Longevity Papers

Neural stem cells (NSCs) in the subventricular zone (SVZ) of the mammalian brain become increasingly quiescent with aging, which correlates to increased inflammatory signals in the SVZ. Targeting cells that secrete inflammatory signals, such as microglia, could potentially re-activate NSCs. In this study, we characterized CD11b-positive microglia isolated from post-mortem SVZ from non-demented control (Aged), Alzheimer's disease (AD), and Parkinson's disease (PD) by single-cell and bulk RNA sequencing. Our transcriptome data revealed changes in gene signature in SVZ microglia from PD and AD, highlighting a disease-dependent response. Culture of iPSC-derived NSCs with supernatant from Aged, PD, and AD SVZ microglia showed an increase in proliferation and neuronal differentiation in the PD condition. Furthermore, we identified NR4A2, a transcription factor that promotes an anti-inflammatory microglia state, as a potential molecular mechanism that promotes a pro-neurogenic microglia phenotype. Altogether, our work identified a pro-neurogenic subpopulation of SVZ microglia that could be a novel target to promote repair in neurodegenerative diseases.

Aging is the strongest risk factor for cognitive decline and Alzheimer\'s disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana\'s potential to combat brain aging and AD through sex-specific mechanisms.

The geroscience hypothesis suggests that understanding underlying ageing mechanisms will enable us to delay aging and lessen age-related disability and diseases. While hallmarks of ageing list multiple contributing factors, role of mechanics has only been recently recognized and increasingly appreciated. Here, we use mouse models of ageing to investigate changes in mechanics of the proximal pulmonary artery, lung and right ventricle function in ageing. We found an age-related decline in the capacity to store energy and increased circumferential stiffness of the proximal pulmonary artery with age that associated with a reorientation of collagen towards the circumferential direction, decreased exercise ability, and decreased function of the lung and right ventricle. The observed compromised mechanics in proximal pulmonary artery is consistent across multiple mouse models of accelerated ageing. Further, transcriptional changes in proximal pulmonary artery indicate that aging is associated with senescence of perivascular macrophages, adventitial fibroblasts, and medial smooth muscle cells. Older pulmonary arteries increase expression of genes associated with ECM turnover (including genes in the TGF{beta} pathway) and increased intercellular signaling amongst perivascular macrophages, fibroblasts and smooth muscle cells. Our results provide promising biomarkers of ageing for diagnosis and potential pathways and molecular targets for targeting anti-ageing therapies.

Mitochondrial quality control is essential for maintaining cellular energy homeostasis, particularly in brown adipocytes where dynamic mitochondrial remodeling supports thermogenesis. Although the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy are two major proteostatic systems, how these pathways intersect to regulate mitochondrial integrity in metabolically active tissues remains poorly understood. Here, using adipocyte-specific genetic mouse models combined with high-resolution 2D and 3D ultrastructural imaging technologies, we reveal an unexpected synergy between SEL1L-HRD1 ERAD and autophagy in maintaining mitochondrial structure and function in brown adipocytes. Loss of ERAD alone triggers compensatory autophagy, whereas combined deletion of both pathways (double knockout, DKO) results in severe mitochondrial abnormalities, including the accumulation of hyperfused megamitochondria penetrated by ER tubules, even under basal room temperature conditions. These phenotypes are absent in mice lacking either pathway individually or in SEL1L-IRE1 DKO, highlighting the pathway-specific coordination between ERAD and autophagy. Mechanistically, dual loss of ERAD and autophagy induces ER expansion, excessive ER-mitochondria contact, upregulation of mitochondria-associated membrane (MAM) tethering proteins, impaired calcium transfer, and defective mitochondrial turnover. As a result, DKO adipocytes accumulate dysfunctional mitochondria, exhibit respiratory deficits, and fail to sustain thermogenesis. Collectively, our study uncovers a cooperative and previously unrecognized mechanism of mitochondrial surveillance, emphasizing the critical role of ERAD-autophagy crosstalk in preserving mitochondrial integrity and thermogenic capacity in brown fat.

Climate change is exacerbating heatwaves, significantly increasing public health risks, including heightened vulnerability to Vibrio vulnificus infections, especially among older adults. While heat stress alone impairs immune regulation and compromises gut integrity, the combined effects of aging and climate-induced heat stress on infectious severity remain insufficiently explored. Using young (12-week-old) and aged (24-month-old) mouse models, we examined how aging and periodic heat stress synergistically influence susceptibility to Vibrio vulnificus by assessing gut microbiome alterations, immune responses, and antibiotic resistance gene dynamics. Heat stress markedly impaired intestinal barrier function, induced significant microbiome shifts, elevated systemic inflammation, and promoted enrichment of antibiotic resistance genes particularly those conferring tetracycline resistance with effects significantly amplified in aged mice. Upon Vibrio vulnificus infection, aged heat-stressed mice demonstrated elevated inflammatory responses, severe intestinal damage, and pronounced immune dysregulation compared to younger counterparts. Gut depletion and probiotic recolonization models further validated microbiota involvement, showing that Roseburia intestinalis significantly reduced heat stress-exacerbated CD4

Mitochondria are known as the powerhouse of the cell as through oxidative phosphorylation, they produce energy in the form of ATP. Nevertheless, mitochondria are also considered as the main producers of free radicals. Several mitochondrial parameters are needed to be examined to fully characterize mitochondria and the outcomes of their positive (i.e. energy production) or negative (i.e. production of free radicals/oxidative stress) function. Oxygen consumption rate (OCR) measurement is an excellent readout for mitochondrial respiratory capacity and it is the most frequently used assessment to examine mitochondrial function or as part of a broader bioenergetic profiling. Given the link between mitochondrial dysfunction, and increased oxidative stress and damage, and the fact that mitochondrial dysfunction is often reflected in OCR, its measurement is important for the complete characterization of the cellular redox status. Although much of this work is being done in cells or isolated mitochondria, there is an increasing need for the measurement of OCR in whole organismal models such as the nematode Caenorhabditis elegans. As a free-living organism with simple maintenance and conserved mitochondrial biology, C. elegans attracts interest as a model for ageing and age-related diseases, among others, in which bioenergetics but also various mitochondria-related redox aspects need to be evaluated. Therefore, the need for platforms suitable for OCR measurements in this model is evident. In this work, we have employed a newly developed system (Resipher) for the measurement of OCR in C. elegans and we outline basic protocols as well as the pharmacological interventions that can be used to assess the function of the respiratory chain. More specifically, we demonstrate the importance of the number of animals used in measurements that include mitochondrial complex inhibitors, how the presence of bacteria when used as a food source for the nematodes should be carefully considered and/or eliminated and how to avoid artefacts when measuring differently sized nematodes. The present work is not only intended to be used as a protocol for a specific measurement system but it can also be used as a guideline when setting up OCR experiments with any device, as it reveals parameters that may be overlooked and should be carefully considered.

Menopause not only affects fertility but also has widespread impact on systemic health. Yet, the molecular mechanisms underlying this process are not fully understood, partly due to the absence of robust, age-relevant preclinical models with comprehensive molecular and phenotypic characterization. To address this, we systematically compared three candidate mouse models of menopause: (1) intact aging, (2) chemical ovarian follicle depletion using 4-vinylcyclohexene diepoxide (VCD) administered at multiple ages, and (3) Foxl2 haploinsufficiency, a genetic model based on a transcription factor linked to human premature ovarian failure. Through histology, serum hormone profiling, single-cell transcriptomics and machine-learning approaches, we uncovered both shared and model-specific features of follicle loss, endocrine disruption, and transcriptional remodeling. The VCD and Foxl2 haploinsufficiency models revealed distinct patterns of hormonal and immune alterations not captured by intact aging alone. This comparative framework enables informed selection of context-appropriate preclinical rodent models to study menopause and the broader physiological consequences of ovarian aging.

Proteomics enables systematic elucidation of the biological mechanisms underlying health states including frailty. Here, through a large-scale proteome-wide association study (PWAS) encompassing 2,911 plasma proteins in 50,506 UK Biobank participants, we identified 1,339 proteins significantly associated with frailty, revealing novel functional modules implicated in frailty pathogenesis, particularly the one characterized by the collagen-containing extracellular matrix and vesicle lumen pathways. Replication analyses in an independent external cohort (TwinGene study) confirmed partial but consistent associations at both protein and pathway levels, supporting the reliability of these findings. Mendelian randomization analyses supported causal associations of 50 proteins with frailty. Protein-protein interaction network and expression quantitative trait loci analyses revealed MMP1 and LGALS8 serving as hub proteins. Moreover, we developed a novel proteome-based frailty measure, termed as Proteomic Frailty Score (PFS), which demonstrated robust predictive performance (C-index > 0.7) for 198 (30.2% = 198/655) incident diseases across 13 categories and broad responsiveness to 85 modifiable risk factors. Incorporating PFS into a conventional risk factors model significantly improved the predictive performance for 510 (77.9% = 510/655) incident diseases. Longitudinal analyses with three assessments (n~1000) revealed an accelerated progression of the PFS with advancing age and increasing baseline frailty severity. To facilitate public use, we further created a publicly accessible online tool for PFS calculation (https://zipoa.shinyapps.io/frailty/). Finally, we observed a biphasic pattern of frailty-associated proteomic dysregulation across lifespan, with peak transitions occurring at approximately ages 50 and 63, implicating distinct biological pathways. Together, we establish PFS as a robust biomarker of biological aging while identifying critical windows and molecular targets for interventions against frailty progression.

Aging is associated with impaired cerebrovascular function, including reduced functional hyperemia (FH), which contributes to cognitive decline and dementia. Unraveling the mechanisms responsible for FH decline during aging is crucial for developing interventions to promote healthy brain aging and mitigate cognitive impairment. Currently, laser speckle contrast imaging (LSCI) serves as the standard method for assessing FH in mouse models of cognitive dysfunction and aging. However, as a terminal procedure, long-term monitoring of changes in FH using LSCI is not possible. Functional ultrasound imaging (fUS) has improved spatial and temporal resolution compared to LSCI and is a promising alternative, but surgical manipulation of the mouse model is necessary to assess FH using fUS.

Aging is a systemic process marked by progressive multi-organ dysfunction, metabolic dysregulation, and chronic low-grade inflammation ("inflammaging"), which collectively drive neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). Emerging evidence underscores the brain-muscle-liver axis as a central hub for maintaining energy homeostasis and neuroimmune crosstalk during aging. Here, we elucidate how exercise orchestrates inter-organ communication to counteract age-related decline through metabolic reprogramming, immunomodulation, and neuroprotection. Mechanistically, exercise enhances mitochondrial biogenesis and oxidative capacity in skeletal muscle via AMPK/PGC-1α signaling, restoring fatty acid oxidation and glucose metabolism while producing myokines (e.g., BDNF and IL-6) that promote neuronal survival and synaptic plasticity. Concurrently, hepatic SIRT1 activation promotes lipid metabolism, mitigates insulin resistance, and reduces systemic inflammation, hence preserving brain energy supply. In the aging brain, exercise stimulates neurogenesis, suppresses neuroinflammation via NF-κB inhibition, and elevates BDNF levels, which synergistically enhance cognitive resilience. vitally, exercise modulates the neuro-immunometabolic axis by balancing pro- and anti-inflammatory cytokines (e.g., IL-6's hormetic role), optimizing immune cell function, and enhancing autophagy-mediated clearance of toxic aggregates (Aβ, α-synuclein). These adaptations are further amplified by epigenetic reprogramming, including but not limited to Nrf2-driven antioxidant responses and circadian rhythm synchronization. Our synthesis highlights exercise as a pleiotropic intervention that transcends single-organ influences, instead leveraging multi-tissue networks to delay aging and neurodegeneration. Unresolved challenges-personalized exercise regimens, molecular biomarkers for efficacy prediction, and combinatorial therapies with pharmacologic agents-underscore the need for translational studies integrating omics technologies and circadian biology. By bridging mechanistic insights with clinical applications, this review positions exercise as a cornerstone of precision medicine for aging populations.

The Obesity pandemic is a global health problem that has been reported to be more prevalent in women than in men. Obesity is a risk factor for numerous diseases and has recently been related to deficits in memory and learning processes. Chronic obesity is associated with senescent cell accumulation, peripheral and central inflammation, and cognitive decline. Hence, we aimed to evaluate the use of senotherapy to avoid these processes in a model of middle-aged female Wistar rats with chronic obesity. Rats received a hypercaloric diet (HD) from day 21 to middle age (14 months). The senomorphic sulforaphane (SFN) (0.5 mg/kg, 5 days/week) or the senolytic combination of Dasatinib + Quercetin (D + Q) (5 mg/kg and 50 mg/kg respectively, monthly) were administered from 12 to 14 months. The composition of the gut microbiota, the serum, cortical and hippocampal expression of pro- (IL-6 and IL-1β) and anti-inflammatory (IL-10) cytokines, as well as markers of cellular senescence (SA-β-gal, p21 and γH2AX) in the brain were determined. Also, the declarative memory (NOR test) and learning (Barnes maze) processes, and the expression of molecules involved in synaptic plasticity (BDNF, PSD95, and synaptophysin) were evaluated. HD-fed rats presented gut dysbiosis, local and systemic inflammation, and severe cognitive impairments. Senotherapy reversed inflammation, with SFN demonstrating greater effectiveness. D + Q treatment failed to prevent cognitive deficits or modulate gut microbial composition. In contrast, SFN significantly improved performance in both behavioral tests, increased SYP and PSD-95, and prevented some of the gut microbial changes induced by the HD.

Intervertebral disc degeneration (IDD) is a progressive and dynamic process in which the senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPC) plays a significant role. While impaired chaperone-mediated autophagy (CMA) has been associated with inflammation and cellular senescence, its specific involvement in the self-perpetuating feedback loop of NPC senescence remains poorly understood. Through LAMP2A knockout in NPC, we identified a significant upregulation of DYRK1A, a core mediator of premature senescence in Down syndrome. Subsequent validation established DYRK1A as the critical driver of premature senescence in CMA-deficient NPC. Combinatorial transcription factor analysis revealed that under IL1B stimulation or CMA inhibition, elevated DYRK1A promoted FOXC1 phosphorylation and nuclear translocation, initiating transcriptional activation of cell cycle arrest. Intriguingly, CMA impairment concurrently enhanced glutamine metabolic flux in senescent NPC, thereby augmenting their survival fitness. Transcriptomic profiling demonstrated that CMA reactivation in senescent NPC facilitated fate transition from senescence to apoptosis, mediated by decreased glutamine flux via GLUL degradation. Therefore, CMA exerts protective effects against IDD by maintaining equilibrium between premature senescence and senolysis. This study elucidates CMA's regulatory role in SASP-mediated senescence amplification circuits, providing novel therapeutic insights for IDD and other age-related pathologies.

Extracellular matrix remodelling of cardiac tissue is a key contributor to age-related cardiovascular disease and dysfunction. Such remodelling is multifaceted including changes to the biochemical composition, architecture and mechanics, clouding our understanding of how and which extracellular matrix properties contribute to a dysfunctional state. Here we describe a decellularized extracellular matrix-synthetic hydrogel hybrid scaffold that independently confers two distinct matrix properties-ligand presentation and stiffness-to cultured cells in vitro, allowing for the identification of their specific roles in cardiac ageing. The hybrid scaffold maintains native matrix composition and organization of young or aged murine cardiac tissue, whereas its mechanical properties can be independently tuned to mimic young or aged tissue stiffness. Seeding these scaffolds with murine primary cardiac fibroblasts, we identify distinct age- and matrix-dependent mechanisms of cardiac fibroblast activation, matrix remodelling and senescence. Importantly, we show that the ligand presentation of a young extracellular matrix can outweigh the profibrotic stiffness cues typically present in an aged extracellular matrix in maintaining or driving cardiac fibroblast quiescence. Ultimately, these tunable scaffolds can enable the discovery of specific extracellular targets to prevent ageing dysfunction and promote rejuvenation.

Age-related central nervous system (CNS) disorders, including neurodegenerative diseases, represent a growing global health burden. Mitochondrial dysfunction is a recognized hallmark in the pathogenesis of these conditions, emphasizing the critical importance of maintaining neuronal energy homeostasis and cellular integrity. Mitochondrial biogenesis, the dynamic process of generating new, functional mitochondria, is paramount for neuronal health and resilience against age-related decline. This review investigates the therapeutic potential of physical activity and polyphenols in modulating mitochondrial biogenesis and offering neuroprotection within the context of age-related CNS disorders. We explore how regular exercise profoundly impacts the brain by enhancing synaptic plasticity, promoting neurogenesis via neurotrophic factors like BDNF, and stimulating mitochondrial biogenesis through pathways such as PGC-1alpha activation. These adaptations collectively improve cognitive function and bolster neuronal resistance to damage. Concurrently, polyphenols, known for their antioxidant and anti-inflammatory properties, demonstrate significant neuroprotective effects. They are capable of crossing the blood-brain barrier and influencing key neuronal signaling pathways, directly stimulating mitochondrial biogenesis, and mitigating oxidative stress, thereby supporting neuronal survival. By synthesizing current evidence, this review highlights the complementary and potentially synergistic roles of exercise and polyphenols in preserving mitochondrial health and function in the CNS. The combined impact of these interventions offers a promising non-pharmacological strategy to combat age-related neurodegeneration. Future research should focus on optimizing exercise protocols and polyphenol interventions in human trials to maximize their neurotherapeutic benefits for CNS disorders.

Presbycusis, one of the most widespread disorders, is in part associated with the loss of temporal precision within the central auditory system. A contributor to the dysfunctional temporal precision during aging is the substantial downregulation of GABA in the central inferior colliculus (ICc), the hub of ascending and descending inputs of the auditory midbrain. However, how GABAergic inputs across the tonotopic axis of the ICc change with age has not been well explored. We sought to determine age-related changes to GABAergic synapses in the lemniscal ICc, and if changes are uniform across the ICc axis. Using immuno-electron microscopy across four age groups of Fisher Brown Norway rats, a model that acquires low frequency presbycusis, our results demonstrate several nonuniform ultrastructural changes to GABAergic synapses in the ICc. There was a significant (∼29-33 %) downregulation of GABAergic synapses in the high and middle frequency regions of old rats, but a loss (∼22 %) in the old low frequency region was not as robust and did not reach statistical significance. Interestingly, in the high and middle frequency regions, GABAergic presynaptic area increased with age, while there was an ultimately decline in the old low frequency region. Also unique to the high and middle frequencies was the increasing proportion of GABAergic synapses onto larger GABAergic dendrites. These changes demonstrate that aging differentially affects the GABAergic ultrastructure of the ICc tonotopic axis.

Lipoprotein retention in Bruch's membrane is a key event in the pathobiology of early and intermediate age-related macular degeneration (AMD). However, the mechanism of lipoprotein retention in BrM is unknown. Given the established role of glycosaminoglycans (GAG) in binding lipoproteins, our laboratory sought to determine the role of GAGs in AMD BrM. In this study, BrM GAG content in AMD pathobiology was analyzed in human postmortem tissue. Strikingly, increased levels of highly sulfated heparan sulfate were present in AMD Bruch's membrane as compared to non-AMD samples. In addition, using scanning electron microscopy of postmortem AMD tissue, we show aggregates of lipoprotein-like particles on the retinal pigmented epithelium side of Bruch's membrane adjacent to heparan sulfate. We also show that heparin displaces lipoproteins rich in apolipoprotein A1 from human BrM, suggesting their identity as high-density lipoproteins. Using human BrM immobilized to quartz crystal microbalance biosensor (QCM) chips, we show that heparan sulfate is required for lipoprotein binding to BrM and soluble heparan sulfate can remove lipoproteins bound to BrM. Thus, our data establish that heparan sulfate regulates lipoprotein deposition in AMD BrM. These findings provide a foundation for targeted therapies capable of either preventing lipoprotein accumulation or removing drusen in the early and intermediate stages of AMD prior to vision loss.

Background: Degenerative protein modifications (DPMs) accumulate with aging and can alter biomolecule structure and function, including via spontaneous conversion of Asn-Gly-Arg (NGR) to isoAsp-Gly-Arg (isoDGR) motifs that can bind integrins and drive chronic inflammation. Since isoDGR-modified extracellular matrix proteins are enriched in atherosclerosis and have been associated with rupture-prone plaque characteristics, we hypothesized that antibody neutralisation can inhibit key pathological features including atherosclerotic vascular plaque formation and metabolic dysfunction. Methods: We first examined Pcmt1-/- mice which rapidly accumulate isoDGR due to lack of the corresponding repair enzyme to assess the extent of vascular protein damage. We then treated 6-8 week old atherosclerosis-prone (ApoE-/-) mice which were fed a high-fat Western diet (WD) with weekly dose of 1mg/kg isoDGR-specific monoclonal antibody (isoDGR-mAb) or isotype-matched control (while on diet) for 2 months duration. A regular chow-fed ApoE-/- group served as baseline control. Aortic atherosclerotic burden, plaque composition, systemic inflammation, lipid profiles, hepatic steatosis, and metabolic parameters (indirect calorimetry) were assessed. Results: Pcmt1-/- mice displayed extensive isoDGR deposition and degeneration of the aortic wall, linking this DPM to vascular structural damage. In the ApoE-/- mice, WD induced large aortic root plaques with abundant isoDGR and macrophage infiltration. IsoDGR-mAb treatment decreased plaque size by ~30% with reduced lipid and collagen content (p=0.001). Furthermore, plaques in treated mice contained significantly fewer CD68+ macrophages that also exhibited limited activation. Systemically, isoDGR-mAb modified lipoprotein profiles by decreasing atherogenic VLDL/IDL/LDL cholesterol (p=0.04) while slightly increasing HDL, accompanied by a reduction in circulating inflammatory proteins. IsoDGR-mAb also protected against hepatic lipid accumulation which was reduced by ~60% in treated animals (p<0.001), with indirect calorimetry confirming ~30% higher oxygen consumption and energy expenditure without change in food intake or physical activity. Conclusion: We identified isoDGR as a key pathological factor involved in the progression of atherosclerosis. Remarkably, isoDGR neutralization diminished plaque inflammation and improved atherosclerotic plaque stability. Our findings support isoDGR neutralization as a promising therapeutic strategy to mitigate both atherosclerosis and aging-associated metabolic dysfunction.

Epigenetic aging measures are novel molecular indicators of biological aging that predict age-related chronic disease. We examined whether several established indices of epigenetic aging mediated the association between life course socioeconomic status (SES) and decrements in kidney function across a decade. Biomarker data were from 252 non-Hispanic (NH) Black and white participants who had consented to genetic analyses in Wave 2 (2004-2009) and 3 (2014-2021) of the Midlife in the United States study (MIDUS). Life course SES included parental education, a proxy of early life SES, and a composite score of adult SES based on the highest education level, household income to poverty line ratio, health insurance coverage, perception of the availability of money to meet needs, and difficulty level paying monthly bills. We included five measures of epigenetic age accelerations (EAA), based on the residuals after each epigenetic clock was regressed on chronological age (Horvath, Horvath blood and skin, Hannum, PhenoAge, and GrimAge) and one measure of the pace of aging (DunedinPACE) obtained during MIDUS 2. Kidney function was based on serum creatinine-based estimated glomerular filtration rate (eGFR), calculated using the CKD-EPI formula (without race adjustment). We calculated absolute decrements in eGFR across 11 years between MIDUS waves 2 and 3. Analyses were adjusted for age, sex, and health-related covariates (currently smoking, obese, hypertension, and insulin resistance). Lower adult SES and accelerated epigenetic aging, especially accelerated GrimAge and faster DunedinPACE pace of aging, mediated the association between lower parental education and larger decrements in eGFR. Accelerated epigenetic aging is associated with larger decrements in kidney function across a decade and may be one of the critical explanatory pathways for the higher burden of chronic kidney disease (CKD) among lower SES individuals.

Axenic dietary restriction (ADR) represents a powerful and unique DR regimen for C. elegans as it robustly extends lifespan independently of well-known key genes associated with DR, such as those of insulin/IGF-1 signaling, skn-1, and pha-4. Here, we analyze C. elegans survival in a dilution series of axenic medium to explore the dependency of lifespan extension on nutrient availability. We find a non-linear relationship between lifespan and axenic nutrient levels with a four-fold axenic dilution yielding peak longevity. Notably, lifespan extension at specific dilutions permits maintenance of reproductive potential and survivability after bacterial reintroduction, indicating a partial reliance on adult reproductive diapause mechanisms. Genetic analyses found the involvement of AMPK/aak-2, sir-2.1, and cbp-1 in mediating lifespan extension across the axenic dilution spectrum, the essential role of daf-16 and hlh-30 under severe nutrient scarcity, and the specific contribution of bli-4 to standard ADR longevity. These findings elucidate that C. elegans lifespan extension under different levels of nutrient restriction is governed by overlapping yet distinct genetic pathways.

The advanced maternal age is strongly correlated with a notable decline in oocyte quality, yet definitive and effective strategies to enhance it remain incompletely identified. In this study, we reported that near-infrared light, administered in vitro, efficaciously improves the quality of post-ovulatory aging (POA) and reproductive aged oocytes by recovering mitochondrial activity. Near-infrared light has the capacity to ameliorate abnormalities in mitochondrial membrane potential, optimize mitochondrial distribution, augment ATP synthesis, and modulate the expression of mitochondrial-related genes. It can consequently enhance the quality of oocytes by reducing the reactive oxygen species (ROS) level, improving the abnormal distribution of spindles and maintaining the fertilization ability. Moreover, transcriptome analysis also shows that the beneficial effect of near-infrared light on POA and reproductive aged oocytes is mediated by restoration of mitochondrial function. Collectively, our data reveal that the near-infrared light treatment, especially of 810 nm or 950 nm with a cumulative dosage of 1.5 J*cm-2, is a feasible approach to protect oocytes from POA and reproductive aged deterioration, contributing to the improvement of reproductive outcomes of aged women and assisted reproductive technology.

Background Senescence identification is rendered challenging due to a lack of universally available biomarkers. This represents a bottleneck in efforts to develop pro-senescence therapeutics - agents designed to induce the arrest of cellular proliferation associated with a senescence response in cancer cells for therapeutic gain. This is particularly true in contexts such as basal-like breast cancer (BLBC), which often express high levels of widely reported senescence hallmarks, which has led to the designation of these subtypes as senescence marker positive (Sen-Mark+). Unfortunately, these are often cancers with the most limited treatment options, where novel pro-senescence compounds would be of potential clinical utility. Results To address these challenges, we have developed SAMP-Score, a machine learning classification tool for identifying senescence induction in Sen-Mark+ cancers. This technique builds upon our previous observation that senescent cells develop distinct senescence-associated morphological profiles (SAMPs), which can be assessed readily in traditionally challenging contexts for senescence identification, including high-throughput screens. Conclusions Through application of SAMP-Score, we have identified QM5928, a novel pro-senescence compound, that is able to induce senescence in a variety of Sen-Mark+ cancers and has potential utility as a tool molecule to explore the mechanisms and pathways through which senescence induction occurs in these cells.

Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimer's model mice and a novel genetically encoded fluorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free-GTP co-localized in the mitochondria decreased with age accompanied by the accumulation of free-GTP labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while bafilomycin inhibition of autophagy raised GTP levels. 24 hr. supplementation of aged neurons with the NAD precursor nicotinamide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endocytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal A{beta} aggregates and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy deficits that impair autophagy and endocytosis. GTP deficits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path.

The study aimed to examine the antioxidant properties in vitro and the in vivo D-galactose-induced oxidative damage model from the fruiting bodies of Hypsizygus ulmarius Polysaccharide (HUP), which have an average molecular weight of 2.076 × 10

Chronological age is commonly used to study aging, but biological aging may more accurately reflect cumulative life experiences and psychosocial stressors. This study examines whether epigenetic clocks function as markers of resilience by assessing how marital status transitions are associated with biological aging and health outcomes in later life. Using data from 1,449 non-Hispanic White participants in the Health and Retirement Study, we analyzed thirteen epigenetic clocks derived from DNA methylation profiles. Ordinary least squares and Cox regression models assessed the associations between marital transitions, depressive symptoms, and mortality, adjusting for genetic and social factors. Interaction terms tested whether epigenetic clocks moderated these associations. Results showed that divorce and widowhood were linked to accelerated epigenetic aging. Marital status changes were associated with increased depressive symptoms but not with mortality risk. GrimAge and DunedinPACE moderated the relationship between marital disruption and depressive symptoms, while Zhang and GrimAge moderated the relationship with mortality risk. Biologically older individuals, particularly men, exhibited greater resilience to these transitions. These findings raise the possibility that epigenetic clocks reflect accumulated life experiences and psychosocial adaptation, potentially including elements of resilience in older adults.

Muscle loss of strength, mass, and function is a natural process that occurs with aging. It is referred to as sarcopenia and represents a major cause of disability. The assessment and quantification of muscle have garnered considerable interest, leading to the recent introduction of shear wave elastography (SWE) as a noninvasive and accessible method for evaluating muscle. Considering this, our systematic review aimed to define the impact of aging on muscle using SWE.

Telomere shortening is a hallmark of aging associated with various diseases, yet its impact on extracellular vesicles (EVs) remains poorly understood. We investigated EV abundance, size, cargo content, and functional implications in a human aging cohort and the telomerase reverse transcriptase null (

Recent research has found that, among some mammal species, differences in environmental conditions among populations of the same species drive changes in infant and juvenile mortality, but not in the rate of senescence, also known as the rate of ageing. Although this pattern has been confirmed in primates and some carnivores, it remains untested on other taxonomic groups with faster life histories, such as rodents. Here, we analysed age-specific survival in Hazel Dormouse, using a 24-year capture-mark-recapture data set from Lithuania. We used Bayesian survival trajectory analysis (BaSTA) and tested different models of age-specific mortality. The population has experienced three distinct demographic phases-increasing (1999-2006), declining (2007-2014) and stable-low abundance (2015-2022). We divided the dataset into these three periods to assess changes in survival over time. During all three periods, the life expectancy of males was larger than that of females, contrary to the general mammalian trend of higher female survival. Differences in survival among the three periods were primarily due to changes in age-independent mortality and ageing rates, but not due to changes in juvenile mortality. Our findings support the notion that the low variance rate of ageing is limited to species with slow life histories. However, they also suggest that rodents, even those like the Hazel Dormouse which can reduce exposure to external threats, can substantially modulate their ageing rates in response to environmental variation.

Dogs serve as ideal research subjects for aging studies. In this study, 9 aging-related cell populations are identified through single-cell RNA sequencing of dogs of different ages. Additionally, 9 CD8+ T cell senescence-specific markers conserved across species are identified. Furthermore, multi-omics technology is employed to characterize 17 transcriptional and protein markers, along with 5 metabolic markers, associated with stem cell aging. Penitrem A and UDP-N-acetylglucosamine are further validated as two consistent metabolic markers of both individual and cellular senescence. A customized metabolic assessment system and blood-based assessment framework specifically for aging dogs are developed. Notably, it is demonstrated that mesenchymal stem cells, particularly those overexpressing NMNAT1, can delay or reverse aging in dogs. This study sheds light on the mysteries of aging from multiple perspectives and provides a broad target for future research efforts aimed at uncovering the complexity of this fundamental biological process.

The apolipoprotein ε4 allele (APOE4) is associated with decreased longevity and increased vulnerability to age-related declines and disorders across multiple systems. Interventions that promote healthspan and lifespan represent a promising strategy to attenuate the development of APOE4-associated aging phenotypes. Here, we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2) to protect against impairments in APOE4 versus the predominant APOE3 genotype using early middle-aged mice with knock-in of human APOE alleles.

Adult neural stem cells exist on a continuum from deep to shallow quiescence that changes in response to injury or aging; however, the transcription factors controlling these stepwise transitions have not been identified. Single-cell transcriptomic analyses of mice with loss of function or increased levels of the essential activation factor

Aging involves the accumulation of various forms of molecular and cellular damage over time. Key features of aging, such as mitochondrial dysfunction, dysbiosis, and oxidative stress, are closely linked and largely driven by inflammation. This study examines the role of succinate, a key metabolite produced and utilized by cells of both host and microbes, and its receptor, succinate receptor 1 (SUCNR1), in age-related oral dysbiosis and inflammation. We examined young and aged wild-type (WT) and SUCNR1 knockout (KO) mice for this analysis. Our findings revealed significant aging-associated alveolar bone loss and succinate elevation in aged WT mice, along with notable changes in the oral microbiome. Conversely, aged KO mice showed reduced bone loss, lower succinate levels, less inflammation, and better-maintained microbial function. These results suggest that SUCNR1 is crucial in influencing aging-related succinate elevation, oral dysbiosis, and inflammation. Analysis of gene families and pathways in the oral microbiome demonstrated distinct aging-related changes between WT and KO mice, with the functional potential being preserved in the KO-aged group. This study underscores the importance of succinate elevation and signaling through SUCNR1 in regulating inflammation, alveolar bone loss, and shifts in the oral microbiome, offering potential targets for therapeutic interventions in age-related oral health issues.

Aging is a natural biological process influenced by endogenous and exogenous factors such as genetics, environment, and individual lifestyle. The aging-dependent decline in resting and maximum heart rate is a conserved feature across multiple species, including humans. Such changes in heart rhythm control underscore fundamental alterations in the primary cardiac pacemaker, the sinoatrial node (SAN). Older individuals often present symptoms of SAN dysfunction (SND), including sinus bradycardia, sinus arrest, and bradycardia-tachycardia syndrome. These can lead to a broad range of symptoms from palpitations, dizziness to recurrent syncope. The sharp rise in the incidence of SND among individuals over 65 years old, coupled with projected longevity over the next decades, highlights the urgent need for a deeper mechanistic understanding of aging-related SND to develop novel and effective therapeutic alternatives. In this review, we will revisit current knowledge on the ionic and structural remodeling underlying age-related decline in SAN function, and a particular emphasis will be made on new directions for future research.

Age-related retinopathy, primarily comprising age-related macular degeneration (AMD), is a major cause of irreversible blindness in the elderly population worldwide. Although its precise mechanisms remain incompletely understood, autophagy deficiency in retinal pigment epithelium (RPE) cells has been associated with AMD in patients; however, the regulatory pathways involved are not fully elucidated. In this study, we report that deficiency in the Dapl1 gene inhibits RPE cell autophagy and leads to age-dependent retinal pathologies in mice. Specifically, 18-month-old Dapl1-/- mice manifest age-related retinal dysfunction and structural abnormities, including increased retinal stress, photoreceptor/RPE cell damage, lipid aggregates and microglial activation. Furthermore, we demonstrate that autophagy is impaired in the RPE cells of Dapl1-/- mice, while overexpression of DAPL1 in RPE cells enhances autophagy activity. Mechanistically, we elucidate that DAPL1 suppresses the expression of E2F1 and c-MYC, which consequently downregulates mTOR and upregulates ATG16 and Beclin1 expression via DAPK1 in RPE cells, thereby promoting autophagy. Taken together, our findings demonstrate that DAPL1 acts as a novel regulator of autophagy in RPE cells, and its deficiency increases susceptibility to age-dependent retinal pathologies in mice.

The age-related decrease in skeletal muscle mass and function, mostly known as sarcopenia, increases the risk of mobility impairments, chronic disease and early mortality. Physical activity and targeted dietary approaches are the most effective intervention to prevent or limit sarcopenia. Omega-3 polyunsaturated fatty acids (PUFA) could alleviate some aspects of age-related diseases. We investigated the effect of a chronic intake of a diet containing a high content of omega-3 PUFA in old mice exposed to a normocaloric or an obesogenic diet. Female C57BL/6J mice received a low-fat or a high-fat diet containing 5 or 6%, respectively, of camelina oil (comprising 27% omega-3 PUFA) for 18 weeks and were compared to animals receiving the similar diets containing high-oleic sunflower oil instead. Circulating parameters, calorimetry and physical performances were evaluated as well as muscle lipid content and molecular adaptations. Consumption of camelina oil increased omega-3 PUFA content in biological membranes, as well as circulating levels of anti-inflammatory oxylipin mediators. High-fat diets induced changes in body composition but these effects were not affected by the intake of camelina oil. However, camelina oil consumption increased motor coordination in the low-fat condition. Some lipidomic adaptations were observed in relation to oil intake. Variations in plasma levels of glycerol, free fatty acids and muscle gene expression suggested improved lipid homeostasis in groups receiving camelina oil. In conclusion, the consumption of an energy-balanced diet with a high content of omega-3 PUFA provided by camelina oil could provide benefits on muscle health. CLINICAL TRIAL REGISTRATION: Not applicable.

Musculoskeletal disorders, particularly those affecting the shoulder, are a significant health concern, especially in aging populations. Nevertheless, the initiating factors of joint degeneration remain poorly understood. Research has primarily focused on age-related changes in individual musculoskeletal tissues, with limited investigation into the complex interactions between tissues. Recent studies on interorgan communication between musculoskeletal tissues and other organs have gained attention, but local interactions within the shoulder remain underexplored. This study aims to investigate age- and sex-related differences in bone-tendon-muscle (BTM) crosstalk, hypothesizing that these interactions vary by age and sex, with older and female tissues exhibiting a reduced secretory phenotype. Using novel in vitro monoculture and co-cultures of explanted whole tissues, we assessed inflammatory responses across bone, tendon, and muscle from young and aged male and female C57BL/6J mice. Our results demonstrate significant age- and sex-dependent differences in cytokine secretion, with aged males and females showing altered inflammatory profiles. We observed a general increase in pro-inflammatory cytokine secretion in monocultures, with aging amplifying this response. Tissue co-cultures revealed that crosstalk between bone and tendon was primarily mediated through secreted factors, while muscle-tendon communication required physical proximity or contact, suggesting a distinct mode of interaction between these tissues. Sex differences were evident in both the individual tissue responses and in the patterns of inter-tissue communication. Importantly, our findings suggest that tendon plays a crucial role in mediating inter-tissue communication, with aging disrupting this crosstalk. However, these sex differences diminished with aging, indicating that the age-related decline in tissue-specific signaling may override sex-based distinctions.

Subtle biological changes related to frailty may be undetected by standard clinical methods, and reliable biomarkers for frailty are still under investigation. This study was conducted to profile plasma metabolite patterns associated with frailty and validate the most significant metabolite for identifying and predicting frailty in cross-sectional and longitudinal analyses.

Aging affects the function of multiple organs, including the spleen, which undergoes age-related structural changes and functional decline. Polygonatum sibiricum, a traditional anti-aging herbal medicine, contains saponins as its primary active components. However, the potential effects and underlying mechanisms of Polygonatum n-butanol extract (PNBE), which is rich in saponins, on splenic aging remain to be elucidated.

Green tea processing creates a hot acidic environment that facilitates reactions between catechins and hydroxycinnamic acids (HCAs), generating new catechins. Accordingly, we developed a one-pot method incorporating a Michael addition reaction to synthesize 13 phenylpropanoid-substituted ester-type catechins (PSECs), whose contents exhibit seasonal changes in tea leaves similar to those observed for common catechins. These PSECs showed antiaging effects in

Senescent bone repair faces significant obstacles due to reduced cellular activity and an unfavorable microenvironment, both of which hinder the osteogenic differentiation of bone marrow-derived stem cells (BMSCs) into osteoblasts (OBs) and subsequent bone formation. Current approaches primarily target senescent cell clearance (senolytics) or suppression of the senescence-associated secretory phenotype (senomorphics), neglecting the complex interactions between BMSCs and the osteogenic microenvironment. In this study, a genetically engineered hydrogel incorporating NAD-dependent deacetylase sirtuins 3 (SIRT3)-loaded nano-vectors and poly (glycerol sebacate)-co-poly (ethylene glycol)/polyacrylic acid (PEGS/PAA) was developed as an "inside-out" strategy for bone regeneration. At the intracellular level, BMSC function is restored, and osteogenesis is promoted through genetically enhanced SIRT3 expression. At the extracellular level, carboxyl functional groups chelate iron ions, simulating a hypoxic environment and promoting synergistic interactions between angiogenesis and osteogenesis. The therapeutic effects of the genetically engineered hydrogel in alleviating senescent damage and enhancing osteogenic differentiation were confirmed in both chemically and naturally induced senescence models

Cellular senescence, a major contributor to aging and age-related pathologies, is characterized by irreversible proliferative arrest and a disease-linked, proinflammatory profile known as the Senescence Associated Secretory Phenotype (SASP). A critical unanswered question is whether these properties are regulated by specific enhancer subsets, potentially licensing strategies that selectively block deleterious SASP components. Here, we identify two functionally distinct and independently regulated enhancer programs underlying senescence that are controlled by different TGF-β family ligands. Whereas Activin A stimulates recruitment of nuclear factor IA/C (NFIA/C) and SMAD2/3 transcription factors to an enhancer network that induces proliferation arrest, TGF-β2 promotes SMAD2/3-mediated suppression of a p65-dependent enhancer cohort driving the SASP. We have also uncovered reciprocal SMAD2/3-super-enhancer-regulated feedback loops that govern expression of the TGF-β2 (

This study aimed to compare the effects of four structured exercise interventions-Tai Chi, Baduanjin, square dance, and Latin dance-on cognitive function, physical health, body composition, and psychosocial outcomes in older adults.

Psoriasis burdens children and adults, but the impact of air pollution and aging is unclear. This study examines the association between air pollution exposure and psoriasis risk, considering the mediating role of biological aging. A prospective cohort study of 284,544 adults (51.3% female, mean age 56.26 ± 8.10 years) from the UK Biobank examined long-term exposure to air pollutants (PM2.5, PM10, PM2.5-10, NO2, and NOX). Biological aging was assessed using phenotypic age algorithms. Cox proportional hazards models were constructed to analyze the relationships with the risk of psoriasis, adjusting for demographic, socioeconomic, and health-related factors. Mediation analysis explored the role of biological aging. During a median follow-up of 15.58 years, 3,446 (1.21%) participants developed psoriasis. After adjusting for all confounders, each ten-unit increase (10 μg/m³) in PM2.5, PM10, NO2, and NOx, corresponded to the significantly increased risk of psoriasis by 95.7% (HR = 1.957, 95% CI 1.435-2.671), 19.7% (HR = 1.197, 95% CI 1.006-1.426), 9.0% (HR = 1.090, 95% CI 1.043-1.138) and 4.4% (HR = 1.044, 95% CI 1.024-1.066), respectively. Moreover, all air pollutants are significantly associated with biologically aging, while each one-year increase in PhenoAge was associated with a 5.0% higher risk of psoriasis (HR = 1.050, 95% CI 1.045-1.056). Finally, accelerated biological aging partially mediated 5.96%-13.86% of these air pollutants. Long-term exposure to air pollution significantly affects psoriasis risk, with biological aging as a partial mediator. Reducing pollution may lower the risk of psoriasis by slowing biological aging.

Sahu et al. (2024) demonstrate that targeted partial reprogramming with Oct4, Sox2, and Klf4 (OSK) delivered via adeno-associated virus (AAV) to Cdkn2a-positive cells rejuvenates senescent cells while maintaining cellular identity. In a progeroid and naturally aged mouse model, a single AAV injection improved lifespan, reduced inflammation, restored tissue integrity, and enhanced wound healing. Complementary results in human fibroblasts confirmed Cdkn2a-driven OSK expression attenuated inflammation-associated genes during replicative senescence and treatments inducing DNA damage. These encouraging results highlight its potential as a safer alternative to systemic senolytic therapies for age-associated disorders.

Inhibition of the activity of Pma1, a widely conserved P-type proton exporting ATPase, has been shown to extend the chronological lifespan (CLS) in fission yeast Schizosaccharomyces pombe. To develop a specific inhibitor for Pma1 of S. pombe, we focused on Si01, a candidate inhibitor of Saccharomyces cerevisiae Pma1. First, we have established a method for synthesis of Si01 and then investigated its Pma1 inhibitory activity and lifespan extension effect in fission yeast. Second, we also synthesized derivatives of Si01 and determined the minimum structure required for inhibition of S. pombe Pma1. Here we showed that the inhibitory activity of Pma1 correlates with the effect of lifespan extension. Si01 reduced the activity of purified Pma1 protein and extended the CLS of not only fission yeast but also budding yeast. These results provide a molecular basis for understanding the mechanism of Pma1 inhibition and the potential for developing molecules that regulate lifespan.

The transient upregulation of cellular senescence within wound tissues has been demonstrated to be an important biological process facilitating efficient tissue repair. Dysregulation of this transient wound-induced senescence-like response can result in impaired healing outcomes. Given the established age-related decline in tissue regenerative capacity, we hypothesized that alterations in this senescence response contribute to the delayed healing of cutaneous wounds in aged individuals. Our investigation demonstrated a significant delay in the closure of full-thickness dorsal skin wounds in aged mice compared to their young counterparts. Analysis of the wound microenvironment revealed a transient upregulation of senescence-associated markers (p16, p21, senescence-associated {beta}-galactosidase) and senescence-associated secretory phenotype factors in the wound tissue of young mice, a response that was markedly attenuated in aged mice. Single-cell RNA sequencing analysis of all cells isolated from day 6 wounds identified a distinct population of p16+/p21+/Ki67- senescent fibroblasts in young mice, characterized by a transcriptional signature indicative of pro-healing extracellular matrix production, a finding corroborated in human wound tissue from young donors. Crucially, in aged wounds, we observed a lower quantity of these senescent cells, a deficit compounded by a qualitative, age-dependent shift in their function, moving away from beneficial extracellular matrix remodeling towards a more detrimental pro-inflammatory state, which ultimately can contribute to the delayed wound healing.

Nicotinamide mononucleotide (NMN) is a nucleotide of significant biological importance, found abundantly in various foods such as meat, fruits, and vegetables. Recently, its potential effects in delaying aging have attracted considerable attention. Although chemical synthesis methods are commonly employed, they do not align with green production standards. In contrast, the biosynthesis of NMN is both safer and more environmentally sustainable. In this review, we established a novel "substrate-pathway-enzymology" framework to analyze the research on NMN biosynthesis. First, we systematically trace four substrates (nicotinamide ribose, nicotinamide, niacin, and nicotinamide adenine dinucleotide) and their respective metabolic routes. Then, we thoroughly investigate key enzymes through structural biology and protein engineering approaches, and converge the fragmented research findings across pathways to construct a comprehensive NMN biosynthesis network, revealing intricate metabolic regulations and pathway interactions. Through comparative analysis, the most promising biosynthetic pathway and prospects are discussed. Additionally, this review also provides original perspectives for NMN industrial development.

Xylo-oligosaccharide (XOS), a prebiotic oligosaccharide, has been reported to exert the beneficial effects on the host, primarily by modulating the gut microbiota and associated metabolism. However, the specific microbes, their metabolic interactions and mechanistic insights remain understudied. In this study, we aim to investigate the response of gut microbiota to XOS at the fine-grained level using combined approaches of microbiome sequencing, genomic analyses, and metabolomic analyses based on in vitro fecal fermentation using healthy human fecal samples. The results showed that XOS significantly altered the composition of the gut microbiota and enriched numerous bacterial taxa, such as Blautia, Bifidobacterium longum subsp. longum, and Faecalibacterium prausnitzii. Functional genomic analyses further confirmed that specifically identified XOS-responsive bacteria harbored varied XOS-utilizing capacities, consistent with the levels of their abundance elevation. The fecal metabolomics analysis revealed that XOS intervention significantly altered the metabolic profile (γ-aminobutyric acid, serotonin, and inosine). The microbe-microbe and microbe-metabolite interaction networks consistently identified three independent groups, potentially representing different levels of XOS degradation and/or other response mechanisms. Finally, the beneficial effects of XOS on the gut microbiota and metabolism were confirmed by the alleviation D-galactose-induced aging in mouse model. This study supports the role of XOS as prebiotics and highlights the potential of XOS in alleviating host aging-associated phenotypes in a D-galactose-induced aging mouse model in terms of improvements on cognitive function, inflammatory markers, and oxidative stress levels.

The relationship between gut microbiota and host health and disease is intricate, with microbiota-derived metabolites playing a crucial role in the gut-organ axis. In this study, we observe significantly decreased levels of microbial metabolites, particularly tryptophan derivatives in osteoporosis mice. Loss of tryptophan induced intestinal epithelial barrier dysfunction which compromised intestinal barrier integrity, leading to bone inflammatory responses and pathological osteoporosis. Through supplementation of tryptophan-producing bacteria, we effectively repair damaged intestinal barriers in colitis mice and mitigate bone loss, indicating the link between chronic colitis and osteoporosis. This approach offers a promising synthetic biology-based strategy to improve osteoporosis therapy by targeting gut tryptophan. This intervention also alleviates age-related osteoporosis in an aged mouse model, providing a potential therapeutic avenue for combating osteoporosis, a disease of growing concern in aging populations.

Many countries in the world are entering society with an aging population. The kidney is one of the most sensitive organs in the body to aging. Kidney function gradually declines with aging. Renal aging is one of the main triggers of CDK. Therefore, many researchers in the field are looking for natural, green and healthy anti-renal-aging bioactive molecules.

Calorie restriction has been shown to dramatically extend lifespan in a range of species. Beyond longevity, calorie restriction is also reported to improve cognitive function, ameliorate neurodegeneration and peripheral nerve damage, reduce cancer incidence, and is commonly used to increase motivation in studies of behaviour. The mouse has been the most common species for these experiments and whilst efforts are ongoing to demonstrate the benefits of calorie restriction in humans, the evidence in mice is most compelling. Many mechanisms have been proposed for the beneficial effects of calorie restriction, but we note that one potentially important factor has seldom been considered: namely that mice readily enter torpor in response to food restriction. Torpor is a remarkable protective physiological state characterized by profound reductions in body temperature, oxygen consumption, heart rate, and activity. In this review, we describe the dietary protocols used to study the effects of calorie restriction and present the case that mice in these studies are highly likely to have entered torpor. We discuss the extent to which torpor might influence or mediate the measured outcomes. We highlight that induction of torpor is an important confound that is rarely, if at all, considered in calorie restriction research and make recommendations for the design and conduct of future studies.