Altered dynamic functional connectivity of the language network associated with electronegative L5 in patients with mild cognitive impairment - Ping-Song Chou; Sharon Chia-Ju Chen; Mei-Chuan Chou; Chung-Yao Hsu; Meng-Ni Wu; Ching-Kuan Liu; Chiou-Lian Lai (GeroScience, 2026)

Microglia-derived extracellular vesicles uncover early alterations of inflammatory signaling in Alzheimer’s disease - Chiara Bianchessi; Maria Serpente; Evelyn Ferri; Giulia Giudici; Marina Arcaro; Vittoria Borracci; Caterina Visconte; Francesca Buccellato; Luca Sacchi; Manuela Pintus; Beatrice Arosio; Andrea Arighi; et al. (GeroScience, 2026)
Alzheimer’s disease (AD) is increasingly recognized as a neurodegenerative disorder associated with chronic low-grade inflammation and age-related immune dysregulation. Microglial-derived extracellular vesicles (MDEVs) are emerging as important mediators of neuroimmune communication and potential biomarkers reflecting pathological processes occurring within the central nervous system (CNS). However, how EV-associated inflammatory signalling changes across different stages of AD remains poorly understood. In this study, we characterized the inflammatory molecular profile of serum-derived MDEVs in 22 AD patients, 19 prodromal AD subjects, and 23 healthy controls (HC). Cytokine concentrations were also evaluated in paired serum and cerebrospinal fluid (CSF) samples to compare vesicle-associated and soluble inflammatory signals across biological compartments. MDEVs were isolated by size exclusion chromatography followed by TMEM119-based immunoenrichment. Cytokine quantification was performed using the Ella Simple Plex automated immunoassay platform. MDEVs from AD patients showed a generalized reduction in both pro- and anti-inflammatory cytokines compared to HC, including IL-1β, TNF-α, IL-2, IFN-γ, IL-6, IL-12p70, IL-10, and IL-4. Notably, several alterations were already detectable at the prodromal stage. In contrast, soluble cytokines in serum and CSF displayed a predominantly pro-inflammatory profile in AD patients, with increased levels of IL-1β, TNF-α, and IL-12p70. No significant correlations were observed between cytokine levels measured in MDEVs and those detected in serum or CSF. Overall, these findings support the presence of a compartment-specific reorganization of inflammatory signalling during AD progression. Early alterations in MDEV inflammatory cargo may reflect disrupted EV-mediated neuroimmune communication and highlight the potential of MDEVs as accessible peripheral biomarkers of neuroinflammatory processes in AD.

Workplace stress and healthy aging: assessment strategies, research hypotheses, and pilot insights from the Semmelweis study - Péter Varga; Virág Zábó; Andrea Lehoczki; Annamária Buda; Andrea Zsebe; Monika Fekete; Tamás Csípő; Vince Fazekas-Pongor; Ádám G. Tabák; Stefano Tarantini; Andriy Yabluchanskiy; Róza Ádány; et al. (GeroScience, 2026)
Workplace stress is an increasingly recognized determinant of both workforce well-being and healthy aging. However, few longitudinal studies have systematically integrated stress assessment into large occupational cohorts with an explicit focus on aging processes. The Semmelweis Study, launched in 2024, addresses this gap by embedding validated stress assessment tools into a comprehensive, multidisciplinary framework designed to explore the biological, psychological, and social determinants of healthy and unhealthy aging in a university workforce. This paper presents the conceptual foundation, methodology, and early applications of workplace stress assessment within the Semmelweis Study. We outline research hypotheses linking stress to aging outcomes and describe a pilot investigation among a high-risk subgroup—conductors trained at the András Pető Faculty of Semmelweis University. Stress is assessed using validated psychometric tools, including the Perceived Stress Scale, Effort-Reward Imbalance Questionnaire, Maslach Burnout Inventory, resilience measures, and social support scales. These are integrated with biological aging markers, cognitive assessments, mental health indicators, lifestyle factors, and detailed occupational data. A pilot study applying this framework was conducted among conductors, a professional group known for high emotional demands and role strain. Preliminary findings indicate elevated stress levels and burnout symptoms among conductors, with workload, perfectionism, and emotional burden identified as key stressors. Participants expressed strong interest in workplace-based stress management resources, informing plans for targeted interventions within this group. The integration of workplace stress assessment into the Semmelweis Study offers a novel platform for advancing healthy aging research and informing real-world prevention strategies. By systematically linking stress measurement to aging outcomes, and by addressing occupational stress through targeted interventions, Semmelweis University exemplifies how academic institutions can act as both research leaders and models of healthy workplace practices. These efforts align with the Semmelweis-EUniWell Workplace Health Promotion Model Program and contribute to broader European efforts to promote resilience, well-being, and healthy longevity across the working life course.

PCSK9 inhibition attenuates alcohol-induced cardiovascular dysfunction and links hepatic lipid accumulation to impaired myocardial contractile reserve - Csaba Matyas; Eszter Trojnar; Partha Mukhopadhyay; Suxian Zhao; Burhan Yokus; Bruno Paes-Leme; Yohannes Getiye; Falk W. Lohoff; György Haskó; Pal Pacher (GeroScience, 2026)

Targeting cellular senescence mitigates chemotherapy-induced bone loss in young and aged mice - David J. Izquierdo; Enrique Blancarte-Hernandez; Charles A. Schurman; Birgit Schilling; Anna Woloszyk; Leonardo Aguilar; Adam Salmon; Vaida Glatt (GeroScience, 2026)

Muscle age acceleration shapes resting-state brain connectivity: an EEG study on older adults - Federico Frasca; Chiara Pappalettera; Alessia Cacciotti; Lucia Ventura; Marco Morrone; Andrea Manca; Franca Deriu; Fabrizio Vecchio (GeroScience, 2026)

Intermediate leucine catabolism is associated with longevity and sustained reproduction in grasshoppers - Kerri Conklin; Haley Peters; Morgan Tomlinson; Rebekah Sein; Jeremiah Kaplan; Gabriel Nealy; Alicia Horton; Hayat Husein; Isabella Ihemis; Connor Clark; Marshall D. McCue; John Hatle (GeroScience, 2026)

Frailty assessment in naturally aged mouse models: classification, limitations, and future directions - Fujue Ji; Sihan Li; Lei Yang (GeroScience, 2026)

Reactive agility and motor-cognitive assessments for distinguishing community-dwelling older adults with and without a history of falls: a dual-centre cross-sectional study - Florian Giesche; Ahmed H. Abobakr; Winfried Banzer; David A. Groneberg; Lutz Vogt; Martine Hoffmann; Isabelle Albert; Thorben Hülsdünker (GeroScience, 2026)

Sodium-glucose cotransporter 2 inhibitors are associated with reduced circulating activin A and modulation of BMP/activin signaling in ischemic cardiomyopathy with high echocardiographic probability of pulmonary hypertension - Rosalinda Madonna; Piero Del Boccio; Andrea Borghini; Mattia Alberti; Filippo Biondi; Maria Concetta Cufaro; Riccardo Morganti; Damiana Pieragostino; Maria Grazia Andreassi; Carmine Rocca; Péter Ferdinandy; Letizia Mattii; et al. (GeroScience, 2026)

Association between body roundness index and progression of cardio-renal-metabolic diseases using multistate models - Xinyi Lu; Jieru Cai; Xingge Li; Lulu Pan; Huiling Shi; Yajing Zhou; Yilin Chen; Wei Chen; Guoyou Qin; Yiqian Xu; Yongfu Yu (GeroScience, 2026)

No effect of anodal high-definition transcranial direct current stimulation during motor sequence learning in older people - Silke Kerstens; Sanne Broeder; Moran Gilat; Evelien Nackaerts; Britt Vandendoorent; Alice Nieuwboer; Jean-Jacques Orban de Xivry (GeroScience, 2026)

Different hypothalamic regions in late-onset Alzheimer’s disease and aging: involvement and links with cognitive and non-cognitive features - Giulia Quattrini; Martina Bocchetta; Chiara Bagattini; Silvia Saglia; Giacomo Bertazzoli; Elisabetta Ferrari; Mara Delai; Martina Bulgari; Debora Brignani; Elisa Canu; Federica Agosta; Cristina Festari; et al. (GeroScience, 2026)

Identifying novel druggable targets and repurposable drugs for premature ovarian insufficiency by integrated multiomics and causal inference analysis - Chao Liu; Runzhi Wang; Xinnong Liu; Yuan Li; Lili Ren; Zhiyu Zhao; Zhongkai Fan; Jianying Xiao (GeroScience, 2026)

The Arlington study of healthy aging: a multidisciplinary community cohort study of functional decline with age - Delaney L. Davis; Rajvi Shah; Logan Pixler; Dang M. Mai; Juliana Santos; Camille Chandler; Kendall White; Jennifer Nguyen; Ario S. Moradi; Javed Choudhari; Carrie Arena-Marshall; Chase Johnson; et al. (GeroScience, 2026)

Cognitive vergence and pupillary responses as functional oculomotor signatures to differentiate AT(N) biological profiles in older adults with mild cognitive impairment - Ricardo Martínez-Flores; Isabel Martín-Sobrino; Neus Falgàs; Oriol Grau-Rivera; Marc Suárez-Calvet; Carlos Cristi-Montero; Agustín Ibañez; Aida Fernández-Lebrero; José Contador; Irene Navalpotro-Gómez; Albert Puig-Pijoan; Hans Supèr (GeroScience, 2026)
The locus coeruleus (LC), the earliest site of tau accumulation in Alzheimer’s disease, directly influences pupillary and vergence oculomotor systems. Whether task-evoked oculomotor dynamics can non-invasively differentiate AT(N) profiles, A+T+ (biological Alzheimer’s disease) and A−T+ (suspected non-Alzheimer’s tauopathy), remains unexamined despite their differential impact on LC-mediated modulation and cortical network integrity. Thirty-eight MCI individuals (12 A−T+, 26 A+T+), classified using validated CSF biomarker thresholds, completed a visual oddball paradigm under binocular eye-tracking. Linear mixed-effects models examined profile × condition interactions across full time series and six trial-level features; participant-level associations were tested using Firth-penalized logistic regression to account for the small and imbalanced sample. Profiles did not differ in oculomotor magnitude but diverged in temporal organization. Profile × condition interactions were significant for vergence global slope, vergence time to peak, and pupillary time to peak (all p-Holm ≤ 0.048). Timing differences were condition-dependent: A−T+ showed later responses during distractor trials, while A+T+ showed the most delayed timing during target trials. Subject-level associations were significant for vergence and pupillary time to peak, with greater condition-dependent modulation predicting higher A+T+ probability (ORs = 0.43 and 0.35; both p < 0.05); vergence global slope delta did not reach significance at the subject level. A−T+ showed superior target detection accuracy (89.7% vs. 82.5%, p = 0.003). Cognitive vergence and pupillary dynamics showed condition-dependent patterns differentiating AT(N) biological profiles in this MCI sample, supporting portable, low-cost eye-tracking as a non-invasive complement to CSF-based characterization, pending confirmation in larger, independent cohorts.

Whole-brain cholinergic modulation following computerized cognitive training in healthy older adults: a [18F]FEOBV PET study - Ana de Figueiredo Pelegrino; Paule-Joanne Toussaint; Mouna Attarha; Lydia Ouellet; Sarah-Jane Grant; Thomas Van Vleet; Etienne de Villers-Sidani (GeroScience, 2026)

Calcium dysregulation in neurovascular function in Alzheimer’s disease: mechanisms, therapeutic targets - Yvan Hanscom-Trofy; Andrew Gregory; Gilbert C. Morgan; Hongwei Yu; Rui Dong; Fan Fan (GeroScience, 2026)

Linking modifiable risk factors to vascular and neurodegenerative brain changes - Tamara Khudair; Shima Raeesi; Yashar Zeighami; Farooq Kamal; Mahsa Dadar; Cassandra Morrison (GeroScience, 2026)

Bridging structure and function: triple network remodeling driven by white matter hyperintensities in vascular cognitive impairment - Jing Jin; Jie Ma; Jia-Jia Wu; Mou-Xiong Zheng; Juan-Juan Lu; Xu-Yun Hua; Jian-Guang Xu (GeroScience, 2026)

Integrating biological aging into clinical practice: a review and path forward for precision longevity medicine - Stephanie Tuminello; Rubaiya Anika; Wiley Turner; Yuki Joyama; Lauren Lazaro; Emanuela Taioli (GeroScience, 2026)

Mild cognitive impairment and pre-frailty show distinct plasma multi-omic signatures: a cross-sectional study - Jelle C. B. C. de Jong; Marjanne D. van der Hoek; Koen W. W. Koopman; Anita M. van den Hoek; Nic J. G. M. Veeger; Ondřej Kuda; Feike R. van der Leij; Lars Verschuren; Jaap Keijer; Arie G. Nieuwenhuizen (GeroScience, 2026)
Frailty and cognitive impairments frequently co-occur in older adults. It remains unclear whether this overlap reflects shared underlying biological mechanisms or parallel but distinct disease pathways. We hypothesize that physical weakness and cognitive impairment share circulating markers already in an early disease stage. We therefore recruited and analyzed a relatively healthy population with partially overlapping pre-frailty and mild cognitive impairment (MCI), and applied a multi-omics approach to identify shared and distinct molecular signatures in plasma. Community-dwelling older adults were recruited, and frailty status was determined using the Fried frailty criteria. Cognitive function was assessed in all subjects using the Montreal Cognitive Assessment (MoCA) and MemTrax tests. Blood samples were collected in the fasted state, and plasma was used for multi-omics analyses, including proteomic profiling using the SomaLogic 11 k platform, Nightingale metabolomics, and liquid chromatography–tandem mass spectrometry (LC–MS/MS). A total of 50 community-dwelling older adults (79.9 ± 0.5 years) were recruited, comprising 29 fit individuals (14 females, 15 males) and 21 pre-frail individuals (9 females, 12 males). Pre-frail individuals scored significantly lower on the MoCA test (− 12%, P = 0.006) and MemTrax accuracy (− 4%, P = 0.03), indicating worse cognitive performance. Proteomics analysis identified 21 biomarkers associated with MCI, including APP, ACHE, and ADGRB1, and 24 biomarkers associated with pre-frailty, including FABP2, KNG1, and MTMR14. Contrary to our hypothesis, no biomarkers were shared between the pre-frailty and MCI proteomic signatures. Metabolomics analyses identified two biomarkers associated with pre-frailty and ten associated with MCI, again with no overlap between the two conditions. LC–MS/MS identified C18:0 acylcarnitine as a biomarker for pre-frailty, but not MCI. Despite consistent differences in cognitive performance between fit and pre-frail individuals, pre-frailty and MCI were characterized by distinct proteomic and metabolomic signatures, with no detectable molecular overlap. These findings suggest that the frequently observed clinical co-occurrence of frailty and cognitive impairment arises from parallel but biologically distinct disease processes, at least in early disease stages. If confirmed in a larger cohort, this suggests that both conditions will benefit from disease-specific treatments. Trial registration: The FITAAL study was registered in the Dutch Trial Register, with registration code NTR6124.

Sex and age-specific medication interaction in osteoporosis risk - Matthew Bratton; Audrey Ulfers; Gregory Laborde; Vinod Dasa; Peter C. Krause; Lauren Leslie; Deryk Jones; Anand Paul (GeroScience, 2026)
Osteoporosis, characterized by low bone mineral density (BMD) and increased fracture risk, is common yet underdiagnosed in older adults. Medications such as corticosteroids, levothyroxine, and antiepileptic drugs are well-documented contributors to BMD loss. This study examines how long-term use of these medications affects osteoporosis prevalence, specifically focusing on sex and age differences. This retrospective electronic health record study included adults aged 50–90 years. In the revised primary analysis, osteoporosis was defined using diagnosis codes only; osteoporosis screening codes and DXA procedure codes were excluded from the primary outcome. Associations between chronic exposure to corticosteroids, levothyroxine, or antiepileptics and osteoporosis ascertainment were estimated using modified Poisson regression with robust standard errors, adjusting for demographics, healthcare utilization, medication-specific indication diagnoses, and bone health covariates. Adjusted prevalence ratios and adjusted prevalence differences were reported. In the revised diagnosis-only analysis, associations were attenuated relative to the original broad outcome definition. Chronic corticosteroid exposure retained a positive but imprecise association with osteoporosis ascertainment (aPR 1.57, 95% CI 0.79–3.12; aPD +1.15 percentage points), whereas antiepileptic exposure (aPR 0.92, 95% CI 0.66–1.30; aPD −0.15 percentage points) and levothyroxine exposure (aPR 0.71, 95% CI 0.42–1.21; aPD −0.59 percentage points) were not associated with higher adjusted prevalence. Long-term use of corticosteroids, levothyroxine, or antiepileptics increases osteoporosis risk, with sex- and age-specific patterns. Men, especially younger ones, showed greater relative risk, while women exhibited higher absolute prevalence. These findings support targeted screening and early intervention strategies based on medication exposure, age, and sex.

Human-analogue age-related dynamics of dog–human attachment - Melitta Csepregi; Cecília Carreiro; Sara Świerkosz; Tifenn de Jong; Fanni Lehoczki; Ádám Miklósi; Márta Gácsi (GeroScience, 2026)
Family dogs’ human-analogue attachment to the owner has long been recognised; however, how this dog﻿–owner attachment develops and changes with age remains an open question. We examined age-related variation and the effect of training experience on the attachment behaviour in family dogs ( N = 222) using the Strange Situation Test (SST). Across three age groups (puppy﻿–juvenile, adult, and senior dogs), dogs were assessed by scores for three behavioural factors: attachment to the owner, anxiety in the strange situation, and acceptance of a friendly stranger. Based on three basic behaviours, young puppies under 6 months of age already showed attachment behaviour towards their owners. In puppies–juveniles (2.8–12 months), age was not associated with any of the three factors. In adult dogs (1–7 years), age was positively associated with acceptance scores. In senior dogs (≥ 7 years), attachment scores increased with higher age. Training experience influenced behaviour in adulthood: dogs with greater training experience received lower attachment, higher acceptance, and lower anxiety scores. Further analyses revealed that the association between training and lower attachment was mediated by lower anxiety, likely indicating underactivation of the attachment system in the SST in highly trained dogs. Our findings show that the attachment between dogs and owners develops early, remains fairly consistent through adulthood, and becomes more pronounced in later life as dogs become increasingly dependent on human care. This pattern parallels the increased reliance on attachment figures observed in older humans and highlights family dogs as a unique model for investigating how ageing influences attachment.

Examination of DNAm PhenoAge as an epigenetic biomarker for perioperative risk in adult spinal deformity surgeries - Michael P. Kelly; Jeffrey Hills; Justin S. Smith; Lawrence G. Lenke; Han Jo Kim; Shay Bess; Breton Line; Virginie Lafage; Renaud Lafage; Eric Klineberg; Ferran Pellise; Khaled Kebaish; et al. (GeroScience, 2026)

Hyaluronan deficiency disrupts endothelial glycocalyx integrity and contributes to age-related arterial dysfunction - Jisok Lim; John Kim; Venkateswara R. Gogulamudi; Adelola Adeyemo; Colton Bramwell; Lisa A. Lesniewski; Anthony J. Donato (GeroScience, 2026)

BRAIN-DISC: a novel analytical approach integrating data-driven brain pattern discovery with cohort studies for evaluating findings in brain modulation interventions - Meishan Ai; Adam Turnbull; Kanhao Zhao; Yang Liu; Yu Zhang; Feng Vankee-Lin (GeroScience, 2026)

Endothelial IGF-1/IGF-1R signaling supports young-blood-induced restoration of blood–brain barrier integrity and microvascular architecture in aged mice: evidence from the heterochronic parabiosis model - Rafal Gulej; Rebeka Kristof; Roland Patai; Siva Sai Chandragiri; Shoba Ekambaram; Mark Nagykaldi; Evelyn Brunner; Peter Mukli; Adam Nyul-Toth; Dorina Nagy; Kiana Vali Kordestan; Raghavendra Yelahanka Nagaraja; et al. (GeroScience, 2026)
Aging is associated with blood–brain barrier (BBB) breakdown and microvascular rarefaction, key contributors to cerebral neuroinflammation, hypoperfusion, and vascular cognitive impairment and dementia (VCID). Exposure to a young systemic milieu through heterochronic parabiosis has been shown to restore BBB integrity and enhance cerebrovascular function in aged mice, suggesting that circulating factors can rejuvenate the aging brain. However, the molecular mediators responsible for these effects remain poorly defined. Circulating insulin-like growth factor-1 (IGF-1) declines markedly with age and has been implicated in endothelial dysfunction and BBB disruption, raising the possibility that IGF-1/IGF-1 receptor (IGF-1R) signaling contributes to the vascular rejuvenation induced by young blood. To test this hypothesis, we combined heterochronic parabiosis with complementary transgenic approaches targeting either endothelial IGF-1R deletion (VE-Cadherin-CreERT2/Igf1rfl/fl) or systemic IGF-1 knockdown (TBG-Cre-AAV8/Igf1fl/fl). BBB permeability to fluorescent tracers and cortical microvascular density were quantified by intravital two-photon microscopy through chronic cranial windows. We found that exposure of aged mice to young circulation markedly reduced BBB leakage and increased cortical capillary density. These beneficial effects were significantly attenuated in aged parabionts lacking endothelial IGF-1R or paired with young partners deficient in systemic IGF-1, demonstrating that both endothelial receptor activation and circulating IGF-1 availability are required for full cerebrovascular rejuvenation. Despite this attenuation, partial improvement persisted, indicating that IGF-1/IGF-1R signaling contributes to, but does not fully account for, the vascular benefits of young blood. These findings identify the IGF-1/IGF-1R axis as an important mediator of young blood–induced restoration of BBB integrity and microvascular density. Targeting downstream effectors of IGF-1R signaling, together with lifestyle interventions that enhance somatotropic axis responsiveness, may offer geroscience-guided strategies to preserve BBB function and cognitive resilience in aging.

The impact of cumulative obesity and genetic susceptibility on biological aging in Chinese older adults - Jiening Yu; Liming Zhang; Zhenqing Yang; Xueqing Jia; Ciyun Zhao; Jiaxin Liu; Jingyun Zhang; Xingqi Cao; Yinyi Song; Lu Li; Xuehui Sun; Hui Zhang; et al. (GeroScience, 2026)

Dysregulated lncRNAs are associated with the progressive arterial phenotype in Hutchinson–Gilford Progeria Syndrome - Lara G. Merino; Santhilal Subhash; Daniel Whisenant; Shalini Gupta; Gwladys Revêchon; Maria Eriksson (GeroScience, 2026)

CT-based prediction of hematoma expansion and adverse outcomes after intracerebral hemorrhage: evidence appraisal, artificial intelligence translation, and GeroScience perspectives - Shuai Liu; Weihao Fu; Xiaoying Tang; Yingwei Fan (GeroScience, 2026)

Reduced dynamic functional connectivity in older ages: are older brains less adaptable? - Natalia Zhukova; Camilla Mendl-Heinisch; Christiane Jockwitz; Svenja Caspers (GeroScience, 2026)
Understanding how brain connectivity reorganizes with age is essential for characterizing healthy aging. While static functional connectivity (sFC) has revealed broad age-related shifts in network segregation and integration, recent work underscores the need to examine how these patterns dynamically fluctuate over time to better understand cognitive decline and resilience in aging. The present resting-state fMRI study was conducted to enhance comprehension of the temporal variability and dynamics of the brain’s functional architecture in the context of the aging process. To this end, dynamic functional connectivity (dFC) was extracted in 817 older adults between 55 and 85 years from the 1000BRAINS study. Using a sliding window and clustering approach, we identified four recurring dFC states and quantified temporal metrics, e.g., mean dwell time, or number of transitions. Overall, aging was associated with slower and less flexible network dynamics: integrative states became less frequent, whereas segregated states dominated, reflecting reduced inter-network communication, although the effect size was relatively small. Age-stratified analyses yielded two novel insights, thereby suggesting a refinement of the so far established theories of aging and giving rise to a new model of age-related differences in functional connectivity: First, trajectories of dedifferentiation and segregation shown from younger to older adults seem to stabilize during the transition from mid-to-old age and turn into a process of re-segregation and overcompensation during older-old ages, challenging the assumption of a monotonic increase in integration across the lifespan. Secondly, opposing links between dFC and cognitive performance have been identified, with greater network integration supporting better cognitive performance in mid-to-old adults but poorer cognitive performance in older-old adults. This suggests a shift from dedifferentiated to re-segregated connectivity with advancing age. Sex-stratified modeling further demonstrated stronger age-related reductions in flexibility among females, indicating that pooled analyses might obscure systematic sex-specific dynamics and highlighting divergent adaptive and vulnerability profiles across aging. The findings of this study emphasize the necessity of accounting for temporal variability in age-related changes of functional brain connectivity when studying aging, specifically during advanced age, with the aim of enhancing comprehension of cognitive variability.

Sex-specific circadian and behavioral phenotypes in aged growth hormone receptor knockout mice - Sean M. Hicks; Shelley A. Tischkau (GeroScience, 2026)
Growth hormone (GH) exerts complex effects on metabolism, cognition, and overall physiological well-being, and its secretion is highly regulated by the circadian clock. The Growth Hormone Receptor Knockout (GHR-KO) mouse, a model of GH insensitivity, characterized by chronically elevated circulating GH, provides a unique opportunity to examine the consequences of disrupted GH signaling during aging. Given the close relationship between circadian rhythmicity and GH secretion, we investigated sex- and genotype-specific differences in circadian activity, neuromuscular, and neurocognitive performance in aged GHR-KO mice under varying light–dark (LD), constant dark (DD) conditions, and subsequently examined the impact of circadian disruption (CD) on these parameters. Female GHR-wildtype (fGHR-WT) mice showed greater overall total activity, enhanced circadian activity amplitude, and less fragmented rhythms compared to female GHR-knockout (fGHR-KO) mice. In contrast, fGHR-KO mice demonstrated more rapid re-entrainment following phase shifts, indicating differences in circadian adaptation. Both fGHR-WT and fGHR-KO mice exhibited superior working memory compared to male littermates, while GHR-KO mice displayed enhanced neuromuscular performance compared with GHR-WT controls. CD reduced rhythm stability and was associated with declines in neuromuscular and cognitive performance, particularly in females, as well as increased open field (OF) immobility in fGHR-KO. Collectively, these findings indicate that aged GHR-WT and GHR-KO mice exhibit distinct circadian and behavioral phenotypes, and that disruption of circadian organization exacerbates cognitive and neuromuscular vulnerability.

Protective role of hemokinin-1 against age-dependent spatial memory and attention decline in mice - Brigitta Tekla Tajti; Eszter Kepe; Dávid Vince Simon; Aliz Judit Ernyey; Bence Tamás Varga; Valéria Tékus; Zsuzsanna Helyes; István Gyertyán; Éva Borbély (GeroScience, 2026)

Attentionally directed oculomotor training produces disease-stage-dependent effects on plasma tau, cognition, and oculomotor signatures in patients with mild cognitive impairment - Ricardo Martínez-Flores; Laura Pérez Zapata; Marta Del Campo Milan; Helena Blasco-Forniés; Esther Jiménez-Moyano; Javier Torres-Torronteras; Marc Suárez-Calvet; Agustin Ibáñez; Isabel Martín-Sobrino; Neus Falgàs; Oriol Grau-Rivera; Carlos Cristi-Montero; et al. (GeroScience, 2026)
Attentionally directed oculomotor training may engage circuits implicated in gamma-band modulation and early Alzheimer’s disease (AD) pathophysiology, yet its effects across mild cognitive impairment (MCI) risk strata remain unclear. We aimed to determine whether this training, delivered through a gamified eye-tracking task, is associated with differential effects on plasma neurodegeneration biomarkers, cognitive performance, and oculomotor signatures in individuals with MCI at differential risk of conversion to Alzheimer’s dementia. Twenty-nine participants with MCI were stratified into MCI-HR ( n = 17) and MCI-LR ( n = 12) based on validated MoCA and MoCA-MIS cut-off scores and completed 8 weeks of daily oculomotor training. Outcomes were assessed pre/post using permutation tests, bootstrapped Hedges’ g , and linear mixed-effects models. Cognitive performance improved in both groups (MoCA: g = 1.27–2.17; MoCA-MIS: g = 1.02–1.68), with no between-group difference. Plasma tau diverged by stratum: MCI-LR showed reductions in pTau-181 ( g = −0.64, 95% CI [−1.07, −0.15]) and pTau-217 ( g = −0.72, 95% CI [−1.08, −0.36]), whereas MCI-HR showed an increase in pTau-181 ( g = 0.82, 95% CI [0.53, 1.16]; between-group g = 1.31, 95% CI [0.89, 1.78], p = 0.001). Amyloid, GFAP, and NfL remained stable. MCI-HR showed reduced accuracy and increased reaction times (+196.4 ms, p < 0.001); MCI-LR maintained stable performance. Oculomotor signatures diverged between strata post-training (group × time × stimulus interactions, p = 0.013–0.045). In MCI-LR, oculomotor changes correlated with reductions in pTau-181 ( ρ = −0.60, 95% CI [−0.96, −0.20]) and pTau-217 ( ρ = −0.69, 95% CI [−0.95, −0.20]). Oculomotor training produced stratum-dependent responses: biomarker reductions and oculomotor-molecular coupling in MCI-LR, and dissociated physiological and behavioral outcomes in MCI-HR, suggesting disease-stage-specific neuroplasticity capacity linked to tau-related processes.

Lifestyle correlates of verbal memory in community-dwelling older adults - Zihan Ding; Agnes S. Chan (GeroScience, 2026)
Verbal memory decline is an early marker of dementia. This study aims to identify significant lifestyle correlates of verbal learning and memory among older adults to inform intervention targets for maintaining cognitive health in late life. The sample included 221 community-dwelling Chinese older adults (60–80 years). Verbal learning and memory were assessed using the Hong Kong List Learning Test (HKLLT). Lifestyle factors, emotion, demographics, and medical history were assessed using questionnaires. Body mass index (BMI) and waist-to-hip ratio (WHR) were measured. Pairwise associations were examined using Spearman correlation and polynomial regression to screen linear and non-linear associations, followed by generalized additive models (GAMs) to examine partial effect of each lifestyle factor while controlling for others factors. At the pairwise level, poorer sleep quality, less moderate-to-vigorous housework, and several dietary structure indices (e.g., grain-to-vegetables and fruits ratio, plant protein-to-total protein ratio, and pungent food intake frequency) were significantly associated with poorer verbal learning and memory. In fully adjusted GAMs, poorer sleep quality remained significantly associated with poorer 10-min and 30-min delayed recall, while more moderate-to-vigorous housework remained significantly associated with better Recognition. The plant protein-to-total protein ratio retained a significant nonlinear (inverted U-shaped) association with Recognition, with performance peaking at a moderate proportion of plant protein (approximately 0.35–0.40). Higher pungent food intake frequency was associated with poorer 30-min delayed recall. None of the lifestyle factors remained significantly associated with total learning in GAMs sleep quality, moderate-to-vigorous housework engagement, and dietary structure, particularly a moderate plant protein-to-total protein ratio and reduced pungent food intake, emerged as the most robust lifestyle correlates of verbal memory, though effect sizes were modest and largely specific to memory rather than learning. These modifiable targets may guide lifestyle interventions to support memory maintenance in late life.

Cerebrospinal fluid/plasma albumin quotient in dementia: a systematic review of biomarker potential and clinical associations - Christian Sandøe Musaeus; Steen Gregers Hasselbalch; Gunhild Waldemar; Finn Sellebjerg; Esben Budtz-Jørgensen; Anja Hviid Simonsen (GeroScience, 2026)

Cognitive components derived from traditional neuropsychological tests and their associations with plasma p-tau217 and p-tau181 in mild cognitive impairment: a multisite analysis - Ana Perez; Hugo Lewi Hammer; Vebjørn Andersson; Timo Saarinen; Soraya Alfonsín; Guido Maria Giuffrè; Naike Caraglia; Noemi Martellacci; Federico Ramírez-Toraño; Thomas Tveitstøl; Antti Kinnunen; Mia Liljeström; et al. (GeroScience, 2026)
Background Currently, no single biomarker can reliably identify preclinical Alzheimer’s disease (AD), particularly at or before the mild cognitive impairment (MCI) stage. Given the heterogeneity of MCI, integrative approaches are needed to improve early risk stratification. Objectives (i) To derive robust latent cognitive components from a multicenter, clinically defined MCI cohort using principal component analysis (PCA); (ii) to investigate the associations between these components and plasma p-tau217 and p-tau181 levels. Methods Data from 742 MCI participants in the AI-Mind cohort were analyzed. Cognitive domains were derived using PCA with varimax rotation and tested for associations with plasma p-tau biomarkers using site-specific linear regressions, adjusted for age, sex, and education. Results A reproducible four-component cognitive structure emerged (memory, executive/processing speed, verbal fluency, visuospatial ability), with memory as the most p-tau-sensitive domain. The p-tau217 measure showed stronger associations with memory than p-tau181, though effects varied by site. Conclusion The findings indicate that a robust four-factor cognitive structure can be identified in clinically defined MCI cohorts without prior biological selection. The association between latent memory factors and plasma p-tau217, observed primarily in cohorts with higher biomarker burden or clearer amnestic profiles, highlights the potential for blood-based biomarkers to refine risk assessment in routine clinical practice.

Dose–response effects of physical activity intensity and duration on frailty phenotype, frailty index, and survival: representative evidence from a 10-year national cohort of chinese older adults - Fujue Ji (GeroScience, 2026)

Preserving joint healthspan in knee osteoarthritis: a geroscience-guided review of non-surgical therapies and genicular artery embolization - Ákos Bérczi; Fanni É. Szablics; Dóra Hámori; Edit Dósa; Gergő Merkely; Mark Little; Zoltán Ungvári; György Nagy (GeroScience, 2026)

Stress, mood, and Parkinson’s disease: selective dysregulation of corticotropin-releasing hormone and urocortin neurocircuits - Bence Pytel; Zsombor Márton; János Kocsa; Gergely Berta; László Ákos Kovács; József Farkas; Nóra Füredi; Zsófia Havasi; Viktória Kormos; Balázs Gaszner (GeroScience, 2026)
Parkinson’s disease (PD) is an age-associated neurodegenerative disorder in which affective non-motor symptoms substantially contribute to disease burden, yet their neurobiological basis remains incompletely understood. We investigated region-specific alterations of corticotropin-releasing hormone (CRH) family neuropeptides in a rotenone-induced rat model of PD and evaluated the effects of combined dopaminergic (benserazide/L-DOPA) and antidepressant (fluoxetine) treatment. Motor performance, anhedonia-like behavior, dopaminergic neurodegeneration, and CRH-, urocortin 1 (UCN1)-, urocortin 2 (UCN2)-, and urocortin 3 (UCN3)-related molecular changes were assessed using behavioral testing, immunohistochemistry, and RNAscope in situ hybridization. Rotenone treatment induced robust motor impairment, nigral dopaminergic neurodegeneration with α-synuclein-positive Lewy body-like inclusions, and anhedonia-like behavior. Combined dopaminergic–antidepressant therapy improved affective deficits without reversing dopaminergic neuronal loss. Region-specific analyses revealed pronounced dysregulation of hypothalamic and midbrain stress-related neuropeptide systems, including the paraventricular nucleus/CRH, paraventricular nucleus/UCN2, lateral hypothalamic area/UCN3, and centrally projecting Edinger-Westphal nucleus/UCN1, whereas CRH- and UCN3-expressing populations within the extended amygdala remained largely unaffected. Correlation analyses further supported coordinated regulation among hypothalamic CRH-family systems and their association with affective behavioral alterations. These findings identify selective vulnerability of hypothalamic stress-regulatory neuropeptide circuits in experimental PD and suggest that aging-related impairment of stress resilience may contribute to affective non-motor symptoms. Beyond providing a comprehensive neuroanatomical characterization of CRH-family peptide alterations, this work highlights region-specific neuropeptide signaling as a potential framework for developing more precise biomarkers and targeted therapeutic strategies for PD-associated mood disturbances.

Chronic subdural hematoma through the hallmarks of aging: a geroscience framework for the commonest neurosurgical condition of older adults - David Zammit Dimech (GeroScience, 2026)

Oral anticoagulant use and incident dementia in atrial fibrillation by baseline LIBRA score: a population-based cohort study using the 45 and up study - Eyayaw Ashete Belachew; Gregory M. Peterson; Mohammed S. Salahudeen; Woldesellassie M. Bezabhe (GeroScience, 2026)
Background Oral anticoagulants (OACs), particularly direct oral anticoagulants (DOACs), may lower dementia risk, but existing studies are constrained by incomplete dementia ascertainment, short follow-up, and lack of evaluation of individual agents or baseline lifestyle-related risk profiles. We examined the association of OAC use and incident dementia in atrial fibrillation (AF) and its variation by LIfestyle for BRAin Health (LIBRA) score. Methods In this population-based cohort using linked 45 and Up Study data, participants with a first AF diagnosis between 1 January 2010 and 30 June 2022 were included, excluding those with prior AF or dementia (screened 2004–2009). OAC exposure was ascertained from pharmaceutical benefits scheme dispensing records and classified as warfarin or DOACs (dabigatran, rivaroxaban, and apixaban). A six-month landmark period following AF diagnosis was used to define exposure: participants initiating any OAC during this period were classified as OAC users, whereas those without OAC dispensing were classified as non-users. Participants were followed from AF diagnosis until dementia diagnosis, death, or 30 June 2023. Propensity score (PS) based inverse probability of treatment weighting and matching were applied to balance baseline characteristics. Cox proportional hazards models estimated adjusted hazard ratios (HRs) for incident dementia and dementia-related mortality, accounting for demographic, clinical, and lifestyle-related risk factors. Competing-risk analyses were performed to account for mortality. Results Among 21,671 AF patients (mean age 74.2 years, 45.9% women) with a mean follow-up of 6.0 (3.3) years, OAC use was associated with a lower risk of incident dementia compared with non-use (HR, 0.77; 95% CI, 0.70–0.85). DOAC use was associated with lower dementia risk (HR, 0.63; 95% CI, 0.56–0.70), whereas warfarin use was associated with higher dementia risk (HR, 1.31; 95% CI, 1.16–1.49). Individual DOAC agents were each associated with reduced dementia risk compared with non-use. In head-to-head comparisons, apixaban was associated with a lower dementia risk than dabigatran (HR, 0.79; 95% CI, 0.64–0.96). Findings were consistent across PS-matched, competing-risk, and high-adherence sensitivity analyses. Associations were similar in women and men (P for interaction = 0.528) and were stronger among participants aged ≥ 75 years (HR, 0.66; 95% CI, 0.60–0.74; P for interaction < 0.001). However, there was no statistically significant evidence that the association differed across LIBRA strata (P for interaction = 0.699) or ORBIT bleeding risk categories (P for interaction = 0.069), suggesting no clear effect modification by either score. Use of DOACs was also associated with lower dementia-related mortality (HR, 0.53; 95% CI, 0.44–0.63). Conclusions In people with AF, use of DOACs was associated with a reduced risk of incident dementia and dementia-related mortality, independent of baseline LIBRA score. These findings suggest potential cognitive benefits of DOAC therapy across diverse baseline dementia risk profiles.

Associations between metabolic dysfunction–associated steatotic liver disease and physical and mental health–related quality of life in older adults - Marzieh Nasr Azadani; Mojtaba Lotfaliany; Najmeh Davoodian; Michael Berk; Robyn L. Woods; Joanne Ryan; John J. McNeil; Julie A. Pasco; Nigel Stocks; Stuart K. Roberts; William Kemp; Ammar Majeed; et al. (GeroScience, 2026)

Diet-dependent, beneficial and adverse effects of rapamycin on life span of Drosophila melanogaster - Lauren N. Jackson; Azriel M. Boles; Caitlyn T. Frye; Isha A. Patel; Robin J. Mockett (GeroScience, 2026)
Rapamycin supplementation has been reported to extend life spans in numerous species, including Drosophila melanogaster , but a recent study in this laboratory revealed a marked life-shortening effect in y w male flies. The experiments reported here were performed to characterize conditions under which rapamycin could extend or shorten life spans in five fly strains. On a cornmeal/torula yeast-based medium, rapamycin extended life in one experiment, had no effect in six and was harmful in 19. On a nutrient-rich brewer’s yeast medium favored by 4/5 strains for egg-laying, rapamycin was beneficial in eight, neutral in 14 and not significantly harmful in any experiment. Effects on median life span ranged from -51.3 to + 5.4% and were sex- and strain-specific, with limited differences for rapamycin dissolved in ethanol vs dimethylsulfoxide and for mated vs unmated flies. The life-shortening effect in y w males on the torula medium was greater when food was provided within 1–3 days after preparation vs 4–9 days, but similar under constant darkness vs 12 h light:12 h darkness. As an antifungal agent, rapamycin was expected to rescue shortened life spans when acids and methyl 4-hydroxybenzoate were omitted from the media, but removing these preservatives did not diminish the life span. Rapamycin was not consistently aversive for egg-laying, except in Dahomey flies at 200 µM. It prevented development to adulthood at 10–200 µM and delayed it at 0.1–1 µM concentrations. The results confirm the adverse effects of rapamycin during development and demonstrate its potential to switch between beneficial and harmful effects on adult life span depending on other components of the diet.

DNA methylation signatures in skeletal muscle associated with physical function in healthy older adults - Xiaoxiao Wen; Mingjing Chen; Guanhong Miao; Christopher Wu; Anna Picca; Javier A. Tamargo; Xiangyang Lou; Kevin Wu; Stephen Anton; Christiaan Leeuwenburgh; Jinying Zhao (GeroScience, 2026)

Frailty before disease onset: risk of mortality and chronic conditions in disease-free middle-aged adults - Paula Stürmer; Gabriella C. Silva; Aurore Fayosse; Séverine Sabia; Archana Singh-Manoux; Wolfgang Lieb; Benjamin Landré (GeroScience, 2026)
Frailty, defined by multisystem physiological decline and heightened vulnerability to stressors, is typically associated with aging and chronic disease. However, its relevance in apparently healthy individuals remains poorly understood. Identifying frailty in this population could inform primary prevention, as these individuals often remain outside healthcare systems. We investigated the association between frailty and incident chronic conditions and mortality in middle-aged adults free of chronic disease at baseline. Using UK Biobank data, we included 183,783 participants (53.6% female; median age 54 years) without chronic conditions. Frailty was assessed via the Fried frailty phenotype. Cox regression and multi-state models, adjusted for sociodemographic and lifestyle factors, analyzed associations with all-cause and cause-specific mortality, and with overall and organ system-specific incident chronic conditions. At baseline, 1.4% of participants were frail and 34.7% prefrail. Over a median follow-up of 13.8 years, mortality was 9.1% in frail versus 4.1% in robust (non-frail, fit) individuals, and 60.5% versus 48.2% developed at least one chronic condition. Frailty was associated with higher hazards of all-cause mortality (HR 1.92, 95% CI 1.68–2.20) and incident chronic conditions (HR 1.34, 95% CI 1.27–1.41), as well as increased risk of death following disease onset. Associations persisted after excluding events within 10 years of follow-up and were observed across multiple disease categories, including circulatory diseases, independent of key biological risk markers. Similar patterns were noted for prefrailty. Frailty identifies a subgroup of apparently healthy middle-aged adults at increased long-term risk of mortality and chronic disease, suggesting its potential as an early, actionable marker for prevention strategies.

Corpus callosum fractional anisotropy from routine diffusion tensor imaging predicts dementia in older adults beyond clinical risk factors - Shahar Negev; Benjamin F. Gruenbaum; Vladislav Zvenigorodsky; Shira Bitansky-Brosch; Ilan Shelef; Julia Grinshpun; Vladimir Zeldetz; Israel Melamed; Alexander Zlotnik; Matthew Boyko (GeroScience, 2026)
Dementia arises from multifactorial neurodegenerative processes, with growing evidence implicating blood–brain barrier dysfunction, neuroinflammation, and vascular injury as contributors to progressive brain tissue damage. Because decline in white matter microstructural integrity is a prominent feature of brain aging, biomarkers that capture this process may improve dementia risk stratification beyond conventional clinical factors. Fractional anisotropy (FA), derived from diffusion tensor imaging, reflects white matter microstructural integrity and may provide a sensitive marker of downstream injury associated with chronic vascular and barrier dysfunction. We conducted a retrospective single-center study of 528 participants, including individuals with dementia ( n = 176), age-matched cognitively normal older adults ( n = 176), and a young healthy reference cohort ( n = 176), all of whom underwent standardized 3-Tesla diffusion MRI. Dementia prediction was evaluated using elastic net-regularized logistic regression with nested tenfold cross-validation, incorporating 16 prespecified clinical and imaging predictors. Corpus callosum FA showed the largest standardized coefficient within the penalized model, exceeding all demographic and clinical variables. The model demonstrated strong discrimination between dementia and age-matched controls (area under the receiver operating characteristic curve [AUC] = 0.970; sensitivity = 90.9%; specificity = 93.2%). FA also declined stepwise from young adults to cognitively normal older adults to participants with dementia, consistent with progressive white matter microstructural injury across the aging-dementia continuum. These findings indicate that corpus callosum FA provides additional predictive value beyond conventional risk factors and support diffusion MRI as a potentially scalable biomarker of age-related white matter microstructural injury with potential utility for dementia risk stratification and biologically informed prevention strategies.

Aging is associated with altered estrogen receptor expression and alters redox protein balance in human female skeletal muscle - Andrea Tamariz-Ellemann; Line Boel Nørregaard; Mikkel Oxfeldt; Line Barner Dalgaard; Susana Novella; Mette Hansen; Ylva Hellsten; Lasse Gliemann (GeroScience, 2026)
It has been hypothesized that age‑related declines in skeletal muscle and vascular function in females may be partly estrogen‑dependent. This study investigated skeletal muscle protein expression of estrogen receptor α (ERα), estrogen receptor β (ERβ), and G protein–coupled estrogen receptor 1 (GPER1), and their association with proteins involved in redox regulation and vascular function, in relation to age, menopausal status, and lifelong physical activity. Skeletal muscle biopsies were obtained from 107 healthy females aged 19–70 years, including 26 postmenopausal females who were lifelong exercise trained. Protein expression of ERα, ERβ, GPER1, and downstream redox‑ and vascular‑related proteins was quantified. Age‑ and menopause‑related differences, associations between protein targets, and effects of lifelong exercise were examined. ERα protein expression was lower in older females with a 48% lower expression in the ≥ 55 years age group compared with the < 30-year group. GPER1 protein expression was 22% lower across all older age groups compared with the < 30-year group. ERβ expression was reduced in mid‑life (45–59 years) but not in the oldest age group. Both ERα and ERβ were positively correlated with endothelial nitric oxide synthase (eNOS) expression, whereas GPER1 showed no association with eNOS. ERβ expression was associated with pro‑oxidative NOX2 expression. Aging in females is associated with a lower ERα and GPER1 protein expression in skeletal muscle. Furthermore, lower ER expression by aging is associated with a lower eNOS expression, indicating associations with proteins involved in nitric oxide-related redox regulation in skeletal muscle in aged females. Graphical Abstract Aging in females was associated with a lower expression of estrogen receptor-α (ERα) and G protein–coupled estrogen receptor 1 (GPER1) in skeletal muscle. This age-related downregulation of estrogen receptors coincided with lower endothelial nitric oxide synthase (eNOS) expression, suggesting a shift toward a diminished antioxidant capacity and a more pro-oxidative skeletal muscle environment in aged females. Figure created with BioRender.

Identification and phenotypic profiling of subgroups with distinct cognitive aging trajectories - Lydia M. Federmann; Christian Mychajliw; Ulrike Sünkel; Didem Stark; Serli Kopar; Daniela Berg; Kathrin Brockmann; Andreas Fallgatter; Clint Hansen; Sebastian Heinzel; Walter Maetzler; Florian Metzger; et al. (GeroScience, 2026)

Prioritizing clinical utility to use allostatic load as a biomarker of the consequences of stress - Zoe L. Walts; Melissa Rosenkranz; Anne D. Letocha; Amy Cochran; Amy Trentham-Dietz; Martha J. Shrubsole; Shaneda Warren Andersen (GeroScience, 2026)
Allostatic load measures the physiological consequences of stress and is associated with disease outcomes. Clinical use of allostatic load is limited, in part, because its calculation requires biomarkers not routinely measured in clinical care. Presently, we evaluated associations between high allostatic load and depression as co-occurring consequences of stress among a cohort representing population subgroups largely excluded from existing literature. We emphasize clinical implementation potential by employing both an established and a recent consensus streamlined allostatic load score. Data arise from a nested case–control study within the Southern Community Cohort Study ( N = 982); 72% self-identified as Black, 61% reported income < $15,000. At baseline, participants completed surveys and provided blood samples analyzed for immune, metabolic, and cardiovascular biomarkers. Biomarkers exceeding clinical cutoffs were summed; counts above median indicated high allostatic load. Established and streamlined scores include 10 (albumin, C-reactive protein, estimated creatinine clearance, BMI, HbA1C, homocysteine, systolic and diastolic blood pressure, total cholesterol, triglycerides) and a subset of 5 biomarkers, respectively. Logistic regression models assessed cross-sectional associations between depression and allostatic load at study entry (odds ratios [OR], 95% confidence intervals [CI]). Established and streamlined scores demonstrated 88% agreement in identifying high allostatic load. Depression was associated with high allostatic load using both scores (established: OR: 1.37, 95%CI: 1.02–1.86; streamlined: OR: 1.39, 95%CI: 1.03–1.87). Associations remained in sex, race, and CRC-status stratified analyses. Robust associations were observed between depression, as a proxy measure of stress, with high allostatic load, supporting its validity as a clinically actionable biomarker of physiological and psychological dysregulation within an understudied population. Implementing the streamlined score may increase feasibility of allostatic load as a clinical indicator of stress.

Frailty before chronic disease: multisystem physiological differences in middle-aged adults from the UK Biobank - Paula Stürmer; Gabriella C. Silva; Aurore Fayosse; Romain Pichon; Séverine Sabia; Wolfgang Lieb; Benjamin Landré (GeroScience, 2026)

Lifestyle and psychosocial protective factors drive healthy aging and modulate inflammatory and metabolic pathways - Michele Rossi; Riccardo Rocco Ferrari; Ilaria Pola; Irene Brianzoni; Elisa Pellegrini; Annalisa Davin; Antonio Guaita; Henrik Zetterberg; Nicholas James Ashton; Andrea Lessa Benedet; Elena Rolandi (GeroScience, 2026)

Multimodal MRI prediction of cognitive functioning across the lifespan: separating between-person differences from within-person changes - Kseniia Konopkina; Irina Buianova; Farzane Lal Khakpoor; Sunthud Pornprasertmanit; Micaela Chan; Narun Pat (GeroScience, 2026)
Brain MRI shows promise for predicting cognitive functioning, but its utility depends on its capacity to capture stable between-person differences (e.g., patient stratification), longitudinal within-person changes (e.g., prognosis, treatment monitoring), or both. Using longitudinal data from 450 adults (aged 21–90; up to three waves, five years apart) in the Dallas Lifespan Brain Study, we benchmarked five modalities, task fMRI, functional connectivity (FC), structural MRI (sMRI), diffusion-weighted imaging (DWI), and arterial spin labeling (ASL), across 37 phenotypes and their combination. Stacking all MRI modalities into one marker predicted cognitive functioning with the highest accuracy (R 2 = .51), followed by DWI and FC. Variance decomposition showed MRI markers explained substantial between-person variance (up to 60.3%) but modest within-person changes (up to 17.2%) in cognitive functioning. Commonality analysis revealed most markers, except ASL, overlapped with age-related variance in cognitive functioning. These findings clarify the strengths and limitations of MRI markers for stratifying and monitoring cognitive aging.

Association of neurofilament light chain, CXCL9, IL-6, and TNFRSF11B with intrinsic capacity in community-dwelling older adults - Reshma Aziz Merchant; Yang Liu; Benjamin Y. Q. Tan; Ching-Hui Sia; Andrea Wong; Li Feng Tan; Gustavo Duque; Hidenori Arai; Bruno Vellas; Jean Woo (GeroScience, 2026)

Association between longitudinal trajectories of cognitive functioning and all-cause mortality among middle-aged and older adults in South Korea: Exploring the mediating role of oral health-related quality of life - Seong-Uk Baek; Jin-Ha Yoon (GeroScience, 2026)

Targeting the NO–cGMP axis in age-related vascular dysfunction: a systematic review and meta-analysis of preclinical animal studies - Soroush Mohammadi Jouabadi; Keivan Golshiri; Ehsan Ataei Ataabadi; Youri Boon; Forough Kheiri; Armin Amiri; Mohammad Hosein Khajehali; Arman Amiri; A. H. Jan Danser; Wichor M. Bramer; Anton J. M. Roks; Carlijn R. Hooijmans (GeroScience, 2026)

Are exercise benefits in older adults clinically meaningful?: An ancillary and follow-up analysis of a multicenter randomized controlled trial - Pedro L. Valenzuela; Ángel Buendía-Romero; Iván Antón-Rodrigo; Juan Luis Sánchez-Sánchez; Álvaro Casas-Herrero (GeroScience, 2026)

Understanding temporal changes in intrinsic capacity: analysis of domain-specific intrinsic capacity using SHARE data - Roy Tzemah-Shahar; Khalit Iktilat; Benjamin Seligman (GeroScience, 2026)

Senescent cardiac cells promote thrombus formation and impair fibrinolysis - Tal Shahar; Noa Ezra; Saray Chen; Olga Kryukov; Smadar Cohen (GeroScience, 2026)

Genome-wide analysis of subcortical aging identifies a spatially structured pattern of genetic associations - Nicholas J. Kim; Ayati Mishra; Jeremy S. Yu; Owen M. Vega; Nikhil N. Chaudhari; Fangyun C. Liu; Andrei Irimia (GeroScience, 2026)
Local brain age (LBA) is a spatially resolved biomarker of brain aging that captures regional deviations from chronological age, yet its genetic architecture in the subcortex remains unexplored. Here, we present the first genome-wide association study (GWAS) of subcortical LBA, estimated using a deep neural network applied to T1-weighted MRI scans from 41,957 cognitively normal participants in the UK Biobank. We computed LBA across 14 subcortical structures and identified 14 significant single-nucleotide polymorphisms (SNPs) across nine independent loci. These variants map to genes involved in cellular homeostasis, gene regulation, and synaptic and developmental signaling. A prominent signal emerged at the 17q21.31 haplotype, encompassing MAPT -related regulatory architecture, with significant associations across all subcortical regions. Across loci, we observed a recurring spatial pattern in which effect sizes are relatively larger in metabolically central structures such as the pallidum and thalamus compared to limbic regions. Together, these findings support a spatially structured pattern of genetic associations in subcortical brain aging. This work supports subcortical LBA as a genetically informed phenotype and provides a framework for linking common genetic variation to region-specific vulnerability and resilience in neurodegenerative disease.

Heterogeneity in the association between APOE ε4 carrier status and dementia risk by modifiable and non-modifiable risk factors - Mengrong Zhang; Frederick K. Ho; Jill P. Pell; Carlos Celis-Morales; Mark E. S. Bailey; Rona J. Strawbridge; Donald M. Lyall (GeroScience, 2026)
Dementia is a major public health challenge, and Apolipoprotein E ( APOE ) ε4 is strongly associated with all-cause dementia, particularly Alzheimer’s disease (AD). We aim to quantify the overall contribution of modifiable lifestyle, adiposity, socioeconomic status (SES), and health conditions occurring before dementia, to the association between ε4 genotype and the development of all-cause dementia, with AD examined as a major subtype. A population cohort study of 181,006 white UK Biobank participants aged ≥ 55 years at baseline was conducted, to examine the associations between APOE ε4 and all-cause dementia, and specifically AD, including modification and mediation role of lifestyle factors, adiposity, SES, and health conditions occurring before dementia. All risk factors, except for high alcohol intake, low diet quality, and phenotypic obesity, were associated with higher risk of all-cause dementia. The interaction contributions of lifestyle, adiposity, SES, and health conditions occurring before dementia varied by sex and dementia type. Low educational attainment had the strongest interaction effects with the association of APOE ε4 carriers and AD/all-cause dementia (up to 32.1%). In women, high deprivation level, abnormal sleep duration, anxiety, and depression showed interaction effects with APOE genotype (5–11.6%) as well. Phenotypic adiposity was associated with an increased risk of dementia among APOE ε4 non-carriers, but with a reduced risk among APOE ε4 carriers. Educational attainment explained a meaningful proportion of the APOE ε4 association with dementia. The strength of the association between APOE ε4 and dementia differed by risk factors and sex.

Mistakes matter, age doesn’t: task outcome modulates implicit motor adaptation similarly in young and older adults - Matheus Maia Pacheco; Pauline Hermans; Dante Mantini; Alice Nieuwboer; Jean-Jacques Orban de Xivry (GeroScience, 2026)

Oral LNAD+ rapidly elevates whole blood intracellular NAD and metabolic flux without elevating plasma NAD: evidence from a randomized controlled trial - Sergey A. Kornilov; Waylon J. Hastings; Lynne Fahey McGrath; Michael Leitz-Langan; Andrew T. Magis; Steve M. Coppess; Wendy Komac (GeroScience, 2026)
Declines in nicotinamide adenine dinucleotide (NAD+) are linked to metabolic stress accompanying aging and disease. While precursor-based approaches elevate systemic NAD, their clinical translation can be constrained by biosynthetic bottlenecks and first-pass metabolism. RENEWAL-NAD+ (ClinicalTrials.gov NCT07336836; retrospectively registered 01/04/2026) was a double-blind, randomized, placebo-controlled Phase 0/1b trial in healthy adults aged 45–75 years (60 randomized; primary analysis n = 50) evaluating 5 days of oral LathMized® NAD+ (LNAD+), a physicochemically modulated formulation that alters the supramolecular organization and solution behavior of NAD+ while preserving its native molecular structure. The primary endpoints were change in intracellular NAD (icNAD), measured in whole blood, and circulating NAD (cirNAD), measured in separated plasma, relative to baseline. LNAD+ produced a rapid and pronounced increase in icNAD, with a 53% elevation versus placebo at Day 6 ( p = 5.48e −14 ; Hedges’ g = 3.66), while cirNAD was unchanged ( p = 0.60), demonstrating compartment-selective augmentation. Plasma NAD catabolites increased substantially (1-methyl-nicotinamide, MeNAM p = 5.39e −13 ; N1-methyl-2-pyridone-5-carboxamide, 2PY p = 2.95e −16 ), consistent with downstream engagement of NAD metabolic flux. Exploratory analyses identified non-overlapping correlates for the two compartments (cirNAD tracking inflammatory and metabolic markers, icNAD tracking red blood cell indices and NAM). Treatment was very well tolerated: symptom incidence was comparable between groups ( p = 0.68), only one mild adverse event (nausea, Grade 1) occurred in the LNAD+ arm, and no secondary clinical, vital-sign, wellbeing, or wearable-derived endpoint survived multiplicity correction. These data demonstrate rapid intracellular NAD augmentation after oral LNAD+ dosing with pharmacodynamic evidence of downstream metabolism, compartment-specific physiological signatures, and a favorable short-term safety profile, with exploratory multi-omic analyses ongoing.

Epigenetic aging biomarkers in dietary geroscience: feasibility, participant perceptions, and trial design considerations - Lindsay M. Reynolds; Timothy D. Howard; Carl D. Langefeld; Mara Z. Vitolins (GeroScience, 2026)
Targeting biological processes of aging is a central goal of geroscience; however, limited data exist regarding the feasibility of incorporating biological aging biomarkers into dietary intervention trials. We conducted a pilot feasibility study among 34 adults aged 48–81 years with metabolic syndrome, a condition associated with elevated risk of age-related cardiometabolic disease and advanced biological aging. Participants consumed 1 oz of tree nuts and two tablespoons of extra virgin olive oil daily for 4 weeks. The primary objectives were to evaluate feasibility, adherence, and participant acceptability of epigenetic aging assessments. Exploratory outcomes included DunedinPACE, a measure of the pace of aging, and AgeAccelGrim, a measure of biological age relative to chronological age. At baseline, all participants exhibited a faster pace of biological aging than average as assessed by DunedinPACE, supporting metabolic syndrome as a promising target population for geroscience interventions. Adherence to the dietary intervention exceeded 95%, and most participants reported willingness to participate in a similar longer-term trial. Participants expressed a strong interest in learning their biological age and indicated that evidence of slowed aging would motivate sustained dietary change. No significant changes in epigenetic aging were observed over the 4-week intervention. These findings demonstrate the feasibility and acceptability of incorporating epigenetic aging biomarkers into dietary intervention research and suggest that biological aging measures may serve not only as surrogate outcomes but also as tools to support participant engagement. The results also support metabolic syndrome as a relevant population for dietary geroscience trials and provide practical guidance for designing longer-term studies evaluating whether dietary interventions can slow biological aging and promote healthy longevity. ClinicalTrials.gov Identifier: NCT04361617 (date of registration: 04-23-2020)

Statin therapy optimization in older adults: interim results of a randomized controlled trial of pharmacist-led pharmaceutical care - Anna Artner; Ágnes Szélvári; Ilona Oláh; Irén Ballya; Balázs Hankó; Romána Zelkó; Péter Torzsa (GeroScience, 2026)

Age-related differences in liver damage and inflammation after femoral osteotomy - Helen Rinderknecht; Rui Ding; Tong Wang; Alessa Wagner; Jasmin Maria Bülow; Nils Becker; Kernt Köhler; Katrin Bundkirchen; Claudia Neunaber; Borna Relja (GeroScience, 2026)

Sensory impairment, epigenetic ageing, and later-life functional decline and mortality in older adults - Xiangwei Li; Chongyu Ding; Yaqian Xu; Hui Zhang; Jun Du; Xian Cui (GeroScience, 2026)

Longitudinal association between dietary quality trajectories and cognitive frailty in older adults: a 12-year study of the TIGER cohort - Ting-I. Lee; Bo-Yu Hsiao; Te-Hsuan Huang; Ling-Wei Chen; Yi-Chun Chou; Meei-Shyuan Lee; Jeng-Min Chiou; Yen-Ching Chen; Jen-Hau Chen (GeroScience, 2026)

Joint effects of social determinants of health on NAFLD mortality: the mediating role of phenotypic age acceleration - Xingyong Huang; Xiaoyue Zhang; Xin Yu; Tingting Wang; Yumo She; Mengyao Wang; Yuanyuan Yang; Yicheng Liu; Lianhai Feng; Xuanyu Hao; Kai Zhang (GeroScience, 2026)

Age- and sex- related patterns in hematobiochemical and anthropometric parameters of Macaca monkeys - Hyeon-Mu Cho; Se-Hee Choe; Hye-Ri Park; Ja-Rang Lee; Min-Gyeong Ko; Yun-Jung Lee; Kang Jin Jeong; Bon Sang Koo; Kyung Seob Lim; Gyu-Seo Bae; Eun Su Jeon; Philyong Kang; et al. (GeroScience, 2026)

Late-night dinner, skipping breakfast, and the risk of dementia in Japan: the LIFE Study - Kengo Kawaguchi; Megumi Maeda; Futoshi Oda; Yasuharu Nakashima; Haruhisa Fukuda (GeroScience, 2026)

LINE-1 CpG methylation in canine blood and cortical DNA tracks epigenetic changes with age - Dávid Jónás; Kitti Tátrai; Balázs Egyed; Eniko Kubinyi (GeroScience, 2026)
Aging is accompanied by progressive epigenetic alterations, including changes in DNA methylation affecting both gene-associated regions and repetitive elements such as LINE-1 retrotransposons. Reduced epigenetic repression of transposable elements has been implicated in age-related genomic instability. Circulating cell-free DNA (cfDNA) provides a minimally invasive substrate for monitoring systemic molecular changes; however, age-related LINE-1 methylation dynamics in cfDNA remain poorly characterized in non-human species. Dogs represent a valuable translational model for aging research due to their shared environment with humans and shorter lifespan. We investigated age-associated LINE-1 CpG methylation in plasma-derived cfDNA and in prefrontal cortex genomic DNA from dogs. Sequence analysis of 264 potentially active canine LINE-1 elements identified a highly conserved central region spanning ORF1 and ORF2, with the targeted CpG site located within a locally low-variability segment, supporting multi-copy assessment. Methylation was quantified using methylation-sensitive restriction endonuclease digestion followed by real-time quantitative PCR (MSRED-PCR), with bisulfite conversion–based PCR (BSC-PCR) used for technical validation. In clinically healthy dogs, LINE-1 methylation in blood cfDNA showed a strong negative association with chronological age, best described by a nonlinear (logarithmic) model. In prefrontal cortex samples, older dogs exhibited significantly lower LINE-1 methylation compared to younger individuals. Across tissues, aging was consistently associated with LINE-1 hypomethylation. These findings indicate that age-related LINE-1 hypomethylation is detectable in both brain tissue and circulating cfDNA. While based on cross-sectional cohorts, the results suggest that LINE-1 methylation in cfDNA may represent a candidate minimally invasive marker of chronological aging in dogs.

p38 MAPK and MDT-15 mediate SKN-1-dependent metformin-induced protection against mitis group streptococci in Caenorhabditis elegans - Ali Al Hatem; Boopathi Balasubramaniam; Alissa Villhauer; Ali K. Naji; Ransome van der Hoeven (GeroScience, 2026)
Mitis group streptococci are opportunistic pathogens residing in the oral cavity, where they produce hydrogen peroxide (H 2 O 2 ), a key virulence factor contributing to their pathogenesis. We previously demonstrated that these bacteria kill the nematode Caenorhabditis elegans through H 2 O 2 production. Metformin, a widely used biguanide drug for managing blood glucose levels, has shown promising effects on aging by extending lifespan in worms and mice, and has also demonstrated potential cancer treatment. Additionally, pretreatment with metformin enhances the survival of worms and triggers an immune response via the p38 MAPK pathway against various pathogenic bacteria. Based on these observations, we investigated metformin's potential as a therapeutic agent against mitis group streptococcal infections and its underlying mechanisms in the current study. Pretreatment of worms with metformin provided significant dose-dependent protection from streptococcal-derived H 2 O 2 . This protective effect was attributed to the activation of the oxidative stress response transcription factor SKN-1/NRF2. Further analysis revealed that the p38 MAPK pathway and the transcription mediator complex protein MDT-15 are essential for the activation of SKN-1 by metformin. Interestingly, SKN-1 activity, mediated by MDT-15, was found to be independent of the p38 MAPK pathway. Our findings establish that metformin-mediated protection against mitis group streptococcal infections relies on the coordinated action of SKN-1, the p38 MAPK pathway, and MDT-15. These insights suggest that metformin could be a valuable therapeutic agent in combating these infections. Future research should focus on further elucidating the molecular mechanisms involved and exploring the potential clinical applications of metformin in treating these bacterial infections.

Beyond the linear genome: how reference bias threatens preventive medicine and geroscience - Gyula Richárd Nagy; Gyöngyi Munkácsy; Ankita Murmu; Giuliana Longo; Luis Izquierdo López; Vincenzo Cirigliano; Balázs Győrffy (GeroScience, 2026)

Genetic predisposition to longer lifespan, lifestyle factors, and all-cause mortality: a 17-year prospective cohort study - Niko P. Tynkkynen; Laura Joensuu; Päivi Herranen; Jaakko Kaprio; Timo Törmäkangas; Elina Sillanpää (GeroScience, 2026)
We examined whether a genome-wide polygenic lifespan score (PLS) is associated with all-cause mortality and how this association compares with associations between long-term lifestyle factors and mortality. The PLS was computed for the older Finnish Twin Cohort (mean age 57.4 years; 45.2% men; N = 5575). Cox regression was used to estimate the effects of the PLS on all-cause mortality risk, before and after adding sex, physical activity, BMI, alcohol consumption, smoking behavior, and education level. Concordance indices (C-indices) were used to assess each predictor’s contribution to the model’s discriminatory performance. Over a mean follow-up of 17.5 ± 8.3 years, 1405 deaths (25.2%) occurred. A one standard deviation increase in the PLS was statistically significantly associated with a lower all-cause mortality risk (hazard ratio [HR] = 0.838, 95% confidence interval [CI] = 0.792–0.887). This association remained relatively unchanged after adding all covariates (HR = 0.863, 95% CI = 0.816–0.912). Smoking 20 or more cigarettes per day showed the strongest association with increased mortality risk (HR = 3.341, 95% CI = 2.751–4.056), while female sex was associated with the greatest risk reduction (HR = 0.678, 95% CI = 0.597–0.770). Smoking behavior had the largest impact on model performance (ΔC-index = 0.027); other covariates contributed less (ΔC-index < 0.006). In conclusion, genetic predisposition to a longer lifespan was associated with a modest reduction in all-cause mortality risk, independent of lifestyle and other factors. Smoking behavior and female sex were stronger predictors of mortality than the PLS.

Circulating factors induced by time-restricted eating drive metabolic reprogramming in endothelial cells - Shoba Ekambaram; Tamas Kiss; Zoltan Ungvari; Kiana Vali Kordestan; Dorina Nagy; Rebeka Kristof; Raghavendra Yelahanka Nagaraja; Tripti Gautam; Roland Patai; Rafal Gulej; Siva Sai Chandragiri; Anna Ungvari; et al. (GeroScience, 2026)
Age-related endothelial dysfunction in the cerebral microcirculation contributes significantly to the pathogenesis of vascular cognitive impairment and dementia (VCID). Time-restricted eating (TRE) has emerged as a promising lifestyle intervention with beneficial effects on metabolic and vascular health; however, the mechanisms by which TRE influences the brain microvasculature remain incompletely understood. In particular, the role of circulating factors induced by TRE in modulating endothelial function has not been systematically investigated. Here, we tested the hypothesis that circulating factors derived from humans practicing time-restricted eating (TRE) induce protective and adaptive responses in human cerebromicrovascular endothelial cells. Using a serum transfer bioassay, endothelial cells were treated with serum obtained from aged individuals with or without TRE, followed by transcriptomic profiling. We demonstrate that TRE-associated serum elicits a robust and coordinated transcriptional reprogramming in human cerebromicrovascular endothelial cells, characterized by activation of stress-responsive and metabolic pathways and suppression of anabolic programs. Gene set enrichment analysis revealed significant activation of the integrated stress response (ISR)/ATF4 axis and suppression of mTORC1 signaling, consistent with a shift toward a catabolic, stress-adaptive state. These changes were accompanied by marked induction of the stress-responsive cytokine GDF15 . At the mitochondrial level, TRE serum promoted increased expression of mitochondrial DNA-encoded oxidative phosphorylation components without activation of canonical mitochondrial biogenesis pathways, suggesting functional remodeling. Upstream regulator analysis identified coordinated activation of stress- and metabolism-associated transcription factors, including ATF4, FOXO, and KLF family members, alongside inhibition of anabolic regulators such as SREBF1/2. Notably, canonical endothelial functional programs, including autophagy and blood–brain barrier maintenance, were not coordinately activated. While individual angiogenesis-related genes were modestly upregulated, these changes did not translate into a coordinated pathway-level response. Collectively, these findings demonstrate that circulating factors induced by TRE promote a distinct endothelial phenotype characterized by metabolic reprogramming and stress adaptation rather than classical inflammatory or reparative responses. This work provides new mechanistic insight into how lifestyle interventions may influence cerebrovascular aging and identifies circulating factors as key mediators linking systemic metabolic state to endothelial function.

Interstitial fluid rejuvenation through young-donor plasma exchange in cognitively impaired patients: a pilot safety and feasibility study - Arne Søraas; Andreas Engvig; Dag Alnæs; Lana Nagmadin Karim; Elena Danilova; Mette Stausland Istre; Sara Nygaard; Tone Reinton Utgård; Sandra Ceprnjic; Olaug Reiakvam; Elisabeth Edvardsen; Lars T. Westlye; et al. (GeroScience, 2026)

Micronutrients and omega-3 PUFAs to promote healthy ageing: informing a physiology-based complementation strategy - Mette M. Berger; Renée Blaauw; Patrizia D’Amelio; Nicole Ehrhart; Adrian F. Gombart; Leah Gramlich; Reto W. Kressig; Philip C. Calder (GeroScience, 2026)
Global population ageing is increasing the burden of chronic disease, functional decline, and loss of independence. For most organs, decline in function starts during the 5th decade of life. Micronutrient (MN) insufficiencies/deficiencies are common and may accelerate biological ageing. MNs are required to support multiple physiologic processes, including mitochondrial homeostasis. Age-related declines in organ function are tightly linked to mitochondrial dysfunction, oxidative stress, inflammageing, and immunosenescence. Selected MNs (vitamins B, C, D, E, iron, selenium, zinc) are critical cofactors for mitochondrial function, antioxidant defence, immunity, and resolution of inflammation. Inadequate MN intakes require specific repletion strategies beyond diet for correction. Low intake, (patho)physiological changes, and common medications jointly contribute to compromised MN status. Emerging trials suggest that correcting MN deficiency may restore mitochondrial function and thereby promote healthy ageing. Optimizing intake over the lifespan represents another means to support healthy ageing. Nevertheless, MNs do not work individually but as a web, and may behave differently in different individuals. Further, low status of the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is common in older adults, which favours inflammation and functional decline. EPA+DHA work in combination with MNs on inflammation containment. Routine risk assessment, selected biomarker measurement from midlife onwards, and well-designed trials are needed to complement an insufficient status. MN and EPA+DHA optimization should be integral to healthy ageing strategies.

VCD-induced estropause fails to enhance responsiveness to 17α-estradiol in adult female mice - Sean R. Janovic; Roberto Santín-Márquez; José V. V. Isola; Camila R. C. de Brito; Roshini Sathiaseelan; Jessica D. Hense; Subhasri Biswas; Heather C. Rice; Samim A. Mondal; Michael B. Stout (GeroScience, 2026)

The PERK paradox in aging: how ER stress shapes senescence and neurodegeneration - Vivek Pandey; Rahul Sachdeva; Sanda Despa (GeroScience, 2026)

Hypertension-associated DNA methylation signatures and multi-generational epigenetic clocks in Korean adults - Jangho Lee; Soo-Hyun Park; Jin-Taek Hwang; Jae-Ho Park (GeroScience, 2026)

Olfactory dysfunction is associated with gait impairment in older adults: evidence for a shared amygdala substrate - Jianwei Wang; Jialin Li; Qiu Xiao; Jincheng Li; Hao Wang; Xiao Liang; Siyu Wu; Yingzhe Wang; Mei Cui; Xingdong Chen; Chen Suo; Yanfeng Jiang (GeroScience, 2026)

A metabolomic clock of population ageing: cross-cohort validation and associations with frailty and cognitive function - Chung-Ho E. Lau; Elena Chekmeneva; Rui Pinto; Aisling M. O’Halloran; Daniel K. H. Chu; Abbas Dehghan; Ioanna Tzoulaki; Paul Elliott; Rose Anne Kenny; Cathal McCrory; Oliver Robinson (GeroScience, 2026)
Understanding the links between metabolism, ageing, and age-related phenotypes may clarify the role of ageing in disease onset and improve risk prediction. We conducted a cross-cohort assessment of biological age using broad-spectrum LC–MS metabolomics of 3,686 plasma samples in 2,295 participants, aged 20–89, from the UK Airwave study ( N = 960) and the Irish Longitudinal Study of Ageing ( N = 1,335). The nucleoside N 2 ,N 2 -dimethylguanosine, C-glycosyltryptophan, bile acid glucuronides, and the antioxidant zeta-carotene were associated with chronological age, frailty, and mortality. The noradrenergic metabolite 3-methoxy-4-hydroxyphenylglycol sulphate and the oligosaccharide sialyllactose were strongly associated with both age and mortality. We developed a metabolomic clock that was highly predictive of chronological age ( r = 0.92) in test samples. Metabolomic age acceleration was strongly correlated between study visits ( r > 0.6). Each standard deviation increase in metabolomic age acceleration (~ 5 years) was associated with 43% higher mortality risk, 27% higher risk of mild cognitive impairment, and 10% increased risk of a higher frailty score in fully adjusted models. The metabolites identified here may link ageing and age-related vulnerability and should be further investigated in mechanistic studies. The metabolomic clock has potential for translational applications, including as a prognostic and response marker of generalised age-related disease risk.

Performance of the SmartMe&You serious video games for home telemonitoring is related to cognitive status and resting-state electroencephalographic markers in healthy and Parkinson’s disease participants - Claudio Del Percio; Roberta Lizio; Mina De Bartolo; Matteo Carpi; Giuseppe Noce; Susanna Lopez; Antonio Pio Afragola; Federica Fiorentino; Filippo Carducci; Veronica Henao Isaza; Paolo Barone; Arianna Cappiello; et al. (GeroScience, 2026)
Unsupervised serious video games on the SmartMe&You home telemonitoring platform may enable the assessment of cognitive fluctuations in older individuals, with or without cognitive deficits. Here, we tested their validity in cognitively unimpaired older adults (Healthy) and patients with mild cognitive impairment and mild to moderate dementia due to Parkinson’s disease (PDCD). Such validity was assessed using Mini-Mental State Examination (MMSE) scores and resting-state eyes-closed electroencephalography (rsEEG) activity. Clinical, demographic, and rsEEG datasets were collected from 34 healthy and 68 PDCD participants. The SmartMe&You video games included 7 unsupervised cognitive tasks implemented on a commercial tablet. The rsEEG source activities in the individual delta, theta, and alpha frequency bands were estimated using the eLORETA freeware. As novel findings, we showed that game performance: (1) discriminated between healthy participants and PDCD patients, with overall accuracy exceeding 90%; (2) was positively associated with MMSE scores across all participants ( p < 0.00001); and (3) was negatively associated with global rsEEG source activity in the delta and theta frequency bands ( p < 0.00001). These findings suggest that serious videogames of the SmartMe&You home telemonitoring platform were feasible and sensitive to cognitive status across the spectrum from normal aging to Parkinson’s disease-related dementia. This approach provides a scalable, low-cost, and ecologically valid tool for remote cognitive monitoring, with future potential applications in both early detection and longitudinal tracking of cognitive decline.

Plasma metabolomic signatures of heterogeneous multimorbidity trajectories in ageing: a population-based cohort study - Ryota Toki; Chisato Iba; Yuki Omoto; Minako Matsumoto; Miho Iida; Shun Edagawa; Sei Harada; Aya Hirata; Naoko Miyagawa; Atsuko Miyake; Akiyoshi Hirayama; Masahiro Sugimoto; et al. (GeroScience, 2026)

Changes in collateral status during transfer for thrombectomy are predictive of functional outcome in large vessel occlusion stroke - Máté Pásztor; Esra Zhubi; Alistair Perry; István Szikora; Balázs Kis; Davide Carone; George Harston; Dániel Bereczki; Tímea Takács; Norbert Szegedi; Csilla Rózsa; Ildikó Vastagh; et al. (GeroScience, 2026)
Collateral circulation that determines infarct progression in large vessel occlusion (LVO) is implicitly regarded as stationary. We investigated collateral circulation changes during interfacility transfer for endovascular thrombectomy (EVT) and its association with functional outcome in anterior circulation LVO stroke. Seventy consecutive patients with middle cerebral artery occlusion transferred for EVT from January 2017 to December 2018 within a regional stroke network underwent repeated CTA at the comprehensive center allowing longitudinal assessment of collateral status, quantified by the Tan score, and AI-derived collateral percentage. Demographics, NIHSS, intravenous thrombolysis, blood pressure, stroke-to-reperfusion time, recanalization status, and 90-day mRS were recorded. Ordinal logistic regression was used to identify predictors of outcome. Collateral status was dynamic rather than stationary, with changes observed in 51/70 (73%) patients (median = –3.69% (IQR = − 22.28–4.83)). Collateral change emerged as a significant independent predictor of 90-day functional outcome (OR = 0.98, p = 0.008), with patients showing improvement in collaterals having better outcomes. Additionally, older age (OR = 1.04, p = 0.030), higher baseline NIHSS (OR = 1.20, p = 0.001), and longer stroke-to-reperfusion time (OR = 1.01, p = 0.014) were each significantly associated with worse 90-day functional outcome. Patients with improved/stable collaterals had significantly better 90-day functional outcomes compared to decliners (median mRS 2[IQR 0–4] vs. 4 [1.25–6], p = 0.008). Collateral status is not stationary during a stroke event, and its improvement independently predicts good functional outcome, highlighting the importance of therapeutic efforts to improve collateral circulation.

Auditory and executive determinants of phonetic processing and lexical acquisition in older adults with mild hearing impairment and cognitive decline - Stefan Elmer; Ulrike Lemke; Nathalie Giroud (GeroScience, 2026)
Age-related pure-tone hearing loss (HL) frequently co-occurs with central auditory processing deficits and cognitive decline and is commonly associated with speech processing difficulties. To examine how inter-individual differences in central auditory processing and cognitive capacities contribute to speech processing and lexical acquisition, we investigated the neural encoding and acquisition of novel words using phonetic stimuli as a proxy for speech processing abilities. These stimuli were presented at 80 dB SPL to minimize audibility-related confounds and ensure that differences in learning were not primarily driven by peripheral hearing sensitivity. Older adults with mild-to-moderate peripheral HL and signs of cognitive decline ( N = 21) completed an attentive listening and associative word learning task with Thai words while EEG was recorded, alongside comprehensive psychometric, audiometric, and auditory assessments. Neural markers of word learning were preserved in this population, as reflected in the N400 and late positive component (LPC) event-related potentials (ERPs), with LPC amplitudes predicting word learning performance. Multiple linear regression models controlling for age and HL examined whether sensory ERPs (P50, N100, P200), behavioral auditory-audiometric measures (OLSA, PTA 4000, d -primes for attentive listening), or cognitive variables (attention, language, memory, perception, executive function, n -back, Stroop) predicted learning outcomes. Age accounted for the largest proportion of variance in word learning performance. Sensory ERPs and cognitive measures also emerged as significant predictors, whereas, as expected given the high stimulus intensity, peripheral HL showed a non-significant effect. Larger N100 amplitudes explained variance in sensory ERP models, while executive functions were the strongest predictors in cognitive models. Superior word learning performance was associated with younger age, enhanced central auditory processing, and stronger executive functions. These findings indicate that central auditory processing and executive functions are key determinants of speech learning in older adults with mild-to-moderate peripheral HL and cognitive decline when audibility is controlled.

Adherence to the Eatwell Guide and associations with markers of physical function: a prospective analysis within the UK Biobank cohort - Alex Griffiths; Sarah Gregory; Fiona C. Malcomson; Kirstie Cronin; Jamie Matu; Louisa Ells; Oliver M. Shannon (GeroScience, 2026)
The Eatwell Guide represents the UK’s principal healthy eating model and understanding whether adherence to UK dietary recommendations can attenuate age-related functional decline is essential to inform healthy ageing strategies. In up to 157,457 participants from the UK Biobank, we explored cross-sectional and prospective associations between adherence to the Eatwell Guide and markers of physical function (grip strength, fat-free mass percentage, self-reported walking pace, and falls). Eatwell Guide adherence scores were derived from 24-h dietary recall data (Oxford WebQ), and quantified using a graded, food-based scoring system. Differences between population subgroups including by age, sex, physical activity, and protein intake level were explored. Higher Eatwell Guide adherence was cross-sectionally associated with higher grip strength, greater fat-free mass percentage, higher odds of brisk walking pace, and lower odds of falls (all p < 0.001). Prospectively, greater adherence was associated with attenuated fat-free mass decline (β = 0.02, SE = 0.001, p < 0.001) and slower grip strength decline (β = 0.01, SE = 0.002, p < 0.01). For walking pace, the positive cross-sectional association attenuated over follow-up (EWG × time interaction OR = 0.998, 95% CI 0.997–0.999, p = 0.002), whereas the protective association with falls remained stable over time (OR = 1.000, 95% CI 0.998–1.000, p = 0.89). Higher Eatwell Guide adherence was associated with preserved muscle mass, modest attenuation of grip strength decline over time, and a reduced risk of falls, supporting its relevance for musculoskeletal health and physical function in aging populations.

Personality disorders and related healthcare use among older United States veterans experiencing housing instability and homelessness, 2016–2024 - Hind A. Beydoun; May A. Beydoun; Amanda Edwards-Stewart; Jack Tsai (GeroScience, 2026)

High-velocity resistance training improves the force–velocity profile in middle-aged and older adults - Gustavo Z. Schaun; Peter Raidl; Julian Alcazar; Cristine L. Alberton; Robert Csapo (GeroScience, 2026)
The main goal of the present study was to examine the effects of a high-velocity resistance training (HVRT) program on the force–velocity (F–V) profile of different groups of aging adults. An additional aim was to explore whether individual baseline F–V profiles were associated with training-induced improvements in muscle power and functional capacity. Middle-aged and older adults with and without mobility limitations ( n = 36, 61 ± 13 years) completed a 12-week HVRT program (2 days/week, 40–60% 1-RM). F–V profiles were determined using leg press exercises at loads ranging from 30–90% 1-RM, and a linear position transducer. Functional capacity was assessed via maximal gait speed and 30-s Sit-to-Stand tests. HVRT significantly increased the theoretical maximal force (F 0 ), maximal power (P max ), and the F–V slope (all p < 0.001), while maximal movement velocity (V 0 ) remained unchanged at the group level. Analysis of individual trajectories revealed substantial heterogeneity in F-V adaptations. Lower baseline V 0 was associated with greater improvements in V 0 (r = -0.629, p < 0.001), and this association was attenuated in an Oldham-style sensitivity analysis (r = -0.366, p = 0.028). Stratification by V 0 tertiles showed that velocity-deficient individuals had lower baseline power but experienced the greatest V 0 gains (+ 10.6% vs. -1.0%, p = 0.002). Within this subgroup, improvements in V 0 were associated with improvements in maximal gait speed (r = 0.685, p = 0.010). These findings suggest that, in the present sample, HVRT enhances muscle power primarily via force-related adaptations, while velocity-related adaptations were heterogeneous and may be functionally relevant when they occur.

A comparative evaluation of brain MRI modalities, modality-specific measures, brain regions, and cognitive tests for brain age prediction - Hami Mahdavinataj; Hedieh Sajedi; Seyed Amir Hossein Batouli (GeroScience, 2026)

Association of biological age acceleration with muscle aging phenotype in young and middle-aged adults: a prospective cohort study - Kyeezu Kim; Yoosoo Chang; Hye-Mi Jang; Hyungjin Kim; Soonho Yoon; Seungho Ryu (GeroScience, 2026)

Identifying cognitive subgroups in older adults from community data with hierarchical cluster analysis - J. D. Hall; Yilin Liu; Jacob Green; Reyna Hickey; Emily C. Edmonds; Steven Z. Rapcsak; Ying-Hui Chou (GeroScience, 2026)

Normal spermatogenesis in older men is associated with compensatory transcriptome changes - Yihan Wang; Sven Berres; Henrike Krenz; Tobias Tekath; Marius Wöste; Sarah Sandmann; Amelie Körtje; Anna Henrich; Nicole Terwort; Frank Tüttelmann; Nina Neuhaus; Sabine Kliesch; et al. (GeroScience, 2026)

EEG-based assessment of sustained attention in geriatric inpatients: a feasibility study - Lina Stagneth; Johanna Geritz; Gesine Hermann; Lea Dahl; Leoni Zuber; Christian Neumann; Josephine Lassen; Corina Maetzler; Cornelia Kranczioch; Julius Welzel; Walter Maetzler (GeroScience, 2026)
Sustained attention is a core cognitive function, frequently declines with age and neurological disease, and is highly relevant for functional outcomes in geriatric populations. Electroencephalography (EEG) offers high temporal resolution for assessing attentional processes, but its feasibility in multimorbid geriatric inpatients remains insufficiently characterized. This study evaluated the procedural and methodological feasibility of EEG-based sustained-attention assessments in geriatric inpatients undergoing early rehabilitative geriatric complex treatment (ERGCT). Geriatric participants completed standardized neuropsychological testing and two computerized attention tasks, the Psychomotor Vigilance Task (PVT) and a cued Go-NoGo task, during 32-channel EEG recording, including a resting-state recording. Feasibility was assessed using procedural indicators (recruitment, task completion, follow-up participation) and methodological indicators of EEG data quality, specifically the signal-to-noise ratios (SNR) and identification of expected event-related potential (ERP) components (P100, P300). Of 173 patients referred to the ERGCT programme, 43 could be included. Of those, 38 could undergo structured cognitive testing, and resting-state EEG and task-evoked ERPs could be recorded with adequate signal quality However, procedural feasibility was limited by substantial selection and attrition, resulting in incomplete protocol completion. Exploratory analyses suggest an association between higher resting-state alpha-band signal quality and faster PVT reaction times, whereas no associations were observed with global cognition, executive function, or age. Overall, resting-state and task EEG measures of sustained attention could be acquired with adequate data quality only in a selected subgroup of geriatric inpatients, who were able to participate in structured cognitive assessments, while extended and repeated assessment protocols were constrained by procedural burden, suggesting that EEG-based follow-up assessments are difficult to implement under current clinical conditions.

Distinct epigenetic ageing patterns are associated with heterogeneity in kidney function decline in type 2 diabetes - Resham Lal Gurung; Hao Wu; Huili Zheng; Sylvia Liu; Jia Le Ivan Tan; Jian-Jun Liu; Jian Hua Tay; Kar Seng Sim; Jian Jun Liu; Rajkumar Dorajoo; Su Chi Lim (GeroScience, 2026)

Cognitive network plasticity across divergent aging trajectories: an exploratory graph-theoretic study - Maura Coniglione; Silvia Figini; Sara Assecondi (GeroScience, 2026)

Frailty and incident cognitive impairment in patients with CKD: sex-frailty paradox in the Chronic Renal Insufficiency Cohort (CRIC) - Stephanie Lapierre-Nguyen; Zhiying You; Michel Chonchol; Kristen L. Nowak; Ester Oh (GeroScience, 2026)

Age-associated DNA methylation patterns in mouse blood and tail: feasibility of tissue-specific epigenetic clock development - Jiwon Shin; Seungmin Song; Yerim Han; Jieun Lyu; Yoon Jung Park (GeroScience, 2026)

Long-lived mammals contain more phosphorylation sites in the SIRT6 C-terminus that enhance PARP1 interaction and resistance to oxidative stress - Jonathan Gigas; Michael E. Meadow; Jing Guo; Catherine Lan; Eric Hillpot; John C. Martinez; Gregory Tombline; Philip Bellomio; Valeria Rivera-Almodóvar; Kevin A. Welle; Kyle Swovick; Jennifer R. Hryhorenko; et al. (GeroScience, 2026)

Targeting cellular senescence in dermatology: senolytic and senomorphic strategies - Diala Haykal; Frederic Flament; Lilit Garibyan; Kachiu Lee; Julie Escot; Audrey Gueniche; James Kirkland (GeroScience, 2026)

The dual diversity crisis in alzheimer's disease research: why neuroimaging biomarkers and clinical trials keep failing - Thorsten Rudroff (GeroScience, 2026)
Alzheimer's disease clinical trials have failed at a rate exceeding 99% over two decades, and neuroimaging biomarkers developed in discovery cohorts have repeatedly disappointed in validation and clinical application. Standard explanations address symptoms rather than structural causes. I argue that Alzheimer's disease research is caught in a Dual Diversity Crisis: the simultaneous neglect of population diversity and individual neurobiological heterogeneity as compounding validity threats. The first dimension concerns the systematic over-reliance on Western, young, healthy, and university-affiliated (WYHU) research samples, from which biomarker normative standards are derived and then applied universally to a demographically distinct clinical population. The second concerns the erasure, through group-level analysis, of the substantial neurobiological heterogeneity that exists within any sample regardless of its demographic composition. The critical structural insight is that these two problems do not add; they multiply. A WYHU-derived group average is doubly unrepresentative: it misrepresents the target population demographically and conceals the individual variance that exists even within that already-unrepresentative sample. FDG-PET evidence demonstrates that biological sex accounts for approximately 30 times more metabolic variance than diagnostic category in patients with equivalent symptom profiles, directly challenging the construct validity of threshold-based trial inclusion. Correcting the Dual Diversity Crisis requires treating demographic diversity and individual neurobiological characterization as primary design parameters, not post-hoc corrections. Until this reconceptualization occurs, translational failure in Alzheimer's disease research remains the structurally expected outcome.

Emergence of heartbeat frailty in advanced age II: individual cardiovascular aging trajectories revealed by lifelong echocardiography in male mice - Ismayil Ahmet; Nolan M. Winicki; Jacob S. Roberts; Christopher H. Morrell; Edward G. Lakatta (GeroScience, 2026)

Impact of mixed reality on the care of the elderly: a scoping review - Fátima Avilés-Castillo; Jorge Buele; Guillermo Palacios-Navarro (GeroScience, 2026)
Population aging requires innovative technological strategies that promote autonomy, functionality, and well-being in old age. In this context, mixed reality (MR), a technology that integrates physical and digital elements in a shared and interactive real-time environment, emerges as a promising alternative. To analyze the current state of evidence on the use of MR in the care of older adults, including its theoretical and practical implications. Scientific articles were reviewed in Scopus, Web of Science, PubMed, IEEE Xplore, and EBSCO. Data from 15 studies were organized into an analytical matrix to identify methodological and impact patterns. MR interventions have shown promising preliminary results in physical rehabilitation, cognitive stimulation, emotional well-being, and social interaction by combining sensory feedback, functional tasks, and meaningful experiences. The included studies represent heterogeneous MR configurations along the virtual reality continuum, including transparent or pass-through optical viewers, VR-HMD-based systems with real-world interaction, and sensor- or projection-based platforms. Rather than demonstrating superiority over virtual or augmented reality, the evidence suggests specific advantages related to contextual awareness, physical interaction, and cognitive-motor-affective integration. These features were associated with potential improvements in mobility, executive functions, motivation, positive emotions, and social presence, supporting an interpretive cognitive-motor-emotional framework and the design of safe, meaningful, and context-sensitive interventions. MR shows promising potential for the care of older adults by improving cognitive, motor, emotional, and social outcomes. However, current evidence remains preliminary due to small sample sizes, methodological heterogeneity, a scarcity of comparative studies, and a lack of longitudinal evidence.

Pharmacological management of transient focal neurological episodes in cerebral amyloid angiopathy: a systematic review - Christian Sandøe Musaeus; Andreas Hansen; Hanne Christensen; Andreas B. Sonksen; Louisa M. Christensen (GeroScience, 2026)

Associations of IL-17 and TGF-β1 with physical frailty in older adults - Chiara Ceolin; Marina De Rui; Giulia Musso; Silvia Sturani; Adele Ravelli; Cristina Simonato; Franz Villanova; Sabrina Pigozzo; Luca Busetto; Angelo Antonini; Eleonora Fiorenzato; Martina Montagnana; et al. (GeroScience, 2026)
Background Physical frailty is a prevalent geriatric syndrome associated with reduced physiological resilience and adverse outcomes. Beyond classical inflammaging, age-related changes in immune regulation and tissue repair may contribute to frailty pathophysiology. Biomarkers involved in adaptive immune responses and remodeling pathways, such as IL-17 and TGF-β1, may help characterize the inflammatory-regenerative milieu associated with frailty. We therefore investigated the association between circulating immune biomarkers and physical frailty severity in older adults. Methods In this cross-sectional analysis, 167 community-dwelling outpatients aged ≥ 65 years (mean age 75.2 ± 6.4 years; 54.5% women) were classified as robust, pre-frail, or frail according to a phenotype-based frailty score. Circulating levels of TGF-β1, IL-17, IL-6, TNF-α, IL-10, and IFN-γ were measured. Associations with frailty were assessed using ordinal logistic regression, quantile regression, and component-specific logistic models. Results IL-17 concentrations progressively declined with increasing frailty severity (median 9.24 ng/L in robust vs. 4.91 ng/L in frail participants; p = 0.004). In adjusted ordinal models, higher IL-17 levels were independently associated with lower frailty severity (OR = 0.62, 95% CI 0.46–0.84; p = 0.002), with each doubling of IL-17 corresponding to a 28% reduction in frailty odds. Conversely, higher TGF-β1 levels were independently associated with greater frailty severity (OR = 2.33, 95% CI 1.05–5.13; p = 0.036). IL-17 showed consistent associations with physical frailty domains, including slowness (adjusted OR = 0.57), and low physical performance (adjusted OR = 0.68). Similar associations were observed in exploratory analyses restricted to cognitively intact participants. However, formal interaction analyses did not support significant effect modification by cognitive status. In contrast, classical inflammatory markers (IL-6, TNF-α), as well as IFN-γ and IL-10, were not significantly associated with frailty across any of the models. Conclusions Physical frailty was associated with lower IL-17 and higher TGF-β1 levels, suggesting that immune-related pathways beyond classical systemic inflammation may be associated with physical frailty. Rather than reflecting overt systemic inflammation, these findings suggest that biological pathways involved in immune regulation and tissue remodeling may be associated with physical frailty. IL-17 and TGF-β1 may therefore represent potentially informative biomarkers for future investigations of the biological mechanisms underlying resilience and functional decline in aging. Trial registration Not applicable.

Spatiotemporal profiling of white matter lesions and their contribution in the pathologies of Parkinson’s disease animal models - Yueqi Jiang; Caixia Zang; Hui Liu; Qiuzhu Chen; Yang Yang; Jinrong Wang; Yirong Dong; Ning Zhou; Xing Yang; Fangfang Li; Yang Yu; Huanxiang Liu; et al. (GeroScience, 2026)

PROMETHEUS clinical trial protocol: tailoring healthy ageing with lifestyle and nutraceuticals - Ajla Hodzic Kuerec; Lihuan Guan; Weilan Wang; Duarte Barros; Wejdan M. Alenezi; Jozo Grgic; Vanessa K. Wazny; Jordi Morwani-Mangnani; Mazzarine Dotou; Dingding Zhang; Tong Chen; Jiaqiu Wang; et al. (GeroScience, 2026)
The d emographic shift toward an older population is accelerating the prevalence of age-related diseases. Precision geromedicine represents a paradigm shift in targeting the biological processes of ageing to optimise health and healthspan, which likely requires multimodal tailored interventions. PROMETHEUS, as part of the XPRIZE healthspan semi-finalist competition, is an 8-week feasibility and exploratory study including 20 middle-aged-to-older participants who received a multimodal intervention comprising fundamental and augmented interventions. The fundamental interventions include sleep and dietary recommendations; supplementation with whey protein, creatine, and fucoidan; supervised exercise with an exergaming component (dual-task cognitive-physical training); motivational interviewing; and cognitive behavioural therapy. The augmented intervention is further personalised based on predefined gerotypes, reflecting individual ageing patterns beyond chronological age. At baseline, urolithin A, nicotinamide mononucleotide, and/or multivitamin-multimineral were prescribed to participants based on their muscle mass, VO 2 peak, and cognitive performance. At mid-intervention, interventions were adjusted based on individual response, including dose escalation and/or the addition of ergothioneine for inadequate improvement in cognition. Primary outcomes include measures of muscle strength and mass, immune function and cognitive performance, and feasibility indicators such as adherence and trial completion. Secondary outcomes include assessments of other biological, clinical, and digital biomarkers of ageing, as well as qualitative indicators of motivation and personal values. This study is aimed at investigating the recruitment feasibility, safety, adherence, and exploratory outcome trajectories of a multimodal, personalised precision geromedicine intervention protocol based on individual participant’s baseline characteristics and interim responses. These findings will also inform the design of a subsequent 12-month, randomised controlled trial evaluating personalised lifestyle and nutraceutical strategies with the potential to incorporate repurposed pharmacological agents to optimise age-related health outcomes.

Homebound status and glycemic control among older adults: results from a national survey - Sandra Iregbu; Eyitayo Owolabi; Chris Cho; Sanjay Bhandari; Priya Nambisan; Joni Williams; Katherine A. Ornstein (GeroScience, 2026)
Despite well-documented poor health outcomes among homebound older adults with diabetes, little is known about how homebound status affects glycemic outcomes. This study examined the association between homebound status and glycemic control among community-dwelling older adults with diabetes and identified key factors associated with glycemic outcomes. We conducted a cross-sectional analysis using data from the 2017 National Health and Aging Trends Survey (NHATS). Participants included community-dwelling older adults aged 65 years and older with diabetes. Glycemic control was measured by hemoglobin A1c (HbA1c). Being homebound was defined as the inability to leave one’s home independently. A fully adjusted linear regression model that accounted for predisposing, enabling, and need factors was used to assess the association between homebound status and HbA1c. All analyses accounted for the complex survey design. Homebound status was not independently associated with HbA1c in adjusted models. HbA1c was associated with age ≥ 85 years ( β = −0.25, p = 0.01), number of comorbid conditions ( β = −0.08, p = 0.005), depression ( β = + 0.62, p < .001), anxiety ( β = −0.43, p = 0.003), and receipt of food assistance ( β = −0.51, p = 0.004). These findings suggest that mental health needs and food access are important factors to consider alongside mobility in diabetes care. Collectively, the results highlight the potential value of a holistic, patient-centered approach to diabetes care among older adults that incorporates medical, psychosocial, and social domains.

Adipokines and satiety hormones and incidence of Alzheimer’s disease and dementia in older adults: a nested case-control study - Álvaro Hernáez; Javier Hernando-Redondo; Juan J. Chillarón; Emilio Ros; Miguel Ángel Martínez-González; Dolores Corella; Jordi Salas-Salvadó; Ramon Estruch; Juan Timiraos; Marta H. Hernández; Raquel Cueto-Galán; Miquel Fiol; et al. (GeroScience, 2026)
Obesity is known to have an intricate relationship with the development of Alzheimer’s disease and dementia (mid-life obesity increases risk, whereas late-life adiposity may also have an effect). In this context, adipokines and satiety signals are suggested to play a role in late life, but their association with the incidence of these outcomes remains unclear. Our study aimed to assess whether five selected plasma adipokines and satiety hormones (leptin, ghrelin, resistin, adipsin, and fibroblast growth factor-21) were associated with incident Alzheimer’s disease and dementia in older adults at high cardiovascular risk in a nested case-control study within the PREDIMED trial (90 dementia cases [73 of which were Alzheimer’s disease], 156 controls). Participants were at high cardiovascular disease risk but free from dementia at baseline. Associations with biomarkers were assessed using multivariable conditional logistic regression. Higher resistin levels were associated with higher incidence of Alzheimer’s disease in the multivariable-adjusted model (per one SD increase: OR 1.56, 95% CI 1.02 to 2.38); additional adjustment for body mass index slightly attenuated the association (OR 1.52, 95% CI 0.99 to 2.34). Our findings should be replicated in larger prospective studies but suggest that, despite the complex association between anthropometric measures and the incidence of dementia, high levels of resistin were tentatively associated with greater odds of incident Alzheimer’s disease in older adults at high cardiovascular risk.

Longitudinal lipidomic markers of cardiac aging and risk of coronary heart disease in American Indians: the Strong Heart Family Study - Mingjing Chen; Yixi Sun; Guanhong Miao; Xiaoxiao Wen; Alexander C. Razavi; Camilo Fernandez; Mary J. Roman; Richard B. Devereux; Richard R. Fabsitz; Ying Zhang; Jason G. Umans; Shelley A. Cole; et al. (GeroScience, 2026)
Age-related decline in left ventricular (LV) diastolic function is a hallmark of cardiac aging and an early precursor to cardiovascular disease. While dyslipidemia is a known driver of coronary heart disease (CHD), the molecular pathways linking lipid metabolism to cardiac aging and subsequent CHD risk remain poorly understood. Furthermore, longitudinal lipidomic profiling of cardiac aging in large human populations has not been systematically conducted. Using an untargeted LC–MS, we repeatedly measured 1542 fasting plasma lipid species in 1801 American Indians across two clinical exams in the Strong Heart Family Study (SHFS) (mean age at baseline: 40.0 years; mean interval: 5.5 years apart). We examined longitudinal associations between individual lipid species and measures of cardiac aging (E/A ratio, isovolumic relaxation time, and deceleration time) using generalized estimation equation (GEE), adjusted for demographic, lifestyle, and clinical factors. Significant associations were then replicated in the Bogalusa Heart Study (BHS) (mean age at baseline: 48.1 years). Frailty Cox proportional hazards models were used to examine whether cardiac aging-related lipids predicted incident CHD over a 20-year follow-up. We found that multiple lipid species, primarily glycerophospholipids, glycerolipids, and sphingomyelins, were associated with measures of cardiac aging, with the majority showing inverse associations. Some of these associations were confirmed in a biracial cohort of African American and White participants. Additionally, baseline levels of specific glycerophospholipids and fatty acids associated with diastolic function (E/A ratio and deceleration time) were linked to a reduced risk of CHD (HR range: 0.21–0.86). Conversely, other E/A-associated glycerophospholipids were linked to increased CHD risk (HR range: 1.24–1.34). In summary, we identified distinct lipidomic signatures associated with trajectories of subclinical cardiac aging, several of which also predict later-life CHD risk. These findings highlight molecular correlates of cardiac aging from midlife into older adulthood and suggest that lipidomic pathways may serve as early biomarkers for future: Keywords are required, The following are suggested: “Cardiac aging, Risk, Lipidomic markers”. Please check if correct. CHD.

The influence of aging on graded peripheral venous return and complex blood flow features through human veins - Jeremy N. Cohen; Eudoxia Zafiris; Jessica N. Jasiak; Skye H. T. Ling; Olena M. Decyk; Hassan Nahas; Alfred C. H. Yu; Jason S. Au (GeroScience, 2026)

Age-related differences in motor unit discharge rate modulation across contraction levels - Christopher D. Connelly; Tamara Valenčič; Haydn Thomason; Ed Sadula; Gregory E. P. Pearcey; Mathew Piasecki; Jonathan P. Folland; Jakob Škarabot (GeroScience, 2026)
Age-related strength loss may reflect morphological and neural adaptations that differ between muscles. However, it is unclear how ageing affects motor unit (MU) discharge rate modulation and estimates of persistent inward currents (PICs) across contraction levels. Thirty young (24 ± 4 years) and thirty older adults (73 ± 4 years) underwent magnetic resonance imaging and performed unilateral isometric dorsiflexion and knee extension contractions. Individual MU spike trains were identified from decomposed high-density electromyography recordings of tibialis anterior (TA) and vastus lateralis (VL) during triangular contractions at 30%, 50%, and 70% of maximal voluntary force (MVF). Older adults exhibited lower isometric strength in both tasks and smaller quadriceps but greater shank anterior compartment cross-sectional area compared to young. TA MU discharge rate was lower in older adults at all contraction levels but only at ≤ 50% MVF in VL. Discharge rate hysteresis (∆F), an estimate of PIC contribution to MU discharge, was lower in older adults at all TA contraction levels, but only at 70% MVF in VL, and in both muscles older adults exhibited an attenuated increase in ∆F across contraction levels. The ascending discharge rate non-linearity did not differ between groups, except at 30% MVF in VL where it was greater in older adults. Older adults also exhibited lower acceleration and attenuation slopes in TA, but not VL. These results reveal muscle-specific differences in MU discharge rate modulation with ageing, suggesting that the age-related strength loss is likely underpinned to a greater extent by morphological and neural factors in knee extensors and dorsiflexors, respectively.

Study protocol for FAXAge: a randomized, controlled clinical trial of fasting and exercise to slow aging in humans - Emma Bundgård Fals; Emilie Caroline Springborg; Adam Bjørnholdt Berthelsen; Jonas Nyeman-Nielsen; Steen Larsen; Morten Scheibye-Knudsen (GeroScience, 2026)
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 above 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 Dunedin Pace of Aging DNA methylation age with secondary measures including RNA-sequencing, metabolomics, inflammatory markers, 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.

Long-term intake of statins or renin-angiotensin system inhibitors: associations with sarcopenia-related parameters in older people - Tansu M. I. Aydoğan; Sarah Toepfer; Dominik Spira; Reinhold Kreutz; Ilja Demuth (GeroScience, 2026)

The shaky voice of aging localized to the larynx: dissociation of frequency and amplitude tremor - Braco Bošković; Irena Bilić; Maja Rogić Vidaković; Joško Šoda; Gordan Džamonja; Anita Runjić-Stoilova; Kristina Žuljević; Sanda Pavelin; Ivona Stipica Safić; Anita Markotić; Zoran Đogaš; Jan Hlavnička (GeroScience, 2026)

Plasma proteins associated with disability and mortality risks in Japanese community-dwelling octogenarians - Yusuke Osawa; Takashi Sasaki; Julián Candia; Yukiko Abe; Glenn Wong; Stefania Bandinelli; Luigi Ferrucci; Yasumichi Arai (GeroScience, 2026)
Japan has one of the world’s longest life expectancies, yet biomarkers associated with disability and mortality in very old adults remain uncertain. The goal of this study was to identify plasma proteins associated with incident disability and mortality in community-dwelling octogenarians. Two prospective cohorts were analyzed: the Kawasaki Aging Well-being Project (KAWP; 2017–2018; 4.5-year follow-up) as discovery and Invecchiare in Chianti (InCHIANTI; 1998–2000; 15-year follow-up) for external replication. The discovery sample comprised 230 disability-free adults aged 85–89 years (50.4% women). Twenty-nine plasma proteins were assayed using Luminex xMAP. Associations with incident disability and mortality were estimated with elastic net–regularized Cox models and tested in multivariable Cox models in the full KAWP cohort and in InCHIANTI. Higher beta-2-microglobulin and cystatin C levels were associated with an increased risk of disability (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.11–1.64; HR 1.42, 95% CI 1.14–1.76). For mortality, epidermal growth factor was inversely associated (HR 0.51, 95% CI 0.27–0.96), while interferon gamma–induced protein 10 was positively associated (HR 1.23, 95% CI 1.06–1.44). Associations with disability were broadly replicated in the full KAWP cohort and among InCHIANTI participants aged ≥ 80 years, whereas mortality-related findings were not replicated. In conclusion, beta-2-microglobulin and cystatin C may serve as biomarkers of future disability. These patterns implicate kidney dysfunction and inflammation as drivers of health decline in very old adults and support early risk stratification to guide preventive interventions.

Quantitative Cellular AGing Evaluation system (qCAGEs): a dual-parameter platform for high-throughput senescence screening - Dong-Ju Shin; Young-Sam Lee; Chong Won Choi; Hyun Ju Kang; Jin-Ku Lee (GeroScience, 2026)

Age-adjusted leukocyte telomere length predicts long-term mortality in older patients discharged from acute care hospitals - Rosanna Maniscalco; Deborah Ramini; Mirko Di Rosa; Maurizio Cardelli; Rina Recchioni; Francesca Marchegiani; Francesco Piacenza; Robertina Giacconi; Chiara Giordani; Giulia Matacchione; Matilde Sbriscia; Sonia Fantone; et al. (GeroScience, 2026)
Leukocyte telomere length (LTL) is a widely studied biomarker of biological aging, reflecting cumulative cellular damage beyond chronological age. However, its prognostic relevance in clinically complex populations such as hospitalized older adults remains uncertain. In this prospective observational study, 872 patients aged ≥ 65 years admitted to acute care wards of IRCCS INRCA within the Report-AGE cohort were included. LTL was measured by quantitative real-time PCR and expressed as age-adjusted residuals derived from an external reference population. The primary outcome was 10-year all-cause mortality. Associations between LTL residuals and mortality were assessed using Cox proportional hazards models, both as continuous variables and using a data-driven cut-point. Multivariable models adjusted for demographic characteristics, comorbidity burden, laboratory parameters, and polypharmacy were used. Effect modification by frailty was evaluated through interaction and stratified analyses. Over a median follow-up of 126.8 months, 713 patients died. Shorter age-adjusted LTL was associated with increased mortality risk in univariable analysis (HR per 1 SD decrease = 1.10, 95% CI 1.02–1.19; p = 0.012). When dichotomized using an optimal cut-point, patients with shorter-than-expected telomeres exhibited significantly higher mortality (adjusted HR = 1.30, 95% CI 1.05–1.60; p = 0.016), regardless of clinical and laboratory covariates. A significant interaction with frailty was observed ( p for interaction = 0.031), with the association between LTL and mortality being evident among patients without frailty. Age-adjusted LTL provides independent prognostic information in hospitalized older adults and may reflect biologically meaningful heterogeneity associated with aging, particularly among individuals without frailty.

Gut microbiota profiles across intrinsic capacity strata in community-dwelling older adults using full-length 16S rRNA sequencing - Chi-Hsien Huang; I-Cheng Lu; Chi-Wei Lin; Ming-Ta Hsieh; I-Hui Chiang; Po-Hsuan Lai; I-Ting Liu; Jung-Sheng Chen (GeroScience, 2026)

Unraveling physical performance over time in hospitalized older patients with walking limitation: the role of ultrasound-derived vastus lateralis muscle thickness - Jeppe Grabov Phillip; Hjalti Rúnar Oddsson; Jesper Ryg; Charlotte Suetta; Tahir Masud; Lisbeth Rosenbek Minet (GeroScience, 2026)
Acute hospitalization is a critical stressor that often leads to functional decline in older patients, highlighting the need for simple markers to identify at-risk individuals. Ultrasound is a feasible bedside tool for muscle mass assessment and has been proposed as a marker of physical function, but its prognostic value remains unclear. This study aimed to explore the association between ultrasound-derived muscle thickness (US-MT) and physical performance over time—gait speed (GS) and 30-s sit-to-stand (30s STS)—and selected clinical outcomes. In this prospective cohort study conducted in a geriatric department, adults aged ≥ 65 years with admission-related walking limitations were assessed at admission, discharge, 1 month, and 3 months. US-MT of the vastus lateralis was assessed at admission using ultrasonography. Longitudinal associations between US-MT and GS and 30s STS were examined using mixed-effects models. Associations with length of hospital stay (LOS), 3-month falls incidence, and 3-month mortality were examined using regression models. Among 243 participants, GS and 30s STS increased from admission to follow-up. Greater admission US-MT was modestly associated with faster GS in women (0.037 m/s; 95% CI 0.022–0.051) and with better 30s STS performance across sexes (IRR 1.24; 95% CI 1.00–1.53) across all time points. US-MT was not associated with trajectories of physical performance or with LOS, falls, or mortality. These findings suggest that admission US-MT may provide complementary bedside information on physical performance level, rather than serving as a standalone marker of recovery or clinical prognosis. ClinicalTrials.gov: NCT05798169

Exploring the association between common genetic deletions and aging: insights from the Canadian Longitudinal Study on Aging - Ana Lucia Rivera-Herrera; Michèle Rouleau; Mahukpe Narcisse Ulrich Singbo; Tania Cuppens; Pierre-Hugues Carmichael; Arnaud Droit; David Simonyan; Danielle Laurin; Chantal Guillemette (GeroScience, 2026)

Associations of daily step counts with cognitive, clinical, and resting-state electroencephalographic measures in patients with cognitive decline due to Alzheimer’s disease - Matteo Carpi; Mina De Bartolo; Veronica Henao Isaza; Giuseppe Noce; Claudio Del Percio; Susanna Lopez; Filippo Carducci; Roberta Lizio; Antonio Pio Afragola; Burcu Bölükbaş; Federica Fiorentino; Angelo Barone; et al. (GeroScience, 2026)
Sedentary behavior is a recognized and modifiable risk factor for cognitive decline and dementia across neurodegenerative conditions. This study used a smartwatch-based telemonitoring procedure combined with ecological cognitive assessment to examine whether step counts can capture sedentary behavior and its association with cognitive functioning in patients with mild cognitive impairment (ADMCI) and dementia (ADD) due to Alzheimer’s disease. Then, 19 ADD, 28 ADMCI, and 23 cognitively unimpaired older adults (Nold) were consecutively recruited. Participants underwent clinical assessment, resting-state electroencephalography (rsEEG), and neuropsychological testing. They were then monitored at home for approximately one week using Samsung Galaxy Watch 4–6 devices recording step counts (total, purposeful, and incidental) and activity intensity (peak 30-min cadence), together with the unsupervised SmartMe&You-TELEMAIA serious videogame battery administered on a commercial tablet for cognitive assessment. The ADD group showed reduced step counts and lower peak cadence than both ADMCI and Nold participants, whereas rsEEG markers and cognitive measures discriminated the three groups with a graded pattern. Within the AD sample, smartwatch-derived activity metrics were associated with cognitive functioning as assessed by conventional neuropsychological testing and ecological serious videogame performance, but showed limited associations with rsEEG rhythms. EEG delta and alpha rhythms were also more abnormal in the ADD group than in the ADMCI group. Home-based daytime activity monitoring with commercial smartwatches indicated that step volume and intensity are associated with cognitive status in patients with ADMCI and ADD. These findings suggest that smartwatch-derived activity metrics may provide feasible and cost-effective markers of everyday functioning in Alzheimer’s disease. Graphical abstract a Schematic overview of the study design, including resting-state EEG, one-week smartwatch-based activity monitoring, and unsupervised ecological cognitive assessment with the SmartMe&You-TELEMAIA Platform. b Group differences in daily activity metrics across participants with Alzheimer’s disease with dementia (ADD; N = 19), Alzheimer’s disease with mild cognitive impairment (ADMCI; N = 28), and cognitively unimpaired older adults (Nold; N = 23), indicating reduced daily step volume and peak cadence mainly in ADD. c Representative significant associations within the AD clinical sample (ADD + ADMCI; up to N = 47), showing that step metrics were more closely related to cognition (MMSE) and depressive symptom severity (BDI-II) than to resting-state EEG activity, for which only limited associations emerged.

Exploratory plasma metabolomics of aging-related associations with muscle quality and pulmonary function - C. Navas-Enamorado; X. Capo; A. Sánchez-Polo; S. Marín; M. Cascante; L. Masmiquel; M. Torrens-Mas; M. Gonzalez-Freire (GeroScience, 2026)

Space radiation and microgravity as models of accelerated aging: modulation of hepatic miRNA-TGF-β networks associated with senescence and fibrosis - Natalie Hayslip; JangKeun Kim; Sarah A. Ashiqueali; Xiang Zhu; Ridwan Hussein; Md Tanjim Alam; Driele N. Garcia; Bianka M. Zanini; Angela Kubik; Noah Allen; Elizabeth A. Blaber; Sarah S. Siddiqi; et al. (GeroScience, 2026)

Association between atrial fibrillation and systemic inflammation with muscle mass and strength trajectories in old age - Dilek Celik; Alice Margherita Ornago; Federico Triolo; Anna Picca; Riccardo Calvani; Chukwuma Okoye; Paolo Diego L’Angiocola; Amaia Calderón-Larrañaga; Gregory Y. H. Lip; Nicola Ferri; Davide Liborio Vetrano (GeroScience, 2026)
The long-term impact of atrial fibrillation (AF) and systemic inflammation on muscle health and, hence, functional decline remains unclear. This study investigates the link between AF and longitudinal trajectories of muscle mass and strength, considering the role played by systemic inflammation. Data were obtained from 2048 participants (≥ 60 years) in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), followed for 12 years. Muscle mass and strength were assessed using calf circumference, handgrip strength, and chair stand test. Inflammatory marker interleukin-6 (IL-6) and the stress-response mediator growth differentiation factor-15 (GDF-15) were measured at baseline. Linear mixed models examined the longitudinal changes in muscle outcomes according to AF status and the combination of AF status with inflammatory markers. Participants with AF experienced a steeper increase in the duration of the chair stand test (β = 1.49; 95% CI: 0.82 to 2.16). High levels of GDF-15 amplified declines in muscle mass (β = − 0.12; 95% CI: − 0.20 to − 0.05) and chair stand test performance (β = 2.48; 95% CI: 1.66 to 3.30) in individuals with AF. Participants with AF and high IL-6 levels also experienced an accelerated decline of calf circumference (β = − 0.12; 95% CI: − 0.19 to − 0.05) and chair stand test performance (β = 2.20; 95% CI: 1.39 to 3.01). AF is associated with a steeper decline in muscle mass and strength over time, exacerbated by elevated inflammatory biomarkers, underscoring the importance of systemic inflammation in AF-related functional decline.

Machine learning derived abdominal aortic calcification is associated with physical frailty in community-dwelling adults: the UK Biobank Imaging Study - Abadi K. Gebre; Marion Mundt; Elsa Dent; James Webster; Afsah Saleem; Syed Zulqarnain Gilani; Yuandan Zhang; Cassandra Smith; Parminder Raina; John P. Kemp; William D. Leslie; John T. Schousboe; et al. (GeroScience, 2026)

Resting heart rate and cognitive function in ageing: Insights from a secondary data analysis - Yunrui Gu; Joanne Ryan; Aung Zaw Zaw Phyo; Zimu Wu; Suzanne G. Orchard; Raj C. Shah; Swarna Vishwanath (GeroScience, 2026)
Resting heart rate (RHR) is an accessible measure that may reflect age-related cardiovascular and autonomic dysregulation relevant to cognitive ageing. However, evidence linking RHR with cognitive outcomes is inconsistent, and most studies relied on single baseline measurements that may not capture cumulative exposure. This study examined the associations of baseline and longitudinally averaged RHR with cognitive decline and dementia in older adults. This was a secondary analysis of the ASPirin in Reducing Events in the Elderly (ASPREE) study, including 19,114 community-dwelling participants aged ≥ 65 years without cardiovascular disease or dementia at baseline. RHR was assessed at baseline and follow-up visits using an oscillometric device. Cognitive decline was defined as a decrease of > 1.5 standard deviations from baseline performance in global cognition, episodic memory, psychomotor speed, or verbal fluency. Incident dementia was adjudicated using DSM-IV criteria. Compared with baseline RHR of 60–69 bpm, those with RHR ≥ 80 bpm had a 9% higher cognitive decline risk (hazard ratio [HR] 1.09; 95% confidence interval [CI], 1.01–1.18). Five-year average RHR of 70–79 bpm and ≥ 80 bpm were associated with 10% (HR 1.10; 95% CI, 1.03–1.19) and 16% (HR 1.16; 95% CI, 1.05–1.28) higher cognitive decline risks, respectively. No significant associations were observed with incident dementia. Higher RHR was associated with increased risk of cognitive decline among older adults. These findings suggest that elevated RHR may reflect age-related cardiovascular or autonomic physiological processes relevant to cognitive aging, supporting a role for late-life physiological dysregulation in cognitive trajectories.

Age-related metabolomic signatures and stroke susceptibility in a population-based cohort - Yanfeng Jiang; Qingxia Huang; Jincheng Li; Qinsheng Chen; Jialin Li; Zhenqiu Liu; Mei Cui; Chen Suo; Kelin Xu; Li Jin; Huiru Tang; Xingdong Chen (GeroScience, 2026)

Telomere length and appendicular lean mass over six years in older adults with overweight or obesity and metabolic syndrome: a prospective cohort study - Héctor Vázquez-Lorente; María Fernández de la Puente; Julio Plaza-Diaz; Nancy Babio; Montse Fitó; Miguel Ángel Martínez-González; Sonia García-Calzón; Amelia Marti del Moral; Jordi Salas-Salvadó (GeroScience, 2026)
Telomere length (TL) has been proposed as a marker of appendicular lean mass (ALM) decline; however, longitudinal evidence remains limited. We aimed to investigate the longitudinal association between TL and 6-year trajectories of ALM. This longitudinal study included 185 older adults aged 55–75 years with overweight or obesity and metabolic syndrome at baseline. Baseline TL was assessed using a monochrome multiplex real-time quantitative PCR. ALM from the four limbs was obtained at baseline, and after 1, 3, and 6 years of follow-up using dual-energy X-ray absorptiometry. ALM was also normalized for height, total body weight, or body mass index (BMI). Baseline longer TL in continuous was associated with higher ALM (between-group difference, 0.76; 95% CI, 0.12 to 1.40) and greater lean mass in the lower limbs (between-group difference, 0.50; 95% CI, 0.02 to 0.97), ALM to height ratio (between-group difference, 0.21; 95% CI, 0.02 to 0.41), and higher ALM to BMI ratio (between-group difference, 0.02; 95% CI, 0.01 to 0.04) after 6 years. When analyzed categorically, participants with baseline TL above the median exhibited higher ALM (between-group difference, 0.62; 95% CI, 0.04 to 1.20) and greater lean mass in the lower limbs (between-group difference, 0.49; 95% CI, 0.06 to 0.92) and higher ALM to BMI ratio (between-group difference, 0.02; 95% CI, 0.01 to 0.04) compared with those below the median after 6 years. Longer baseline TL was modestly associated with more favorable long-term ALM trajectories in older adults with overweight or obesity and metabolic syndrome, although these observational findings preclude causal inference and should not be interpreted as evidence that telomere biology directly contributes to muscle aging.

Psychosocial adversity captured by ICD-10 Z-codes and mortality risk: evidence from the UK Biobank - May A. Beydoun; Hind A. Beydoun; Jack Tsai; Indira C. Turney; Osorio Meirelles; Tianyi Huang; Nicole Noren Hooten; Lenore J. Launer; Michele K. Evans; Alan B. Zonderman (GeroScience, 2026)

A local-to-distant shift in dynamic brain connectivity marks early Alzheimer’s risk - Andrea Coca-Pulido; Patricio Solis-Urra; Oren Contreras-Rodríguez; Carles Biarnés; Marcos Olvera-Rojas; Shivangi Jain; Anuradha Sehrawat; Yijun Chen; Yolanda García-Rivero; Manuel Gomez-Rio; Kirk I. Erickson; Jose Mora-Gonzalez; et al. (GeroScience, 2026)
Alzheimer’s disease (AD) involves early disruptions in brain connectivity, yet how AD risk markers relate to resting-state dynamic functional connectivity (rs-dFC) remains unclear. We examined associations of AD pathology, genetic risk, and blood-based biomarkers (BBMs) of neurodegeneration with local and distant rs-dFC in cognitively normal older adults and explored links with cognitive performance. Baseline data from 86 cognitively normal older adults in the AGUEDA trial (NCT05186090) were analyzed. Participants underwent amyloid-beta (Aβ)-PET, APOE4 genotyping, and plasma BBM quantification (Aβ42/40, BD-tau, GFAP, NfL, p-tau181, and p-tau217). rs-fMRI was used to compute voxel-wise local and distant rs-dFC using a stepwise connectivity framework. Models tested associations between AD markers and rs-dFC adjusting for age, sex, and education; secondary models examined extracted cluster values and six cognitive domains. Aβ-positive individuals and APOE4 carriers showed lower local connectivity in frontal regions. APOE4 carriers also exhibited higher distant connectivity in the superior motor area, inferior frontal gyrus, and anterior insula. Among BBMs, only NfL was associated with both lower local (insula and cingulate) and higher distant (precuneus, putamen, thalamus, supramarginal, and superior motor area) connectivity. Secondary analyses suggested additional cluster–cognition associations. Across AD risk markers, higher risk (Aβ-positivity, APOE4 carriage, and higher NfL) converged on a consistent rs-dFC signature characterized by reduced local and increased distant connectivity. This local-to-distant shift may serve as a candidate functional marker of early AD-related network vulnerability in cognitively normal aging and could support risk monitoring and stratification pending longitudinal validation.

Analysis of second-generation epigenetic clocks reveals further associations between disproportionate biological ageing and hippocampal volume - Lidija Milicic; Michael Vacher; Vincent Doré; Pierrick Bourgeat; Rosita Shishegar; James D. Doecke; Paul Maruff; Christopher C. Rowe; Victor L. Villemagne; Michael Weiner; Paul Aisen; Ronald Petersen; et al. (GeroScience, 2026)

Amino acid and appendicular skeletal muscle mass insufficiency are associated to cognitive decline in Chinese population - Ting Tang; Shuxian Zhang; Yanni Pu; Siquan Li; Bin Jiang; Huiting Liang; Kunmu Zheng; Yan Zheng; He Huang; Jin Li; Xiaodong Pan (GeroScience, 2026)

High-resolution MRI evidence for age- and sex-related changes in hippocampal subfield volume during healthy aging - Megan C. Hall; Giorgia Picci; Maggie P. Rempe; Jason A. John; Lauren K. Webert; Kellen M. McDonald; Hannah J. Okelberry; Hallie J. Johnson; Lucy K. Horne; Madelyn P. Willett; Ryan J. Glesinger; Danielle L. Rice; et al. (GeroScience, 2026)

CRT upgrade improves frailty status in patients with HFrEF and RV pacing—a post hoc analysis of the BUDAPEST-CRT trial - Luca Kuthi; Eperke Merkel; Marianna Németh; Boglárka Veres; Zoltán Szakács; Anett Behon; Richárd Masszi; Zsuzsanna Kis; Roland Papp; Levente Molnár; Attila Kovács; Annamária Kosztin; et al. (GeroScience, 2026)

Targeting brain rhythms to support cognition in aging: a systematic review and meta-analysis of tACS across healthy aging, mild cognitive impairment, and Alzheimer’s disease - Brunno Freitas da Costa; Karin Reuwsaat; Nwabunwanne Emele; Cíntia Monteiro Carvalho; Egas Caparelli-Dáquer; Rogério Panizzutti (GeroScience, 2026)
Cognitive decline is a major challenge in aging. Transcranial alternating current stimulation (tACS) modulates neural oscillations, potentially aiding cognition. Due to variation in late-life tACS studies, we conducted the first meta-analysis in older adults (≥ 60 years) to estimate pooled cognitive effects and determine if protocol parameters explain outcome variability. We searched Medline/PubMed, Embase, Cochrane Library, and ClinicalTrials.gov (up to September 17, 2025) for studies examining tACS effects on cognition in adults age ≥ 60 years, including healthy aging, mild cognitive impairment (MCI), and Alzheimer’s disease (AD). Risk of bias was assessed using RoB 2 and ROBINS-I. Random-effects meta-analyses using Hedges’ g were performed, with sensitivity analyses to handle outliers and heterogeneity. Twenty-two studies ( n = 826 participants) were included. The primary meta-analysis revealed a significant moderate effect of tACS on cognition ( g = 0.70, 95% CI 0.38–1.02), though with high heterogeneity ( I 2 = 88.5%). Excluding one influential outlier yielded a more conservative and stable estimate ( g = 0.55, 95% CI 0.39–0.70, I 2 = 47.1%). Subgroup analyses showed homogenous effects in MCI ( g = 0.59, I 2 = 0%). Memory was the most responsive domain. Meta-regressions did not identify significant associations between outcomes and specific stimulation parameters. tACS was associated with improvements in cognitive outcomes in older adults, with more consistent evidence observed for memory in individuals with MCI. However, findings in healthy older adults and AD were more variable and should be interpreted in light of substantial methodological heterogeneity. Overall, the pooled estimate reflects an average across diverse populations and intervention protocols rather than a single, clinically uniform effect. Future research should prioritize standardized, dose-response protocols to support clinical translation. PROSPERO CRD42025629824.

Frailty and major late-life transitions in very old adults: contrasting biomarker patterns of GDF-15 and NT-proBNP in the Kawasaki Aging and Wellbeing Project - Aiko Shiohama; Takashi Sasaki; Yukiko Abe; Ryo Shikimoto; Yasumichi Arai (GeroScience, 2026)

Behavioral variability and preparatory ERPs as neurobehavioral markers of mild cognitive impairment risk in older adults - Francesco Di Russo; Merve Aydin; Valentina Bianco; Luca Boccacci; Roberta Forte; Sabrina Pitzalis (GeroScience, 2026)

Intrinsic capacity and mortality in community-dwelling octogenarians: a network analysis from the ilSIRENTE study - Stefano Cacciatore; Bella Bravo; Rola S. Zeidan; Riccardo Calvani; Hyung-Suk Alex Yoon; Matteo Tosato; Andrea Russo; Christiaan Leeuwenburgh; Stephen D. Anton; Emanuele Marzetti; Francesco Landi (GeroScience, 2026)
Intrinsic capacity (IC) is a key construct within the healthy ageing framework. However, the correlations among IC domains and their association with health outcomes in very old adults remain unclear. This study aimed to characterise the relationships among IC domains using network analysis and to examine their association with mortality in community-dwelling octogenarians from the Invecchiamento e Longevità nel Sirente (ilSIRENTE) cohort. IC was calculated as a summary score rescaled to a 0–100 range across locomotion, cognition, vitality, psychological capacity, and sensory function, derived from routine home-based geriatric assessments (Minimum Data Set for Home Care instruments and supplementary tests). Assessments were conducted at designated centres, with home visits arranged for individuals unable to travel. The final sample included 319 community-dwelling adults aged ≥ 80 years (mean age 85.4 ± 4.8 years; 67.1% women). Network analysis suggested clustered relationships among vitality, psychological, and cognitive domains, whereas sensory domains appeared more peripheral. Hearing and vision were associated with locomotion, while their association with cognition appeared to be mediated by locomotion. In Cox proportional hazards models, higher locomotion scores were independently associated with lower mortality at 4 years [hazard ratio (HR) 0.86, 95% CI 0.80–0.93] and 7 years (HR 0.87, 95% CI 0.81–0.92). Each 10-point increase in IC was associated with lower mortality at 4 years (HR 0.67, 95% CI 0.58–0.77) and 7 years (HR 0.68, 95% CI 0.61–0.77). Among very old adults, locomotion emerged as a central functional domain linking sensory function, cognition, and survival within the IC framework. IC measures derived from routine assessments may provide a pragmatic approach for risk stratification and targeted interventions to promote healthy ageing.

Association of CT-derived muscle quality with multiple geriatric syndromes in older adults: a cross-sectional study - Deng-Chi Yang; Chien-Chou Su; Yu-Hsuan Lai; Yi-Ching Yang; Yi-Shan Tsai (GeroScience, 2026)

Characterization of the plasma proteomic profile of dual trajectories in cognitive status and physical performance - Alan M. Rathbun; Chixiang Chen; Qu Tian; Toshiko Tanaka; Luigi Ferrucci; Michelle D. Shardell (GeroScience, 2026)

Promoting healthy aging in occupational settings: satisfaction with life as a strategic target in the Semmelweis–EUniWell framework - Virág Zábó; Andrea Lehoczki; Annamária Buda; Péter Varga; Monika Fekete; Vince Fazekas-Pongor; Tamás Csípő; Kata Adonicsné-Püski; Giorgia Giovannetti; Yura Loscalzo; Marco Giannini; Beatrix Busse; et al. (GeroScience, 2026)
The growing burden of aging-related disease and functional decline across Europe underscores the urgent need to optimize aging trajectories rather than simply extend lifespan. Achieving this goal requires identifying modifiable determinants that shape biological, psychological, and functional aging across the life course. Satisfaction with life (SWL) is emerging as one such integrative factor, linking adaptive capacity, resilience, and long-term healthspan outcomes. In this conceptual and translational paper, we integrate evidence from geroscience, psychology, and occupational health to position SWL as both a marker and a potentially modifiable determinant of healthspan. We review biological, psychological, and social mechanisms linking SWL to aging processes, including cardiovascular and inflammatory regulation, neural and affective processing, psychological resilience and reserve, and social integration and generativity. Collectively, these pathways suggest that SWL reflects the functional integrity of adaptive systems that shape vulnerability to age-related functional decline. We further argue that occupational settings represent a uniquely powerful and scalable context for targeting SWL, given their sustained influence on behavior, stress exposure, social roles, and meaning across adulthood. Building on this framework, we discuss the Semmelweis Study, a large prospective workplace-based cohort, together with the Semmelweis–EUniWell Workplace Health Promotion Program, as an integrated model for translating geroscience-informed insights into structured interventions. Such workplace health promotion programs can target core psychological capacities—including savoring, self-regulation, creative and executive efficiency, and resilience—that are closely linked to adaptive capacity and aging-related outcomes. Finally, we discuss implications for geroscience, public health, and policy, highlighting how embedding SWL as a strategic target within workplace systems may contribute to extending healthspan, strengthening workforce sustainability, and reducing the societal burden of population aging. Conceptualizing satisfaction with life not merely as a subjective outcome but as a dimension of biological aging and adaptive resilience opens new avenues for intervention at the interface of geroscience and real-world systems.

Effects of transcutaneous electrical nerve stimulation on cognitive function and upper limb motor function in people with chronic stroke: a randomized controlled trial - Nga Huen Chan; Shamay S. M. Ng (GeroScience, 2026)
Transcutaneous electrical nerve stimulation, including transcutaneous vagus nerve stimulation (tVNS) and transcutaneous spinal cord stimulation (tSCS), is potential interventions that can alleviate cognitive decline and promote motor recovery by modulating neurotransmitter systems, but current evidence in people with stroke remains inconclusive. This study investigated the effects of tVNS and tSCS and compared their efficacy in improving cognitive function and upper limb motor function after stroke. In this randomized controlled trial, 90 people with chronic stroke (mean ± standard deviation: 65.12 ± 5.85 years of age) were randomly assigned to receive 18 sessions of either tVNS, tSCS, or sham stimulation, each delivered concurrently with upper limb exercises for 45 min, three times per week, for 6 weeks. The primary outcomes were the Montreal Cognitive Assessment (MoCA) and the Fugl-Meyer Assessment for Upper Extremity (FMAUE). Outcomes were measured at baseline, after 9 and 18 sessions, and at 1 month after the intervention. The tVNS and tSCS groups demonstrated significantly greater improvements than did the sham group in MoCA (mean differences, 2.37 and 1.77, respectively; p < 0.001) and FMAUE scores (mean differences, 3.37 and 2.10, respectively; p < 0.001 and p = 0.007, respectively) after the intervention. Improvements in cognition persisted for 1 month in both groups, as indicated by non-significant within-group changes from post-intervention to follow-up assessments, whereas motor improvements were sustained only in the tVNS group. Both tVNS and tSCS may be potential interventions to combine with exercise for improving cognitive and upper limb function after stroke. ClinicalTrials.gov: NCT05615610.

Muscle Ageing and Sarcopenia Study (MASS) Lifecourse: a valuable resource for understanding skeletal muscle ageing - Rachel Cooper; Christopher Hurst; Holly Syddall; Helen Atkinson; Jonathan G. Bunn; Daniela Carpinelli; Antoneta Granic; Susan J. Hillman; Emma Grace Lewis; Claire McDonald; Katie Sloan; Karen Suetterlin; et al. (GeroScience, 2026)

Feasibility and safety of a home-based physical therapy intervention to reverse frailty in patients with Parkinson’s disease: an exploratory pilot randomized clinical trial - M. C. Sousa-Fraguas; N. M. Conejo; D. Lastra-Barreira; G. Rodríguez-Fuentes (GeroScience, 2026)
The presence of frailty is common in people with Parkinson’s disease (PD), as is cognitive dysfunction. Frailty is a dynamic process that can be reversed, so early detection is essential. The objective of this study is to evaluate the feasibility and safety of a home-based physical therapy program for frail patients with idiopathic Parkinson’s disease and cognitive impairment. An exploratory, pilot, randomized, single-blind experimental study was conducted. Participants were recruited from a Home Rehabilitation Service. Safety was assessed by recording adverse events such as falls, motor deterioration, and treatment-related complications, while feasibility was determined by whether the intervention could be delivered as planned, taking into account resources, time, and patient acceptance. The intervention group completed a 16-session supervised home-based physiotherapy program over 8 weeks, whereas the control group maintained usual activities. Fifteen patients were recruited. The intervention demonstrated excellent feasibility, with a 100% session completion rate and no adverse events recorded. Exploratory analyses suggested potential benefits in frailty levels, functional performance, disease severity, and quality of life in the intervention group; however, these findings should be interpreted with caution given the pilot nature of the study and the small sample size. A multicomponent home physiotherapy program in frail patients with PD and cognitive impairment is safe and feasible, while reducing the level of frailty. In this patient profile, it is necessary to continuously assess frailty and cognitive impairment, and to implement tailored and prolonged intervention programs, with constant follow-up, to address functional difficulties that arise during the evolution of the disease. ClinicalTrials.gov ID: NCT05388526

Seven-year progression of white matter hyperintensities and age-related cognitive change in healthy middle-aged and older adults - Jin Liu; Ana M. Daugherty; Cheryl L. Dahle; Paolo Ghisletta; Naftali Raz (GeroScience, 2026)

External validation of a US claims-based frailty indicator and development of a population-specific model for the German healthcare system - Nina Mielke; Damiano Ferrari; Muhammad Helmi Barghouth; Natalie Ebert; Janine Kaiser; Elke Schaeffner (GeroScience, 2026)
Frailty increases the risk of adverse outcomes in older adults and is an important target for preventive care. Clinical frailty measures are established but rarely available at scale due to limited functional data in routine healthcare records. Claims-based frailty prediction models offer a pragmatic approach for population-level risk stratification but are often developed in specific healthcare systems and lack external validation. We aimed to externally validate and recalibrate the Claims-Based-Frailty-Indicator (CFI) and develop a claims-based frailty model for the German healthcare context. We used data from the Berlin Initiative Study, a cohort of older adults with assessment of the frailty phenotype, linked to individual health insurance claims and cause-of-death data. External validation of CFI was assessed by discrimination and calibration. Additionally, a new claims-based frailty model was developed. Model performance and application were evaluated through associations with mortality and hospital admission. Reporting followed TRIPOD statement. Among 1,151 participants (mean age 84.4 years; 55% women), the CFI demonstrated good discrimination (AUC 0.78) but poor calibration; recalibration of intercept improved calibration. Maximizing the Youden Index identified an optimal frailty threshold corresponding to a predicted probability of 0.39. The new model showed improved discrimination (AUC 0.82). Predicted frailty was similarly associated with mortality and hospital admissions as the frailty phenotype. Claims-based frailty models can be validated, recalibrated, and adapted to the German healthcare system. They provide a feasible approach for population-level frailty assessment and may support health services research, risk stratification, and care planning for older adults.

oral functional limitation and long-term frailty trajectories: a 6-year cohort study of community-dwelling older adults in Korea - Kyung-Yi Do; Chang Won Won; Miji Kim; Joong-Yeon Lim (GeroScience, 2026)

Using kidney transplantation to explore epigenetic markers of frailty - Y. Yang; F. Giddens; S. Neupane; L. Tran; R. Tannenberg; N. Reid; R. E. Hubbard; A. Shaw; R. S. Francis; J. Gratten; E. H. Gordon (GeroScience, 2026)
The aetiology of frailty remains unknown. It has been hypothesised that individual differences in epigenetic mechanisms, particularly DNA methylation (DNAm), may help to explain why some individuals become frail while others do not. Relating epigenetic measures to transitions in age-related frailty in individual patients requires longitudinal studies over many years. To overcome this barrier, we study associations between DNAm and the Frailty Index in a cohort of adults with kidney failure who experience accelerated transitions of frailty with and without kidney transplantation. While transplantation was associated with reduced frailty, there was minimal evidence for an association between frailty and epigenetic markers.

Amyloid and tau pathologies are drivers of white matter damage in aging and Alzheimer’s disease - Farooq Kamal; Mahsa Dadar (GeroScience, 2026)

Cognitive trajectories and mortality risk in older adults: a 9-year follow-up study - Gabriela Cabett Cipolli; Daniela de Assumpção; Ivan Aprahamian; Mallak Khalid Alzahrani; Ligiana Pires Corona; Yeda Aparecida de Oliveira Duarte; Mônica Sanches Yassuda; Qian-Li Xue (GeroScience, 2026)
Cognitive decline is a central feature of aging and a major determinant of disability and mortality. Understanding cognitive trajectories is essential for identifying individuals at risk and informing preventive strategies. In this study, we estimated transition probabilities across cognitive states and examined predictors of cognitive deficit and mortality among 1,413 community-dwelling older adults for nine years. Cognitive status was assessed at baseline and at two follow-up waves (2006, 2010, and 2015) using the Mini-Mental State Examination and categorized into four trajectories: stable, worsening, improving, or fluctuating. Transition probabilities and associated predictors were estimated using discrete-time Markov models via multinomial logistic regression, including baseline cognitive status, age, sex, frailty, multimorbidity, and depressive symptoms. During follow-up, 51.1% of participants experienced cognitive decline, 46.6% remained stable, 1.3% improved, and 1.1% fluctuated. Frailty increased the odds of both cognitive deficit (OR = 3.1; 95% CI 1.86–5.18) and mortality (OR = 4.2; 95% CI 2.66–6.69). Participants aged ≥ 80 years had higher risks of cognitive deficit (OR = 5.2; 95% CI 3.63–7.48) and death (OR = 11.9; 95% CI 8.30–17.21). Prior cognitive deficit predicted subsequent decline (OR = 7.5; 95% CI 4.77–11.77) and mortality (OR = 7.2; 95% CI 4.63–11.28), whereas female sex was associated with lower mortality risk (OR = 0.50; 95% CI 0.38–0.66). These findings indicate that cognitive decline in late life follows a progressive trajectory and highlight frailty and advanced age as key predictors of cognitive deterioration and mortality, emphasizing the importance of early identification and preventive strategies.

In memoriam: Thomas Eugene Johnson - Caleb E. Finch; Steven N. Austad (GeroScience, 2026)

Health insurance, healthcare access, and their roles in the association between blood lead levels and epigenetic aging in United States adults - Jamaji C. Nwanaji-Enwerem; Dennis Khodasevich; Nicole Gladish; Hanyang Shen; Anne K. Bozack; Saher Daredia; David H. Rehkopf; Andres Cardenas (GeroScience, 2026)
Lead exposure remains a significant public health problem, and even within current standards, most individuals have limited means to avoid it. Regulating or removing toxic exposures remains a priority, but complementary nearer-term protections are needed. We previously observed that health insurance coverage attenuated associations of blood lead levels with two DNA methylation–based biomarkers of morbidity and mortality: GrimAge2 and DunedinPoAm. In this study, we evaluated whether healthcare access could account for or modify these relationships. We conducted a cross-sectional analysis of 2,312 adults aged 50–84 years from the 1999–2002 National Health and Nutrition Examination Survey (NHANES). Survey-weighted generalized linear models were used to test effect modification of the lead–epigenetic aging relationship by health insurance and by healthcare access, defined as having a routine place of healthcare. In models adjusted for demographic, socioeconomic, lifestyle, and health factors, insurance significantly modified associations of lead with epigenetic age. Although model estimates remained comparable, interactions were no longer statistically significant after healthcare access was added as a covariate for GrimAge2 (β insured = 0.08, 95%CI insured : -0.08, 0.23, β uninsured = 0.60, 95%CI uninsured : -0.10, 1.28, P interaction = 0.09) and DunedinPoAm (β insured = 0.001, 95%CI insured : -0.002, 0.003, β uninsured = 0.01, 95%CI uninsured : -0.003, 0.02, P interaction = 0.09). Healthcare access alone did not significantly modify the associations of lead with either biomarker in models with or without insurance as a covariate. These findings suggest that healthcare access may partially contribute to the attenuation of lead-related epigenetic aging observed among insured adults and a need for further research to better understand these complex relationships.

Neurovascular decoupling and compensatory network recruitment during speech perception in aging: evidence from EEG-fNIRS - Liu Yang; Yu Gu (GeroScience, 2026)

Associations of cardiorespiratory fitness with structural brain networks in ageing: insights from The Maastricht Study - Kristina Ukropcova; Kay Deckers; Annemarie Koster; Joost J. A. de Jong; Jacobus F. A. Jansen; Walter H. Backes; Hans H. C. M. Savelberg; Carla van der Kallen; Miranda T. Schram; Sebastian Köhler; Veerle van Gils (GeroScience, 2026)

Licochalcone a enhances cognitive resilience in APP/PS1 Mice by modulating glucose metabolism, Aβ burden, and neuroinflammation - Marina Carrasco; Laura Guzman; Emma Barroso; Jordi Olloquequi; Amanda Cano; Jesús Ureña; Ester Verdaguer; Rafel Prohens; Ana Fortuna; Carme Auladell; Miren Ettcheto; Antoni Camins (GeroScience, 2026)

Expected lifespan and healthspan among rural and urban individuals in Java, Indonesia - Siti Masfiah; Anna Szücs; Budi Aji; Paul A. O’Keefe; E. J. Horberg; Sonny Rosenthal; Johannes Jacobus Meij; Andrea B. Maier (GeroScience, 2026)

Quantitative sleep EEG identifies CSF core biomarker-related subgroups in Alzheimer’s disease - Anna Michela Gaeta; Lorena Gallego Viñarás; Ferran Barbé; Pablo Martínez Olmos; Arrate Muñoz-Barrutia; Gerard Piñol-Ripoll (GeroScience, 2026)

Combating Alzheimer’s through sleep and exercise (CASE): A study protocol - Debbie Chung; Brittany A. Larsen; Laurent G. Garchitorena Gomez; Alberto R. Ramos; Neva J. Kirk-Sanchez; Girardin Jean-Louis; Azizi A. Seixas (GeroScience, 2026)
Dementia affects over 55 million people worldwide, with Alzheimer’s disease (AD) comprising most cases. Because curative therapies remain unavailable, there is an urgent need for prevention strategies that target modifiable risk factors. Behavioral interventions—particularly sleep improvement and physical activity—can independently benefit cognition, brain function, and cardiometabolic health, yet their combined (potentially synergistic) effects and scalable delivery models remain underexplored. This exploratory, hypothesis-generating, three-arm randomized controlled trial will evaluate: (1) whether improvements in sleep metrics are associated with improvements in cognitive performance and biomarker panels reflecting brain and cardiometabolic health; (2) the effects of structured, moderate-intensity aerobic and anaerobic exercise on cognitive performance and biomarker panels; (3) the combined effects of sleep and exercise interventions on cognitive performance and biomarker panels, including potential synergy; and (4) the role of light exposure as a modulator of sleep parameters. Over 8 weeks at a single site, 60 community-dwelling adults, aged 55–80 years, with and without mild cognitive impairment, will be randomized to exercise-only, sleep-only, or combined sleep-plus-exercise interventions. Programs will be delivered in-person and/or using Elemind Neuromodulation headbands, Fitbit trackers, and Lys light sensors. Cognitive function will be assessed with the Digital Neuro-Signature Platform, and plasma biomarkers will index cardiometabolic health and AD-related neuropathology. Findings will inform larger, multi-site trials targeting modifiable AD risk factors using scalable, digital, and decentralized intervention platforms. ClinicalTrials.gov NCT04855630; https://clinicaltrials.gov/study/NCT04855630 . Registration date 04/19/2021.

Andes virus and the aging host: lessons from the 2026 outbreak and a framework for age-related disease severity - Jorge Quarleri; Patricio Jarmoluk; Ignacio Mazzitelli; M. Victoria Delpino (GeroScience, 2026)

Age and sex dependent shift in murine gut microbiome reveals pathological links to host cardiovascular and metabolic pathways - Meena Kumari Palani Kumar; Krishna S. Iyer; Shailesh K. Shahi; Juan Antonio Raygoza Garay; Ashutosh Mangalam; Sanjana Dayal (GeroScience, 2026)
The gut microbiome undergoes dynamic, sex-dependent changes across the lifespan. However, comprehensive studies examining the combined effects of age and sex are limited. This study investigated both compositional and functional alterations in the gut microbiome of young (4 months, n = 14) and aged (20 months, n = 20) C57BL/6 J mice of both sexes using 16S rRNA gene (V3–V5) sequencing. Microbial community structure and predicted functional profiles were analyzed via QIIME2 and PICRUSt2, with pathway annotation based on MetaCyc. Compared to aged mice, young mice exhibited higher alpha diversity, with the highest increase observed in young females. This sex-specific difference was lost in aged mice. Aging was also associated with an increased Firmicutes-to-Bacteroidetes ratio, and distinct shifts in key taxa, including increased Lactobacillus and Roseburia and reduced Bacteroides and Lachnospiraceae. Functional prediction revealed substantial age-related metabolic shifts, especially in females showing alteration in 45 pathways including upregulation of branched-chain amino acid (BCAA) metabolism, uric acid metabolism, and lipopolysaccharide biosynthesis. To directly link alterations in microbial BCAA metabolism with host metabolic outcomes, fecal abundance of the bacterial BCAA aminotransferase gene (ilvE) was quantified and found to be significantly increased in aged mice. Concurrently, aged mice exhibited higher plasma levels of BCAA, insulin, and random glucose, indicating age-associated metabolic dysregulation. Fecal ilvE abundance associated positively with plasma BCAA levels, and negatively with blood glucose in aged mice, suggesting a link between microbial BCAA metabolism and host glucose homeostasis. Our findings demonstrate that gut microbiome composition and function are influenced by both age and sex. We also showed that these alterations in microbial BCAA metabolism are associated with host metabolic parameters during aging. Our findings underscore the importance of incorporating both age and sex as biological variables in microbiome research and may inform development of age- and sex-specific microbiome-targeted interventions.

Association of high-intensity evening light exposure with risk of incident age-related macular degeneration, cataract, and glaucoma: a prospective cohort study of 82,826 participants - Xiaoqian Wu; Xinyu Zhang; Yujin Jiang; Zhiyi Gu; Chenxin Li; Xinyu Zhu; Yikeng Huang; Bo Li; Mingming Ma; Shuzhi Zhao; Zhi Zheng (GeroScience, 2026)

The role of cellular senescence in immune-metabolic features and prognosis of ovarian cancer: an integrated analysis based on single-cell sequencing and multi-omics data - Yuan Li; Mengying Bai; Ziqiong Zhou; Wenbo Wu; Haifeng Wu; Shuyi Ling; Liping Wang; Yuehui Zheng (GeroScience, 2026)

Multimorbidity as a predictor of mortality in companion dogs - Eric R. Foreman; Laura Corlin; Kate E. Creevy; Jessica M. Hoffman; Joshua M. Akey; Rozalyn M. Anderson; Elhanan Borenstein; Marta G. Castelhano; Amanda E. Coleman; Matthew D. Dunbar; Virginia R. Fajt; Erica C Jonlin; et al. (GeroScience, 2026)

Correction to: High‑resolution glutamate‑weighted mapping of in vivo mouse brain across age with chemical exchange saturation transfer MRI - R. Gaudin; T. Delebarre; M. Glatigny; E. Selingue; C. Debacker; L. Ciobanu; D. Boido (GeroScience, 2026)

Epileptiform discharges in neurodegenerative diseases linked to atrophy but not associated with iron depositions - Christian Sandøe Musaeus; Kristian Steen Frederiksen; Gunhild Waldemar; Troels Wesenberg Kjær; Mark B. Vestergaard; Birgitte Bo Andersen; Peter Høgh; Steen Gregers Hasselbalch; Preben Kidmose; Martin Christian Hemmsen; Mike Lind Rank; Henrik Bo Wiberg Larsson; et al. (GeroScience, 2026)
Epileptiform discharges in Alzheimer’s disease (AD) and Lewy body dementia (DLB) may be associated with cognitive decline. Iron accumulation has been implicated in neurodegenerative processes; however, its relationship to epileptiform discharges remains unknown. In addition, the relationship between iron deposition, structural brain changes, and epileptiform discharges remains unclear. The objective is to investigate whether iron deposition and structural brain atrophy are associated with epileptiform discharges in patients with AD, DLB, and healthy controls (HCs). A total of 25 patients with AD, 10 patients with DLB, and 15 HCs were included in the analysis. The participants underwent MRI including quantitative susceptibility mapping (QSM) and structural T1-weighted imaging. We examined the four regions of interest, which are tied to iron deposition and AD pathology. Ear-EEG recordings were used to quantify spike frequency (epileptiform discharges/24 h). No significant group differences were found for susceptibility across regions. Susceptibility was not associated with spike frequency. Patients with AD exhibited significant hippocampal atrophy. Higher hippocampal volume was associated with lower spike rates in adjusted models. Susceptibility and hippocampal volume were associated, and in a multilinear model with age, hippocampal volume accounted for a larger proportion of the explained variance. This study found no evidence linking iron deposition to epileptiform discharges in AD or DLB. Instead, hippocampal atrophy appears more strongly associated with epileptiform discharges, which could indicate that the underlying pathological processes rather than iron are the primary driving factor for epileptiform discharges.

Telomere length dynamics do not predict subclinical atherosclerosis progression over a six-year period - Vicente Andrés; Juan M. Fernández-Alvira; Beatriz Dorado; Ana Guío-Carrión; Ana García-Álvarez; Inés García-Lunar; Antonio Fernández-Ortiz; José J. Fuster; Stuart Pocock; Borja Ibáñez; María A. Blasco; Valentín Fuster (GeroScience, 2026)

Transglutaminase and its role in Alzheimer’s disease: focus on mitochondria, aging, defective mitophagy, synaptic degeneration, and metabolomics - Samson Prince Hiruthyaswamy; Dinesh Rao; Sreeja Balakrishna; Nazarene Marylene Nicky Macarius; Yukesh Kumar Sakthivel; Kanagavel Deepankumar; Murali Vijayan (GeroScience, 2026)

Interaction of moderate-to-vigorous physical activity and brain amyloid accumulation on longitudinal cognitive change - Keitaro Makino; Takashi Kato; Kengo Ito; Osamu Katayama; Ryo Yamaguchi; Hiroyuki Shimada (GeroScience, 2026)

Plasma metabolomic and inflammatory profiles associated with low physical function in heart failure: an integrated cardiac–metabolic–muscular phenotype - Konstantinos Prokopidis; Sima Jalali Farahani; Beyza Gulsah Altinpinar; Omid Khaiyat; Adam Burke; Amy Nortcliffe; Gregory Y. H. Lip; Rajiv Sankaranarayanan; Howbeer Muhamadali; Masoud Isanejad (GeroScience, 2026)

TTV virome marks immune exhaustion, α7nAChR alteration, and mortality in elderly patients with severe COPD - Laura Vitiello; Stefania Proietti; Dolores Limongi; Carla Prezioso; Paola Checconi; Paola Fortugno; Marco Quaranta; Fabrizio Maggi; Guido Antonelli; Stefano Bonassi; Patrizia Russo (GeroScience, 2026)

Genetic associations with longevity in a Calabrian cohort: an exploratory genome-wide study - Livia Beccacece; Paolina Crocco; Benedetta Torbidoni-Baldassari; Stefano Pallotti; Jie Huang; Michaël E. Belloy; Annibale A. Puca; Harold T. Bae; Paola Sebastiani; Giuseppe Passarino; Giuseppina Rose; Serena Dato; et al. (GeroScience, 2026)

Carotid plaque vulnerability and circle of Willis anatomy predict ipsilateral brain infarcts and long-term mortality in carotid endarterectomy patients - Andrea Varga; Milán Vecsey-Nagy; Csongor Péter; Andrea Lehoczki; Péter Banga; Balázs Lengyel; Sarolta Borzsák; Gyopár Bálint; Zoltán Ungvári; Péter Sótonyi (GeroScience, 2026)

Longitudinal analysis of cytokines, chemokines, and inflammatory markers in a middle-aged cohort - Nicole Noren Hooten; Nicolle A. Mode; Ngozi Ezike; Alan B. Zonderman; Michele K. Evans (GeroScience, 2026)
Systemic chronic low-grade inflammation increases with aging and contributes to the risk or progression of a myriad of chronic diseases. Greater midlife inflammation has detrimental effects on future health outcomes. However, few studies have quantified inflammatory markers from midlife longitudinal measurements. Here, we measured cytokines, chemokines, and clinical biomarkers of inflammation at three different time points in a cohort of middle-aged (mean age 48) African American and White men and women. We analyzed longitudinal data for these inflammatory markers examining possible interactions across time, age, race, and sex. We report sex differences in the levels of CXCL10/IP-10, CXCL11/ITAC, and uric acid. Ferritin levels differed by sex and race; the highest levels were in White men and lowest in White women. MCP-1 and WBC count were higher in White participants than African American participants, and uric acid levels were lower for older White participants, but higher for older African American participants. In this longitudinal study, we found that IL-22 levels decreased over time while ferritin levels increased over time. For high sensitivity C-reactive protein (hsCRP), values changed differently over time across sex where men’s values increased and women’s values decreased over time. In addition, IL-10, CXCL11/ITAC, and hsCRP levels decreased over time in White participants, but not for African American participants. These data indicate that cytokine, chemokine, and clinical inflammatory biomarkers vary across time, age, sex, and race in a middle-aged cohort. Understanding inflammation at midlife may provide keys to reducing negative health outcomes later in life.

Molecular predictors of incident frailty: a systematic review and critical appraisal of longitudinal evidence - João Antunes; Rita Ferreira; Lúcio Lara Santos; Daniel Moreira-Gonçalves (GeroScience, 2026)
Frailty is a multisystemic syndrome that significantly compromises quality of life. Current management strategies are largely reactive, often leading to suboptimal mitigation outcomes. Identifying predictors of incident frailty is therefore critical to shift this paradigm. This systematic review conducted in PubMed, Scopus and Web of Science (on 3 October 2023) included 45 longitudinal studies analysing biomarkers in human biological fluids and their associations with widely established frailty assessment tools. A total of 80 candidate biomarkers were identified, 20 of which were investigated in multiple studies. Notably, only one biomarker analysed in multiple studies was found to have broadly similar directionality in adjusted analyses, but overall certainty remains limited. While our findings suggest that some progress has been made towards the discovery of molecular predictors of incident frailty, a reliable biomarker set remains elusive, hindered by several methodological limitations. Nevertheless, frailty assessment has shown tremendous promise in the clinical setting, warranting further efforts to integrate existing tools with biomarkers. This systematic review highlights the untapped potential of biomarker discovery, as well as the current shortcomings in the field of frailty prediction, and offers direction for improving study design and reproducibility in future studies.

Workaholism as a neglected risk factor for unhealthy aging: implications for the Semmelweis–EUniWell Workplace Health Promotion Program - Yura Loscalzo; Marco Giannini; Zoltan Ungvari (GeroScience, 2026)

Skin as a sentinel and modulator of systemic aging: a translational framework for evidence-based gerotherapeutics - Diala Haykal; Frederic Flament (GeroScience, 2026)

Abnormal periodic and aperiodic resting-state electroencephalographic markers in Lewy body and Alzheimer’s diseases with cognitive decline - Matteo Carpi; Antonio Pio Afragola; Mina De Bartolo; Susanna Lopez; Burcu Bölükbaş; Claudio Del Percio; Veronica Henao Isaza; Roberta Lizio; Giuseppe Noce; Lorenc Barjami; Filippo Carducci; Andrea Soricelli; et al. (GeroScience, 2026)
Lewy body disease (LBD) and Alzheimer’s disease (AD) are the most common causes of cognitive decline and dementia and are associated with characteristic alterations in resting-state electroencephalographic (rsEEG) activity. This multicenter exploratory study investigated periodic and aperiodic rsEEG features in patients with cognitive decline due to Lewy body disease (LBCD) and Alzheimer’s disease (ADCD), compared with cognitively unimpaired older adults (Nold), and examined the clinical relevance of these markers in LBCD. A total of 140 LBCD, 135 ADCD, and 118 Nold datasets from the PDWAVES archive underwent spectral parameterization to decompose rsEEG power spectra (1–30 Hz) into periodic peaks and aperiodic background activity. Both clinical groups showed a significant slowing of the individual alpha frequency (IAF), more pronounced in LBCD, along with reduced periodic alpha and beta power reflected in a lower vigilance index. The aperiodic exponent was elevated in both groups, and the aperiodic offset was also higher in LBCD, suggesting steeper spectral profiles consistent with increased inhibitory cortical tone. Within the LBCD group, poorer cognition was associated with higher low-frequency alpha power, whereas better cognition was predicted by higher high-frequency alpha power. A reduced vigilance index was associated with the presence of visual hallucinations, while no associations emerged for other symptoms. These findings suggest that combined periodic and aperiodic rsEEG features may provide relevant markers of altered vigilance regulation in LBCD. Future studies should evaluate whether these EEG markers can inform targeted interventions, such as neuromodulatory or audiovisual stimulation, to stabilize quiet-vigilance states and improve clinical outcomes. Graphical abstract Panel A shows the spectral parameterization of rsEEG activity into periodic and aperiodic components. Panel B summarizes the main group differences in key rsEEG markers across LBCD, ADCD, and Nold participants. Panel C shows the topographical associations between the vigilance index and cognition and visual hallucinations in LBCD; colors reflect the direction and strength of the associations. For the visual hallucinations map, negative log-odds indicate lower odds of hallucinations for higher vigilance index values, whereas positive log-odds indicate higher odds; values around ± 1.5 correspond approximately to odds ratios of 0.22 and 4.5, respectively. Abbreviations: rsEEG, resting-state electroencephalography; LBCD, cognitive decline due to Lewy body disease; ADCD, cognitive decline due to Alzheimer’s disease; Nold, cognitively unimpaired older adults; IAF, individual alpha frequency; MMSE, Mini-Mental State Examination; p , standardized regression coefficient; log-odds, logistic regression coefficient.

Oral health, genetic susceptibility, and risk of dementia: a prospective cohort study of UK Biobank - Yunrui Liu; Xiang Qi; Ruotong Liu; Zhijing Xu; Huabin Luo; Bei Wu (GeroScience, 2026)

Feasibility of home-based, remotely delivered exercise training to improve physical function in older sepsis survivors: a pilot randomized controlled trial - Yi Lin; Rola S. Zeidan; Rezvan Ghaderpanah; Margaret K. Ohama; Min-Han Jung; Naveen Baskaran; Juan Sarmiento Delgado; Stephen D. Anton; Barbara K. Smith; Christiaan Leeuwenburgh; Fang-Chi Hsu; Philip A. Efron; et al. (GeroScience, 2026)
Sepsis survivors frequently experience post-discharge physical function decline and encounter logistical barriers to participation in traditional outpatient rehabilitation. This pilot study examined the feasibility, safety, and preliminary efficacy of a remotely delivered, home-based exercise program on physical function in older sepsis survivors. In this single-blinded, randomized controlled trial (RCT), sepsis survivors aged ≥ 55 years were randomized to (a) 12 weeks of avatar-guided, progressive exercise training group (EX) or (b) a standard care control group (CO). Primary outcomes were feasibility (retention, adherence) and safety (adverse events), whereas secondary outcomes were changes in the 30-s Sit-to-Stand (30SSTS), 4-Stage Balance Test (4SBT), Timed Up-and-Go (TUG) tests, and Eastern Cooperative Oncology Group/Zubrod's (ECOG/Zubrod) performance status score. Twenty-one participants were randomized to either EX ( n = 10, mean age = 69.6 ± 8.5 years, 40% females) or CO ( n = 11, mean age = 72.3 ± 7.9 years, 45% females). Mean retention was 95% and adherence to exercise training was 76%. Thirty-four adverse events (AEs) occurred (EX = 11; CO = 16; consented but not randomized = 7 events), including four serious AEs that were unrelated to the study. The EX group showed trends toward improvements in lower-extremity strength (30SSTS: 1.14 ± 2.91 repetitions, Cohen’s d = 0.393) and balance (4SBT: 5.07 ± 4.75 s, d = 1.07), whereas the CO group showed no change in balance on the 4SBT (0.01 ± 4.38 s, d = 0.003) and trends toward decline in lower-extremity strength on the 30SSTS (− 0.88 ± 0.99 repetitions, d = − 0.883). TUG performance showed modest trends toward reductions in completion time in both groups (EX: − 1.42 ± 6.58 s, d = − 0.216; CO: − 1.27 ± 2.73 s, d = − 0.466). ECOG/Zubrod scores showed a modest trend toward improvement in the EX group subset. This pilot RCT demonstrated that a 12-week, remotely delivered exercise program was safe and feasible for older sepsis survivors and showed preliminary signals of positive change in lower-extremity strength, balance, and functional status, which warrants testing efficacy in an adequately powered Phase IIb RCT. ClinicalTrials.gov NCT05568511.

Impact of an online-guided physical activity intervention on cognition, resting-state brain connectivity, and the gut microbiome in healthy older adults—a randomized controlled trial - Simon J. Schrenk; Corinna Bang; Lena Best; Thomas Dost; Stefano Flor; Christiane Frahm; Christian Gaser; Rami Abou Hamdan; Marco Herbsleb; Christoph Kaleta; Fabian Kattlun; Hans-Josef Müller; et al. (GeroScience, 2026)
Introduction Physical activity may enhance cognition in older adults, yet evidence from randomized controlled trials (RCTs) on mechanistic pathways remains inconclusive. Methods This single-blinded RCT examined the effects of an 8-week, online-guided, multicomponent physical activity intervention on cognitive function, resting-state functional brain connectivity (rsFC), and the gut microbiome in 92 healthy older adults (M age = 66.35). Participants were randomized to a physical activity group performing moderate-to-vigorous-intensity aerobic, coordination, and balance exercises, or to an active control group engaging in progressive muscle relaxation and listening to aging-related podcasts. The primary outcome was change in visual processing speed (items/s) from pre- to post-assessment. Secondary outcomes included changes in additional cognitive measures, rsFC, cardiorespiratory fitness (CRF), and the gut microbiome. Results The primary outcome showed no significant between-group differences. However, exploratory analyses revealed potential improvements in inhibition ( η 2 = 0.061; p = 0.025) and visual memory ( η 2 = 0.047; p = 0.040) in the physical activity group. This group also showed a potential increase in rsFC between visual and dorsal attention networks ( η 2 = 0.101; p = 0.009). Visual memory gains correlated with improvements in rsFC ( p = 0.013). No between-group differences were observed in CRF or gut microbiome composition. Discussion While the primary outcome (visual processing speed) and predefined mechanistic pathways (e.g., gut microbiome composition) remained unaffected, this may partly reflect the sample’s high baseline fitness, which likely limited observable improvements. Exploratory findings suggest potential cognitive and associated rsFC benefits in memory and attention-related networks. The online format enabled a structured, scalable intervention while minimizing potential confounding from social interaction. Trial registration https://drks.de/search/de/trial/DRKS00028022 (date of registration: 14.02.2022).

A new sparse Bayesian quantile neural network-based approach and its application to discover physiological sweet spots in the Canadian Longitudinal Study on Aging - Joosung Min; Olga Vishnyakova; Angela Brooks-Wilson; Lloyd T. Elliott (GeroScience, 2026)

Anti-inflammatory diet and mental health outcomes in an aging population: evidence from a preventive population-based target trial emulation - Belayneh Mengist; Mojtaba Lotfaliany; Julie A. Pasco; Bruno Agustini; Michael Berk; Malcolm Forbes; Wolfgang Marx; Suzanne G. Orchard; Joanne Ryan; Alice J. Owen; Robyn L. Woods; John J. McNeil; et al. (GeroScience, 2026)
Population-based preventive trials are rare in psychiatry, especially in an aging population, and the effects of potentially modifiable lifestyle risk factors such as diet on mental health outcomes are largely unexplored. This study aimed to estimate the effects of an anti-inflammatory diet on mental health outcomes in older adults and the potential effect of lifestyle modification. A preventive population-based target trial was emulated using data from the ASPirin in Reducing Events in the Elderly (ASPREE) study among community-dwelling older adults (≥ 70 years) in Australia. An anti-inflammatory diet was considered as an intervention, with a pro-inflammatory diet as a control. Additional analyses explored an anti-inflammatory lifestyle as an effect modifier and the combination of diet and lifestyle. Depressive symptoms and mental health quality of life were the study outcomes. A target trial protocol was prospectively designed, and a range of potential confounders was balanced using the inverse probability treatment weighting. A total of 10,955 participants (54.3% in the intervention group) were included in the target trial emulation. The risk of depressive symptoms was significantly lower in the intervention group compared to the control (RR, 0.92; 95% CI, 0.87–0.97). The between-group mean difference of mental component score in the intervention group was larger by 0.30 units compared to the control group ( β , 0.30 (0.08–0.52)). When diet and lifestyle were combined, the anti-inflammatory group was associated with a lower risk of depressive symptoms and better mental health quality of life than the pro-inflammatory group (RR, 0.79 (0.70–0.89); β, 0.63 (0.23–1.03)), respectively. An anti-inflammatory diet intervention, especially when combined with an anti-inflammatory lifestyle, is associated with a reduction in depressive symptoms and better mental health quality of life. Graphical Abstract

Identifying a fitness tool in early old-age to predict long-term risk of disability, severe disability, and mortality - Céline Ben Hassen; Aurore Fayosse; Damien Vitiello; Pauline Maillot; Benjamin Landré; Ian Meneghel Danilevicz; Séverine Sabia; Archana Singh-Manoux (GeroScience, 2026)

Speech as a dynamic biomarker of physical aging: a longitudinal study - Eloïse Da Cunha; Raphaël Zory; Frédéric Chorin; Olivier Guérin; Valeria Manera; Auriane Gros (GeroScience, 2026)

Development of 5-year risk prediction models for incident dementia and mortality in a community-dwelling older Japanese population: The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC‐AD) - Xiangyin Meng; Takanori Honda; Tomoyuki Ohara; Yoshihiko Furuta; Mao Shibata; Jun Hata; Yasuyuki Taki; Tatsuya Mikami; Tetsuya Maeda; Kenjiro Ono; Masaru Mimura; Ritsuko Hanajima; et al. (GeroScience, 2026)
Improving cognitively healthy survival is important for achieving healthy aging. Therefore, it would be valuable to estimate the future risk of either incident dementia or death in community-dwelling older adults. This study aimed to develop a set of risk prediction models for either incident dementia or death that can be applied according to data availability across diverse clinical settings, using longitudinal data from community-dwelling older Japanese adults. A total of 8,334 participants aged ≥65 years were prospectively followed up from 2016 to 2023. Logistic regression was used to develop multivariable prediction models. The developed models were translated into simplified scoring systems based on the β coefficients. The discrimination abilities of the models were assessed by C-statistics, and the calibration was assessed by calibration plots. During the follow-up period, 1,151 participants developed either dementia or death. In the multivariable model using potential predictors commonly available in the primary care setting, age, male sex, formal education ≤9 years, diabetes mellitus, use of lipid-lowering agents, leanness, history of stroke, history of heart disease, history of respiratory disease, history of cancer, current smoking, no regular exercise habit, and low frequency of social interactions were selected as predictors. Adding cognitive status, depressive symptoms, apolipoprotein E-ε4 carrier status, and brain MRI markers to the model further enhanced its predictive performance. The developed models and simplified scores showed good discrimination and calibration. Risk stratification with our models may be useful for assessing the risks of incident dementia and death and, consequently, for prolonging cognitively healthy survival.

Aging beyond diagnosis: the MRI brain age gap across disorders - Hamad Yahia Abu Mhanna; Lena K. L. Oestreich; Rajat Vashistha; Yanan Wang; Viktor Vegh (GeroScience, 2026)
The brain age gap (BAG), the difference between magnetic resonance imaging–predicted brain age and chronological age, is a proposed marker of neurobiological aging, yet its transdiagnostic significance remains uncertain. This meta-analysis evaluated BAG in Alzheimer’s disease (AD), mild cognitive impairment (MCI), multiple sclerosis (MS), Parkinson’s disease (PD), schizophrenia (SCZ), stroke, and bipolar disorder (BD) to determine shared and disorder-specific patterns of accelerated brain aging. Sixty-five MRI-based studies were included. For each cohort, BAG was extracted or calculated, and standardized mean differences (Hedges’ g ) were computed between patient and healthy control groups using random-effects models. Subgroup analyses and meta-regressions were conducted to assess the influence of age and disorder characteristics. Publication bias and heterogeneity were evaluated using Egger’s test, I 2 statistics, and trim-and-fill procedures. BAG was significantly elevated across all disorders. The largest effects were observed in MS (mean adjusted BAG = 7.81 years; g = 0.89) and AD (5.57 years; g = 0.66). Meta-analyses of adequately powered disorders showed moderate elevations in SCZ (4.40 years; g = 0.42) and MCI (3.77 years; g = 0.43), while PD showed smaller but significant acceleration (3.52 years; g = 0.37). Descriptively, stroke (2 cohorts; mean adjusted BAG = 4.63 years) and BD (1 cohort; mean adjusted BAG = 4.84 years) also showed elevated BAG, though insufficient study numbers precluded formal meta-analysis for these disorders. BAG was largely independent of chronological age in neurodegenerative disorders but increased with age in SCZ. These findings support BAG as a transdiagnostic indicator of apparent accelerated brain aging in conditions where the meta-analytic evidence base is robust (AD, MCI, MS, PD, SCZ), while stroke and BD remain preliminary owing to limited cohort numbers. The magnitude of BAG varies substantially across conditions, and very high between-study heterogeneity ( I 2 > 90% in most disorders) means pooled effect sizes should be interpreted alongside prediction intervals. Graphical abstract The graphical abstract was created using BioRender. Abu Mhanna, H. (2026) https://BioRender.com/2b8823g .

Intestinal T cells in aging: implications for gut barrier integrity and inflammaging - Christina M. Stevens; Cecilia R. Schaaf; Theodore M. DeConne; Kylie Kavanagh (GeroScience, 2026)
Aging is accompanied by a progressive decline in intestinal barrier integrity, resulting in increased permeability to luminal microbes and microbial products and contributing to chronic low-grade inflammation (“inflammaging”). While epithelial and microbial changes have been extensively studied, the role of intestinal T cells as active regulators of barrier homeostasis during aging remains underappreciated. The gut harbors the largest population of T cells in the body, including diverse conventional and unconventional subsets that directly shape epithelial differentiation, mucus production, antimicrobial defense, and tight junction organization through cytokine-mediated signaling. In this review, we synthesize current evidence linking age-related alterations in intestinal T-cell composition and function to epithelial barrier decline. We focus on key T-cell subsets including Th1, Th17, Th22, regulatory T cells, γδ T cells, mucosal-associated invariant T (MAIT) cells, and intraepithelial lymphocytes, and discuss how aging-associated shifts in their cytokine profiles may disrupt the balance between barrier maintenance, repair, and inflammation. We further examine how T-cell dysfunctions characteristic of aging, including senescent-like and exhausted phenotypes, may exacerbate epithelial injury, microbial translocation, and systemic immune activation. Insights from age-accelerated conditions such as HIV/SIV infection and inflammatory bowel disease are used to inform emerging models of T-cell-driven barrier decline in older adults. Graphical abstract

Neuromuscular control mechanism during posture-cognition dual task in mild cognitive impairment: a concurrent fNIRS-sEMG-COP study - Ruochen Fu; Jinjin Ma; Yao Zu; Yingying Fang; Yan Li; Arnold Y. L. Wong; Xue Cheng; Yan Leng; Jiajia Yang; Chuhuai Wang; Qiuhua Yu (GeroScience, 2026)

Risk of falls and syncope across frailty levels in hypertensive older adults: a longitudinal study - Giulia Rivasi; Marco Capacci; Alessandro Mengozzi; Greta Ceccarelli; Michele Vinci; Vincenzo Giosuè Giambusso; Giuseppe D’Ambrosio; Virginia Gori; Alessandra Liccardo; Maria Francesca Bisignano; Noemi Pardini; Valeria Calsolaro; et al. (GeroScience, 2026)
In older hypertensive adults, frailty may increase the risk of adverse events associated with blood pressure lowering, including syncope and falls. However, the degree of frailty at which these risks become clinically significant remains uncertain. The study aimed to compare clinical characteristics and the incidence of falls and syncope across different frailty levels among older hypertensive adults. We analyzed data from the longitudinal HYPER-FRAIL study, involving hypertensive outpatients ≥ 75 years undergoing comprehensive geriatric assessment. Frailty was defined according to the Clinical Frailty Scale (CFS). The incidence of a composite outcome of falls and syncope was compared between fit (CFS < 4), mildly frail (CFS = 4–5) and frailer participants (CFS ≥ 6). Among 194 participants (mean age 81 years, 45% male), frailty was absent in 53.6%, mild in 31.4% and moderate-to-severe in 14.9%. A history of falls was more commonly reported among frailer (48.3%) and mildly frail patients (45.9%) compared to fit individuals (21.2%; p < 0.001 for both frailty groups vs fit). Over a median 12-month follow-up, the composite outcome occurred in 13.5% of fit, 31.1% of mildly frail and 31% of frailer participants ( p = 0.012 for mild vs absent frailty). Kaplan-Meier curves showed a greater risk in mild frailty ( p = 0.003 vs fit participants), with no differences compared to the moderate-to-severe frailty group ( p = 0.599). Mild frailty predicted syncope and falls independently of age, prior falls, orthostatic hypotension and depression, but not dementia. Mild frailty (i.e. CFS = 4–5) is common among hypertensive older adults and confers a risk of falls and syncope similar to that of moderate-to-severe frailty.

Brain senescence drives sarcopenia-like transcriptomic remodeling in skeletal muscle - Shoba Ekambaram; Roland Patai; Rafal Gulej; Tamas Kiss; Siva Sai Chandragiri; Dorina Nagy; Kiana Vali Kordestan; Tamas Lakat; Stefano Tarantini; Peter Mukli; Andriy Yabluchanskiy; Anna Ungvari; et al. (GeroScience, 2026)
Aging is accompanied by a progressive decline in skeletal muscle mass and function, culminating in sarcopenia, a major contributor to frailty, disability, and mortality in older adults. While skeletal muscle aging has traditionally been attributed to cell-autonomous and local tissue mechanisms, increasing evidence suggests that systemic, cell non-autonomous processes play a central role in coordinating aging across organs. The brain, particularly the hypothalamus, has emerged as a key regulator of organismal aging, yet its contribution to skeletal muscle aging remains poorly defined. Here, we tested the hypothesis that senescence confined to the brain is sufficient to induce aging-like molecular remodeling in skeletal muscle via systemic mechanisms. To model brain senescence, young mice were subjected to fractionated whole-brain irradiation (WBI), a well-established approach that induces widespread cellular senescence and neuroinflammation in the brain while sparing peripheral tissues. Two months after WBI, transcriptomic profiling of quadriceps muscle was performed and compared with that of naturally aged mice. WBI-induced robust gene expression changes in skeletal muscle that closely mirrored those observed during chronological aging. Pathway-level analyses revealed marked downregulation of mitochondrial organization, respiratory chain assembly, and metabolic processes, alongside enrichment of remodeling- and stress-associated pathways. Upstream regulator analysis identified FOXO1, FOXO3, KLF15, and STAT3, which are key drivers of muscle catabolism and atrophy, as central mediators of the observed transcriptional program. Semantic similarity analysis further demonstrated a high concordance between WBI-induced and aging-associated biological processes. Collectively, these findings demonstrate that brain senescence is sufficient to drive sarcopenia-like transcriptomic remodeling in skeletal muscle, implicating central nervous system aging as an upstream regulator of peripheral muscle decline. This brain–muscle aging axis may contribute to frailty in individuals with accelerated brain aging and in cancer survivors exposed to cranial irradiation, highlighting brain senescence as a potential therapeutic target to mitigate systemic aging and skeletal muscle dysfunction.

Multiorgan transcriptomics and circulating extracellular vesicle profiling reveal age-dependent systemic vulnerability to isoflurane anesthesia and surgery - Balaji Krishnamachary; Hangnoh Lee; Zihui Wang; Wendy W. Yang; Hui Li; Zhuofan Lei; Junfang Wu; Yun Li (GeroScience, 2026)

Group training classes for dogs with canine cognitive dysfunction: effects on sleep, activity, and caregiver burden - Tracey L. Taylor; Jonathan Tuke; Eduardo J. Fernandez; Susan J. Hazel (GeroScience, 2026)
Canine Cognitive Dysfunction (CCD) is a progressive neurodegenerative condition of ageing dogs, sharing pathological and clinical features with Alzheimer’s disease. Despite the growing prevalence of CCD, non-pharmacological interventions for affected companion animals remain underexplored. This study evaluated the effects of structured group training classes on signs of CCD, sleep, daily activity, and caregiver burden. Forty-two dogs (≥ 8 years) with mild to moderate CCD were enrolled in either a scent-based (S; n = 21) or physical structured training (PST; n = 21) program. Each dog completed five consecutive weekly sessions, with outcomes assessed through the Canine Dementia Scale (CADES), accelerometry (FitBark), and validated caregiver burden measures at baseline, treatment, and post-treatment. CCD scores remained stable across all phases, suggesting no measurable cognitive changes. However, a significant interaction between training type and treatment phase was observed for sleep: dogs in the PST group demonstrated improved Fitbark sleep scores over time, while those in the S group declined. Daily activity followed expected bimodal patterns, with scent-trained dogs exhibiting reductions in morning and evening activity peaks. Caregiver burden decreased significantly across time in both groups, and caregivers reported high satisfaction with class participation, citing enhanced confidence and social support. These findings indicate that while structured training did not alter CCD severity scores, PST was associated with a small improvement in sleep, S was associated with reduced activity, and participation in both classes was linked to reduced caregiver burden. Further research is needed to confirm these changes and determine their effect on dog and human wellbeing. Group training classes may represent an accessible, welfare-focused intervention for managing CCD in companion dogs.

Bench to bedside: is rapamycin headed for the docTOR? - Dudley W. Lamming (GeroScience, 2026)
Almost a century ago, calorie restriction (CR) was identified as a robust intervention for extending lifespan and healthspan, a discovery that captured the imagination of both scientists and the public. If the powerful mechanisms engaged by CR can be uncovered and harnessed through a pill, humans might be able to live longer and healthier lives. Here, we will discuss the evolution of rapamycin, an inhibitor of the mTOR (mechanistic Target Of Rapamycin) protein kinase, from an immunosuppressant to the most reproducible pharmacological geroprotector in geroscience. This is a rapidly evolving field, with the number of basic science studies, clinical trials, and off-label use of mTOR inhibitors by the general public expanding quickly. We review findings in model organisms that have revealed potent benefits of rapamycin not only for longevity but for the function of multiple organ systems and on the hallmarks of aging. We review completed and ongoing clinical trials of rapamycin and analogs for diseases of aging in humans, and discuss the challenges and side-effects of rapamycin that may limit its translation from the laboratory to the clinic. While the jury is still out, we conclude that rapamycin—or molecules that similarly act to inhibit mTOR—may yet realize the century-old dream of extending healthspan and lifespan with a small molecule.

Associations of antihypertensive, antidiabetic, and antihyperlipidemic medications with cognitive performance in an Asian population - Lam-Quang Nguyen; Xiangyuan Huang; Wei Ying Tan; Baizura Binte Abu Bakar; Jiannan Huang; Narayanaswamy Venketasubramanian; Saima Hilal (GeroScience, 2026)

Regulation of survival, growth, and metabolism by neuronal mTOR - Stacy A. Hussong; Raquel Burbank Roberts; Jonathan J. Halloran; Stephen F. Hernandez; Candice E. Van Skike; Angela O. Dorigatti; Nicholas DeRosa; Michael E. Walsh; Vanessa Y. Soto; Daniel A. Pulliam; Holly Van Remmen; Steven N. Austad; et al. (GeroScience, 2026)

Tissue-specific autoantibody signatures reveal immune alterations undetected by routine serology in long COVID - Ottó Tatai; Szilárd Nagy; Trai Huynh Thanh Nguyen; Beáta Lajszné Tóth; Péter Antal-Szalmás; Ivetta Mányiné Siket; Tamás Bence Pintér; Miklós Fagyas; Zoltán Papp; Péter Csécsei; Andrea Lehoczki; Ágnes Szappanos; et al. (GeroScience, 2026)
Long COVID affects a substantial proportion of individuals recovering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, yet its underlying pathophysiology remains poorly understood. Although autoimmunity is increasingly implicated in disease pathogenesis, routine diagnostics frequently fail to detect relevant immune dysregulation. To address this gap, we analyzed sera from Long COVID patients ( n = 114) and pre-pandemic controls ( n = 36) using tissue-based Western blotting targeting cardiac, pulmonary, and vascular antigens, alongside standard ANA HEp-2 testing. Longitudinal samples were additionally evaluated to assess autoantibody dynamics. Autoantibodies were detected in the majority of patients (83% vs. 53% in controls; p < 0.05), showing a dominant cardiovascular pattern. While cardiac (54% vs. 33% in controls; p = 0.16) and pulmonary (34% vs. 30% in controls; p = 0.50) prevalences did not reach significance, vascular autoreactivity was markedly elevated in Long COVID (34% vs. 8% in controls; p < 0.05). Responses exhibited broad polyreactivity and IgM dominance, with longitudinal follow-up showing persistent IgM and the emergence of additional isotypes. Clinically, cardiac autoreactivity was associated with hypertension and headache, while the overall autoreactivity correlated with anosmia and ageusia. In contrast, ANA HEp-2 testing showed no discriminatory value or clinical associations. Distinct autoreactivity patterns further aligned with female sex and clinical parameters (C-reactive protein, creatinine, troponin, body mass index). Together, these findings reveal a high burden of tissue-specific autoantibodies invisible to standard ANA screening. This persistent, IgM-skewed profile suggests ongoing immune dysregulation and may reflect a previously underrecognized component of the immunological response in long COVID, highlighting the need for targeted immunodiagnostic approaches beyond routine serology.

Quantification and visualization of 3D facial aging in individuals of European ancestry - Yi Fan; Harold Matthews; Chenda Meng; Nina Claessens; Seth M. Weinberg; Mary L. Marazita; Susan Walsh; Mark D. Shriver; Anthony Penington; Marie A. Cornelis; Paolo M. Cattaneo; Tianmin Xu; et al. (GeroScience, 2026)
Facial features undergo continuous transformations across the lifespan. This study quantified and visualized the effects of aging on facial morphology in individuals of European ancestry. Three-dimensional facial photographs of 4,038 individuals (1,455 males and 2,583 females), aged 5 to 85 years and of European descent, were analyzed. Morphological changes in the face were modeled using kernel linear regression, with a focus on age-related changes. Age- and sex-specific expected facial shapes were generated for individuals aged 10 to 60 years in 5-year intervals. Changes in the face were analyzed in the sagittal, vertical, and horizontal directions, with linear distances and angular variations in the upper, middle, and lower regions of the face evaluated. Our results show that facial shape changes decelerate progressively after the age of 25 for both males and females. Facial aging is characterized by the loss of fullness in the forehead, sunken temples, formation of eye bags, deepening nasolabial folds, cheek hollowness and thinning, lengthening, and retrusion of the lips. Notable changes begin in the 30s, with the most pronounced alterations occurring in the 40s and 50s, intensifying in the 50s and 60s. Although the overall aging trajectory is similar in males and females, the magnitude and rate of change demonstrate sexual dimorphism. This study provides comprehensive insights into age-related facial morphological changes in healthy individuals of European ancestry using 3D photogrammetric analysis. These findings have important implications for clinical disciplines such as dentistry, plastic and maxillofacial surgery, and forensic medicine.