forms and describe the crosstalk between aging-related signals and cancer. In addition, we discuss how targeting regulated cell death could be harnessed in therapeutic interventions for cancer. ABBREVIATIONS: Abbreviations that are not standard in this field are defined at their first occurrence in the article and are used consistently throughout the article.

Mitochondrial dysfunction caused by aging leads to decreased energy metabolism, resulting in functional decline and increased frailty in multiple tissues. Strategies for protecting and activating mitochondria under stressful conditions are required to suppress aging and age-related diseases. However, it is challenging to develop drugs capable of boosting mitochondrial respiration and compensating for the reduced intracellular adenosine triphosphate (ATP) levels. In this study, we developed a prodrug that stimulates the metabolism of intracellular adenine nucleotides (AXP: adenosine monophosphate (AMP), adenosine diphosphate (ADP), and ATP). It enhances AMP-activated protein kinase activity, fatty acid oxidation, oxidative stress resistance, and mitochondrial respiration, thereby increasing the intracellular ATP levels. Furthermore, this prodrug markedly extended the lifespan of Caenorhabditis elegans. The stimulation of the AXP energy metabolism (AXP stimulation) proposed in this study is expected to offer a new strategy against aging and pave the way for a novel approach in the bioenergetic molecules drug discovery.

Metabolic stress-induced pancreatic β cell senescence plays a pivotal role in the type 2 diabetes progression, and yet the precise molecular mechanisms remain elusive. Through cellular experiments and bioinformatics analyses, we identified aquaporin 1(AQP1)-mediated transmembrane transport of hydrogen peroxide as a key driver of glucolipotoxicity-induced senescence in MIN6 cells. A PPI network analysis was used to cross-reference 17 differentially expressed genes associated with type 2 diabetes from three independent GEO databases with 188 stress-induced senescence-related genes from CellAge. AQP1 was revealed as a critical molecular nexus connecting diabetes, oxidative stress, and cellular senescence. AQP1 inhibition, through Bacopaside II and si-AQP1, significantly reduced critical senescence markers in MIN6 cells, demonstrated by the reversal of glucolipotoxicity-induced upregulation of p16, p21, and p-γH2A.X, activation of the senescence-associated secretory phenotype genes, and an elevated percentage of senescence-associated-β-galactosidase positive cells. These effects were primarily mediated through oxidative stress MAPK signaling pathway modulation. AQP1 inhibition is crucial in alleviating glucolipotoxicity-induced β cell senescence. It underscores its potential as a molecular target for therapeutic strategies to delay pancreatic β cell senescence by modulating antioxidant pathways during metabolic stress.

Aging impairs bone marrow mesenchymal stem cell (BMSC) functions as well as associated angiogenesis which is critical for bone regeneration and repair. Hence, repairing bone defects in elderly patients poses a formidable challenge in regenerative medicine. Here, the engineered dental pulp stem cell-derived exosomes loaded with the natural derivative of adenosine Cordycepin (CY@D-exos) are fabricated by means of the intermittent ultrasonic shock, which dually rejuvenates both senescent BMSCs and endothelial cells and significantly improve bone regeneration and repair in aged animals. CY@D-exos can efficiently overcome the senescence of aged BMSCs and enhance their osteogenic differentiation by activating NRF2 signaling and maintaining heterochromatin stability. Importantly, CY@D-exos also potently overcomes the senescence of vascular endothelial cells and promotes angiogenesis. In vivo injectable gelatin methacryloyl (GelMA) hydrogels with sustained release of CY@D-exos can accelerate bone injury repair and promote new blood vessel formation in aged animals. Taken together, these results thus demonstrate that cordycepin-loaded dental pulp stem cell-derived exosomes display considerable potential to be developed as a next-generation therapeutic agent for promoting aged bone regeneration and repair.

Skeletal muscle mitochondrial dysfunction is a key characteristic of aging muscle and contributes to age related diseases such as sarcopenia, frailty, and type 2 diabetes. Mitochondrial oxidative stress has been implicated as a driving factor in these age-related diseases, however whether it is a cause, or a consequence of mitochondrial dysfunction remains to be determined. The development of flexible genetic models is an important tool to test the mechanistic role of mitochondrial oxidative stress on skeletal muscle metabolic dysfunction. We characterize a new model of inducible and reversible mitochondrial redox stress using a tetracycline controlled skeletal muscle specific short hairpin RNA targeted to superoxide dismutase 2 (iSOD2).

Brain age, an emerging biomarker for brain diseases and aging, is typically predicted using single-modality T1-weighted structural MRI data. This study investigates the benefits of integrating structural MRI with diffusion MRI to enhance brain age prediction. We propose an attention-based deep learning model that fuses global-context information from structural MRI with local details from diffusion metrics. The model was evaluated using two large datasets: the Human Connectome Project (HCP, n = 1064, age 22-37) and the Cambridge Center for Aging and Neuroscience (Cam-CAN, n = 639, age 18-88). It was tested for generalizability and robustness on three independent datasets (n = 546, age 20-86), reproducibility on a test-retest dataset (n = 44, age 22-35), and longitudinal consistency (n = 129, age 46-92). We also examined the relationship between predicted brain age and behavioral measures. Results showed that the multimodal model improved prediction accuracy, achieving mean absolute errors (MAEs) of 2.44 years in the HCP dataset (sagittal plane) and 4.36 years in the Cam-CAN dataset (axial plane). The corresponding R

A major goal of aging research is to identify ways of extending productive and disease-free lifespans. Here we present the catabolic - anabolic cycling hormesis (CACH) model for optimizing health. The CACH model is based on the concept that cells and organ systems respond to catabolic challenges in ways that bolster their resilience and that an anabolic recovery period is required to effectuate the benefits of the catabolic challenge. As two prominent real-world examples we highlight the literature on the molecular and cellular mechanisms by which physical exercise and intermittent fasting bolster cellular and organismal performance and resilience, and suppress disease processes. Over periods of weeks and months the CACH of exercise and fasting promote optimal health. The hormesis concept is integral to the CACH model and predicts an upper limit to the beneficial effects of catabolic - anabolic cycling that reflects a limit of biological plasticity. This paper extends the hormesis model of health by proposing that 1) it is comprised of two complementary phases: catabolic (adaptive stress responses and conservation of resources) and anabolic (growth and plasticity) and, 2) that CACH is metabolically integrated, quantitatively flexible and dynamically regulated. This model has important implications for future basic and translational research in the fields of aging and related disease processes.

The risk of many human diseases including cardiovascular diseases, cancer, neurodegenerative diseases, and musculoskeletal disorders rises significantly in the elderly. With the increase in the aging population, it is becoming increasingly important to understand the biology of healthy aging and develop interventions that slow down the aging process or prevent age-related diseases. In this study, by a high-throughput screen in Caenorhabditis elegans (C. elegans), we identified 11 small molecules that promote healthy aging. Among them, Carbamazepine (a voltage-gated channels inhibitor) and Calmagite (a calcium and magnesium indicator) enhanced serotonin (5-HT) and dopamine (DA) levels, extended lifespan, and preserved several important behaviors in aging C. elegans. These behaviors include slowing responses to food, pharyngeal pumping, locomotion, and male mating. Interestingly, we further found that administration of Carbamazepine or Calmagite alleviated hyperexcitability of aging male diagonal muscles and improved behavioral performance by ameliorating Ca

Exercise is a common strategy for disease prevention or management, including for diabetes and cardiac dysfunction. However, exercise response varies immensely between individuals, and in humans, the same exercise treatment can lead both to positive and negative responses. Drosophila melanogaster is an established model for exercise research that can be leveraged to understand this variation in exercise response. Here, we investigated how two early life exercise treatments differing in duration (5 and 20 days) impact the animals' health- and lifespan in four genotypes. Specifically, we measured lifespan, activity level, body condition, physical ability, and reproductive output in this exploratory study to gain insights into potential trade-offs. For most measures, we found both immediate and long-term effects, with some effects persisting weeks past the cessation of exercise. The effect of the exercise treatment was context-dependent, with treatment, sex, and genotype interactions determining phenotypes. For example, the 20-day treatment did not exhibit a consistently larger effect than the 5-day treatment. Similarly, neither the 5-day nor the 20-day treatment impacted lifespan, but two specific genotype/sex combinations showed altered lifespan after exercise. The 20-day treatment decreased climbing performance compared to controls up to several weeks after treatment ended in some genotypes. Together, our results highlight the complex, interacting factors controlling exercise response and demonstrate that early life exercise can have long-lasting effects in the Drosophila exercise model even though most individual groups show no response.

Sarcopenia is an age-related, insidious, crippling but curable degenerative disease if diagnosed and treated early. However, no accessible and accurate early screening method is available for community settings that does not require specialized personnel. One of the hallmarks of sarcopenia is the pathological changes of muscle fiber type composition and motor unit firing patterns. Surface electromyography (sEMG) may serve as an effective tool for detecting differences between healthy and sarcopenic individuals due to its superior wearability and accessibility compared to other screening methods such as medical imaging and bioimpedance measurements, making it ideal for community-based sarcopenic screening. Our study aims to explore sEMG biomarkers that can be used for screening or diagnosis of sarcopenia.

Arterial stiffness is a significant predictor of cardiovascular disease and mortality. Physical activity (PA) has been extensively studied for its potential to reduce arterial stiffness, but the relationship between different types, durations, and intensities of PA and arterial stiffness remains a topic of ongoing research. Therefore, in this narrative review, we evaluated the current evidence focusing on the effect of PA on arterial stiffness and vascular health and discussed the known underlying physiological mechanisms. PA, irrespective of its intensity or pattern, is consistently associated with lower arterial stiffness. Aerobic exercise, particularly at higher intensities, is the most effective strategy for reducing arterial stiffness. These benefits are especially significant in populations with higher cardiovascular risk, such as those with type 2 diabetes mellitus and hypertension. Therefore, maintaining an active lifestyle into older age is crucial for vascular health and may contribute to healthy aging.