GeroScience最新文献

{"title":"Novel evidence of age-related cortical and subcortical constraints in cross-education.","authors":"Ummatul Siddique,Ashlyn K Frazer,Jamie Tallent,Oliver Hayman,Justin Andrushko,Matt S Stock,Joshua Carr,Yonas Akalu,Mohamad Rostami,Sergio Uribe,Simon Walker,Dawson J Kidgell","doi":"10.1007/s11357-025-01886-1","DOIUrl":"https://doi.org/10.1007/s11357-025-01886-1","url":null,"abstract":"Cross-education (CE), the phenomenon whereby unilateral strength training induces neuromuscular adaptations in the contralateral limb, is underpinned by distributed cortical and subcortical plasticity. This study evaluated acute neural responses to a single bout of metronome-paced unilateral strength training in younger (n = 17; 27 ± 6 years) and older adults (n = 18; 67 ± 5 years). Neurophysiological assessments included corticospinal excitability and inhibition via transcranial magnetic stimulation (TMS), intracortical inhibition through short-interval intracortical inhibition (SICI), and reticulospinal drive using the StartReact paradigm. Following training, younger adults exhibited a significant reduction in the responsiveness of intracortical inhibitory interneurons, reflected as a release of SICI (pre: 58.05, 95% CI 48.83-67.27; post: 68.88, 95% CI 59.69-78.06; p < 0.01), consistent with diminished GABA-A -mediated synaptic efficacy. In contrast, older adults showed no changes (pre: 65.73, 98% CI 57.00-74.46; post: 60.71, 95% CI 52.03-69.39; p = 0.13), indicating no significant modulation of GABA-A-mediated inhibitory circuits with ageing. No changes in corticospinal excitability were observed in either group. StartReact responses remained stable across timepoints, implying insufficient acute engagement of the reticulospinal tract. Notably, younger adults exhibited a decline in rate of force development (RFD; pre: 912.70, 95% CI 821.97-1003.44 N/s; post: 791.02, 95% CI 700.29-881.75 N/s; p < 0.05), potentially reflecting central fatigue, while older adults displayed no significant change. These findings reveal age-dependent asymmetries in the neural mechanisms underpinning CE, with older adults exhibiting a lack of adaptive modulation in intracortical and subcortical systems. The absence of reticulospinal adaptation underscores the need for sustained or higher-intensity training stimuli to elicit subcortical plasticity. These results inform the development of targeted, age-sensitive neuromuscular rehabilitation strategies.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"40 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nα-p-tosyl-L-lysine chloromethyl ketone and Nα-p-tosyl-L-phenylalanine chloromethyl ketone are potent inhibitors of β-amyloid-induced lamin fragmentation.","authors":"Md Selim Hossain,Vijay Sankar Ramasamy,Md Aminul Haque,Il-Seon Park","doi":"10.1007/s11357-025-01975-1","DOIUrl":"https://doi.org/10.1007/s11357-025-01975-1","url":null,"abstract":"Cellular toxicity induced by β-Amyloid (Aβ) peptide involves lamin A and lamin B fragmentation (LF),and inhibiting LF mitigates cytotoxicity; therefore, we aimed to identify novel inhibitors of Aβ-induced LF. We identified Nα-p-tosyl-L-lysine chloromethyl ketone (TLCK) and Nα-p-tosyl-L-phenylalanine chloromethyl ketone (TPCK) as inhibitors that reduce Aβ42-induced LF, alter nuclear morphology, and activate apoptotic caspases in Aβ42-treated cells. TLCK demonstrated a suppressive effect on Aβ42-induced cell death, whereas TPCK, which is inherently cytotoxic, did not. Both TLCK and TPCK decreased the activation and activity of cathepsin L (CL) which known to be implicated in catalyzing Aβ42-induced LF. TLCK and TPCK have a suppressive effect on Aβ42-induced LF in which CL is implicated. Our findings will contribute to the further investigation of Aβ-related pathology and cell death induced by other agents inhibited by TLCK and TPCK. While our findings highlight potential mechanisms underlying AD-related pathology in HeLa and SH-SY5Y cells but future validation in primary neurons, astrocytes, or animal models will be necessary to confirm these observations.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"73 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuromechanistic causes of timber falls in older adults with mild cognitive impairment: Is response initiation or motor execution the problem?","authors":"Jessica Pitts,Shuaijie Wang,Tanvi Bhatt","doi":"10.1007/s11357-025-01910-4","DOIUrl":"https://doi.org/10.1007/s11357-025-01910-4","url":null,"abstract":"Older adults with mild cognitive impairment (OAwMCI) show reactive balance deficits compared to cognitively intact older adults (CIOA), which could increase the likelihood of 'Timber' falls (i.e., backward falls caused by extremely delayed reactive stepping). This study investigated potential neuromechanistic causes of Timber falls in OAwMCI, including delayed muscle onset latencies and/or altered muscle synergies during reactive stepping. 36 OAwMCI, 38 CIOA, and 20 young adults were exposed to a large anterior stance perturbation, with electromyography collected from the biceps femoris (BF), vastus lateralis (VL), medial gastrocnemius (MG), and tibialis anterior (TA). Timber falls were identified by falling (> 30% weight in harness) without initiating stepping within 430 ms (perturbation duration). Timber falls only occurred in OAwMCI, who were subcategorized into MCI: Timber (36%) or MCI: Step (intact stepping, 64%). MCI: Timber had higher fall rate, lower reactive stability, shorter step length, and longer step initiation time compared to groups with intact stepping (p < 0.05), and delayed onsets of stepping limb muscles and the stance limb MG (p ≤ 0.03). MCI: Timber also showed many structural differences in muscle synergies (M1-6), such as recruiting a unique synergy (M4) which might affect coordination of the stepping limb MG, and failing to recruit M6, which might be involved in taking a long recovery step (stepping limb VL). These results suggest that reactive balance deficits in OAwMCI may be related to problems with both initiating and executing reactive stepping, possibly due to neural pathology and sensorimotor processing deficits which delay response initiation and/or affect motor command execution.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"42 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frailty elements, direct oral anticoagulants and mortality risk in atrial fibrillation patients aged ≥ 80 or ≥ 90 years from the nationwide Italian START registry: a propensity score matching analysis.","authors":"Danilo Menichelli,Emilia Antonucci,Daniela Poli,Francesco Baratta,Angela Sciacqua,Giuseppe Armentaro,Gianluca Gazzaniga,Federica Moscucci,Gualtiero Palareti,Alessio Farcomeni,Evaristo Ettorre,Giovambattista Desideri,Francesco Violi,Pasquale Pignatelli,Daniele Pastori, ","doi":"10.1007/s11357-025-01936-8","DOIUrl":"https://doi.org/10.1007/s11357-025-01936-8","url":null,"abstract":"This study aims to investigate the use of direct oral anticoagulants (DOACs) in elderly frail patients with atrial fibrillation (AF). In 4244 patients aged ≥ 80 years and 533 aged ≥ 90 years from the nationwide START registry, we examined factors associated with DOACs use (vs warfarin) and its association with all-cause and cardiovascular (CV) death, CV events (CVEs) and bleeding. Propensity score-matching (PSM) analysis was also performed. Mean age was 84.8 years, 54.9% were women and 64% received DOACs. Frailty elements as tendency to falls (odds ratio [OR] 0.66, p = 0.030), living alone (OR 0.74, p = 0.027) and lack of familial/social support (OR 0.74, p < 0.001) were inversely associated with DOACs use, while wheelchair use was directly associated (OR 1.57, p = 0.014). During a mean of 686 ± 538 days follow-up, 492 all-cause deaths, 110 CV deaths, 548 CVEs and 221 bleedings occurred. Multivariable Cox regression and Fine-Gray analyses showed that DOAC use inversely associated with all-cause mortality (hazard ratio [HR] 0.35, p < 0.001), CV death (subdistribution HR [sHR] 0.43, p < 0.001), CVEs (sHR 0.46, p < 0.001) but not with bleeding. These associations were confirmed after PSM and persisted between sexes, in patients with Charlson Comorbidities Index > 5 or aged ≥ 90 years. At 24 months, the number needed to treat (NNT) for all-cause, CV death and CVEs were 11.0, 40.2 and 13.4. In patients aged ≥ 90 years, NNTs were 4.2, 4.5 and 12.0. In very elderly AF patients, DOACs prescription is influenced by frailty elements. DOACs inversely associated with mortality and CVEs risk independently from age, sex and comorbidities burden.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"101 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methylation patterns associated with TTV load in geriatric hospitalized patients: an exploratory functional analysis.","authors":"Carlo Fortunato,Pietro Giorgio Spezia,Federica Novazzi,Gretta Veronica Badillo Pazmay,Laura Cianfruglia,Francesca Drago Ferrante,Davide Gentilini,Luciano Calzari,Paolo Antonio Grossi,Nicasio Mancini,Luigi Rosa,Mirko Di Rosa,Anna Rita Bonfigli,Roberta Galeazzi,Antonio Cherubini,Leonardo Biscetti,Riccardo Sarzani,Fabrizia Lattanzio,Maurizio Cardelli,Fabiola Olivieri,Marco Malavolta,Francesco Piacenza,Fabrizio Maggi,Robertina Giacconi","doi":"10.1007/s11357-025-01938-6","DOIUrl":"https://doi.org/10.1007/s11357-025-01938-6","url":null,"abstract":"Torque Teno Virus (TTV) is a widespread commensal virus within the human virome, characterized by a high prevalence in human population and an unclear pathogenic role. Over the past three decades, TTV has garnered increasing attention due to its ability to establish lifelong chronic viremia, which intriguingly fluctuates among individuals in relation to immune competence status, with a typical peak after an organ transplantation, followed by a plateau and a slow decrease. The regulatory mechanisms underlying TTV infection remain elusive, and factors influencing its interactions with the immune system have yet to be identified. To explore this complex interplay, we analyzed DNA methylation patterns associated with TTV load in older adult hospitalized patients (mean age: 83.15 ± 7.49) from the PROMOTERA cohort. In this study, we present for the first time the identification of differentially methylated probes (DMPs) correlated to TTV load in our cohort. The statistically significant DMPs were located in genes involved in immune regulation and lipid metabolism. To further characterize these findings, we performed an exploratory enrichment analysis by applying several p-value thresholds, which yielded multiple gene lists derived from the sets of significant probes. Genes associated with this epigenetic signature were found to enrich functional pathways related to immune activation, leukocyte differentiation, and cytokine production, while additional significantly enriched gene sets were involved in cell-cell adhesion and cell migration processes. Since our analysis followed an exploratory approach, these results should be interpreted as hypothesis-generating and warrant further investigation.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"7 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative evaluation of relative fat mass and body mass index in predicting cardiometabolic multimorbidity in older adults: results from the English Longitudinal Study of Ageing.","authors":"Setor K Kunutsor,Sae Young Jae,Richard S Dey,Jari A Laukkanen","doi":"10.1007/s11357-025-01954-6","DOIUrl":"https://doi.org/10.1007/s11357-025-01954-6","url":null,"abstract":"Relative fat mass (RFM) is a more accurate measure of body fat percentage than body mass index (BMI). However, its association with cardiometabolic multimorbidity (CMM) and its predictive value have not been examined. This study evaluated and compared the associations and predictive utility of RFM and BMI for CMM. We analyzed data from 3,348 adults (mean age 64 years; 45.1% male) in the English Longitudinal Study of Ageing who were free of hypertension, coronary heart disease, diabetes, and stroke at wave 4 (2008-2009). RFM was derived from height and waist circumference. CMM was defined at wave 10 (2021-2023) as the presence of two or more of hypertension, cardiovascular disease, diabetes, or stroke. Odds ratios (ORs) with 95% confidence intervals (CIs) and measures of discrimination were estimated. Over 12-15 years of follow-up, 197 participants developed CMM. Restricted cubic spline models showed linear dose-response relationships for both RFM and BMI (p for nonlinearity > .05). Higher RFM was strongly associated with CMM (per 1-SD increase: OR 1.66, 95% CI 1.29-2.15; top vs bottom tertile: OR 2.70, 95% CI 1.46-4.99). Associations for BMI were weaker (per 1-SD increase: OR 1.28, 95% CI 1.12-1.47; top vs bottom tertile: OR 1.88, 95% CI 1.24-2.85). Adding RFM to a conventional risk model modestly increased discrimination (ΔC-index = 0.0088, p = .29) and significantly improved model fit (-2 log likelihood, p < .001). Corresponding values for BMI were ΔC-index = 0.0049 (p = .46) and -2 log likelihood (p < .001). The C-index gain from RFM was 0.0039 greater than BMI (p = .39). In an older UK population, RFM was a stronger indicator and predictor of CMM risk than BMI.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"69 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of chronic pain and analgesic use with the risks of Parkinson's and Alzheimer's disease.","authors":"Fatemeh Vazirian,Jing Tian,Jane Alty,Dawn Aitken,Michele L Callisaya,Anna King,James C Vickers,Flavia Cicuttini,Graeme Jones,Feng Pan","doi":"10.1007/s11357-025-01932-y","DOIUrl":"https://doi.org/10.1007/s11357-025-01932-y","url":null,"abstract":"Chronic pain and analgesic use are linked to increased Parkinson's disease (PD) and dementia risk, but the effects of each individually and when both are present remain unclear. This study examined whether chronic pain and analgesic use, separately and together, are associated with the incident risk of these conditions. A total of 355,709 participants (mean age 56.51, 48.4% male) free of parkinsonism and dementia at baseline were included. Chronic musculoskeletal pain lasting ≥ 3 months and regular use of analgesics, including paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and antidepressants, were recorded. Incidence of PD, Alzheimer's disease (AD), all-cause parkinsonism, and all-cause dementia was recorded. Cox regression assessed associations with covariate adjustments. During a 13-year follow-up, 2035 individuals developed PD, 2052 developed AD, 2281 developed all-cause parkinsonism, and 4778 developed all-cause dementia. Compared to participants without chronic pain and analgesic use, those with chronic pain, those using analgesics, and those with both had higher risks of developing PD and AD. In the fully adjusted model, chronic pain showed hazard ratios (HRs) ranging from 1.16 to 1.22 for PD and 1.18 to 1.24 for AD. Among analgesics, only antidepressants increased PD risk (HR 1.77, 95% CI 1.37-2.29), while HRs for AD ranged from 1.22 to 1.57. Those with chronic pain who regularly used analgesics had a higher risk, with HRs ranging from 1.23 to 1.98 for PD and 1.44 to 2.19 for AD. Similar patterns emerged for all-cause parkinsonism and all-cause dementia. Chronic pain and analgesic use are associated with developing parkinsonism and dementia, with an additive effect in individuals with chronic pain who regularly use analgesics.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"134 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age and associated hypertension impair hippocampal circuitry function and memory.","authors":"Marcia H Ratner,Kayla M Nist,Richard D Wainford,David H Farb","doi":"10.1007/s11357-025-01831-2","DOIUrl":"https://doi.org/10.1007/s11357-025-01831-2","url":null,"abstract":"Chronic hypertension with aging induces significant alterations in the structure and function of brain parenchyma and memory dysfunction. While therapeutic control of hypertension reduces risk, the functional changes in neural circuitry that underlie memory deficits are unknown. Identifying possible early onset changes in the hippocampal trisynaptic circuit (HTC) may reveal opportunities for therapeutic intervention. A large-scale clinical study revealed a direct relationship between reduced prospective memory score and reduced hippocampal functional connectivity in subjects with a history of chronic hypertension. Here, we report a potential mechanistic linkage between hypertension/aging and hippocampal neural circuitry dysfunction. We used chronically implanted multi-electrode silicon probes in awake freely behaving rats to monitor synchronous high frequency oscillations (at 140-200 Hz or the \"ripple band\") in the HTC CA1 subregion. This hippocampal subregion is known to participate in memory consolidation, in part via HTC ripples. The nootropic drug, α5IA, that inhibits α5GABA-A receptors, was administered orally, under conditions for target engagement, and ripple amplitude measured within subject in awake resting Sprague-Dawley (SD) rats. Significant HTC and memory dysfunction was observed in aged-hypertensive SD rats. The results reveal an hypertension/age-associated anomaly in ripple band activity in SD males, characterized by reductions in mean peak ripple amplitude and in the ability of α5IA to potentiate peak ripple amplitude, without effect upon ripple frequency or duration. Thus, the population of large peak amplitude sharp wave ripples is reduced and becomes insensitive to potentiation by α5IA. Having identified a specific change in peak ripple amplitude that is resistant to potentiation by α5IA, a nootropic probe-drug, this finding could lead to nuanced circuitry level approach for the treatment of memory dysfunction with aging and hypertension.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"54 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eye-tracking-based tablet application for enhanced cognitive assessment: a clinical trial for software as a medical device (SaMD).","authors":"Yoichi Takami,Tetsuro Miki,Yasushi Takeya,Hiromi Rakugi,Ryuichi Morishita,Shuko Takeda","doi":"10.1007/s11357-025-01941-x","DOIUrl":"https://doi.org/10.1007/s11357-025-01941-x","url":null,"abstract":"Efficient screening tools for cognitive decline and dementia are in high demand. We previously reported on a novel cognitive assessment tool using eye-tracking technology and its utility in dementia screening. In this study, we developed a tablet version of the eye-tracking-based cognitive assessment (ETCA) app and conducted a clinical trial to verify its clinical utility as software as a medical device (SaMD). Participants with and without dementia were enrolled between December 1, 2020, and July 31, 2021. They used the ETCA app and completed the most widely applied screening test, the Mini-Mental State Examination (MMSE), on the same day. The primary outcome was the correlation between the ETCA and MMSE scores. The key secondary outcomes were the administration time for the ETCA, questionnaire-based assessments of test-related burdens, and correlations of the subscores. Performance for detecting dementia was evaluated exploratorily. Analyses of the full analysis set population revealed a strong positive correlation in total scores between the tests (r = 0.831; 95% CI, 0.743-0.891; p < 0.0001). The median ETCA administration time was 254.0 s, and more than 70% of participants reported experiencing less or a similar test-related burden with the ECTA app, compared to the MMSE. Significant correlations were observed for all subscores. The ETCA achieved an area under the curve of 0.864 in detecting participants with dementia. These results verified the clinical utility of the tablet-based ETCA app as a rapid cognitive assessment tool. Based on the results, the ETCA app has obtained regulatory approval as SaMD.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"38 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of aging on post-translational modifications of wild-type human SOD1 and the A5V ALS mutant.","authors":"Gabriel Freitas de Souza, Rayne Stfhany Silva Magalhães, José Raphael Monteiro-Neto, Michele Martins, Cristian Follmer, Magno Junqueira, Elis Cristina Araujo Eleutherio","doi":"10.1007/s11357-025-01934-w","DOIUrl":"https://doi.org/10.1007/s11357-025-01934-w","url":null,"abstract":"<p><p>Cu/Zn superoxide dismutase 1 (SOD1) is essential for maintaining neural health. Its functions include modulating metabolism, maintaining redox balance, regulating transcription, besides eliminating superoxide radicals, which are achieved through various post-translational modifications (PTMs). Consequently, unusual PTMs in SOD1 can impair its functionality and stability, leading to the accumulation of misfolded SOD1 and the increase of oxidative stress markers, hallmarks of Amyotrophic Lateral Sclerosis (ALS). Although SOD1 has been extensively studied, especially regarding its role in ALS, relatively little is known about how aging and mutations affect SOD1 PTMs. This study aimed to evaluate the effect of oxidative stress induced by chronological aging on PTMs of human SOD1: wild-type (WT) and A5V SOD1, a severe ALS-related mutant. To do this, both hSOD1 forms were expressed in Saccharomyces cerevisiae lacking the SOD1 gene, and then purified from extracts of stressed and non-stressed cells. PTMs were analyzed using mass spectrometry, observing the modification of WT and mutant human SOD1 in both conditions. We observed changes in the levels of damage, including oxidation, formylation, and carboxylation, such as oxidized tryptophan 33, associated with prion-like propagation of SOD1 misfolding. Increased levels of this PTM appeared in WT SOD1 after aging and in A5V SOD1. Acetylation and succinylation were also found on lysines. Some of these modifications already have described functions in the literature, while others still lack a defined role. Interestingly, the levels of these physiological PTMs differed between WT and mutant SOD1, providing important information for elucidating the molecular mechanisms of ALS involving SOD1.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}