Longevity Papers

Aging impairs cerebrovascular structure and function, contributing to cognitive decline and dementia. Here, a novel, high-resolution, intravital imaging platform is presented that combines functional ultrasound (fUS) and ultrasound localization microscopy (ULM) through a chronically implanted, polymethylpentene (TPX) cranial window, a transparent implant that enables ultrasound imaging through the skull. This approach enables intravital, longitudinal, minimally invasive assessment of cerebrovascular structure and function across cortical and deep brain regions. Leveraging this platform, a new method is developed to estimate resting cerebral blood flow (CBF) by integrating microbubble (MB) velocity data from fUS with microvascular geometry derived from ULM. Notably, a significant age-related decline in the cortical arteriole-to-venule ratio (AVR) is discovered, introducing a novel biomarker of structural cerebrovascular remodeling. It is also validated that fUS can reliably assess neurovascular coupling (NVC) responses in aged mice. This study establishes a powerful, non-invasive, and repeatable investigative tool for future preclinical studies aimed at evaluating the efficacy of therapeutic interventions targeting vascular contributions to cognitive impairment and neurodegeneration.

In this report, we aim to systematically investigate the neural changes related to healthy aging in the presupplementary motor area (pre-SMA) and how these changes are associated with the semantic fluency task difficulty. We quantified a spatial cerebral blood flow (CBF) gradient based on previously identified task-specific subregions of the pre-SMA using pseudo-Continuous Arterial Spin Labeling, and we assessed the excitatory-inhibitory balance (EIB) using the ratio of gamma-aminobutyric acid (GABA+) to glutamate and glutamine complex (Glx) using magnetic resonance spectroscopy. We identified an ascending gradient in CBF from anterior to posterior among younger participants, which was absent in older participants. We interpret this loss of the CBF gradient in the context of neural dedifferentiation. There was a notable difference in tissue-corrected EIB between younger and older participants. Older participants exhibited a stronger inhibitory tone in the pre-SMA, driven by reduced tissue-corrected Glx in the older cohort. We interpret the increased EIB as a potential marker of under- or over-compensated synaptic scaling. Additionally, we found no relationship between neural dedifferentiation, as indicated by the CBF gradient, and synaptic scaling (EIB), suggesting that these are two distinct processes related to age-related neural changes. The tissue-corrected EIB exhibited a positive relationship with the difficulty of the semantic fluency task. However, we found no correlation between behavior and the CBF gradient. Our findings indicate that the inhibitory tone and synaptic scaling in the pre-SMA, rather than the CBF gradient and neural dedifferentiation, are crucial for managing the challenges posed by the semantic fluency task.

Mitochondrial dysfunction and impaired mitophagy are hallmarks of ageing and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, Urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analysis reveals that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In

Mosaic loss of the Y chromosome (mLOY) is the most common somatic event in men, strongly associated with aging and various health conditions. Current methods for detecting mLOY primarily rely on DNA genotyping arrays. Here, we present MosCoverY, a method for estimating mLOY from exome or whole-genome sequencing data. MosCoverY addresses the challenges posed by the structure of the Y chromosome by focusing on single-copy genes and normalizing their coverage against autosomal exons matched by length and GC content. We validated it using data from 212,062 male participants in the UK Biobank, comparing the results to those obtained using genotyping- or whole-genome-sequencing-based methods. MosCoverY identified mLOY in 5.6% of men, demonstrating performance that was comparable to the other methods. We validated our approach by replicating known mLOY associations with age, smoking, all-cause mortality, and germline genetic loci. We further confirmed the robustness of our method at lower sequencing depth and demonstrated its applicability in single-sample analysis. Finally, we used data from The Cancer Genome Atlas to demonstrate that MosCoverY can also reliably detect variable mLOY in tumoral genomes. MosCoverY offers a valuable tool for detecting mLOY from exome or genome data in population-scale studies.

Life expectancy is increasing worldwide, with older adults expected to account for 16% of the population within 30 years. Understanding age-related declines in muscle function is crucial for prevention and maintaining independence in Activities of Daily Living (ADL). Additionally, a major consequence of these declines is the development of the physical frailty phenotype. Therefore, this study aimed to identify changes in muscular coordination during elbow flexion and extension with aging and varying movement velocities. Twelve older adults (76 ± 6.5 years) performed the movements at varying angular velocities using a constant 1 kg external load (0.4 Nm). Elbow joint kinematics and muscle activity (biceps brachii, brachioradialis, and triceps brachii) were recorded using motion capture and surface electromyography and compared to 15 healthy young adults (26.2 ± 3.2 years) under identical conditions. Clinical assessments in the older group also evaluated comorbidities, ADL dependency, and frailty risk. Despite being considered healthy, older adults showed indicators of physical decline and exhibited increased muscular coactivation, possibly as a compensatory mechanism to maintain joint stability. However, coordination patterns remained unchanged across velocities, indicating stability with age. These findings suggest changes may occur before clinical decline and should be considered in training strategies for older adults.

Although dermatologic conditions primarily manifest on the skin, an increasing amount of evidence demonstrates that these inflammatory conditions can have a deeper impact on our systemic health. The use of epigenetics to measure biological age, instead of chronological age, can give us insight into the systemic burden of these diseases on aging. We aimed to understand the degree to which each dermatological condition affects biological aging. A systematic review was performed of PubMed, Embase, and Web of Science to identify all publications that measured biological age in dermatological patients using epigenetic clocks. Six articles involved the following conditions: atopic dermatitis (AD) (1), hidradenitis suppurativa (HS) (1), and psoriasis (PsO) (4). Notably, patients with psoriatic arthritis, but not psoriasis alone, demonstrated significantly increased epigenetic aging compared to controls. Pediatric AD patients had an increase in the rate of biological aging as measured by the Horvath, Skin and Blood, PhenoAge, and GrimAge clocks. HS patients were found to have an increased biological age when assessing tissue from affected skin. Further research is needed to investigate correlations between disease severity and epigenetic aging, and for expansion into other dermatological diseases. Additionally, epigenetic clocks need to be developed that utilize different subsets of inflammation more broadly and skin biomarkers to provide a more accurate estimation for chronic inflammatory dermatological conditions.

Aging is accompanied by degeneration of the intervertebral discs (IVDD), which leads to a poor quality of life and a significant socioeconomic burden. The present study aimed to explore the effect of transcription factor Yin and Yang 1 (YY1) on IVDD and to elucidate the potential underlying mechanism.

Scientific discovery has long relied on human creativity, with computation limited to analysis. Here we report an AI-guided system, K-Dense, that accelerates hypothesis testing and delivers robust scientific discoveries. Trained on ARCHS4 (57,584 samples, 28 tissues, 1,039 cohorts, ages 1-114), the unified ensemble clock achieved R2 = 0.854 and MAE = 4.26 years, while uniquely providing calibrated confidence intervals. This self-aware design flags predictions made at transitional or extreme ages, where biological heterogeneity peaks, suggesting clinical utility for uncertainty itself. Development revealed stage-specific markers, including CDKN2A/p16 (senescence), AMPD3 (muscle wasting), MIR29B2CHG (progeroid traits), and SEPTIN3 (neurodegeneration resistance). Sliding-window analysis across 85 overlapping ranges uncovered wave-like shifts in gene importance, showing that transcriptomic aging signatures evolve continuously, not discretely. By transforming biological age assessment from static point estimates to calibrated predictions with explicit uncertainty, this approach establishes reliable and interpretable clocks. Beyond the clock itself, K-Dense demonstrates how guided AI can compress months of exploration into weeks, pointing toward a scalable framework for accelerated scientific discovery.

Peripheral nerve injuries (PNI) present a significant challenge, particularly in aging populations where Schwann cell dysfunction, reduced c-Jun expression, increased senescence, and impaired myelin clearance hinder regeneration. Targeted therapies aim to restore Schwann cell plasticity and improve nerve repair. These include gene therapy to upregulate c-Jun, senolytic agents to eliminate senescent Schwann cells, pharmacological activation of JNK, ferroptosis inhibition, and stem cell-based transplantation. Biomaterial advancements, such as nerve guidance conduits, extracellular matrix hydrogels, and 3D-printed scaffolds, provide structural and biochemical support. Despite these advances, clinical translation remains challenging due to patient heterogeneity, the need for personalized approaches, and regulatory considerations. Integrating multimodal strategies holds promise for optimizing peripheral nerve repair in aging individuals. Future research must refine these therapies to develop clinically viable solutions that enhance functional recovery and improve quality of life for patients with PNI.

Bioactive compounds from food-compatible medicinal herbs have shown promise as preventive agents against age-related neurodegenerative conditions, particularly Alzheimer's disease (AD). The present work aimed to find Lobetyolin as a new suppressor of Aβ aggregation and its interventions on abnormal metabolism in AD. Aβ-expressing Caenorhabditis elegans (strain CL4176) and wild-type worms were employed to evaluate paralysis onset, lifespan, cerebral Aβ deposition, and intracellular reactive oxygen species (ROS) after Lobetyolin administration. Untargeted ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) metabolomics coupled with RNA-seq transcriptomics was carried out to profile systemic metabolic and gene-expression changes. Differential metabolites and transcripts were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and pathway-impact analyses; hub targets were prioritized by integrating enrichment scores with in-silico docking. Lobetyolin (12.5-50 µM) markedly protected C. elegans from Aβ-driven toxicity and oxidative stress. In CL2006 worms, β-amyloid deposits fell by 54.8 ± 9.4%, while paralysis in CL4176 was delayed by 20.9 ± 4.5%. Lifespan increased by up to 18.2% in CL4176 and 25.0% in wild-type N2 worms. Concomitantly, intracellular ROS declined maximally by 28.1 ± 8.9% (N2) and 22.4 ± 3.8% (CL4176). Integrative metabolomic-transcriptomic analyses, validated by RT-qPCR, revealed selective remodeling of glutathione metabolism: gst-38 expression was suppressed, whereas gst-1 was elevated. Lobetyolin confers neuroprotective and geroprotective benefits in vivo, primarily through reprogramming glutathione-centered redox metabolism and selectively modulating glutathione-S-transferases (GST) isoforms. These findings position Lobetyolin as a promising dietary lead compound for AD prevention and healthy aging interventions.

Exercise protects against age-related declines in skeletal muscle mass and function while improving overall health. Exercise can also prime long-term muscle health to enhance adaptations upon exercise retraining, a phenomenon termed muscle memory that remains largely understudied. To assess how prior endurance training elicits a lasting metabolic memory in skeletal muscle, we utilized C57BL/6 mice fed either a control (CD) or obesogenic diet (HFD) that underwent 4-week training, detraining, and retraining periods. Our results show that exercise retraining attenuated weight gain and potentiated muscle growth, even with reduced voluntary running volumes. Training increased fiber size (fCSA), which disappeared with detraining and was recovered with retraining regardless of diet, pointing to a glycolytic-to-oxidative fiber shift. Transcriptomic analysis (bulk RNA-seq) of the retrained muscle revealed a robust enhancement of mitochondrial oxidative phosphorylation (OxPhos) and mitoribosomal genes, paralleled by increases in OxPhos protein complex IV levels, higher long-chain fatty acid oxidative capacity (ACADL), and sustained citrate synthase activity 1 week after retraining, reinforcing the optimization of mitochondrial metabolism. While transcriptomic evidence revealed a major overlap between HFD- and CD-fed mice, discrepancies in protein abundance emerged, which point to an intricate regulation of mitochondrial programming that supports the muscle memory of growth. Our study identifies common and selective mechanisms by which the muscle memory of exercise overrides dietary challenges and promotes fiber hypertrophy, offering insight into potential mechanisms to leverage to promote healthy aging.

A multidimensional social exposome (MSE)-the combined lifespan measures of education, food insecurity, financial status, access to healthcare, childhood experiences, and more-may shape dementia risk and brain health over the lifespan, particularly in underserved regions like Latin America. However, the MSE effects on brain health and dementia are unknown. We evaluated 2211 individuals (controls, Alzheimer's disease, and frontotemporal lobar degeneration) from a non-representative sample across six Latin American countries. Adverse exposomes associate with poorer cognition in healthy aging. In dementia, more complex exposomes correlate with lower cognitive and functional performance, higher neuropsychiatric symptoms, and brain structural and connectivity alterations in frontal-temporal-limbic and cerebellar regions. Food insecurity, financial resources, subjective socioeconomic status, and access to healthcare emerge as critical predictors. Cumulative exposome measures surpass isolated factors in predicting clinical-cognitive profiles. Multiple sensitivity analyses confirm our results. Findings highlight the need for personalized approaches integrating MSE across the lifespan, emphasizing prevention and interventions targeting social disparities.

The environment experienced by children, such as exposure to chronic early life adversity (ELA), increases lifespan brain disorder risk. The mechanisms that link ELA exposure to functional brain disruptions are not well understood. A limited-bedding and nesting paradigm, in which ELA is induced in mouse pups over the first postnatal week through disruption of maternal care, is characterized by limited resources, environment unpredictability, and disruption of reward and cognitive behaviors. Studies using this model demonstrated sex-selective alterations in hippocampal mitochondrial-associated proteins in response to ELA compared to care as usual (CAU). Further, oxidative phosphorylation (OXPHOS) capacity and complex I activity are increased in ELA juveniles, yet decreased in adults, with the impact of ELA moderated by sex in female adults. Given that altered mitochondrial function is a key mediator in metabolic adaptations, the goal of the present study was to evaluate the possibility of reversing mitochondrial dysfunction and the anhedonia that accompanies ELA by addressing oxidative stress. Treatment with the antioxidant MitoQ began at weaning and extended to 3 months. Measures of complex I activity demonstrated full recovery in adults. Female-specific deficits in the sucrose preference task, which is a measure of rewarding behavior in rodents, also exhibited recovery, with preference for sucrose comparable to that of CAU mice. These data indicate that mitochondrial health is one component of responses to early life adversity that has lifespan implications, but with the capacity to recover normal functioning in adults.

BackgroundGrowing epidemiologic evidence suggests long-term exposure to air pollution increases the risk of Alzheimer's disease and related dementias (ADRD) in older adults but research on its effect on early indicators of ADRD is limited.ObjectiveWe examined the effect of fine particulate matter (PM

The relationship between the geographic environment and human health has been a long-standing focus of scientific inquiry. Sn as an essential trace element for the human body, play vital roles in individual health and may influence longevity. However, the extent to which the statistical characteristics of population longevity are associated with elemental geochemical background values at a regional scale remains an important question. Based on the geochemical survey data of Yunnan Province and Chinese census data, the article utilizes Arcgis spatial analysis and mathematical statistics to explore the relationship between ω(Sn) and regional longevity level. The results of the study show that: (1) There is a close correlation between ω(Sn) and regional longevity levels. Within Yunnan Province, regions with high ω(Sn) have higher levels of longevity index and Ultra-octogenarian Index. (2) Spearman's correlation coefficient shows that ω(Sn) is significantly positively (P < 0.01) correlated with both the longevity index and the Ultra-octogenarian Index; Linear regression further reveals that ω(Sn) always has a significant positive influence on the longevity index. For the Ultra-octogenarian Index, although the strength of the influence of ω(Sn) is not as significant as that of the longevity index, its influence on the healthy longevity of the population cannot be ignored. At the county scale in Yunnan Province, there is a significant positive correlation between ω(Sn) and longevity index, which may be related to the exposure of Sn in the natural environmental background into the human body and thus affecting the incidence of cancer, but the biogeochemical cycling mechanism of its association with longevity still needs to be further investigated.

Biological age is a major risk factor in the development of common degenerative retinal diseases such as age-related macular degeneration and glaucoma. To systematically characterize molecular mechanisms underlying retinal aging, we performed integrated single-cell RNA- and ATAC-Seq analyses of the retina and retinal pigment epithelium (RPE) across the natural lifespan in zebrafish, mice, and humans. By profiling gene expression and chromatin accessibility, we identified extensive cell type- and species-specific aging-dependent changes, with a much smaller number of broadly expressed and conserved genes that include regulators of inflammation and autophagy. We constructed predictive aging clocks for retinal cell types and observed dynamic, reversible shifts in cellular age following acute injury. Spatial transcriptomic analysis revealed region-specific aging signatures and proximity effects, with Muller glia exhibiting pro-rejuvenating influences on neighboring neurons. Targeted Muller glia-specific induction of Yamanaka factors reduced molecular age in rod photoreceptors and bipolar cells without altering glial age. Our findings define conserved and divergent regulatory and signaling pathways mediating retinal aging, highlighting Muller glia as potential therapeutic targets for combating age-associated retinal dystrophies.

Influenza A virus (IAV) infection causes significantly greater morbidity and mortality in the elderly population, but the molecular mechanisms in the aging process responsible for severe infection remain unclear. In this study, we found that increased severity in IAV infection and reduced innate immune response correlated with extensive mitophagy in senescent human cells and in the lung of aged mice. Apolipoprotein D (ApoD) was identified as strongly elevated in the lungs and sera of aged human (>65 y old) and mouse (>21 mo old). ApoD was able to localize to mitochondria and interact, through its WXXI motif in the LC3B-Interacting Region domain, with LC3B to trigger mitophagy during IAV infection, in a PINK1 pathway independent manner, which attenuated type I interferon response and promoted virus replication. ApoD deficiency, on the other hand, protected older mice from severe influenza and improved survival. Likewise, depletion of senescent cells by ABT-263, a senolytic compound, in aged mice lowered ApoD level and restored innate immune antiviral response, limiting virus propagation and associated pulmonary damage. Thus, age-induced ApoD drives IAV-mediated mitophagy, and promotes virus replication and infection severity, and is therefore a promising target for inhibition to improve disease outcome in older patients.

The mechanisms linking hearing ability, inflammation, glymphatic system function, and cognitive impairment in older adults are largely unknown. To investigate this issues, magnetic resonance imaging (MRI) was used to test for dysfunctions in the glymphatic system of older adults with hearing loss and to determine the relationship of glymphatic dysfunction, inflammation and cognitive deficits. This cross-sectional observational study included participants with ARHL and healthy controls (HCs) between January 2021 and December 2023. Participants underwent MRI scans of the glymphatic indices and clinical assessment of auditory, neuropsychological, and inflammatory measures. Multimodal MRI indices were used as proxies of glymphatic function and compared with measures of inflammation and cognition dysfunction in the older adults with hearing loss and control groups. Mann-Whitney U test, Spearman rank correlation and Mediation analysis were conducted. A total of 130 hearing loss patients (mean age years, 64.10 ± 3.43 [SD], 67 males) and 121 healthy controls (mean age years, 63.55 ± 3.49 [SD], 68 males) were included. The hearing loss group differed significantly from normal hearing control on MRI glymphatic measures of choroid plexus volume (CPV) (1.48 vs 1.37, p = 0.0004), enlarged perivascular spaces (EPVS) (1.74 vs 1.55, p < 0.0001) and diffusion tensor image analysis along the perivascular space (DTI-ALPS) (1.47 vs 1.63, p < 0.0001). Hearing loss severity was associated with higher values of CPV and EPVS and lower values of ALPS and strongly correlated with higher levels of inflammation (all FDR q < 0.05). Mediation analysis showed that ALPS and CPV mediate the relationship between hearing loss and scores on the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST), respectively. Our findings support a potential associative pathway that inflammation and glymphatic dysfunction act as plausible intermediate factors facilitating the pathological relationship linking the increase in hearing loss in older adults to decline in cognition.

Cellular aging associated with telomeric shortening plays an important role in female fertility. In addition to natural decline, due to the loss of telomeric repeats during cell division, other factors such oxidative stress (OS), accelerate telomere shortening by causing a dramatic loss of telomeric repeats. Thus, mathematical models to better understand the accelerated aging leading to infertility are lacking in the literature. An initial and boundary value problem (IBVP) with a diffusion-advection equation was considered to describe the evolution of a cell population undergoing a gradual decrease of the proliferation potential due to the end-replication problem (Olovnikov, 1973). In this paper we propose a continuum model that attempts to capture the random telomere shortening caused by OS, replacing the advection term with a Caputo's fractional derivative of order β, 0<β<1, with respect to the generational age. The distance between the order of the Caputo derivative and 1 was considered the oxidation parameter. The mathematical model was applied to the human follicular growth from preantral to pre-ovulatory follicle, in young and older women to study the influence of oxidation and low telomerase activity on the aging rate of the pre-ovulatory follicle. We observed that as OS increases, the generational age of granulosa cells (GCs) increases as well, suggesting that telomeres of these GCs will be aged. Although middle-aged women treated with antioxidants could reduce the negative effects of OS on telomeres, antioxidants in combination with good levels of telomerase activity yield the best results regarding the reduction of generational aging of GCs.

Aging is a major risk factor for various neurological disorders, including Alzheimer's disease, and is associated with the accumulation of senescent cells, which can themselves propagate the senescence process through paracrine signaling. Migrasomes are organelles that form during cellular migration, detach from parent cells and mediate intercellular communication. Here we demonstrate that border-associated macrophages (BAMs) acquire senescence-associated properties during early brain aging, possibly due to prolonged exposure to amyloid beta. Senescent-like BAMs show elevated production of migrasomes, which convey senescence-associated signals including the apoptosis inhibitor of macrophage to neighboring cells. We show that microglia are prominent recipients of senescent-like BAM-derived migrasomes, and that through activation of CD16 in recipient cells, the apoptosis inhibitor of macrophage inhibits apoptosis and promotes senescence induction. Blocking migrasome induction in senescent-like BAMs through treatment with Tspan4-targeting siRNA-encapsulated liposomes ameliorates cognitive deficits in aged mice. Our findings suggest that migrasomes are potent vehicles of senescence-regulatory signals and represent a promising target for senomorphic therapy.

The brain continuously tracks signals from the body, including the heartbeat, which influence internal states such as the perception of time, well-known to accelerate with age and disrupted in disorders such as Parkinsons disease and dementia. The present study examined whether the representation of cardiac events onto spontaneous neural oscillations maps to regions responsible for processing time-perception, show age-related differences, and uncovered the mechanisms that may underlie any such reorganization. From a large cohort (N = 620), cortical heartbeat-evoked responses (HERs) were characterized and their sources were pinned to frontotemporal regions. Phase-based analyses demonstrated that cardiac signals affect phase of ongoing neural oscillations in the theta frequency band, rather than altering overall power, with this effect consolidating in older adults. Advanced statistical analysis further indicated that these changes are primarily driven by enhanced bottom-up heart-to-brain influences, revealing that altered interoceptive signaling can shape the age-related changes in time perception.

Biological age (BA) is increasingly recognized as a valuable alternative to chronological age (CA) for assessing an individual's health and aging status. However, existing models are based on limited clinical parameters and have not thoroughly integrated morbidity and mortality data.

Cardiolipins (CLs) are primarily expressed in the inner mitochondrial membrane where they play essential roles in membrane architecture and mitochondrial functions. CLs have a unique structure characterized by four acyl chains with different stoichiometries such as chain length and degree of saturation. CL composition changes with disease and age, but it is largely unknown how dynamic changes affect mitochondrial function. Here, we compared CL profiles in different mouse tissues across different age groups using liquid chromatography and triple quadrupole mass spectrometry. A key finding was that CLs in the brain differ significantly from those in peripheral organs, with a tendency towards longer-chain variants. We hypothesized that these differences may be influenced by the availability of fatty acids (FA), which in the brain could be affected by the blood-brain barrier. In support of this notion, we found that FA concentrations varied in the different compartments. In addition, we found that CL profiles changed during aging. In cultivated macrophages supplemented with different FAs, we tested how altered CL profiles may affect both, mitochondrial morphology and function such as cristae density, and mitochondrial membrane potential and respiration, respectively. Finally, we validated our in vitro results in vivo by altering the CL profile in mice by using palmitic acid and oleic acid enriched diets. Our study highlights a dynamic adaptation of CL profiles in response to FA availability and aging and emphasizes its functional importance for mitochondrial function. Furthermore, FA supplementation may be a promising therapeutic strategy to address disease- and age-related mitochondrial malfunctions.

The ketogenic diet (KD), a high-fat, low-carbohydrate regimen, has been shown to exert neuroprotective effects in various neurological models. This study explored how KD-alone or combined with antibiotic-induced gut microbiota depletion-affects cognition and neuroinflammation in aging. Thirty-two male rats (22 months old) were assigned to four groups (n = 8): control diet (CD), ketogenic diet (KD), antibiotics with control diet (AB), and antibiotics with KD (KDAB). Diets were maintained for 10 weeks; during the final week, AB and KDAB groups received a broad-spectrum antibiotic cocktail (ampicillin 1 g/L, vancomycin 0.5 g/L, neomycin 1 g/L, and metronidazole 1 g/L) in drinking water. Cognitive abilities were evaluated using the Morris Water Maze and Novel Object Recognition Test. BDNF and inflammatory cytokines (TNF-α, IL-1β, IL-10) were measured in the hippocampus and prefrontal cortex. KD and KDAB groups exhibited increased β-hydroxybutyrate and reduced glucose levels, enhanced cognitive performance, elevated BDNF and IL-10, and decreased TNF-α and IL-1β compared to non-KD groups. Although antibiotic treatment alone caused only a transient impairment in spatial memory and was associated with reduced TNF-α levels, the ketogenic diet-irrespective of microbiota status-consistently improved cognitive performance and elevated neuroprotective markers. These findings suggest that KD appears to promote brain resilience during aging, even in the presence of microbiota disruption.

The global surge in the population of people 60 years and older, including that in China, challenges healthcare systems with rising age-related diseases. To address this demographic change, the Aging Biomarker Consortium (ABC) has launched the X-Age Project to develop a comprehensive aging evaluation system tailored to the Chinese population. Our goal is to identify robust biomarkers and construct composite aging clocks that capture biological age, defined as an individual's physiological and molecular state, across diverse Chinese cohorts. This Perspective outlines the core objectives, methodological framework and key deliverables of the X-Age Project, including cohort recruitment, standardized sample collection, multimodal data acquisition and clock model development. By integrating interdisciplinary expertise, we aim to provide a practical and scalable platform for understanding aging complexity and heterogeneity, early detection of accelerated aging and evaluation of aging interventions.

Understanding how sleep affects the risk of incident chronic conditions in midlife may reinforce the importance of a healthy sleep pattern for healthy aging and cardiometabolic health. The objective of the study was to examine associations of sleep duration and quality with incident obesity, diabetes and metabolic syndrome in mid-aged adults. Participants without obesity (

Work-related stress is a well-established contributor to mental health decline, particularly in the context of burnout, a state of prolonged exhaustion. Epigenetic clocks, which estimate biological age based on DNA methylation (DNAm) patterns, have been proposed as potential biomarkers of chronic stress and its impact on biological aging and health. However, their role in mediating the relationship between work-related stress, physiological stress markers, and burnout remains unclear.

Peripheral sensory neurons regenerate their axons after injury to regain function, but this ability declines with age. The mechanisms behind this decline are not fully understood. While excessive production of endothelin 1 (ET-1), a potent vasoconstrictor, is linked to many diseases that increase with age, the role of ET-1 and its receptors in axon regeneration is unknown. Using single-cell RNA sequencing, we show that satellite glial cells (SGCs), which completely envelop the sensory neuron soma residing in the dorsal root ganglia (DRG), express the endothelin B receptor (ETBR), while ET-1 is expressed by endothelial cells. Inhibition of ETBR ex vivo in DRG explant cultures improves axon growth in both adult and aged conditions. In vivo, treatment with the FDA-approved compound, Bosentan, improves axon regeneration and reverses the age-dependent decrease in axonal regenerative capacity. Single-nuclei RNA sequencing and electron microscopy analyses reveal a decreased abundance of SGCs in aged mice compared to adult mice. Additionally, the decreased expression of connexin 43 (Cx43) in SGCs in aged mice after nerve injury is partially rescued by Bosentan treatment. These results reveal that inhibiting ETBR function enhances axon regeneration and rescues the age-dependent decrease in axonal regenerative capacity, providing a potential avenue for future therapies.

The Arctic ground squirrel (AGS, Urocitellus parryii), an extreme hibernator, exhibits remarkable resilience to stressors like hypoxia and hypothermia, making it an ideal model for studying cellular metabolic adaptation. The underlying mechanisms of AGS resilience are largely unknown. Here, we use lipidomic and metabolomic profiling to discover specific downregulation of triglyceride lipids and upregulation of the lipid biosynthetic precursor malonic acid in AGS neural stem cells (NSC) versus murine NSCs. Inhibiting lipid biosynthesis recapitulates hypoxic resilience of squirrel NSCs. Extending this model, we find that acute exposure to hypoxia downregulates key lipid biosynthetic enzymes in C. elegans, while inhibiting lipid biosynthesis reduces mitochondrial fission and facilitates hypoxic survival. Moreover, inhibiting lipid biosynthesis protects against APOE4-induced pathologies and aging trajectories in C. elegans. These findings suggest triglyceride downregulation as a conserved metabolic resilience mechanism, offering insights into protective strategies for neural tissues under hypoxic or ischemic conditions, APOE4-induced pathologies and aging.

The disparity between the global increase in life expectancy and the steady decline in health outcomes with age has been a major driver for developing new ways to research aging. Although this current tools for studying aging outside of the human body-such as animal models and cells in a dish-have improved this fundamental understanding of the markers and key mechanisms underlying this process, several limitations remain. Animal models are poor biological representations of humans and have a weak track record of translating pre-clinical results into successful clinical applications. Similarly, current 2D cellular models do not recapitulate the dynamic 3D environment of human tissue. This gap between the need for accurate biological mimicry and the limitations of current aging models presents an exciting opportunity for the field of biofabrication. Over the past decade, the combination of biofabrication and advanced biomaterials has shown potential to engineer high-resolution features that change over time or respond to specific stimuli. In this perspective, the current state of in vitro aging models is reflected, identify the key features that new models must emulate, discuss the technologies available to meet these complex specifications, and consider some of the potential challenges facing the field.

Cycloastragenol (CA), the triterpenoid aglycone of astragaloside (ASI), is a telomerase activator and potential anti-aging drug with broad application prospects. Due to the rapid increase of its market demand in recent years, efficient production of CA has attracted increasing attention. In this study, the novel β-xylosidase XylO2 from Aspergillus aculeatus was identified through genome mining. It is capable of hydrolyzing ASI into cycloastragenol-6-O-β-D-glucoside (CMG), a significant precursor in the preparation of CA. Subsequently, structure-guided semi-rational design and virtual screening were used to obtain the highly active variant C23T, which exhibited more than 1.94 and 2.10-fold improvement of catalytic activity with ASI and p-nitrophenyl-β-D-xylopyranoside, respectively. According to structural modelling and molecule docking, the reduced volume of the binding pocket as well as the decreased distance between the substrate and active site residues positively influenced the catalytic activity. Moreover, the conversion yield of 1 g/L ASI increased to 99.10 %, suggesting the potential application of this variant in CA production. This study not only provides a novel enzyme for glycoside hydrolysis, but also offers theoretical insights for understanding and modifying these enzymes.

The planetary health diet (PHD) proposed by the EAT-Lancet Commission, advocates for reduced meat and dairy intake while emphasizing the consumption of whole grains, fruits, vegetables, nuts, and legumes. Existing studies have shown that the PHD can lower mortality rates and slow cognitive decline in various populations. However, its specific effects on cognitive impairment among elderly individuals in China remain unclear, primarily due to regional socioeconomic and cultural differences. This study utilizes data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) to create the animal diet index (ADI) and the planetary health diet index (PHDI). We employed multivariable Cox proportional hazards regression models to assess the associations between these dietary indices and the risk of cognitive impairment in elderly participants. The research also examines the impact of grain intake and its relationship with environmental indicators, including greenhouse gas emissions, water footprint, and land use. Our results reveal that a higher PHDI is significantly correlated with a lower risk of cognitive impairment (HR = 0.539), while a higher ADI is associated with an increased risk (HR = 1.379). Furthermore, increased grain intake is associated with reduced cognitive impairment (HR = 0.729). Notably, the PHDI is linked to greater environmental burdens, contrasting with the ADI's association with lower grain-related environmental impacts. Stratified analyses indicate the PHD is protective across most regions, while the risks associated with animal-based diets are consistent. These findings suggest that while adherence to the PHD and increased grain intake may enhance cognitive health, they may also reflect trade-offs with environmental sustainability across China. Consequently, this study informs dietary strategies that aim to balance health and environmental concerns, emphasizing the need for context-specific approaches to dietary transitions.

Thyroid hormones (TH), primarily triiodothyronine (T3) and thyroxine (T4), are critical regulators of metabolic rate, mitochondrial function, and cellular repair mechanisms. Emerging evidence suggests that thyroid status may significantly influence aging trajectories and longevity through modulation of key cellular pathways. Objective: This review explores the role of thyroid hormones in aging biology, with a focus on their interaction with longevity-associated signaling pathways and the hallmarks of aging. Both physiological and subclinical thyroid states in the context of healthspan, cognitive preservation, metabolic resilience, and mitochondrial integrity are explored. A narrative synthesis of human and animal studies was conducted, including mechanistic, epidemiologic, and clinical data, to evaluate how thyroid hormone levels affect aging pathways such as mTOR, AMPK, IGF-1, sirtuins, FOXO transcription factors, and mitochondrial biogenesis. Thyroid hormones modulate several hallmarks of aging, including mitochondrial dysfunction, genomic instability, epigenetic drift, and deregulated nutrient sensing. T3 enhances mitochondrial respiration and autophagy while interacting with mTOR and AMPK to regulate energy balance. Altered thyroid function-particularly subclinical hypothyroidism, has been paradoxically associated with increased longevity in some centenarian cohorts, possibly due to reduced oxidative metabolism. However, overt thyroid dysfunction is linked to increased metabolic risk in aging populations. Thyroid hormones serve as metabolic gatekeepers that influence both cellular aging and organismal longevity. A deeper understanding of their role in aging pathways may inform novel strategies for promoting healthy aging, including thyroid hormone modulation, and personalized endocrine optimization.

Ergothioneine (EGT) is a naturally occurring thiol-containing amino acid derivative synthesized by certain fungi and bacteria, with humans acquiring it exclusively through dietary intake. It has gained increasing attention due to its exceptional antioxidant, cytoprotective, and metal-chelating properties. EGT shows high stability under physiological conditions and can accumulate in specific tissues

Polyamines (PAs), including spermidine, spermine and their precursor, putrescine, are ubiquitous molecules that are vital for a variety of physiological processes. Recently, PAs gained research attention because of their roles in promoting longevity and preventing age-related diseases. Circulating and tissue levels of PAs appear to decline with age, while higher intake of PAs in humans is correlated with better health during aging. Many foods, including plants and offal (organ meats), are good sources of dietary PAs, but are consumed much less in regions with prevailing Western diets. Elevating the circulating levels of PAs through dietary supplementation with PA-rich plant extracts or foods, on the other hand, has proven to be challenging, most likely due to their low bioavailability. In this study, we evaluated the effectiveness of nutritional supplements derived from bovine glandular tissues and/or plant material in elevating blood and tissue levels of spermidine, spermine and putrescine in adult rats. We detected appreciable amounts of PAs in the following materials: 1) spermidine-rich supplement (SRS), containing wheat germ, 2) a cytosolic fraction extract of bovine thymus gland (Thymus Cytosolic Fraction - TCF) and 3) a nuclear fraction extract of bovine thymus gland (Thymus Nuclear Fraction - TNF). We showed that all three PA-containing supplements also contain liposomes, with TNF displaying the largest amounts of liposomal PAs, as well as RNAs, among the tested supplements. We demonstrated that oral administration of SRS, TCF and TNF induce rapid changes in blood PA concentrations. Finally, we showed that TNF supplement is superior to SRS and TCF in elevating the levels of spermidine in the blood, liver and heart following a 28-day supplementation period. Considering the importance of PAs in prevention of age-related disease, supplementation with TNF could be a plausible approach towards the maintenance of proper cellular PA homeostasis during aging.

Frailty, characterized by a reduction in intrinsic capacity across multiple physiological systems, is a key concern in healthy aging. Insight in the trajectory of an individual's functional ability and intrinsic reserve capacity in a relatively younger population of older adults is lacking. This study aims to investigate the early stages of frailty by tracking trajectories of physical indicators of intrinsic capacity before frailty becomes clinically evident.

DNA damage is a major driver of the aging process. The progression of Alzheimer\'s disease (AD) worsens the situation as evidenced by the finding that the neurons of the AD brain have elevated levels of DNA damage. AD is also associated with the amyloid precursor protein (APP) known for its proteolytic peptide fragment, A{beta}. In the current work we find that these three elements - age, DNA damage, and APP - are associated with each other and present evidence in the mouse brain supporting the hypothesis that DNA damage is the likely cause of the increased APP levels. Using the TUNEL reaction to track DNA damage, we show that the TUNEL staining increases significantly with age (6 months to 24 months). Next, we used immunostaining of intracellular APP to show that it too increases over this same time period. To separate correlation from causality we repeated these analyses using tissue from mice genetically deficient in the ATM (ataxia-telangiectasia mutated) kinase, an enzyme associated with part of the DNA damage repair mechanism. TUNEL signal in neurons of 6-month Atm-/- animals was equivalent to that seen in 24-month wild type. Significantly, the APP signal in the Atm-/- cells increased in consort and the relationship between DNA damage and APP was found in both neuronal and non-neuronal cells. These results suggest that the loss of genomic integrity associated with aging is a cellular stressor that increases the levels of APP and thus increases vulnerability to the pathogenesis of AD.

The pace of organ ageing varies substantially between individuals, yet drivers of variability remain poorly understood. This gap is critical, given only 20-30% of longevity is genetically inherited and age-related diseases are leading causes of morbidity and mortality. Proteomic clocks allow organ ageing to be estimated from blood sampling, facilitating study of how life course exposures shape biological ageing heterogeneity. Here, we leverage the unique design of the MRC National Survey of Health and Development (NSHD), the world's oldest continuously followed birth cohort, to track 1,803 individuals across eight decades since birth in 1946. At mean age 63.2 years, we estimated proteomic ageing in seven organs. Despite near identical chronological ages, participants' proteomes revealed biological ageing disparities spanning decades. Extreme ageing in multiple organs was a strong prognostic indicator for all-cause mortality over the following 15 years (HR=6.62 for [≥]4 extremely aged organs). Adversity and being overweight in adolescence associated with accelerated ageing decades later in life. Completing secondary school education and maintaining physical activity linked to relative biological youth. Mediation analyses indicated liver, kidney and immune ageing linked life course exposures to mortality. Across 10,776 plasma protein targets, we identified 143 predictors of longevity, including MED9, strongly linked to diverse socio-behavioural exposures. These findings provide unique insights into which factors are likely to shape how we age, when in life they may be influential, and how biological effects emerge, informing healthy ageing promotion.

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

Impaired proteostasis is a hallmark of aging and is associated with several neurodegenerative diseases, including Huntington\'s Disease (HD) where the polyglutamine (polyQ) expanded Huntingtin aggregates to form insoluble inclusions bodies (IBs) associated with neurotoxicity. Chronological lifespan (CLS) in yeast resembles many aspects of aging of non-dividing cells such as neurons. During chronological aging, acidification of the culture media due accumulation of acetic acid is one of the major cell-extrinsic factors contributing to age-related cell death. Thus, buffering media pH to prevent acidification significantly extends longevity. Here, we found that cells expressing pathogenic polyQ expansion proteins display increased sensitivity to acetic acid and shortened CLS. Buffering media pH promotes both polyQ aggregation into IBs and promotes longevity. We also found that growth at alkaline pH induces the activation of heat shock response (HSR) in young cells. Such hormetic HSR activation subsequently allowed aged cells to mount a proper HSR in response to stresses such as heat shock or polyQ misfolding, leading to lifespan extension. Our study thus provides new insight into how pH can promote proteotoxic stress resistance and longevity by modulating the HSR.

The gut microbiome is widely accepted to play a crucial role in human health and disease. These intestinal microbiota are not only involved in gastrointestinal physiology, but they also contribute to essential immune modulation and metabolic homeostasis. Growing evidence suggests that alterations in the gut microbiota composition are linked to various metabolic disorders, including obesity and age-related diseases. Obesity, a global public health concern, is associated with shifts in microbial diversity and functionality, which influence energy extraction, fat storage, and systemic inflammation. Similarly, age-related disorders, such as neurodegenerative diseases, sarcopenia, and metabolic syndromes are linked to gut microbiome alterations that exacerbate chronic inflammation and metabolic dysfunction. Understanding the intricate relationship between the gut microbiome, obesity, and aging-related pathologies is essential for developing targeted microbiome-based interventions to mitigate these health challenges. In this review, after a brief summary of the development of the gut microbiome across the lifespan and its modulating factors, we will focus on the mechanisms underlying the relation between the gut microbiome and metabolic and aging-related disorders. Finally, the findings of interventional studies underscoring causality and the potential future directions will be discussed, with a focus on the possibility of modifying the progression of metabolic and age-related diseases through the modulation of the gut microbiome.

To investigate the functional significance of mitophagy in age-related osteogenic decline and the underlying mechanisms using in vivo and in vitro models.

Ageing is one of the most significant risk factors for heart disease; however, it is still not clear how the human heart changes with age. Taking advantage of a unique set of pre-mortem, cryopreserved, non-diseased human hearts, we performed omics analyses (transcriptomics, proteomics, metabolomics, and lipidomics), coupled with biologically informed computational modelling in younger (≤ 25 years old) and older hearts (≥ 50 years old) to describe the molecular landscape of human cardiac ageing. In older hearts, we observed a downregulation of proteins involved in calcium signalling and the contractile apparatus. Furthermore, we found a potential dysregulation of central carbon generation of fuel, glycolysis, and fatty acids oxidation, along with an increase in long-chain fatty acids. This study presents and analyses the first molecular data set of normal human cardiac ageing, which has relevant implications for understanding the human cardiac ageing process and the development of age-related heart disease.

Anaphase-promoting complex/cyclosome (APC/C) regulates the cell cycle by destruction of target proteins ubiquitination. However, understanding the control of APC/C has remained elusive. We identify APC2, the catalytic core subunit of APC/C, as a binding partner of active regulator of SIRT1 (AROS). Subsequent immunoprecipitation assays confirm the interaction in vivo. We reveal that AROS competes with APC11 for APC2 binding, thereby impeding the destruction of Cyclin B1. By contrast, the APC/C coactivator CDH1 ubiquitinates and degrades AROS in a D-box-dependent manner. Finally, we demonstrate that CDH1 suppresses the AROS-mediated protection of DNA damage-induced senescence. Overall, our findings provide evidence of the reciprocal role of AROS and APC/C-CDH1 in regulating APC/C activity and DNA damage-induced senescence, and highlight a potential role for AROS in the control of senescence.

The concept of the central nervous system (CNS) reserve emerged from the mismatch often observed between the extent of brain pathology and its clinical manifestations. The cognitive reserve reflects an "active" capacity, driven by the plasticity of CNS cellular components and shaped by experience, learning, and memory processes that increase resilience. We propose that neuroglial cells are central to defining this resilience and cognitive reserve. These cells maintain CNS homeostasis through allostatic mechanisms and modulate responses to injury and/or disease. In this review, we first outline the concept of the CNS reserve and then explore the role of neuroglia in maintaining brain function throughout development and adulthood. We highlight astrocytes and oligodendrocytes in gray and white matter learning, respectively, and examine the function of microglia in immune surveillance. We conclude that neuroglia are key contributors to the cognitive reserve, with systems such as the noradrenergic pathway supporting tissue under stress and mitigating pathology through compensatory responses.