npj Aging

Background: Accelerated biological aging (BioAgeAccel) has been implicated in type II diabetes (T2D) mellitus development; however, its dynamic changes and their links to T2D incidence, mortality and glycemic traits remain unclear. Methods: Leveraging repeated measures from the UK Biobank, we first calculated two BioAgeAccel metrics (KDMAccel and PhenoAgeAccel) and derived three burdens (slope, cumulative, and relative cumulative change). We then assessed associations of BioAgeAccel transitions and these burdens with incident T2D and mortality. Secondary analyses extended the two primary outcomes by incorporating glucose, HbA1c, and six IR surrogates, which were also evaluated as potential mediators. Results: Among 13,751 included participants, 412 (3.0%) new T2D cases and 609 (4.4%) all-cause deaths were identified within a median follow-up of 9.5 years. Dynamic transition from non-accelerated to accelerated aging was markedly related to elevated T2D risk (KDMAccel: HR=1.65 [1.24~2.20]; PhenoAgeAccel: HR=1.50 [1.12~2.00]) and all-cause mortality risk (KDMAccel: HR=1.32 [1.06~1.64]; PhenoAgeAccel: HR=2.17 [1.73~2.71]). BioAgeAccel burdens demonstrated dose-response effects, with cumulative BioAgeAccel showing the greatest influence on T2D (KDMAccel: HR=1.25 [1.03~1.51]; PhenoAgeAccel: HR=1.26 [1.06~1.49]) and all-cause mortality (KDMAccel: HR=1.25 [1.07~1.47]; PhenoAgeAccel: HR=1.51 [1.31~1.74]). Similar association patterns were observed for all the eight glycemic traits. Mediation analyses revealed that these glycemic traits on average mediated 19~32% of the KDMAccel burden-T2D effect and 16~24% of the PhenoAgeAccel burden-T2D effect. Incorporating BioAgeAccel burden into FINDRISC significantly enhanced prediction accuracy, reaching up to 10.9% improvement in some specific aging transition statuses. Conclusion: Dynamic biological aging trajectories and BioAgeAccel burdens are independently related to elevated risks of T2D and all-cause mortality, partly via glycemic dysregulation, highlighting biological aging as a potential intervention target.

Mouse lifespan studies are slow and costly, limiting the number of interventions that have demonstrated robust anti-aging effects. This highlights the need for rapid early-stage screening tools capable of assessing both efficacy and potential side effects. Here, we present a short-term performance assay designed to rapidly profile functional benefits and early toxicity of longevity interventions in mice. Over an 8-week period, mice received one of five candidate anti-aging treatments: 17-estradiol, rapamycin + Smer28, berberine + resveratrol, sildenafil and pinealon. The protocol longitudinally monitored body weight and temperature, and food intake, alongside post-treatment assessments of grip strength, locomotor activity, Y-maze cognition, social behavior, and hematological and urinary parameters. The screen revealed compound-specific phenotypes: 17-estradiol induced significant weight loss, increased grip strength, and dorsal alopecia, consistent with metabolic remodeling. Sildenafil reduced basal body temperature and preserved locomotor activity. Berberine + resveratrol decreased food intake and fasting glucose without major changes in physical performance, resembling caloric restriction-like metabolic effects. Rapamycin + Smer28 modestly improved strength and sociability but induced anemia in 2 of 5 mice, indicating potential dose-dependent toxicity. Pinealon showed a trend toward improved working memory without detectable adverse effects. This multi-parametric approach enables discover healthspan extending interventions facilitating prioritization and dose refinement before committing to full lifespan studies. Finally, to our knowledge, this represents the first comprehensive preclinical aging study in mice fully funded through tokenized decentralized science (DeSci), demonstrating how community-governed, on-chain funding can support resource-intensive in vivo research.

BackgroundAutophagy and mitophagy are essential for cellular homeostasis and play key roles in longevity and healthy aging, whereas their age-associated decline contributes to the development of age-related diseases. The identification of small-molecule activators of these pathways therefore represents an important therapeutic objective. MethodsIn this study, we investigated a series of compounds based on a 2'-deoxycitidine-derived scaffold and systematically analyzed the impact of structural substitutions on their ability to induce autophagy and mitophagy. Chemical optimization and functional assays were combined with pathway analysis, cellular readouts of proteostasis, and in vivo lifespan assessment in Caenorhabditis elegans. ResultsThe lead compound enhanced autophagy predominantly via activation of the AMPK-ULK1 signaling pathway and induced mitophagy in a Parkin-independent manner. It promoted autophagosome formation and facilitated functional clearance of aggregation-prone mutant huntingtin. Conjugation of the lead compound with the mitochondria-targeting Cy5 dye further potentiated mitophagy induction, likely through preferential mitochondrial accumulation, while reducing cytotoxicity. Importantly, the conjugated compound significantly extended C. elegans lifespan at lower concentrations compared with the unconjugated analogue. ConclusionsTogether, these results identify a promising chemical scaffold for the development of auto-and mitophagy activators and validate mitochondria-targeted conjugation as an effective strategy to enhance their biological performance. The demonstrated in vivo efficacy supports the potential relevance of these compounds for interventions aimed at preserving proteostasis and mitochondrial quality control, with possible implications for geroprotective applications.

The effect of biological aging on brain structure is widespread and apparent. However, little is understood regarding which regions exhibit similarities in vulnerability, and what biological processes drive regional patterns of senescence-associated atrophy. Here, we investigated whether associations between age and brain structure exhibit distinct patterns of regional vulnerability, and if so, whether they are related to patterns of cerebral physiology which also show age-related decline. Using both data-driven and hypothesis-driven approaches, we identified recurring patterns of accelerated and delayed decline across the lifespan. Notably, the results mapped using unsupervised clustering methods mirrored the organization of major arterial flow territories, suggesting that vascular architecture may serve as a key organizing principle in brain aging. These results provide support for future research on aging and neurodegenerative disorders that aim to link patterns of structural deterioration to physiological processes that may be useful for identifying at risk individuals and developing novel therapeutics.

Aging is associated with colon epithelial barrier integrity and upregulation of myelopoiesis in the bone marrow (BM). Alamandine (Ala) and MrgD are novel members of the renin angiotensin system (RAS). This study tested the hypothesis that Ala restores the colon epithelial barrier integrity in aging via modulating gut-BM axis. Mice of age 2-3 (Young) or 22-24 months (Old) were treated with saline or Ala by using Osmotic pumps. The intestinal permeability was evaluated by using FITC-dextran. Lgr5+Olfm4+ intestinal stem cells (ISCs), Wnt3a and {beta}-catenin were evaluated by immunohistochemistry or western blotting. Fecal microbiome was analyzed by 16S rRNA sequencing. Monocyte-macrophages were characterized by flow cytometry. Cecal or serum bacterial metabolites were analyzed. The pro-myelopoietic potential of cecal supernatants (CS) was tested in the Young-BM cells. MrgD was expressed in ISCs, which was decreased in the Old. Increased intestinal permeability in aging was reversed by Ala. In the colon organoids, Ala increased Wnt3a levels that were antagonized by the NF449, SQ22536 or 666-15. Ala restored phospho-CREB and active {beta}-catenin levels that were decreased in the Old colon-organoids. Ala increased the richness and {beta}-diversity of the aging microbiome and decreased Bacillota/Bacteroidota. Ala decreased the CD80+ and increased CX3CR+ cells in the Old colons. Old-CS induced myelopoiesis in vitro in BM cells with higher number of monocytes and pro-inflammatory macrophages which was not observed in the CS derived from Ala-treated Old mice. Ala is a promising pharmacological agent for reversing the leaky gut of aging by restoring homeostasis in the gut-BM axis.

Frailty is an age-related syndrome characterized by biological dysfunction and reduced physiological reserve in response to stressors. Its prevalence is increasing with population aging, resulting in a substantial health burden due to adverse outcomes on health, such as cardiovascular disease and mortality. Ultra-processed foods (UPFs), defined as industrial formulations made primarily from processed ingredients, have received increasing attention due to their potential role in the development and progression of frailty. This systematic review and meta-analysis examined the association between ultra-processed food intake and the risk of frailty in older adults. This study systematically searched for all relevant studies published up to January 2026. Ten observational studies involving 105327 participants, comprising 6 prospective and 4 cross-sectional studies, were included in the systematic review, of which 6 were eligible for meta-analysis. Random-effects models were employed to estimate pooled effect sizes and 95% confidence intervals (95% CIs). Meta-analysis showed that higher consumption of UPFs was significantly associated with an increased risk of frailty (pooled OR = 1.43, 95% CI = [1.02-2.005], p = 0.041). Narrative synthesis further supported a positive association between UPF intake and frailty or related outcomes. Our findings suggest that a higher consumption of ultra-processed foods may contribute to frailty risk, potentially through inflammatory pathways. However, given the high heterogeneity, results should be interpreted with caution. Overall, our findings suggest that reducing UPF consumption may be a promising target for public health strategies to prevent frailty in ageing populations.

Biomarkers of aging, particularly DNA methylation-based clocks, have shown promise as tools to assess whether interventions may impact the rate of biological aging. Among possible interventions physical exercise has shown protective effects against many age-associated diseases, while time-restricted feeding (TRF), has shown metabolic benefits in preclinical models. The combined effect of exercise and TRF on aging biomarkers remains largely unexplored. In this 52-week four-armed, randomized, controlled trial (clinicaltrials.gov: NCT07207044) 240 healthy adults aged 65 and over will be allocated to four groups: combined cardio and strength training (EXE), TRF, combined EXE and TRF, or control. Participants will undergo assessments at baseline, 3, 6, and 12 months, with follow-ups at 2, 5, and 10 years. The primary outcome measure is DNA-methylation age with secondary measures including RNA-sequencing, metabolomics, inflammatory marker, microbiome analysis, cognitive and physical measures. By deeply phenotyping participants the Fasting And eXercise (FAXAge) study will provide novel insights into whether TRF, EXE, or a combination can slow or reverse biological aging in older adults.

Many overgrowth syndromes are associated with increased risk of tumorigenesis and malignancies. Our group recently identified a frameshift variant in histone reader SPIN4 located on the X chromosome to be a new genetic cause for human overgrowth. In the current study, we investigated the prevalence of malignancies, along with body weight, body length, body composition and bone mineral density, in Spin4 knockout mice at 18 months of age. We found that male mice lacking Spin4 have increased number of tumors and increased body length, while body weight, body composition and bone mineral density were comparable with wild-type mice. We also analyzed publicly available expression data in various types of human cancers and looked for increased or decreased expression of genes that are implicated in overgrowth syndromes and act through epigenetic mechanisms. We found that the expression of SPIN4, EZH2, and DNMT3A to be elevated in many human cancers compared to the corresponding non-malignant tissue samples. Taken together, our current findings confirm that loss of SPIN4 causes overgrowth in mice (in terms of body length) and is associated with increased prevalence in neoplasia; but does not appear to affect adiposity or bone density.

While aging manifests differently across organs and individuals, existing approaches to measure it lack the spatial resolution to capture this complexity. Here, we develop an approach that applies multi-modal imaging, segmentation algorithms, and deep-learning to assess organ-specific aging across 39 anatomical regions in a total of 134K individuals in the UK Biobank. Our analysis reveals significant organ aging heterogeneity across and within individuals and a remarkable prevalence of organ-specific extreme aging. We validate that our imaging measures capture pathophysiologically meaningful aging through correlation with organ-specific biomarkers, revealing biologically coherent patterns. We find that accelerated organ aging is robustly predictive of corresponding organ disease. We identify the cerebrum as one of the strongest predictors of organismal aging. We investigate organ aging patterns underlying disease risk and find that each disease is linked to aging of highly distinct subsets of organs. Exploring lifestyle factors and interventions reveals a range of divergent organ-specific effects. Our work establishes a powerful paradigm for noninvasively evaluating human aging at anatomical resolution and population scale.

Background: Epigenetic clocks based on DNA methylation (DNAm) have emerged as promising biomarkers of biological aging, yet their associations with cognitive performance remain inconsistent. This study investigates the relationship between epigenetic age acceleration and cognitive performance in older adults using 14 DNAm clocks from five generations of development. Methods: We analyzed data from the Berlin Aging Study II (BASE-II) using genome-wide DNAm profiles and cognitive assessments ascertained at baseline (T0) and two follow-up time points (T1, T2) in up to 1,014 individuals. DNAm-based age and age acceleration estimates were calculated using Biolearn and MethylCIPHER. Analyses focused on cross-sectional and longitudinal associations between DNAm clock estimates and cognitive performance, including sex-specific effects and comparisons with frailty as non-cognitive positive control. Results: Among all tested DNAm clocks, DunedinPACE (a third-generation clock) showed the strongest and most consistent associations with cognitive performance. In addition, the fifth-generation SystemsAge framework also demonstrated robust associations with cross-sectional and longitudinal cognitive outcomes. In contrast, second-generation clocks (GrimAge [v2], PhenoAge) showed occasional nominal associations, while first-generation clocks (Horvath [v1], Hannum) and the causally-informed, fourth-generation clocks (e.g. YingCausAge, YingDamAge) showed no noteworthy signals. Likewise, telomere length estimated from DNAm was not strongly associated with cognitive performance in this dataset. Conclusions: Our findings highlight DunedinPACE as a particularly informative biomarker for various aspects of cognitive aging, while other DNAm aging measures showed no consistent associations. Future work should further refine domain-specific epigenetic biomarkers to improve biological aging assessments and achieve a more reliable early detection of cognitive decline.

Aging leads to cognitive decline due to reduced neuronal plasticity and increased brain inflammation. Disruption of perineuronal nets (PNNs) is a recognized strategy to enhance neuroplasticity. Hyaluronan forms the backbone of PNNs, and 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthesis, has been proposed to disrupt PNNs and enhance neuroplasticity in young rodents. In addition, 4-MU is also known as an immune response regulator, although its effects within the central nervous system (CNS) have been less characterized. In this study, we investigated the impact of long-term oral 4-MU administration in aged mice (20-22 months old), focusing on PNNs intensity, memory, and neuroinflammation. PNN intensity increased with age, and 4-MU treatment reduced it in 22-month-old mice to levels observed in 10-month-old animals; in the novel object recognition test, treated 22-month-old mice performed comparably to or better than 10-month-old controls. Moreover, markers of aging-associated neuroinflammation--including astrocytic and microglial activation as well as peripheral immune cell infiltration--were normalized to 10-month-old levels or further diminished following 4-MU treatment. Importantly, chronic 4-MU administration was well tolerated in aged mice, with no serious adverse effects observed. Together, these results suggest that 4-MU mitigates PNNs accumulation and neuroinflammaging while enhancing recognition memory, supporting its potential as a safe therapeutic approach for age-related cognitive decline.

Purpose: To evaluate whether chest radiograph-derived age acceleration is associated with incident lung cancer and whether it improves discrimination beyond established lung cancer risk factors. Materials and Methods: This retrospective analysis used prospectively collected data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline digitized chest radiographs from the initial screening year were analyzed using a previously validated deep learning model that estimates chest radiograph-derived age (Xp-age). Age acceleration (AgeAccel) was defined as the residual of Xp-age after calibration to chronological age using a regression model from the development dataset. A 1-year landmark design excluded participants diagnosed with lung cancer or censored within 1 year of baseline. Associations with incident lung cancer were assessed using multivariable Cox proportional-hazards models adjusted for prespecified demographic and clinical predictors, including smoking variables used in the PLCOm2012 risk prediction model. Discrimination was evaluated using the concordance index and 6-year time-dependent area under the receiver-operating-characteristic curve. Results: The analytic cohort included 23,213 participants (mean age, 62.5 years); 790 developed incident lung cancer after the landmark (mean follow-up, 16.7 years). Higher AgeAccel was associated with increased lung cancer incidence (hazard ratio, 1.10 per 1-SD increase; 95% confidence interval: 1.03- 1.17); however, addition of AgeAccel to an established risk factor model resulted in minimal change in discrimination (C-index, 0.840 vs. 0.839; time-dependent AUC at 6 years, 0.852 vs. 0.852). Attribution maps emphasized the aortic arch/mediastinal region with similar spatial patterns across smoking and lung cancer strata. Conclusion: Chest radiograph-derived age acceleration was independently associated with future lung cancer incidence.

Risky decision-making under uncertainty reflects complex cognitive processes supported by distributed brain networks that are vulnerable to aging. However, it remains unclear whether risk-taking behavior can serve as a behavioral marker of brain aging. In the present study, we combined behavioral tasks, computational modeling, and structural magnetic resonance imaging to investigate the relationship between risky decision-making, chronological age, and brain age. A total of 55 young adults and 112 healthy older adults completed the Iowa Gambling Task (IGT) and the Balloon Analogue Risk Task (BART), along with neuropsychological assessments and neuroimaging scanning. Decision processes were quantified using computational models, including the Value-Plus-Perseveration model and Exponential-Weight Mean-Variance. Brain age was estimated from gray matter volume. The results showed significant age-related alterations in parameters reflecting feedback sensitivity, learning rate, and loss aversion in both tasks. Within older adults, several decision parameters were significantly associated with both chronological age and brain age. Regression analyses further showed that computational parameters significantly predicted chronological age and brain age, whereas traditional cognitive screening measures did not show significant predictive effect. Structural brain analyses indicated that IGT-related parameters were primarily associated with the basal ganglia, while BART-related parameters were linked to a broader network including prefrontal, cingulate, and temporal regions. These findings suggest that computational markers of risk-taking behavior capture subtle age-related changes in cognitive processes and brain deterioration. Therefore, risk-taking parameters may serve as reliable functional markers of brain aging, providing critical insights into the mechanisms underlying successful aging.

Risk-taking behavior is a complex cognitive function that often declines with aging, contributing to impaired decision-making and reduced quality of life. While transcranial direct current stimulation (tDCS) has shown promising effects in modulating cognitive function, its influence on ecologically valid, complex behaviors like risky decision-making in older adults remains poorly understood. We investigated whether a single-session stimulation over the medial orbitofrontal cortex (MOFC) combined with cognitive training could enhance decision-making in healthy older adults. In a randomized, sham-controlled study, bilateral MOFC stimulation (left/anode, right/cathode) was applied during a training task based on the Iowa Gambling Task. Pre- and post-intervention assessments utilized conventional behavioral measures and the Values-Plus-Perseveration computational model, alongside task-related fMRI to examine MOFC network changes. Compared to sham, tDCS significantly enhanced the ability to distinguish advantageous from disadvantageous options. Modeling analysis revealed stimulation-induced changes in multiple latent components, such as learning rate, loss aversion, and perseveration decay. Generalized Psychophysiological Interaction analysis showed that tDCS reconfigured the MOFC network by reducing fronto-frontal hyper-connectivity and enhancing fronto-striatal connectivity. These behavioral improvements were specifically associated with the left MOFC network targeted by anodal stimulation. Our results provide causal evidence that tDCS can mitigate age-related impairments in risk-taking by reconfiguring MOFC-related networks. These findings advance the mechanistic understanding of tDCS in aging and highlight its potential as an intervention to prevent age-related decline in decision making.

AbstractAs organisms age, mitochondrial metabolic activity declines, and disrupted gene expression regulation mediated by histone acetylation induces the emergence of senescent physiological phenotypes in tissues. In this study, we found that periodic exposure to red light significantly increased histone H3 Lys9 acetylation (H3K9ac) levels in the tissues and organs of aged mice. Following red light exposure, silent information regulation factor 4 (SIRT4) protein levels in keratinocytes were notably reduced, whereas glycolysis, fatty acid metabolism, and the tricarboxylic acid (TCA) cycle were significantly activated in keratinocytes. The reduction in mitochondrial SIRT4 levels enhances the acetylation of mitochondrial metabolic proteins, particularly malonyl-CoA decarboxylase (MCD), a potent inhibitor of the key rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) in fatty acid oxidation. This process promotes mitochondrial fatty acid oxidation and TCA cycle. Additionally, the decrease in SIRT4 activates SIRT1 through feedback mechanisms, thereby alleviating its inhibition on PPAR- in senescent keratinocytes and comprehensively activating the expression of genes related to lipid metabolism. This lipid metabolism activation ultimately facilitates the accumulation of acetyl-CoA within keratinocytes, increases H3K9ac levels, and reshapes the expression patterns of senescence-related genes. Eventually, cellular aging is effectively mitigated by the synergistic regulation of metabolism, inflammation, and gene expression. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/717004v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@a3387dorg.highwire.dtl.DTLVardef@1d1b083org.highwire.dtl.DTLVardef@19ba6f0org.highwire.dtl.DTLVardef@1ecf20e_HPS_FORMAT_FIGEXP M_FIG Mechanism of anti-aging action of red light: Red light can reduce SIRT4 signalling in keratinocytes, thereby reactivating lipid metabolism and increasing levels of acetyl-CoA. This promotes histone acetylation, which in turn reverses the expression of age-related inflammatory factors and genes. C_FIG

Biological-age models quantify the physiological aging process by relating biomarker profiles (e.g., blood biochemistry, DNA methylation) to all-cause mortality risk. These models outperform chronological age in predicting disease and mortality, making them useful metrics for preventative health. However, in existing biological-age models, biomarker contributions do not align with the non-linear associations biomarkers exhibit with long-term mortality risk, nor do they account for normative trajectories that occur in healthy aging, limiting their utility in a clinical setting. To address these limitations, we developed a biological-age framework (NiaAge) where biomarker contributions are derived directly from non-linear associations with long-term mortality risk and aligned with normative trajectories observed in healthy aging. As a result, biomarker contributions to NiaAge are consistent with known biomarker risk profiles and normative reference ranges. We trained NiaAge in the 1999-2000 cohort of the US National Health and Nutrition Examination Survey (NHANES; N=2028) on 59 biomarkers spanning multiple physiological domains (e.g., hematology, metabolism, inflammation), then evaluated it in the 2001-2002 cohort (N=2346). NiaAge predicted long-term mortality, physical-health, and cognitive-health significantly better than chronological age. It also outperformed several DNA-methylation age clocks on mortality and physical/cognitive health-span metrics, while performing comparably to leading physiological age clocks. These results position NiaAge as a valuable tool for preventative health.

Caenorhabditis elegans (C. elegans) is a well-established model for investigating the mechanisms of aging and age-related disorders like neurodegeneration. However, maintaining age-synchronized populations of C. elegans for aging studies without genetic or pharmacological interventions presents significant challenges, given their high reproductive rate: each nematode produces over 300 progeny. The traditional method for maintaining an age-synchronized population for multi-day studies without interventions is labor-intensive and low-throughput, hindering research on aging mechanisms and the identification of novel interventions for aging. To address these limitations, a novel, robust method was developed to sustain age-synchronized populations in a 96-well plate liquid culture format for up to 12 days without custom-made apparatuses. The robustness of this method was substantially improved by optimizing the surface composition of the multi-well plate and disposables, refining culture parameters, including life stage, medium composition, and bacterial food concentration. To facilitate unbiased phenotype assessment throughout the lifespan, we used a Wmicrotracker ONE reader to monitor worm movement and viability in a multi-well plate. The overall fitness decline with aging using our method is comparable to that of worms maintained on solid agar. Lastly, using transgenic C. elegans carrying tauopathy, we demonstrated the ability of applying our optimized platform for high-throughput screening with a Z-factor of 0.7. Our novel method simplifies age-synchronized population maintenance, enhances progeny separation, and reduces costs, enabling high-throughput screening of compounds and RNAi libraries. These advancements greatly enhance the versatility of C. elegans as a model organism, offering a scalable platform for genetic and compound screening and for comprehensive investigations into drug discovery and disease mechanisms.

BackgroundCaloric restriction (CR) improves markers of biological aging, yet long-term effects on the human metabolome remain unclear. ObjectiveThis study examined the effects of CR (2 years) in healthy adults without obesity on circulating metabolites linked to aging and metabolic adaptations. MethodsUntargeted metabolomics was performed using fasted plasma samples collected at baseline, 12, and 24 months (BL, 12M, 24M) from CALERIE participants randomized to CR or ad libitum (AL) control. A total of 864 known metabolites were identified and grouped into nine biologically coherent super pathways to support pathway-level interpretation (amino acid, peptide, carbohydrate, energy, lipid, nucleotide, cofactors and vitamins, xenobiotics, and partially characterized molecules). Principal component analysis (PCA) summarized metabolite variation, and linear mixed models assessed intervention effects on each PC in group-by-time interactions. ResultsThree principal components showed significant group-by-time interactions: PC2 (carbohydrate), PC5 (partially characterized molecules), and PC4 (lipid). Carbohydrate (PC2) and partially characterized metabolites (PC5) decreased from baseline to 12M in both groups; from 12M to 24M, levels stabilized in CR but increased in AL for PC2, while PC5 continued to decline in CR and increased in AL. Lipid metabolites (PC4) decreased in CR and increased in AL at 12M, with the pattern reversing from 12M to 24M. Key contributors included malto-saccharides and related carbohydrate intermediates for PC2, glutamine degradants and lactone sulfates for PC5, and sphingolipids for PC4. ConclusionThis study provided insights into metabolic changes during CR, particularly for carbohydrate and lipid metabolism. Carbohydrate and lipid metabolites that were reduced by CR during the weight loss phase (BL to 12M) followed by stabilization or compensatory responses during the weight maintenance phase (12M to 24M) may link CR-induced changes in metabolism to inflammation. Future research is needed to tease out CR adaptations versus diet related changes in metabolites and explore the functional significance of these metabolic changes during CR for aging and long-term metabolic health. ConclusionCR produced distinct, time-dependent shifts in carbohydrate and lipid pathways. Early reductions during weight loss followed by stabilization or compensatory responses during weight maintenance suggest dynamic metabolic remodeling that may relate to inflammation-linked mechanisms. Further work is needed to distinguish CR-specific adaptations from dietary influences and to clarify the functional significance of these metabolic changes for aging and long-term metabolic health.

Background: The role of biological age acceleration (BioAgeAccel) in the dynamic progression from single cardiovascular-kidney-metabolic disease (CKMD) to multimorbidity, and subsequently to dementia and mortality remains elusive. Methods: We conducted a longitudinal study with data of 433,911 UK Biobank participants. Cardiovascular-kidney-metabolic multimorbidity (CKMM) was defined as the coexistence of two or more CKMDs, including cardiovascular disease (CVD), stroke, type 2 diabetes (T2D), and chronic kidney disease. Biological aging was measured via PhenoAge and KDM-BA. Multistate models examined the association between BioAgeAccel and disease transitions, ranging from healthy to the first occurrence of CKMD (FCKMD), then progression to CKMM, dementia, and mortality. Restricted mean survival time estimated the disease transition time or life expectancy between states. Results: BioAgeAccel was significantly associated with increased risks across all disease transitions. Specifically, during CKMM progression, the hazard ratios (HRs) of the transition from healthy to FCKMD were 1.24 [95%CI 1.23-1.25] for PhenoAgeAccel and 1.16 [1.15-1.17] for KDM-BA-Accel. For subsequent transition to CKMM, the HRs were 1.20 [1.18-1.22] and 1.19 [1.17-1.21], respectively. In dementia-related transitions, PhenoAgeAccel showed the higher risk for CKMM to dementia (HR=1.13 [1.04-1.22]) than for the transition from healthy or from FCKMD to dementia. These associations were further moderated by age, physical activity, educational, and lifestyle factors. BioAgeAccel also accelerated disease progression and reduced life expectancy; for example, during CKMM progression, BioAgeAccel shortened the time between disease transitions by about 1.09 years from healthy to FCKMD, and an additional 1.75 years to CKMM. Regarding life expectancy, individuals with CKMM experienced an average reduction of about 1.36 years under PhenoAge, while those with dementia showed a decrease of about 0.77 years. Among individuals with CVD or T2D as the initial diagnosis, the impact of BioAgeAccel on progression to CKMM or dementia was stronger. Conclusions: BioAgeAccel exerts significant promotive role in the onset of CKMD and their subsequent progression to CKMM, dementia, and mortality, helping identify high-risk individuals. Implementing biological age assessments and health lifestyle interventions in middle-aged populations serves as an effective strategy for alleviating the burden of CKMDs and dementia.

Loneliness, conceptualized as a multi-dimensional construct of unmet social needs, has been linked to adverse health outcomes across the lifespan, prompting significant interest in its underlying neural processes. Our study aimed to address the limitations of prior neuroimaging studies of loneliness by leveraging the Lifespan Human Connectome Project Aging dataset and applying graph theory to characterize its relationship with age and resting-state brain network organization. Socio-demographic measures confirmed prior work that higher loneliness was associated with younger age, being male, unmarried, and living alone. While loneliness showed no main effects on neural graph measures, a significant interaction between loneliness and age emerged for the local interconnectivity of the Default Model and Frontoparietal networks after adjusting for key socio-demographic factors. Conversely, older age was associated with lower functional connectivity, reduced global efficiency, and less modular brain network organization. Different graph measures showed distinct age-related associations, highlighting the heterogeneous nature of brain aging. The absence of a main effect of loneliness, while unexpected, underscores the complex, subjective nature of loneliness and suggests that its neural correlates may manifest differently across ages.