Olfactory impairment is common in older age and is a known early feature of several dementia diseases. Blood-based biomarkers of Alzheimer's disease (AD) now offer a scalable method for detecting pathophysiological mechanisms related to olfactory decline in the general population. However, few studies have examined how these biomarkers relate to long-term olfactory trajectories. Most existing work has been limited to cross-sectional settings. In this population-based study, we used biomarker data collected at baseline and followed participants for up to 15 years, enabling us to test whether early biological changes are temporally linked to subsequent olfactory decline. Data came from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study with baseline assessments from March 21, 2001, through August 30, 2004. We included participants without prevalent neurodegenerative diseases who completed olfactory assessment at baseline. The 15-year follow-up was finished in December 2019. Data were analysed from December 2023 to April 2024. Serum-derived biomarkers of tau phosphorylated at threonine 217 (p-tau217) and at theorine181 (p-tau181), total tau (t-tau), amyloid-β ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were obtained at baseline. Linear mixed models examined associations between biomarker quartiles and Sniffin' Sticks odor identification performance over 15 years, adjusting for demographics, health conditions, and semantic knowledge. We included 1868 participants (mean [SD] age 71.3 [9.9] years; 1122 females [60.1%]). In fully adjusted models, higher quartiles of p-tau217, p-tau181, NfL, and GFAP, and lower quartiles of Aβ42/Aβ40, were associated with steeper olfactory decline, with the steepest decline among participants in the highest quartiles (β for Q4 vs Q1: -0.20 [95% CI: -0.26 to -0.15] for p-tau217; -0.19 [95% CI: -0.25 to -0.13] for p-tau181; -0.23 [95% CI: -0.29 to -0.17] for NfL; β = -0.17 [95% CI: -0.23 to -0.11] for GFAP. Participants in the lowest Aβ42/Aβ40 quartile declined more steeply than those in the highest (β = -0.09 [95% CI: -0.14 to -0.04]). Associations appeared stronger in the oldest participants, in APOE ε4 carriers for p-tau181, in non-carriers for NfL and GFAP, and among former smokers for NfL. Blood-based biomarkers of AD were consistently associated with faster olfactory decline in older adults, particularly in the highest biomarker quartiles. These results provide large-scale longitudinal evidence, across up to 15 years of follow-up, that olfactory decline in the general population is linked to AD-related blood biomarkers, supporting the hypothesis that common olfactory losses in ageing partly reflect dementia-related processes.
{"title":"Blood-based biomarkers of Alzheimer's disease and olfactory decline over 15 years in older adults.","authors":"Ingrid Ekström,Davide Liborio Vetrano,Martina Valletta,Robert Ruane,Maria Larsson,Claudia Fredolini,Bengt Winblad,Giulia Grande,Erika J Laukka","doi":"10.1007/s11357-025-02038-1","DOIUrl":"https://doi.org/10.1007/s11357-025-02038-1","url":null,"abstract":"Olfactory impairment is common in older age and is a known early feature of several dementia diseases. Blood-based biomarkers of Alzheimer's disease (AD) now offer a scalable method for detecting pathophysiological mechanisms related to olfactory decline in the general population. However, few studies have examined how these biomarkers relate to long-term olfactory trajectories. Most existing work has been limited to cross-sectional settings. In this population-based study, we used biomarker data collected at baseline and followed participants for up to 15 years, enabling us to test whether early biological changes are temporally linked to subsequent olfactory decline. Data came from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study with baseline assessments from March 21, 2001, through August 30, 2004. We included participants without prevalent neurodegenerative diseases who completed olfactory assessment at baseline. The 15-year follow-up was finished in December 2019. Data were analysed from December 2023 to April 2024. Serum-derived biomarkers of tau phosphorylated at threonine 217 (p-tau217) and at theorine181 (p-tau181), total tau (t-tau), amyloid-β ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were obtained at baseline. Linear mixed models examined associations between biomarker quartiles and Sniffin' Sticks odor identification performance over 15 years, adjusting for demographics, health conditions, and semantic knowledge. We included 1868 participants (mean [SD] age 71.3 [9.9] years; 1122 females [60.1%]). In fully adjusted models, higher quartiles of p-tau217, p-tau181, NfL, and GFAP, and lower quartiles of Aβ42/Aβ40, were associated with steeper olfactory decline, with the steepest decline among participants in the highest quartiles (β for Q4 vs Q1: -0.20 [95% CI: -0.26 to -0.15] for p-tau217; -0.19 [95% CI: -0.25 to -0.13] for p-tau181; -0.23 [95% CI: -0.29 to -0.17] for NfL; β = -0.17 [95% CI: -0.23 to -0.11] for GFAP. Participants in the lowest Aβ42/Aβ40 quartile declined more steeply than those in the highest (β = -0.09 [95% CI: -0.14 to -0.04]). Associations appeared stronger in the oldest participants, in APOE ε4 carriers for p-tau181, in non-carriers for NfL and GFAP, and among former smokers for NfL. Blood-based biomarkers of AD were consistently associated with faster olfactory decline in older adults, particularly in the highest biomarker quartiles. These results provide large-scale longitudinal evidence, across up to 15 years of follow-up, that olfactory decline in the general population is linked to AD-related blood biomarkers, supporting the hypothesis that common olfactory losses in ageing partly reflect dementia-related processes.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"22 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765520","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}
Pub Date : 2025-12-17DOI: 10.1007/s11357-025-02061-2
Molly K Courish,Abigail V Wickens,Said Mekary,Myles W O'Brien,Derek S Kimmerly
Decreased resting cerebral blood flow and cerebrovascular reactivity (CVR) are important age-related factors associated with an increased risk of stroke or dementia. However, these declines may be exaggerated by a sedentary lifestyle or blunted by engaging in more aerobic-based physical activity. The objective of the present project was to explore differences in resting middle cerebral artery velocity (MCAv), CVR, moderate-to-vigorous intensity physical activity (MVPA), light-intensity physical activity, and sedentary time between healthy younger and older adults. Transcranial Doppler assessed resting right MCAv, and repeated breath hold-derived CVR between 15 younger (27 ± 10 years, 11 females) and 14 older adults (67 ± 9 years, 9 females). Habitual activity was assessed via a thigh-worn activPAL monitor worn 24-h/day for (6.0 ± 0.8 days). As expected, younger adults had higher resting MCAv (65 ± 11 versus 40 ± 22 cm/s, p = 0.003) and CVR (5.2 ± 3.2 versus 2.0 ± 0.7 cm/s/mmHg, p = 0.004). Older adults engaged in less habitual MVPA (202 ± 103 versus 269 ± 81 min/week, p = 0.05) and sedentary time (10.2 ± 2.7 versus 12.2 ± 1.8 h/day, p = 0.048) but accrued more light physical activity (575 ± 91 versus 402 ± 89 min/week, p = 0.015). Despite engaging in more habitual light physical activity and less sedentary time, older adults still exhibited lower MCAv and CVR compared with their younger peers.
静息脑血流量和脑血管反应性（CVR）降低是与中风或痴呆风险增加相关的重要年龄相关因素。然而，这种下降可能会被久坐的生活方式夸大，或者通过参加更多的有氧体育活动而减弱。本研究的目的是探讨健康的年轻人和老年人在静息大脑中动脉流速（MCAv）、CVR、中高强度体力活动（MVPA）、轻强度体力活动和久坐时间方面的差异。经颅多普勒评估15名年轻人（27±10岁，11名女性）和14名老年人（67±9岁，9名女性）的静息右侧MCAv和重复屏气衍生CVR。通过穿戴在大腿上的activPAL监测仪评估习惯性活动，每天佩戴24小时，持续（6.0±0.8天）。正如预期的那样，年轻人的静息MCAv（65±11比40±22 cm/s， p = 0.003）和CVR（5.2±3.2比2.0±0.7 cm/s/mmHg, p = 0.004）更高。老年人的习惯性MVPA（202±103比269±81分钟/周，p = 0.05）和久坐时间（10.2±2.7比12.2±1.8小时/天，p = 0.048）较少，但积累了更多的轻度身体活动（575±91比402±89分钟/周，p = 0.015）。尽管老年人从事更多的习惯性轻体力活动和更少的久坐时间，但与年轻人相比，老年人的MCAv和CVR仍然较低。
{"title":"Engagement in more light physical activity and less sedentary time does not protect against age-related declines in cerebrovascular reactivity in healthy older adults.","authors":"Molly K Courish,Abigail V Wickens,Said Mekary,Myles W O'Brien,Derek S Kimmerly","doi":"10.1007/s11357-025-02061-2","DOIUrl":"https://doi.org/10.1007/s11357-025-02061-2","url":null,"abstract":"Decreased resting cerebral blood flow and cerebrovascular reactivity (CVR) are important age-related factors associated with an increased risk of stroke or dementia. However, these declines may be exaggerated by a sedentary lifestyle or blunted by engaging in more aerobic-based physical activity. The objective of the present project was to explore differences in resting middle cerebral artery velocity (MCAv), CVR, moderate-to-vigorous intensity physical activity (MVPA), light-intensity physical activity, and sedentary time between healthy younger and older adults. Transcranial Doppler assessed resting right MCAv, and repeated breath hold-derived CVR between 15 younger (27 ± 10 years, 11 females) and 14 older adults (67 ± 9 years, 9 females). Habitual activity was assessed via a thigh-worn activPAL monitor worn 24-h/day for (6.0 ± 0.8 days). As expected, younger adults had higher resting MCAv (65 ± 11 versus 40 ± 22 cm/s, p = 0.003) and CVR (5.2 ± 3.2 versus 2.0 ± 0.7 cm/s/mmHg, p = 0.004). Older adults engaged in less habitual MVPA (202 ± 103 versus 269 ± 81 min/week, p = 0.05) and sedentary time (10.2 ± 2.7 versus 12.2 ± 1.8 h/day, p = 0.048) but accrued more light physical activity (575 ± 91 versus 402 ± 89 min/week, p = 0.015). Despite engaging in more habitual light physical activity and less sedentary time, older adults still exhibited lower MCAv and CVR compared with their younger peers.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"1 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765522","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}
Pub Date : 2025-12-17DOI: 10.1007/s11357-025-02051-4
Anouck Matthijs,Anda de Witte,Dante Mantini,Jean-Jacques Orban de Xivry
Aging significantly impacts motor performance, especially in multi-joint movement tasks where the nervous system needs to adequately coordinate mechanical interactions between joints. Effective coordination of multiple joints relies on intact feedforward control to predict movement dynamics in the initial phase of the movement, and on feedback control to fine-tune the execution in the final phase. The effect of aging on these specific control mechanisms remains controversial. Here, we investigated a pure-elbow motion task with a group of 50 young (20-35 years old), 80 old (55-70 years old) and 30 older-old (80 + years old) healthy participants. They performed 30° elbow flexions and extensions under two speed conditions as higher elbow velocities increase interaction torques at the shoulder, and demand greater neuromuscular effort for stabilization. The timing and magnitude of anticipatory EMG activity of the agonist shoulder muscle, necessary to counteract interaction torques, were similar across all age groups. Moreover, increasing elbow velocity did not result in any performance differences between young and older adults, indicating that shoulder stabilization during movement initiation remained intact with age. However, older adults exhibited reduced ability to stabilize the shoulder position until the end of the movement, leading to decreased accuracy with older age. These results suggest that feedforward control, which is essential for shoulder stabilization during movement initiation, is functionally stable during healthy aging and remains resilient to increased motor demands. In contrast, feedback control appears to deteriorate with age, potentially contributing to reduced movement precision in the final phase of the multi-joint movement.
{"title":"Adults up to 80 years old maintain effective movement planning when facing complex body dynamics.","authors":"Anouck Matthijs,Anda de Witte,Dante Mantini,Jean-Jacques Orban de Xivry","doi":"10.1007/s11357-025-02051-4","DOIUrl":"https://doi.org/10.1007/s11357-025-02051-4","url":null,"abstract":"Aging significantly impacts motor performance, especially in multi-joint movement tasks where the nervous system needs to adequately coordinate mechanical interactions between joints. Effective coordination of multiple joints relies on intact feedforward control to predict movement dynamics in the initial phase of the movement, and on feedback control to fine-tune the execution in the final phase. The effect of aging on these specific control mechanisms remains controversial. Here, we investigated a pure-elbow motion task with a group of 50 young (20-35 years old), 80 old (55-70 years old) and 30 older-old (80 + years old) healthy participants. They performed 30° elbow flexions and extensions under two speed conditions as higher elbow velocities increase interaction torques at the shoulder, and demand greater neuromuscular effort for stabilization. The timing and magnitude of anticipatory EMG activity of the agonist shoulder muscle, necessary to counteract interaction torques, were similar across all age groups. Moreover, increasing elbow velocity did not result in any performance differences between young and older adults, indicating that shoulder stabilization during movement initiation remained intact with age. However, older adults exhibited reduced ability to stabilize the shoulder position until the end of the movement, leading to decreased accuracy with older age. These results suggest that feedforward control, which is essential for shoulder stabilization during movement initiation, is functionally stable during healthy aging and remains resilient to increased motor demands. In contrast, feedback control appears to deteriorate with age, potentially contributing to reduced movement precision in the final phase of the multi-joint movement.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"12 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765521","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}
Pub Date : 2025-12-17DOI: 10.1007/s11357-025-02044-3
Phuong-Anh Dinh,HyeRim Han,Seungsoo Kim,Qinghua Guo,Zhengdong D Zhang,Jan Vijg,Yousin Suh
The growing epidemiological burden of multimorbidity among older adults underscores an urgent need to develop interventions that can address multiple age-related diseases (ARDs) at once. Yet, the biological mechanisms driving their co-occurrence remain poorly understood. In this study, we conducted a multivariate genome-wide association analysis to dissect the shared genetic architecture of five common ARDs: heart attack, high cholesterol, hypertension, stroke, and type 2 diabetes. We defined this shared genetic component as the multivariate age-related disease factor (mvARD) and identified 263 independent variants across 180 genomic loci associated with mvARD. These variants were significantly enriched for associations with extreme human longevity, lending empirical support for the geroscience hypothesis in humans. Integrative gene prioritization using transcriptome-wide association studies, colocalization analysis, and Mendelian randomization identified four high-confidence genes in blood-DCAF16, PHF13, MGA, and GTF2B-with putative causal roles on mvARD. Using two-sample Mendelian randomization, we also found several modifiable lifestyle factors, including body mass index and dietary intake, that causally influenced the risk for multiple ARDs. Together, our findings revealed a shared genetic basis for common ARDs that overlapped with the biology of human aging and pointed to potential molecular and behavioral targets for delaying disease onset and promoting healthy aging.
{"title":"Genetic links between multimorbidity and human aging.","authors":"Phuong-Anh Dinh,HyeRim Han,Seungsoo Kim,Qinghua Guo,Zhengdong D Zhang,Jan Vijg,Yousin Suh","doi":"10.1007/s11357-025-02044-3","DOIUrl":"https://doi.org/10.1007/s11357-025-02044-3","url":null,"abstract":"The growing epidemiological burden of multimorbidity among older adults underscores an urgent need to develop interventions that can address multiple age-related diseases (ARDs) at once. Yet, the biological mechanisms driving their co-occurrence remain poorly understood. In this study, we conducted a multivariate genome-wide association analysis to dissect the shared genetic architecture of five common ARDs: heart attack, high cholesterol, hypertension, stroke, and type 2 diabetes. We defined this shared genetic component as the multivariate age-related disease factor (mvARD) and identified 263 independent variants across 180 genomic loci associated with mvARD. These variants were significantly enriched for associations with extreme human longevity, lending empirical support for the geroscience hypothesis in humans. Integrative gene prioritization using transcriptome-wide association studies, colocalization analysis, and Mendelian randomization identified four high-confidence genes in blood-DCAF16, PHF13, MGA, and GTF2B-with putative causal roles on mvARD. Using two-sample Mendelian randomization, we also found several modifiable lifestyle factors, including body mass index and dietary intake, that causally influenced the risk for multiple ARDs. Together, our findings revealed a shared genetic basis for common ARDs that overlapped with the biology of human aging and pointed to potential molecular and behavioral targets for delaying disease onset and promoting healthy aging.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"43 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765523","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}
Pub Date : 2025-12-15DOI: 10.1007/s11357-025-02055-0
Semere Bekena,Ramkrishna K Singh,Yiqi Zhu,David B Carr,Ganesh M Babulal
Early identification of markers of cognitive decline in cognitively normal older adults is essential for dementia prevention strategies. Sensorimotor measures, such as gait speed, grip strength, and reaction time, may provide sensitive indicators of current and future impairment. This study examined associations between baseline sensorimotor function and cognitive decline in cognitively normal older adults. In this prospective cohort, 246 cognitively normal older adults from the DRIVES Project completed baseline assessments of grip strength, gait speed, simple reaction time, and the Preclinical Alzheimer Cognitive Composite (PACC). Participants were followed for a mean of 4 years. Linear mixed-effects models adjusted for demographics, APOE ε4 status, and neighborhood deprivation. Cross-sectional analyses evaluated the associations between sensorimotor measures and cerebrospinal fluid (CSF) biomarkers of amyloid, tau, and plasma neurofilament light chain (NfL). Participants (mean age: 74.9 ± 5.17 years; 48.8% female) had a mean baseline PACC score of 1.06 ± 0.50. Cross-sectionally, slower gait speed was associated with higher CSF tau/Aβ42 ratio (p = 0.027), CSF tTau/Aβ42 ratio (p = 0.009), and plasma NfL (p = 0.024). A slower reaction time was associated with lower baseline PACC scores (p = 0.028). Longitudinally, low grip strength (p = 0.002) and slow gait speed (p < 0.001) were predictive of lower cognitive performance, with slow gait speed also predicting a faster decline (p = 0.015). Sensorimotor function measures are associated with current and future cognitive performance, supporting their role in early identification of older adults at risk for cognitive decline.
{"title":"Sensorimotor function as an early marker of cognitive decline and alzheimer's biomarker burden.","authors":"Semere Bekena,Ramkrishna K Singh,Yiqi Zhu,David B Carr,Ganesh M Babulal","doi":"10.1007/s11357-025-02055-0","DOIUrl":"https://doi.org/10.1007/s11357-025-02055-0","url":null,"abstract":"Early identification of markers of cognitive decline in cognitively normal older adults is essential for dementia prevention strategies. Sensorimotor measures, such as gait speed, grip strength, and reaction time, may provide sensitive indicators of current and future impairment. This study examined associations between baseline sensorimotor function and cognitive decline in cognitively normal older adults. In this prospective cohort, 246 cognitively normal older adults from the DRIVES Project completed baseline assessments of grip strength, gait speed, simple reaction time, and the Preclinical Alzheimer Cognitive Composite (PACC). Participants were followed for a mean of 4 years. Linear mixed-effects models adjusted for demographics, APOE ε4 status, and neighborhood deprivation. Cross-sectional analyses evaluated the associations between sensorimotor measures and cerebrospinal fluid (CSF) biomarkers of amyloid, tau, and plasma neurofilament light chain (NfL). Participants (mean age: 74.9 ± 5.17 years; 48.8% female) had a mean baseline PACC score of 1.06 ± 0.50. Cross-sectionally, slower gait speed was associated with higher CSF tau/Aβ42 ratio (p = 0.027), CSF tTau/Aβ42 ratio (p = 0.009), and plasma NfL (p = 0.024). A slower reaction time was associated with lower baseline PACC scores (p = 0.028). Longitudinally, low grip strength (p = 0.002) and slow gait speed (p < 0.001) were predictive of lower cognitive performance, with slow gait speed also predicting a faster decline (p = 0.015). Sensorimotor function measures are associated with current and future cognitive performance, supporting their role in early identification of older adults at risk for cognitive decline.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"13 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760002","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}
Pub Date : 2025-12-15DOI: 10.1007/s11357-025-02028-3
Bretton Badenoch, Oliver Fiehn, Noa Rappaport, Pranjal Srivastava, Kengo Watanabe, Sriram Chandrasekaran, Richard A Miller
Tests that can predict whether a drug is likely to extend mouse lifespan could speed up the search for anti-aging drugs. We have applied a machine learning algorithm, XGBoost regression, to seek sets of plasma metabolites (n = 12,000) and peptides (n = 17,000) that can discriminate control mice from mice treated with one of five anti-aging interventions (n = 278 mice). When the model is trained on any four of these five interventions, it predicts significantly higher lifespan extension in mice exposed to the intervention which was not included in the training set. Plasma peptide data sets also succeed at this task. Models trained on drug-treated normal mice also discriminate long-lived mutant mice from their respective controls, and models trained on males can discriminate drug-treated from control females. Triglycerides are over-represented among the most influential features in the regression models. Triglycerides with longer fatty acid chains tend to be higher in the slow-aging mice, while triglycerides with shorter fatty acid chains tend to decrease. Plasma metabolite patterns may help to select the most promising anti-aging drugs in mice or in humans and may give new leads into physiological and enzymatic targets relevant to the discovery of new anti-aging drugs.
{"title":"Discrimination of normal from slow-aging mice by plasma metabolomic and proteomic features.","authors":"Bretton Badenoch, Oliver Fiehn, Noa Rappaport, Pranjal Srivastava, Kengo Watanabe, Sriram Chandrasekaran, Richard A Miller","doi":"10.1007/s11357-025-02028-3","DOIUrl":"10.1007/s11357-025-02028-3","url":null,"abstract":"<p><p>Tests that can predict whether a drug is likely to extend mouse lifespan could speed up the search for anti-aging drugs. We have applied a machine learning algorithm, XGBoost regression, to seek sets of plasma metabolites (n = 12,000) and peptides (n = 17,000) that can discriminate control mice from mice treated with one of five anti-aging interventions (n = 278 mice). When the model is trained on any four of these five interventions, it predicts significantly higher lifespan extension in mice exposed to the intervention which was not included in the training set. Plasma peptide data sets also succeed at this task. Models trained on drug-treated normal mice also discriminate long-lived mutant mice from their respective controls, and models trained on males can discriminate drug-treated from control females. Triglycerides are over-represented among the most influential features in the regression models. Triglycerides with longer fatty acid chains tend to be higher in the slow-aging mice, while triglycerides with shorter fatty acid chains tend to decrease. Plasma metabolite patterns may help to select the most promising anti-aging drugs in mice or in humans and may give new leads into physiological and enzymatic targets relevant to the discovery of new anti-aging drugs.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756066","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}
Pub Date : 2025-12-15DOI: 10.1007/s11357-025-02052-3
Giovanni Zuliani,Gloria Brombo,Tommaso Romagnoli,Michele Polastri,Francesco di Paola Dario,Marco Zuin
The efficacy of acetylcholinesterase inhibitors (AChEI) and memantine (ME) in severe dementia remains uncertain, and real world data are limited. We evaluated the progression of cognitive decline and mortality rates in a cohort of outpatients with severe dementia treated with AChEI and/or ME or not treated, from the National Alzheimer's Coordinating Center Uniform Data Set (NACC-UDS). Overall, 703 patients (mean age:78.3 ± 7.2 years; females:56.1%) with severe dementia (Mini-Mental State Examination-MMSE ≤ 10/30) were included [407 late-onset Alzheimer's disease (LOAD), 126 Lewy body dementia (LBD), 170 vascular dementia (VD)]. Patients were grouped by treatment status: untreated (AChEI - /ME - ; n.70), AChEI only (AChEI + ; n.294), ME only (ME + ; n.215), combined therapy (AChEI + /ME + ; n.124). During follow-up (mean:1.7 ± 0.3 years; range:0.2-2.9 years) the mean MMSE scores declined by - 1.7 points (Standard Deviation: -1.55 to -1.9) in AChEI - /ME - (p for trend:0.001), - 1.5 points (-1.55 to -1.9) in AChEI + (p:0.001), - 0.7 points (-0.5 to -0.9) in ME + (p:0.09), while it increased by + 0.7 points (+ 0.4 to + 1.0) in AChEI + /ME + (p:0.001). Survival rates were 8% in AChEI - /ME - , 10% in AChEI + , 28% in ME + , and 49% in AChEI + /ME + . In Cox proportional hazards analysis (age and sex adjusted), AChEI + /ME + exhibited a 39% reduction in total mortality compared with no treatment (HR:0.61; 95%CI:0.49-0.77; p < 0.001), ME + displayed a 22% reduction (HR:0.78; 95%CI:0.65-0.94; p:0.007), while AChEI + showed no association (HR:0.97; 95%CI:0.80-1.18; p:0.75). When the Cox proportional hazards models were stratified by dementia subtype, consistent significant patterns were observed in LOAD and LBD. In this real-world cohort of older adults with severe dementia, the combination therapy (ME + AchEI) seems to be associated with the best outcomes, including a stabilization of cognitive function and reduced total mortality.
{"title":"Effectiveness of acetylcholinesterase inhibitors and memantine in patients affected by severe dementia.","authors":"Giovanni Zuliani,Gloria Brombo,Tommaso Romagnoli,Michele Polastri,Francesco di Paola Dario,Marco Zuin","doi":"10.1007/s11357-025-02052-3","DOIUrl":"https://doi.org/10.1007/s11357-025-02052-3","url":null,"abstract":"The efficacy of acetylcholinesterase inhibitors (AChEI) and memantine (ME) in severe dementia remains uncertain, and real world data are limited. We evaluated the progression of cognitive decline and mortality rates in a cohort of outpatients with severe dementia treated with AChEI and/or ME or not treated, from the National Alzheimer's Coordinating Center Uniform Data Set (NACC-UDS). Overall, 703 patients (mean age:78.3 ± 7.2 years; females:56.1%) with severe dementia (Mini-Mental State Examination-MMSE ≤ 10/30) were included [407 late-onset Alzheimer's disease (LOAD), 126 Lewy body dementia (LBD), 170 vascular dementia (VD)]. Patients were grouped by treatment status: untreated (AChEI - /ME - ; n.70), AChEI only (AChEI + ; n.294), ME only (ME + ; n.215), combined therapy (AChEI + /ME + ; n.124). During follow-up (mean:1.7 ± 0.3 years; range:0.2-2.9 years) the mean MMSE scores declined by - 1.7 points (Standard Deviation: -1.55 to -1.9) in AChEI - /ME - (p for trend:0.001), - 1.5 points (-1.55 to -1.9) in AChEI + (p:0.001), - 0.7 points (-0.5 to -0.9) in ME + (p:0.09), while it increased by + 0.7 points (+ 0.4 to + 1.0) in AChEI + /ME + (p:0.001). Survival rates were 8% in AChEI - /ME - , 10% in AChEI + , 28% in ME + , and 49% in AChEI + /ME + . In Cox proportional hazards analysis (age and sex adjusted), AChEI + /ME + exhibited a 39% reduction in total mortality compared with no treatment (HR:0.61; 95%CI:0.49-0.77; p < 0.001), ME + displayed a 22% reduction (HR:0.78; 95%CI:0.65-0.94; p:0.007), while AChEI + showed no association (HR:0.97; 95%CI:0.80-1.18; p:0.75). When the Cox proportional hazards models were stratified by dementia subtype, consistent significant patterns were observed in LOAD and LBD. In this real-world cohort of older adults with severe dementia, the combination therapy (ME + AchEI) seems to be associated with the best outcomes, including a stabilization of cognitive function and reduced total mortality.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"9 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752520","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}
Pub Date : 2025-12-15DOI: 10.1007/s11357-025-02024-7
Renjie Li,Kaylee Rudd,Eddy Roccati,Lynette R Goldberg,Aidan D Bindoff,Katherine Lawler,Mimieveshiofuo Aiyede,Cristina Simonet,Diriba Mulisa,Anna E King,James C Vickers,Quan Bai,Jane Alty
Scalable remote-monitoring tools of motor function are vital for early detection and tracking of neurodegenerative diseases. This study evaluated the reliability and usability of TapTalk, a 2-min validated smartphone-based self-assessment of hand and speech motor function, in older adults. Community-dwelling adults aged 50 + completed TapTalk daily for 7 days: once in the research center and six consecutive days at home. Motor features were extracted using validated algorithms. Test-retest reliability was analyzed using intraclass correlation coefficient (ICC) and usability via descriptive analysis of user-experience questionnaires. Four-hundred and twenty-five sessions of TapTalk were completed by 68 participants (68.6 ± 6.6 years; range 57-80; 75% female) across 43 smartphone models. All tests had features with ICC > 0.5 except for one, indicating acceptable reliability for a self-administered in-home test. Usability scores averaged 95.9% reflecting high satisfaction with ease-of-use, clarity, and performance. Findings support TapTalk's potential for scalable longitudinal monitoring. Establishing reliability and usability in older adults is a critical step toward TapTalk's broader use by those with neurodegenerative diseases.
{"title":"Smartphone self-testing of hand and speech motor functions: a study of reliability and usability in older adults.","authors":"Renjie Li,Kaylee Rudd,Eddy Roccati,Lynette R Goldberg,Aidan D Bindoff,Katherine Lawler,Mimieveshiofuo Aiyede,Cristina Simonet,Diriba Mulisa,Anna E King,James C Vickers,Quan Bai,Jane Alty","doi":"10.1007/s11357-025-02024-7","DOIUrl":"https://doi.org/10.1007/s11357-025-02024-7","url":null,"abstract":"Scalable remote-monitoring tools of motor function are vital for early detection and tracking of neurodegenerative diseases. This study evaluated the reliability and usability of TapTalk, a 2-min validated smartphone-based self-assessment of hand and speech motor function, in older adults. Community-dwelling adults aged 50 + completed TapTalk daily for 7 days: once in the research center and six consecutive days at home. Motor features were extracted using validated algorithms. Test-retest reliability was analyzed using intraclass correlation coefficient (ICC) and usability via descriptive analysis of user-experience questionnaires. Four-hundred and twenty-five sessions of TapTalk were completed by 68 participants (68.6 ± 6.6 years; range 57-80; 75% female) across 43 smartphone models. All tests had features with ICC > 0.5 except for one, indicating acceptable reliability for a self-administered in-home test. Usability scores averaged 95.9% reflecting high satisfaction with ease-of-use, clarity, and performance. Findings support TapTalk's potential for scalable longitudinal monitoring. Establishing reliability and usability in older adults is a critical step toward TapTalk's broader use by those with neurodegenerative diseases.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"20 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760000","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}
Pub Date : 2025-12-13DOI: 10.1007/s11357-025-02019-4
Nathan D McCoy,Steven P Gawrys,Samuel G Mackintosh,Stephanie Byrum,Negar Kosari,Anhong Zhou,Mishfak A M Mansoor,Yuji Ikeno,José V V Isola,Michael B Stout,Augusto Schneider,Michal M Masternak,Jeffrey B Mason
Women experience more pronounced lipidomic changes with aging than men, which may contribute to the higher rates of Alzheimer's disease seen in postmenopausal women. Our earlier findings showed that transplantation of young ovarian somatic tissues or cells produced positive health-enhancing results in postreproductive females. In the current experiments, we looked to find key health-enhancing ovarian cells and pathways involved in this phenomenon. We conducted physiological and molecular analysis on animals/samples from old, postreproductive mice that received young ovarian tissue/cell transplants. Our analysis revealed a loss with age and a restoration with ovarian tissue/cell exposure, of serum biomarkers of lipid signaling and histological and behavioral markers of cognitive function. We further found, with single-cell transcriptomics and Raman spectroscopy, two candidate ovarian somatic cell types implicated in the restoration of health through a lipid signaling-based process. These results have identified key factors toward the determination of how germ cell-independent ovarian somatic tissues restore health through regulation of lipid signaling and dementia in postreproductive female mice.
{"title":"Ovarian somatic tissue rejuvenates circulating apolipoproteins and promotes cognitive health in postreproductive female mice.","authors":"Nathan D McCoy,Steven P Gawrys,Samuel G Mackintosh,Stephanie Byrum,Negar Kosari,Anhong Zhou,Mishfak A M Mansoor,Yuji Ikeno,José V V Isola,Michael B Stout,Augusto Schneider,Michal M Masternak,Jeffrey B Mason","doi":"10.1007/s11357-025-02019-4","DOIUrl":"https://doi.org/10.1007/s11357-025-02019-4","url":null,"abstract":"Women experience more pronounced lipidomic changes with aging than men, which may contribute to the higher rates of Alzheimer's disease seen in postmenopausal women. Our earlier findings showed that transplantation of young ovarian somatic tissues or cells produced positive health-enhancing results in postreproductive females. In the current experiments, we looked to find key health-enhancing ovarian cells and pathways involved in this phenomenon. We conducted physiological and molecular analysis on animals/samples from old, postreproductive mice that received young ovarian tissue/cell transplants. Our analysis revealed a loss with age and a restoration with ovarian tissue/cell exposure, of serum biomarkers of lipid signaling and histological and behavioral markers of cognitive function. We further found, with single-cell transcriptomics and Raman spectroscopy, two candidate ovarian somatic cell types implicated in the restoration of health through a lipid signaling-based process. These results have identified key factors toward the determination of how germ cell-independent ovarian somatic tissues restore health through regulation of lipid signaling and dementia in postreproductive female mice.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"20 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732826","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}
The genetics of human longevity has been primarily studied using classical methods developed in genome-wide association studies. With the recent advances in paleogenomics, it is now possible to investigate to what extent ancient population ancestries contribute to complex traits. In this study, we explored the role of ancient genetic components in human longevity by focusing on the Italian Peninsula, whose genetic heritage includes several past genetic ancestries that have contributed to the current European genetic make-up. We analyzed genome-wide data of 333 Italian centenarians and 690 geographically matched healthy controls, and compared their genetic composition to 103 ancient genomes representative of the main past European population ancestries. Our findings indicate that Italian centenarians have a higher genetic affinity with Western Hunter-Gatherer (WHG)-related ancestry compared to controls, according to PCA and f4-statistics. Logistic regression models based on supervised admixture revealed a significant association between higher WHG ancestry and the centenarian status. Additionally, residual-based predictive analysis showed that centenarians exhibit a significantly higher WHG contribution independent of the genetic structuring of the general Italian population. By painting the chromosomes of modern Italians, we also showed a significantly higher number of WHG alleles at pro-longevity SNPs. In the present study, we demonstrate the contribution of ancient genetic components to the longevity phenotype. In particular, we showed a greater contribution from Western Hunter-Gatherer-related ancestry to Italian centenarians, thus suggesting that this pre-Neolithic genetic component, which has been linked to population shifts occurring within Europe after the Last Glacial Maximum, could be beneficial for longevity today.
{"title":"Western Hunter-Gatherer genetic ancestry contributes to human longevity in the Italian population.","authors":"Stefania Sarno,Vincenzo Iannuzzi,Marco Sazzini,Chiara Pirazzini,Maria Giulia Bacalini,Davide Gentilini,Giuseppe Passarino,Daniela Mari,Daniela Monti,Benedetta Nacmias,Sandro Sorbi,Davide Pettener,Donata Luiselli,Claudio Franceschi,Paolo Garagnani,Cristina Giuliani","doi":"10.1007/s11357-025-02043-4","DOIUrl":"https://doi.org/10.1007/s11357-025-02043-4","url":null,"abstract":"The genetics of human longevity has been primarily studied using classical methods developed in genome-wide association studies. With the recent advances in paleogenomics, it is now possible to investigate to what extent ancient population ancestries contribute to complex traits. In this study, we explored the role of ancient genetic components in human longevity by focusing on the Italian Peninsula, whose genetic heritage includes several past genetic ancestries that have contributed to the current European genetic make-up. We analyzed genome-wide data of 333 Italian centenarians and 690 geographically matched healthy controls, and compared their genetic composition to 103 ancient genomes representative of the main past European population ancestries. Our findings indicate that Italian centenarians have a higher genetic affinity with Western Hunter-Gatherer (WHG)-related ancestry compared to controls, according to PCA and f4-statistics. Logistic regression models based on supervised admixture revealed a significant association between higher WHG ancestry and the centenarian status. Additionally, residual-based predictive analysis showed that centenarians exhibit a significantly higher WHG contribution independent of the genetic structuring of the general Italian population. By painting the chromosomes of modern Italians, we also showed a significantly higher number of WHG alleles at pro-longevity SNPs. In the present study, we demonstrate the contribution of ancient genetic components to the longevity phenotype. In particular, we showed a greater contribution from Western Hunter-Gatherer-related ancestry to Italian centenarians, thus suggesting that this pre-Neolithic genetic component, which has been linked to population shifts occurring within Europe after the Last Glacial Maximum, could be beneficial for longevity today.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"29 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732824","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}
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