Virginia Byers Kraus

Traditional clinical metrics fail to capture the complex interplay among metabolic health, inflammation, and nutritional status contributing to aging-related morbidity and mortality. The Metabolic Vulnerability Index (MVX) integrates measures of inflammation and metabolic health to assess mortality risk. Using clinical nuclear magnetic resonance spectra and a validated MVX algorithm, MVX scores were generated for the Duke Established Populations for Epidemiologic Studies of the Elderly (D-EPESE) longitudinal cohort (n = 1507, mean age 78.1 ± 5.4 years; 36% men). MVX comprises markers of chronic inflammation (small high density lipoproteins and the inflammation marker, GlycA) and metabolic malnutrition (citrate and branched chain amino acids). Incident all-cause deaths were ascertained over a median follow-up of 7.0 years (95% confidence interval (CI):1.0–18.9). In models adjusted for age, sex, and race, greater MVX scores were strongly associated with 1-year mortality [hazard ratio (HR) per 1 standard (SD): 3.00 (CI: 2.34–3.85, p < 0.0001)]. After further adjustment for body mass index, type 2 diabetes, smoking, systolic blood pressure, total cholesterol, triglycerides, eGFR, and qualitative measures of health and physical function, the association persisted, with only modest attenuation [HR: 2.35 (CI: 1.76–3.14, p < 0.0001)]. Similar associations were observed for 2-, 5- and 10-year mortality, with some attenuation over longer follow-up. Participants in the greatest MVX quartile had significantly greater mortality risk (Kaplan-Meier, p < 0.0001). The 1-year AUROC for mortality was 0.77 (CI: 0.71–0.84), outperforming questionnaire-based measures of health and physical function, as well as the individual MVX components (p < 0.0001). Our findings suggest that MVX is a prognostic, biomarker-derived test that integrates markers of inflammation, metabolic dysfunction, and malnutrition to predict short- and long-term mortality in adults >70 years. MVX may provide additional clinical information to support personalized risk stratification and guide targeted approaches for older adults.

1. Many microRNAs (miRNAs) regulate tissue remodeling, cellular plasticity, and repair across evolutionarily distant vertebrate lineages that are capable of regenerating appendages such as amputated limbs, fins, and antlers, as well as in human articular cartilage responding to injury. These miRNAs often belong to the same families and exert conserved, though occasionally inverted, regulatory effects. This strong cross-species overlap motivates the present literature-derived analysis. Osteoarthritis (OA), the most prevalent joint disease, still lacks disease-modifying therapies, in part because of the longstanding assumption that adult mammalian cartilage demonstrates no intrinsic reparative capacity. Yet human cartilage retains a latent repair program activated by mechanical and inflammatory stress. Some injured or degenerating joints may never be clinically recognized as osteoarthritic because their intrinsic repair capacity is sufficient to restore tissue integrity; in others, where repair capacity is diminished or damage exceeds it, the repair program is insufficient and OA becomes clinically manifest. MiRNAs are established post-transcriptional regulators of cartilage homeostasis, degeneration, and appendage regeneration, yet because the OA and regeneration research fields have advanced largely independently, the insights available at their intersection have gone unrecognized. To close this gap, we systematically mined both literatures to construct an auto-updating, cross-referenced atlas of OA- and appendage regeneration-associated miRNAs. Integrating these datasets identified a core set of shared miRNA families, delineated miRNAs unique to each field, and mapped convergent families onto common pathways governing matrix remodeling, dedifferentiation, senescence, and inflammation. We propose that regeneration-competent species can inform the identification of therapeutic miRNAs, such as miR-133, miR-21, and let-7, capable of activating endogenous cartilage repair. Collectively, this synthesis and its accompanying web-based miRNA atlas ( https://mirnaatlas.shinyapps.io/mirnaatlas/ ) establish a comparative framework for regenerative miRNA biology and provide a continually updated resource to accelerate discovery of disease-modifying, RNA-based therapies for OA. 2. Graphical Figure 1. Graphical : The miRNA Atlas is a web-based, continually updated literature-mining application that indexes PubMed, PubMed Central, Crossref, and arXiv to identify shared microRNA regulators in studies of osteoarthritis and appendage regeneration. We highlight three candidates involved in both osteoarthritis (OA) and appendage regeneration (AR) with therapeutic potential to enhance innate regenerative capacity.

Postoperative resilience varies widely among older adults, yet the biological drivers of recovery remain unclear. We evaluated whether preoperative immune profiles—measured in plasma and through ex vivo whole-blood stimulation—predict resilience to the acute stress of total knee arthroplasty. A total of 152 adults (≥60 years) in the PRIME-KNEE cohort underwent elective total knee arthroplasty and had available blood samples for measurement of 45 immune biomarkers, quantified in plasma and in whole blood stimulated ex vivo for 24 hours with lipopolysaccharide (LPS) or influenza antigen (FLU). Resilience was assessed using Expected Recovery Differential (ERD) and Resilience Trajectory (RT) across pain severity, pain interference, lower-extremity physical activities of daily living (LE-PADLs), and step counts. An exploratory stability-selection framework using LASSO identified biomarker predictors of postoperative outcomes. Plasma and stimulated biomarkers showed broadly similar predictive performance. A shared set of biomarkers—including LBP, leptin, TNFR1, CD30, and LIF—was consistently selected across models. Immune predictors explained ∼12-24% of the variance in resilience outcomes. Distinct immune signatures emerged for pain versus functional recovery: pain-related predictors mapped to local inflammatory and neuroimmune pathways, whereas function-related predictors reflected systemic inflammatory load and cytokine signaling. Preoperative immune biomarkers, whether measured in plasma or after ex vivo stimulation, capture meaningful variance in postoperative resilience. The divergence between pain-related and function-related immune signatures highlights biologically distinct pathways underlying different dimensions of recovery and supports further development of immune-based perioperative risk assessment. Author Summary: In this study, we explored why recovery after knee replacement surgery varies so widely among older adults. While many people regain mobility and experience pain relief, others continue to struggle with discomfort and limited function. We asked whether differences in the immune system before surgery might help explain these outcomes. To do this, we measured a wide range of immune signals in blood samples collected before surgery and then followed participants over several months, tracking their pain, daily activities, and physical movement. We found that patterns in these immune signals were linked to how well people recovered. Importantly, some of the signals that predicted pain recovery were different from those linked to improvements in physical function, suggesting that these aspects of recovery are driven by distinct biological processes. Our findings place the immune system at the center of recovery from major surgery and highlight its potential as a tool for identifying who may need more support. In the future, this knowledge could help guide more personalized approaches to care and improve recovery for older adults undergoing surgery. Graphical Overview of the PRIME-KNEE Study Workflow and Immune Signatures Predicting Postoperative Resilience.: Pre-operative blood was collected from older adults undergoing elective total knee arthroplasty. Whole blood was incubated under three conditions—unstimulated (NULL), lipopolysaccharide (LPS), or influenza antigen (FLU)—using the TruCulture® system to assess dynamic immune responsiveness. Forty-five pro- and anti-inflammatory biomarkers were quantified in plasma and stimulated culture supernatants. Postoperative pain, pain interference, lower-extremity physical activities of daily living (LE-PADLs), and step counts were used to derive two resilience metrics: Expected Recovery Differential (ERD) and Resilience Trajectory (RT). Stability-selection LASSO models identified pre-operative immune predictors of postoperative resilience. Panels A and B illustrate distinct immune signatures associated with pain versus functional outcomes. Panel A: Pain-related predictors (IFN-α2a, IL-15, IL-1Ra, LBP, LIF, SAA) cluster around local inflammatory and neuroimmune pathways implicated in nociceptor sensitization. Panel B: Function-related predictors (CRP, eotaxin, gp130, IL-6) reflect systemic inflammatory load and broad cytokine signaling associated with reduced functional capacity. Together, these findings highlight biologically distinct immune pathways underlying pain and functional recovery after knee arthroplasty. Graphic created in BioRender.

Purpose: This prospective cohort study with a nested case–control analysis aimed to identify gut microbial taxa associated with type 2 diabetes in older Chinese adults and to examine whether dietary balance influences diabetes-related microbial features. Patients and Methods: This study included 507 community-dwelling adults aged 65 years and older from the Surveillance and Management of Disability and Cognitive Impairment in Older Adults (SUM-DCI) cohort. Fecal samples were collected at baseline and analyzed using 16S ribosomal RNA gene sequencing to characterize gut microbial composition. Diabetes status was defined by fasting plasma glucose concentration ≥ 7.0 mmol/L or a self-reported physician diagnosis. A nested case–control study of 93 individuals (31 cases) was conducted within the baseline non-diabetic population to evaluate prospective associations. Metastats and Multivariate Association with Linear Models (MaAsLin) were used to identify diabetes-associated microbial taxa. Dietary intake was assessed using a self-reporting food frequency questionnaire, dietary balance was quantified using the Chinese Dietary Balance Index-22. Multivariable logistic regression was used to evaluate associations between dietary balance and gut microbial abundance. Results: Roseburia abundance was significantly lower in individuals with type 2 diabetes (FDR -adjusted P < 0.05). Higher baseline Roseburia abundance was associated with a lower risk of incident diabetes (OR: 0.225, 95% CI: 0.115– 0.818, P< 0.05). Low soybean intake was independently associated with reduced Roseburia abundance (OR: 0.61, 95% CI: 0.39– 0.94, P< 0.05), whereas overall dietary imbalance scores were not significantly related. Conclusion: Reduced Roseburia abundance is linked to both prevalent and future incident type 2 diabetes among older adults. Low soybean intake may contribute to this microbial depletion, suggesting a potential mechanism by which dietary habits influence diabetes risk through modulation of the gut microbiota.

To investigate the relevance of small RNAs to human longevity, we pursued three goals: (a) to validate epigenetic (small RNA) factors underlying survival of older adults, (b) to develop and validate prediction models of survival for potential clinical application, and (c) to identify plausible druggable targets prolonging longevity. We evaluated 828 small non-coding RNAs-687 microRNAs (miRNAs) and 141 piwi-interacting RNAs (piRNAs)-in baseline plasma from 1271 community-dwelling older adults (≥ 71 years) in the Duke-EPESE study. Our predictive model incorporating smRNAs, clinical variables (demographics, lifestyle, mood, physical function, standard clinical laboratory tests, NMR-derived lipids and metabolites, and medical conditions) and age achieved strong performance, with cross-validated AUCs of 0.92 for 2-year survival in Discovery and 0.87 in external Validation. Nine piRNAs, all reduced in longer-lived individuals, were identified as potential therapeutic targets. Under the assumption of causal sufficiency, these data provide causal evidence linking circulating small RNAs with survival outcomes in humans. While such inference does not replace experimental validation, it complements mechanistic studies by identifying candidate molecular drivers most relevant to human longevity. Supporting biological plausibility, reduced piRNA biogenesis has been shown to double lifespan in C elegans. Together, our findings identify circulating piRNAs and miRNAs as promising biomarkers and potential therapeutic targets to advance human longevity.