Li Z, Xia Z, Hu Y
… +9 more, Wu E, Liang M, Liu J, Cai H, Niu X, Guan X, Su Z, Chen C, Chen H
J Gerontol A Biol Sci Med Sci
· 2026 May · PMID 41955433
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Human aging is associated with testosterone decline and spermatogenic defects, impacting fertility and health, yet the underlying cellular mechanisms remain poorly understood. This study aimed to establish a regulatory c...Human aging is associated with testosterone decline and spermatogenic defects, impacting fertility and health, yet the underlying cellular mechanisms remain poorly understood. This study aimed to establish a regulatory cell atlas of Leydig cells in aging rat testes and characterize intercellular interactions. Using single-cell RNA sequencing and immunohistochemistry, interstitial cells from young (3-month) and aged (21-month) BN rat testes were analyzed. Among 8 identified interstitial cell types, aging was not synchronous, but with remarkable heterogeneity and stochasticity. Mesenchymal cells exhibited reduced expression of genes involved in detoxification and extracellular matrix maintenance, alongside increased immune regulation genes. Endothelial cells, the most communicatively active population, showed decreased angiogenesis and cell adhesion/migration but enhanced immune responses and leukocyte chemotaxis. In immune populations, dendritic cells decreased while lymphocytes increased, with no significant change in macrophages. Transcriptomic shifts indicated a transition from innate to adaptive immunity. The loss of dendritic cells and gain of lymphocytes may be linked to CCL7 and CXCL9-12, as receptors Ccr1/Ccr5 and Cxcr3 were upregulated in lymphocytes but downregulated in dendritic cells. Overall, inflammatory activation and functional losses occurred in both immune and non-immune cells during testicular aging. This innate-to-adaptive immune shift may further compromise non-immune cell functions, accelerating testicular aging.
Fang Z, Nie S, Chen H
… +3 more, Deng C, Zhang C, Zhang L
J Gerontol A Biol Sci Med Sci
· 2026 May · PMID 41955428
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Vascular aging, which is characterized by the progressive decline in the structure and function of blood vessels, is a primary driver of cardiovascular morbidity and mortality in older adults. Although chronic low-grade...Vascular aging, which is characterized by the progressive decline in the structure and function of blood vessels, is a primary driver of cardiovascular morbidity and mortality in older adults. Although chronic low-grade inflammation (inflammaging) and cellular senescence are central to this process, the molecular nodes that integrate these pathways are not well understood. This review proposes that interferon-stimulated gene 15 (ISG15), a well-established ubiquitin-like modifier in antiviral defense, acts as a critical nexus linking these pathological hallmarks in vascular aging. ISG15 is proposed to function through a dual mechanism: extracellularly, it propagates pro-inflammatory signaling; intracellularly, its covalent conjugation to target proteins (ISGylation) disrupts core homeostatic processes. The review presents evidence demonstrating that the ISG15 system, when activated by sterile triggers via the cGAS-STING pathway, drives endothelial dysfunction and vascular smooth muscle cell phenotypic switching by exacerbating oxidative stress, inducing cellular senescence, and disrupting proteostasis. Consequently, the ISG15 axis is established as a compelling therapeutic target. The rationale behind strategies that range from the direct inhibition of ISGylation and the neutralization of extracellular ISG15, to the repurposing of existing upstream interferon-pathway inhibitors, is discussed. Key outstanding questions are outlined to guide future research, paving the way for novel diagnostics and interventions aimed at preserving vascular health during aging.
Baltasar-Fernandez I, Valenzuela PL, Rodríguez-Gómez I
… +34 more, Quiñonez-Bareiro F, Alegre LM, Prokopidis K, Rodriguez-Mañas L, Ara I, Rosas-Carrasco O, Williams LJ, Ramirez-Vélez R, Pasco JA, Hajj-Boutros G, Agnihotram R, Sim M, Lok Ok Choo W, Imani M, Ayala-Copete AM, Chabot J, Borda MG, Neto NJ, Godard-Sebillotte C, Bergman H, Andrianova A, Arai H, Gaudreau P, Chen LK, Samhat H, Alexandre TDS, Guerra R, Faust A, Papaioannou A, Sekhon H, Connolly E, Duque G, García-García FJ, Transforming Health and Resilience for Healthy Lives (THRIVE) Project Group
J Gerontol A Biol Sci Med Sci
· 2026 May · PMID 41955333
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BACKGROUND: Osteosarcopenia-the coexistence of osteopenia/osteoporosis and sarcopenia-is associated with numerous adverse health outcomes, but its association with intrinsic capacity (IC) remains unknown. We aimed to exp...BACKGROUND: Osteosarcopenia-the coexistence of osteopenia/osteoporosis and sarcopenia-is associated with numerous adverse health outcomes, but its association with intrinsic capacity (IC) remains unknown. We aimed to explore the associations of osteosarcopenia with IC and all-cause mortality in older adults. METHODS: We conducted a cross-sectional analysis of IC and a prospective analysis of all-cause mortality in 1142 participants from the Toledo Study for Healthy Aging (75.1 ± 6.0 years, 53.1% women). Participants were classified as having no musculoskeletal disorders, osteopenia/osteoporosis, sarcopenia, or osteosarcopenia (DXA- and EWGSOP2-based criteria). IC was operationalized as a composite score integrating locomotion, cognition, psychological, vitality, and sensory domains. RESULTS: Older adults with osteosarcopenia exhibited lower total IC (76.6 ± 1.1 points) than those without musculoskeletal disorders (83.7 ± 0.5 points; p < .001) or with osteopenia/osteoporosis (81.3 ± 0.3 points; p < .001), with significant differences also found between the latter groups (p < .001). Specifically, osteosarcopenia was associated with poorer results in the locomotion, cognition, vitality, and sensory domains (all p < .01), but not in the psychological domain. Over a median 6.2-year follow-up, osteosarcopenia-but not osteopenia/osteoporosis-was associated with a higher risk of mortality compared to those without musculoskeletal disorders [HR (95% CI)=1.96 (1.02-3.77); p = .045]. In joint analyses with IC status (high vs low, segregated by the median), this association was specifically observed among participants with osteosarcopenia and low IC [HR = 2.55 (1.31-4.96); p = .004]. CONCLUSIONS: Osteosarcopenia is associated with lower total IC and impairments across most IC domains. This finding is of clinical relevance, as the combination of this condition and low IC is associated with an increased mortality risk.
Cathey H, Hernández-Bonilla D, Cortez-Lugo M
… +2 more, Mejia-Arango S, Wong R
J Gerontol A Biol Sci Med Sci
· 2026 Apr · PMID 41950395
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BACKGROUND: Previous epidemiological studies have examined the relationship between metal exposures and cognitive function in older adults. However, results regarding copper suggest that both deficient and excessive conc...BACKGROUND: Previous epidemiological studies have examined the relationship between metal exposures and cognitive function in older adults. However, results regarding copper suggest that both deficient and excessive concentrations can be detrimental to cognitive function. METHODS: This cross-sectional study analyzed the association between hair copper concentrations and cognitive function in 2371 Mexican adults aged 50 and older from the 2018 Mexican Health and Aging Study. An adapted version of the Cross-Cultural Cognitive Examination, referred to as the cognitive battery, was used to assess cognitive function. Hair copper concentrations were determined by inductively coupled plasma mass spectrometry and divided into approximately normally distributed (0.05-20.95 µg/g, 91% of the cohort) and high-concentration (>21.11 µg/g, 9% of the cohort) groups. RESULTS: Linear regression revealed a positive association between raw cognitive scores and normally distributed copper concentrations (βstd = 0.04; 95% CI [0.01, 0.07]) after adjusting for sociodemographic, health, and environmental factors. Post hoc analysis revealed that socioeconomic status moderates the association between copper and cognitive performance. CONCLUSIONS: The findings suggest that normally distributed copper concentrations were associated with better cognitive performance, and this effect is specific to the medium socioeconomic level after controlling for covariates. Further studies are needed to confirm the beneficial relationship between copper and cognition and to explore which aspects of socioeconomic status may moderate the effects of copper and other metal exposures.
Espeland MA, Olson K, Tangney CC
… +15 more, Gitelman DR, Cleveland M, Thro AA, Demesie YN, Snyder HM, Whitmer RA, Desai P, Alam R, Crivelli L, Holland TM, Preissle O, Raman R, York MK, Baker LD, U.S. POINTER Study Group
J Gerontol A Biol Sci Med Sci
· 2026 Apr · PMID 41950390
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BACKGROUND: Multidomain lifestyle interventions hold promise as approaches to slow aging. Deficit accumulation frailty indices (FIs) are increasingly used to capture aging processes. Frailty is highly associated with inc...BACKGROUND: Multidomain lifestyle interventions hold promise as approaches to slow aging. Deficit accumulation frailty indices (FIs) are increasingly used to capture aging processes. Frailty is highly associated with increased mortality and chronic disease risk, but the degree to which multidomain lifestyle changes impact frailty is not clear. METHODS: The U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) was a 2-year randomized clinical trial to compare two multidomain lifestyle interventions designed to increase exercise, improve diet, and promote social and cognitive stimulating activities and health monitoring. The Structured intervention incorporated greater structure, intensity, and accountability than the Self-Guided intervention. A modified FI (mFI) was developed from data collected at baseline, 12, and 24 months. RESULTS: The trial enrolled 2111 adults (ages 60-79 years) who were at increased risk for accelerated cognitive decline. At 24 months, the mean (standard error) changes from baseline of a 31-component mFI were -0.009 (0.002) for Self-Guided and -0.024 (0.002) for Structured participants, a difference averaging -0.014 [-0.019, -0.008] (P < .0001). Group differences were similar across subgroups based on age, sex, body mass index, diabetes, and baseline mFI. Changes in mFI did not account for the relative cognitive benefits provided by the Structured intervention compared to the Self-Guided intervention. CONCLUSIONS: Multidomain lifestyle interventions may decrease frailty and slow aging processes with greater structure and intensity, resulting in greater benefits. CLINICAL TRIAL REGISTRATION NUMBER: NCT03688126.
Zeng L, Chen L, Wei L
… +4 more, Li J, Liang S, Jiang H, Gao F
J Gerontol A Biol Sci Med Sci
· 2026 Apr · PMID 41942101
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Human aging is associated with declining renal function, potentially worsened by gut microbiota-derived uremic toxins. Although the gut-kidney axis is implicated in disease, its dynamic role in physiological aging remain...Human aging is associated with declining renal function, potentially worsened by gut microbiota-derived uremic toxins. Although the gut-kidney axis is implicated in disease, its dynamic role in physiological aging remains unclear. Through integrated 16S rDNA and transcriptomic analyses in young (3 months), middle (12 months), and old-aged (24 months) mice, we identified age-dependent shifts in gut microbiota and renal gene expression. The shifts are nonlinear, with midlife (12 months) representing a key transitional point. The gut microbiota shifts from a commensal metabolic partner in youth to a driver of a pro-inflammatory microenvironment in old age. Concurrently, the kidney shows enhanced inflammatory, pro-fibrotic, and pro-coagulant transcriptional signatures. These changes are synchronized, revealing a stage-specific gut-kidney interplay: an adaptive peak in midlife precedes a coordinated functional shift toward a pro-aging microenvironment in late life. Our findings introduce the concept of "stage-specific aging" and suggest that aging-related changes in both the gut microbiota and the kidney transcriptome are non-linear, with midlife representing an important transitional stage in gut-kidney aging.
Oyedeji CI, Mohamed RE, Faldowski R
… +13 more, Callaway T, Poole T, Denis Oliva F, Mathis V, Subramaniam A, Whitson H, Reeve BB, Pieper C, Telen MJ, Ashley-Koch A, Cohen HJ, Hall K, Strouse JJ
J Gerontol A Biol Sci Med Sci
· 2026 May · PMID 41926751
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BACKGROUND: People with sickle cell disease (SCD) are at risk for accelerated biological aging and functional decline due to both age and SCD-related stressors. Frailty is characterized by decreased physiologic reserve a...BACKGROUND: People with sickle cell disease (SCD) are at risk for accelerated biological aging and functional decline due to both age and SCD-related stressors. Frailty is characterized by decreased physiologic reserve and increased vulnerability to stressors that can lead to disability and death. The purpose of this study was to evaluate frailty phenotype in adults with SCD and identify factors associated with frailty. METHODS: Frailty was defined by meeting ≥3 of the following criteria: slowness, weakness, weight loss, low physical activity, and exhaustion. Participants meeting 1-2 criteria were prefrail and "robust" if no criteria were present. RESULTS: We analyzed frailty in 137 adults (age ≥ 18) with SCD in a single-center cross-sectional study (mean age 45; range 19-82). Three (2%) participants were frail, 47% prefrail, and 51% robust. Compared to robust, frail/prefrail participants were more likely to have emergency department visits in the past year (66% vs 46%; p < .02), hypertension (42% vs 19%; p < .003), diabetes (16% vs 4%; p < .02), more SCD complications (2.8 vs 2.1; p < .02), and significantly worse socioeconomic status, cognitive function, depression, physical function, and disability in activities of daily living. CONCLUSIONS: The prevalence of prefrailty in this sample of young and predominantly middle-aged adults with SCD was similar to older adults in the general population, further supporting that accelerated aging occurs in this population and emphasizing the need for early identification and initiation of interventions to prevent and attenuate frailty in SCD. In future studies, we will evaluate SCD-specific cutpoints for frailty components that predict clinically meaningful outcomes.
Liu S, Huang J, Calderon R
… +5 more, Spira AP, Mcphillips MV, Gooneratne N, Gill J, Li J
J Gerontol A Biol Sci Med Sci
· 2026 May · PMID 41925207
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BACKGROUND: Sleep disruption is common in older adults and is a significant risk factor for developing Alzheimer's disease (AD). This study examines the association between self-reported sleep quality, actigraphy- and el...BACKGROUND: Sleep disruption is common in older adults and is a significant risk factor for developing Alzheimer's disease (AD). This study examines the association between self-reported sleep quality, actigraphy- and electroencephalogram (EEG)-measured sleep parameters, and plasma amyloid-tau-neurodegeneration (ATN) biomarkers in older adults without dementia. METHODS: We analyzed baseline data from a randomized controlled trial of 103 sedentary community-dwelling older adults with insomnia symptoms but without dementia. Participants completed the Pittsburgh Sleep Quality Index (PSQI) and wrist actigraphy, provided blood samples for plasma biomarker assays (amyloid-beta [Aβ] 42, Aβ40, Aβ42/40 ratio, total tau, and neurofilament light [NfL]), and a subsample (n = 56) underwent a 2-night ambulatory EEG. Multiple regression models tested associations between sleep measures and plasma ATN biomarkers. RESULTS: Participants averaged 70.0 ± 6.0 years old, and 80.6% were female. Adjusted analyses showed greater rapid eye movement (REM) sleep percentage was associated with lower Aβ40 (β = -0.018; 95% confidence interval [CI] = -0.027, -0.010) and higher Aβ42/40 ratio (β = 0.016; 95% CI = 0.007, 0.025). Higher PSQI scores were nominally associated with higher Aβ42 (β = 0.017, 95% CI = 0.004, 0.031) and NfL (β = 0.034, 95% CI = 0.007, 0.062), but these associations did not sustain false discovery rate correction. CONCLUSIONS: Greater REM sleep was associated with a more favorable plasma amyloid profile, whereas associations between subjective sleep quality and plasma biomarkers were nominal and require confirmation in larger studies. These findings suggest that REM sleep architecture measured using ambulatory EEG may be particularly sensitive to amyloid-related changes prior to dementia. Clinical Trial Registration Number: NCT03959202.
Colón-Emeric CS, Peskoe S, Ashner MC
… +7 more, Kraus VB, Huebner JL, Hall KS, Smith P, Feld JA, Acker LC, Whitson HE
J Gerontol A Biol Sci Med Sci
· 2026 Apr · PMID 41915019
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BACKGROUND: We aimed to describe recovery trajectories over 6 months in pain intensity, pain interference, lower extremity disability, and physical activity in older adults undergoing elective total knee arthroplasty (TK...BACKGROUND: We aimed to describe recovery trajectories over 6 months in pain intensity, pain interference, lower extremity disability, and physical activity in older adults undergoing elective total knee arthroplasty (TKA), and to identify clinically feasible measures predicting recovery. METHODS: Prospective cohort study in a single academic medical center. Adults ≥60 years (n = 203) scheduled for elective TKA had preoperative assessments of physical reserve (3-min walk test, grip strength), psychological reserve (PHQ-9, Resilience Scale), social support (emotional support scale, financial resource sufficiency, education level), and cognitive reserve (3MS, Trail Making Test Part B, Digit Symbol Substitution Test, 15-item recall). Provocative tests with experimental stressors included dual-task gait speed, and functional near infrared spectroscopy (fNIRS). Outcomes were the PROMIS pain scales, the lower extremity gain scale, and average daily step counts measured at postoperative day 1-7 and months 1, 2, 4, and 6. Latent class trajectory analysis defined common recovery patterns for each outcome. RESULTS: For each outcome, 3-4 recovery trajectory groups were defined. Overall, 7% of participants were in the highest recovery group in all 4 outcomes and 20% in the lowest for all outcomes. Preoperative depression score, cognitive tests, emotional support scale, 3-min walk distance, and grip strength were significantly different across resilience groups in multiple outcomes. Provocative tests were not predictive of recovery. CONCLUSIONS: Recovery trajectories after TKA are predicted by physical, cognitive, and psychological reserve measures. Results inform future resilience research and may allow for shared decision-making and targeted preoperative optimization.
Natarajan D, Milan M, Reyff Z
… +6 more, Negri S, Ekambaram S, Varshney RR, Rudolph MC, Tarantini S, Balasubramanian P
J Gerontol A Biol Sci Med Sci
· 2026 Apr · PMID 41913046
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Adipose dysfunction contributes to age-related systemic decline primarily through its adverse effects on energy metabolism, insulin sensitivity, circulating adipokines, and inflammation. Time-restricted feeding (TRF) has...Adipose dysfunction contributes to age-related systemic decline primarily through its adverse effects on energy metabolism, insulin sensitivity, circulating adipokines, and inflammation. Time-restricted feeding (TRF) has emerged as a promising approach to correct adipose and metabolic dysfunction. However, most of these studies were carried out in young animals. Whether TRF could exert similar beneficial effects in the adipose tissue during aging remains unknown. To address this, 18-month-old C57BL/6 mice were placed on either a TRF diet (food intake restricted to a 6-h time window every day in the dark phase) or an unrestricted diet for 6 months. Young animals on an unrestricted diet acted as additional controls to compare the effects of aging. Here, we demonstrate that a 6-month TRF regimen induces a biphasic pattern in whole-body energy metabolism characterized by a selective increase in energy expenditure and oxygen consumption during the active dark phase, aligning with the feeding schedule. TRF increased uncoupling protein 1 (UCP1) expression in the white adipose tissue (WAT) and reverses age-associated whitening of brown adipose tissue (BAT) in aged mice. In addition, TRF selectively enhances mitochondrial metabolism in WAT depots. Furthermore, TRF reduces macrophage infiltration, induces a favorable shift in macrophage polarization (lower M1/M2 ratio), and decreases fibrosis in adipose tissue. Overall, our findings indicate that TRF promotes a metabolically beneficial adipose phenotype characterized by beiging and reduced fibro-inflammation during aging. These results underscore the potential of TRF as a dietary intervention to mitigate adipose dysfunction and promote metabolic health in the aging population.
Perez NB, Xu K, Xu Y
… +12 more, Lang L, Anastos K, Alcaide ML, Cohen M, Shrestha S, Edmonds A, Meyers J, Kassaye S, Ofotokun I, D'Souza G, Aouizerat B, Rubin LH
J Gerontol A Biol Sci Med Sci
· 2026 May · PMID 41883137
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Depression disproportionately affects women living with HIV, yet symptom heterogeneity and the lack of observable biomarkers can impede detection. Accelerated aging of monocytes-key innate immune cells-may contribute to...Depression disproportionately affects women living with HIV, yet symptom heterogeneity and the lack of observable biomarkers can impede detection. Accelerated aging of monocytes-key innate immune cells-may contribute to depression, particularly in this population. A DNA methylation clock, MonoDNAmAge, estimates monocyte biological age and has shown evidence of epigenetic age acceleration (EAA) in women with HIV. Here, we examine MonoDNAmAge as a biomarker of depression in women with and without HIV, differentiating non-somatic from somatic symptom domains. DNA methylation data and Center for Epidemiologic Studies Depression Scale (CES-D) scores were available from 440 Women's Interagency HIV Study participants. Two biological age estimates (HorvathDNAmAge and MonoDNAmAge) were calculated and orthogonalized with chronological age. In the total sample and subsamples stratified by HIV status, we used multiple linear regression to assess how EAAMono and EAAHorvath were associated with depressive symptoms. Standardized β coefficients are reported. The sample included 261 women with HIV (mean chronological age = 43.7 (8.9) years; 38% Black; 48% Hispanic) and 179 women without HIV (mean chronological age = 39.5 (10.0) years; 31% Black; 49% Hispanic). In the overall sample, EAAMono was associated with the non-somatic depressive symptom domain (β = 0.125, p = .018), and anhedonia specifically (β = 0.354, p = .007), adjusting for HIV, race, and ethnicity. This pattern persisted in the subsample with HIV (β = 0.112, p = .085). EAAHorvath was not associated with depression severity or symptom domains. Monocyte aging may represent a sensitive biomarker of non-somatic depression symptoms in women with HIV. The dynamics of monocyte aging and depression warrant further study to clarify mechanistic links.
Byun JY, Jones R, Iriarte E
… +16 more, Xavier Hall CD, Krause KD, Wang CX, Pahwa S, Lam JO, Falutz J, Masters MC, Corley M, Marzolini C, Greene M, Vera J, Siegler EL, Margolick JB, Ellis RJ, Letendre S, Moore DJ
J Gerontol A Biol Sci Med Sci
· 2026 May · PMID 41872027
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The 15th Annual International Workshop on Aging and HIV (October 24-25, 2024) centered on integrating aging-related science into HIV research and care and aimed to advance interdisciplinary exchange and identify actionab...The 15th Annual International Workshop on Aging and HIV (October 24-25, 2024) centered on integrating aging-related science into HIV research and care and aimed to advance interdisciplinary exchange and identify actionable priorities for research and practice. This article summarizes keynote presentations on geroscience-informed aging mechanisms; clinical manifestations of aging with HIV, including frailty, neurocognitive impairment, and perinatally acquired HIV; polypharmacy; scalable geriatric-HIV care models and implementation; and career development. It identifies priorities for advancing the field, including geroscience-informed trials, frailty and cognitive screening, deprescribing, scalable geriatric-HIV care models, and research addressing aging challenges in perinatally acquired HIV.
Singh R, Calderon VE, Holstein D
… +7 more, Diaz V, Martinez PA, Galvan V, Javors M, Fernandez E, Lechleiter J, Strong R
J Gerontol A Biol Sci Med Sci
· 2026 May · PMID 41863332
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Interventions Testing Program identified rapamycin as a robust lifespan-extending agent at multiple testing sites and in both sexes, with particularly strong effects in females, making it a leading candidate in aging res...Interventions Testing Program identified rapamycin as a robust lifespan-extending agent at multiple testing sites and in both sexes, with particularly strong effects in females, making it a leading candidate in aging research. We used genetically heterogeneous UM-HET3 mice of both sexes to determine whether rapamycin can prevent or delay age-sensitive traits. Mice were supplemented with microencapsulated rapamycin at 14 ppm starting at 12 months of age. Chronic rapamycin supplementation prevented the age-related decline in motor function, with females benefiting more than males. We further determined that rapamycin attenuated the age-related increase in protein carbonyls, principally in the insoluble protein fraction of brain regions that subserve motor function. We also found increased protein expression of glial fibrillary acidic protein (GFAP) across several brain regions, surprisingly, rapamycin treatment further increased GFAP levels in the striatum of both sexes, however this increase is not supporting evidence for a decrease in oxidative stress. Age-related increase in ER stress has been reported to be associated with increased protein carbonyls. We observed that rapamycin reduced the expression of C/EBP homologous protein (CHOP), a marker of ER stress-mediated apoptosis, in the striatum region of female mice. Our data show a novel beneficial effect of rapamycin on age-related motor deficits that is not sex-specific and that these changes are associated with reduction in protein carbonyls in brain regions linked to motor function. Furthermore, our results are consistent with the idea that rapamycin's beneficial effects are mediated, at least in part, by reducing oxidative stress and ER stress-mediated apoptosis.
Yang T, Wei Q, Pang D
… +11 more, Cheng Y, Huang J, Lin J, Xiao Y, Jiang Q, Wang S, Liu J, Zhang S, Ma Y, Li C, Shang H
J Gerontol A Biol Sci Med Sci
· 2026 Mar · PMID 41863330
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BACKGROUND: Symptom-based indicators suggestive of autonomic dysfunction are common but underrecognized in Parkinson's disease (PD), with potential implications as a biomarker of aging for early detection and prognosis....BACKGROUND: Symptom-based indicators suggestive of autonomic dysfunction are common but underrecognized in Parkinson's disease (PD), with potential implications as a biomarker of aging for early detection and prognosis. We aimed to examine the associations between autonomic dysfunction and PD in a large, population-based cohort. METHODS: We analyzed 374 657 UK Biobank participants who were free of PD at baseline. Autonomic symptoms-including orthostatic hypotension, constipation, urinary and sexual dysfunction, hyperhidrosis, and other autonomic disorders-were identified via hospital records. Incident PD and subsequent outcomes, including dementia and all-cause mortality, were tracked through June 2023. Cox models estimated hazard ratios for PD and adverse outcomes, and conditional logistic regression assessed the temporal trajectory of autonomic dysfunction relative to PD diagnosis. RESULTS: Over a median 14.1-year follow-up, 2568 participants developed PD. Orthostatic hypotension (HR: 2.91; 95% CI: 1.39-6.13), constipation (HR: 1.63; 95% CI: 1.19-2.24), urinary dysfunction (HR: 1.45; 95% CI: 1.04-2.02), and sexual dysfunction (HR: 3.56; 95% CI: 1.60-7.95) independently predicted PD risk. Prediagnostic and postdiagnostic autonomic dysfunction was associated with a higher risk of PD dementia and mortality. Autonomic dysfunction was detectable over 10 years before PD diagnosis (OR: 4.46; 95% CI: 3.76-5.29), with the strongest association observed within 5 years after PD onset (OR: 8.59; 95% CI: 7.58-9.74). CONCLUSIONS: Symptom-based indicators suggestive of autonomic dysfunction serve as early clinical signals and robust prognostic markers in PD, highlighting their potential utility for early risk stratification and long-term patient management in large population-based settings.
Xu T, Qiu X, Hang Q
… +7 more, Qi X, Mei H, Guo J, Zheng Y, Ji M, Xu Q, Wu B
J Gerontol A Biol Sci Med Sci
· 2026 Mar · PMID 41857777
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BACKGROUND: Frailty is associated with increased risks of disability, hospitalization, and mortality. Emerging evidence suggests that the oral microbiome may influence frailty development, but population-based evidence i...BACKGROUND: Frailty is associated with increased risks of disability, hospitalization, and mortality. Emerging evidence suggests that the oral microbiome may influence frailty development, but population-based evidence is limited and causal relationships remain unclear. This study explored the link between oral bacteria and frailty, using genetic analysis to investigate causality. METHODS: We analyzed data from 2,696 adults aged ≥50 years in NHANES 2009-2012. Oral microbiome diversity was assessed using 16S rRNA gene sequencing. Frailty was measured using a 36-item Frailty Index. Survey-weighted linear regression and restricted cubic spline models examined associations between four α-diversity indices and frailty. β-diversity was quantified using Bray-Curtis dissimilarities and compared by frailty status using PERMANOVA. Bidirectional two-sample Mendelian randomization (MR) using GWAS data assessed causal relationships between taxa and frailty. RESULTS: Lower α-diversity across all four indices were associated with higher frailty scores (P < 0.050). β-diversity differed by frailty (P = 0.001). MR analyses indicated that in saliva, Campylobacter_A, Saccharimonadaceae, and TM7x were protective, whereas Gemella was associated with increased frailty risk. In tongue samples, Saccharimonadaceae was a risk factor, while Fusobacterium, TM7x, and Solobacterium showed protective effects. CONCLUSIONS: Oral microbiome diversity is inversely associated with frailty in U.S. adults, and MR analyses identify specific oral taxa potentially involved in frailty development. These findings provide population-level evidence and genetic support for the oral microbiome as a potential modifiable target to promote healthy aging.
Imms P, Wang H, Bhattacharya S
… +6 more, Chaudhari NN, Vega OM, Solis Galvan JA, Chen S, Li R, Irimia A
J Gerontol A Biol Sci Med Sci
· 2026 May · PMID 41844537
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BACKGROUND: Predicting Alzheimer's disease (AD)-related cognitive impairment (CI) among cognitively normal (CN) adults enables meaningful disease modification through early intervention and enrichment of clinical trials....BACKGROUND: Predicting Alzheimer's disease (AD)-related cognitive impairment (CI) among cognitively normal (CN) adults enables meaningful disease modification through early intervention and enrichment of clinical trials. METHODS: A deep survival model is trained to predict CI conversion risk in 1415 CN adults from the National Alzheimer's Coordinating Center. Converters' (N = 212) and non-converters' (N = 1203) baseline clinical measures and magnetic resonance images are used to estimate their conversion probability up to 22 years after baseline observation. RESULTS: After 20-fold cross-validation, the model predicts conversion probability with a c-index of 0.88, classification accuracy of 75%, and AUC ROC of 0.89, outperforming previous machine learning models. CONCLUSIONS: This is one of few studies on the important challenge of predicting future CI among unimpaired subjects. Deep survival modeling can improve the identification of preclinical AD and suggests that uncertainty in AD risk estimation is due to potentially modifiable lifestyle factors.
Abdi L, Lockwood G, Le Couteur D
… +7 more, Handelsman DJ, Naganathan V, Blyth F, Waite LM, Cogger V, Willcox B, Allsopp R
J Gerontol A Biol Sci Med Sci
· 2026 Apr · PMID 41837379
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Recent findings from the Honolulu Heart Program cohort in Hawaii suggest a longevity-associated variant of Forkhead box O3 (FOXO3) may provide resilience against cardiometabolic diseases (CMDs), such as hypertension, dia...Recent findings from the Honolulu Heart Program cohort in Hawaii suggest a longevity-associated variant of Forkhead box O3 (FOXO3) may provide resilience against cardiometabolic diseases (CMDs), such as hypertension, diabetes, and angina. The present study utilizes data from the Concord Health and Ageing in Men Project (CHAMP) cohort in Australia to further investigate the impact of the longevity-associated FOXO3 variant on CMD and longevity. Specifically, the protective "G" allele of rs2802292 was examined for potential protective effects against mortality in individuals with hypertension, diabetes, or angina (p-value: .01). Although no significant impact on mortality was observed in individuals with hypertension or diabetes, a reduced risk of mortality was observed for G allele carriers with angina. These findings are consistent with prior research linking longevity-associated FOXO3 variants to increased lifespan in individuals with heart disease and provide further evidence of its importance as a genetic factor influencing CMD risk. The protective effects against heart disease may arise from FOXO3's ability to enhance cellular resilience against oxidative stress and regulate metabolic pathways crucial for cardiovascular function. Additional studies are needed to fully understand the mechanisms behind FOXO3's influence on CMD, in particular heart disease, and to explore its potential for therapeutic development. This research highlights the relevance of genetic factors, specifically FOXO3, in CMD prevention and longevity in the elderly.
J Gerontol A Biol Sci Med Sci
· 2026 Apr · PMID 41837377
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As the global population over age 65 is projected to triple by 2050, understanding the physiological mechanisms of aging and the role of sex as a biological variable is critical. Research conducted on old mice demonstrat...As the global population over age 65 is projected to triple by 2050, understanding the physiological mechanisms of aging and the role of sex as a biological variable is critical. Research conducted on old mice demonstrates that age-related cardiac dysfunction is differentially linked to markers of frailty and resilience in a sex-dependent manner. We assessed post-anesthesia recovery time, wire hanging test, and a deficit accumulation-based frailty index as markers of whole-body frailty and resilience, and correlated these variables with cardiac parameters obtained by echocardiography and Doppler imaging in 25-26-month-old mice. The results demonstrated significant heterogeneity across all functional parameters in both groups. Male and female aging profiles are distinct: in males, higher frailty scores are primarily associated with cardiac hypertrophy and increased body surface area. In contrast, female mice exhibit a more complex relationship in which hyperdynamic cardiac markers (such as increased aortic peak velocity) correlate with prolonged recovery from systemic stressors like anesthesia. Crucially, the three primary functional assessments used-the frailty index, anesthesia recovery time, and the wire hanging test-did not strongly correlate with each other, indicating that they measure interrelated yet distinct aspects of biological vulnerability and physiological reserve. These findings underscore the necessity of sex-disaggregated data and multi-metric assessments in geroscience to develop effective, personalized strategies for extending healthspan.
Kaufmann CN, Yang KH, Tseng CY
… +7 more, Chang G, Amjad H, Albrecht JS, Spira AP, Gross AL, Wickwire EM, Malhotra A
J Gerontol A Biol Sci Med Sci
· 2026 Apr · PMID 41837374
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BACKGROUND: Prior research indicates a connection between obstructive sleep apnea (OSA) and cognitive deficits, prompting interest in whether OSA treatment can prevent or slow cognitive decline. Past clinical trials on O...BACKGROUND: Prior research indicates a connection between obstructive sleep apnea (OSA) and cognitive deficits, prompting interest in whether OSA treatment can prevent or slow cognitive decline. Past clinical trials on OSA treatment and cognitive impairment have shown inconsistent results. However, observational data might help by examining more diverse populations and larger sample sizes, increasing the ability to detect subtle effects. Therefore, we reviewed literature to characterize studies evaluating cognitive outcomes from OSA treatment using observational study data. METHODS: We conducted a scoping review of studies retrieved on PubMed and Embase. Studies were screened by title/abstract, and then full text, for inclusion. We extracted data characterizing data source, study design, population, sample size, follow-up time, treatments assessed, cognitive outcome variables, and key associations. RESULTS: Of 3655 unique articles obtained from PubMed and Embase, 13 met eligibility criteria. All were retrospective cohort studies. Ten studies evaluated positive airway pressure (PAP) therapies, one examined uvulopalatopharyngoplasty, and 2 evaluated any type of OSA treatment. No studies evaluated mandibular advancement devices. Cognitive outcomes assessed included dementia diagnosis (8 studies), and changes in cognitive performance (5 studies). Results from studies for the most part found OSA treatment was associated with better cognitive outcomes, although effects varied in magnitude and statistical significance based on the data source, outcomes, and sample size. CONCLUSIONS: Observational data has the potential to help evaluate cognitive outcomes from OSA treatment, but more studies are needed, especially for OSA therapies beyond PAP alone.