Differential striatal dopamine binding in Parkinson’s Disease with and without REM sleep behavior disorder: A Tc-99 m TRODAT-1 SPECT study - Pei-Hsuan Wang; Yang-Pei Chang; Ching-Fang Chien; Poyin Huang (GeroScience, 2025)

Prognostic impact of glucagon-like peptide-1 receptor (GLP1R) expression on cancer survival and its implications for GLP-1R agonist therapy: an integrative analysis across multiple tumor types - Zoltan Ungvari; Áron Bartha; Anna Ungvari; Monika Fekete; Giampaolo Bianchini; Balázs Győrffy (GeroScience, 2025)
Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exenatide (Byetta, Bydureon), liraglutide (Victoza, Saxenda), albiglutide (Tanzeum), dulaglutide (Trulicity), lixisenatide (Lyxumia, Adlyxin), semaglutide (Ozempic, Rybelsus, Wegovy), and tirzepatide (Mounjaro, Zepbound), are widely used for the treatment of type 2 diabetes mellitus (T2DM) and obesity. While these agents are well known for their metabolic benefits, there is growing interest in their potential effects on cancer biology. However, the role of GLP-1R agonists in cancer remains complex and not fully understood, particularly across different tumor types. This study aimed to evaluate the prognostic significance of GLP1R expression on overall survival across various cancer types. Using a comprehensive analysis of gene expression data and survival outcomes a large cohorts of different tumor types, we employed Cox proportional hazards survival analyses, coupled with false discovery rate determinations, to explore correlations between GLP1R expression and survival. The integrated database included thousands of cancer specimens with available overall survival time and event data from numerous independent cohorts, providing a robust platform for survival analysis. Our findings reveal that increased GLP1R expression is associated with improved overall survival in cancers such as bladder cancer, breast cancer, esophageal adenocarcinoma, renal clear cell carcinoma, and thyroid carcinoma. Conversely, higher GLP1R expression is linked to poorer survival outcomes in cervical squamous cell carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Additionally, GLP1R expression showed no significant impact on overall survival in cancers such as esophageal squamous cell carcinoma, colon cancer, head-neck squamous cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, ovarian cancer, and pancreatic cancer. In conclusion, GLP1R expression levels serve as an important biomarker with potential prognostic significance across multiple cancers, demonstrating both protective and adverse associations depending on the tumor type. These findings highlight the complex role of GLP-1R agonists in cancer risk and survival, suggesting that the therapeutic use of these agents should be carefully tailored to the individual patient’s cancer risk profile.

Cerebromicrovascular mechanisms contributing to long COVID: implications for neurocognitive health - Monika Fekete; Andrea Lehoczki; Ágnes Szappanos; Attila Toth; Mohamed Mahdi; Péter Sótonyi; Zoltán Benyó; Andriy Yabluchanskiy; Stefano Tarantini; Zoltan Ungvari (GeroScience, 2025)
Long COVID (also known as post-acute sequelae of SARS-CoV-2 infection [PASC] or post-COVID syndrome) is characterized by persistent symptoms that extend beyond the acute phase of SARS-CoV-2 infection, affecting approximately 10% to over 30% of those infected. It presents a significant clinical challenge, notably due to pronounced neurocognitive symptoms such as brain fog. The mechanisms underlying these effects are multifactorial, with mounting evidence pointing to a central role of cerebromicrovascular dysfunction. This review investigates key pathophysiological mechanisms contributing to cerebrovascular dysfunction in long COVID and their impacts on brain health. We discuss how endothelial tropism of SARS-CoV-2 and direct vascular infection trigger endothelial dysfunction, impaired neurovascular coupling, and blood–brain barrier disruption, resulting in compromised cerebral perfusion. Furthermore, the infection appears to induce mitochondrial dysfunction, enhancing oxidative stress and inflammation within cerebral endothelial cells. Autoantibody formation following infection also potentially exacerbates neurovascular injury, contributing to chronic vascular inflammation and ongoing blood–brain barrier compromise. These factors collectively contribute to the emergence of white matter hyperintensities, promote amyloid pathology, and may accelerate neurodegenerative processes, including Alzheimer’s disease. This review also emphasizes the critical role of advanced imaging techniques in assessing cerebromicrovascular health and the need for targeted interventions to address these cerebrovascular complications. A deeper understanding of the cerebrovascular mechanisms of long COVID is essential to advance targeted treatments and mitigate its long-term neurocognitive consequences.

Impact of adherence to the Mediterranean diet on stroke risk - Zoltan Ungvari; Mónika Fekete; Péter Varga; János Tibor Fekete; Annamaria Buda; Ágnes Szappanos; Andrea Lehoczki; Noémi Mózes; Giuseppe Grosso; Otilia Menyhart; Gyöngyi Munkácsy; Stefano Tarantini; et al. (GeroScience, 2025)
Stroke is a leading cause of morbidity and mortality worldwide, and dietary patterns have emerged as a significant modifiable factor in stroke prevention. The Mediterranean diet, characterized by high intake of fruits, vegetables, whole grains, nuts, olive oil, and fish, has been widely recognized for its cardiovascular benefits. However, its specific impact on stroke risk requires further elucidation. We conducted a comprehensive meta-analysis of 30 studies, including both cohort and case–control designs, to evaluate the relationship between adherence to the Mediterranean diet and the risk of stroke. A systematic search was performed across multiple databases, and a random-effects model was used to estimate pooled hazard ratios (HRs) with 95% confidence intervals (CIs). Heterogeneity was assessed using the I 2 statistic, and publication bias was examined through funnel plots and Egger’s regression test. Additionally, trial sequential analysis was conducted to determine the adequacy of the sample size. The meta-analysis revealed a significant reduction in stroke risk among individuals adhering to the Mediterranean diet, with a pooled HR of 0.88 (95% CI: 0.84–0.91). Notably, a significant heterogeneity was detected ( I 2 = 34%). The Z-score plot from trial sequential analysis confirmed that the sample sizes were sufficient to draw definitive conclusions. However, a potential publication bias was identified. The case–control studies confirmed a highly significant effect (HR = 0.54, 95% CI: 0.4–0.73). The funnel plots in both settings hinted at the presence of a potential publication bias, supported by a significant Egger’s test. Our findings provide robust evidence supporting the protective effect of the Mediterranean diet against stroke. Despite the presence of some heterogeneity and potential publication bias, the cumulative evidence suggests that promoting the Mediterranean diet could serve as an effective public health strategy for stroke prevention. Further research is recommended to explore the underlying mechanisms and to assess the diet’s impact across diverse populations.

Associations between physical activity, brain health, cognitive function, and circulating GPLD1 in healthy older (65–85 years) individuals - Kara L. Marlatt; Adam C. Lowe; Guillermo Sanchez-Delgado; Robbie A. Beyl; Matthew K. Viverito; Jeffrey N. Keller; Owen T. Carmichael; Eric Ravussin (GeroScience, 2025)

Digital cognitive training for functionality in mild cognitive impairment: a randomized controlled clinical trial - Cíntia Monteiro Carvalho; Bruno Costa Poltronieri; Karin Reuwsaat; Maria Eduarda Alves Reis; Rogerio Panizzutti (GeroScience, 2025)

Disentangling the effect of sex from brain size on brain organization and cognitive functioning - Aliza Brzezinski-Rittner; Roqaie Moqadam; Yasser Iturria-Medina; M. Mallar Chakravarty; Mahsa Dadar; Yashar Zeighami (GeroScience, 2025)

Sex-specific mechanisms in vascular aging: exploring cellular and molecular pathways in the pathogenesis of age-related cardiovascular and cerebrovascular diseases - Anna Ungvari; Rafal Gulej; Roland Patai; Zoltan Papp; Attila Toth; Attila Á. Szabó; Bruno K. Podesser; Péter Sótonyi; Zoltán Benyó; Andriy Yabluchanskiy; Stefano Tarantini; Andrea B. Maier; et al. (GeroScience, 2025)

Impact of physical activity and exercise training on health-related quality of life in older adults: an umbrella review - Beverly D. Schwartz; Haoxuan Liu; Emily E. MacDonald; Said Mekari; Myles W. O’Brien (GeroScience, 2025)

SNP rs6543176 is associated with extreme human longevity but increased risk for cancer - Anastasia Gurinovich; Zeyuan Song; Harold Bae; Anastasia Leshchyk; Mengze Li; Hannah Lords; Stacy L. Andersen; Marianne Nygaard; Kaare Christensen; E. Warwick Daw; Konstantin G. Arbeev; Michael R. Brent; et al. (GeroScience, 2025)

Complex genetic interactions affect susceptibility to Alzheimer's disease risk in the BIN1 and MS4A6A loci - Alireza Nazarian; Marissa Morado; Alexander M. Kulminski (GeroScience, 2025)

BayesAge 2.0: a maximum likelihood algorithm to predict transcriptomic age - Lajoyce Mboning; Emma K. Costa; Jingxun Chen; Louis-S. Bouchard; Matteo Pellegrini (GeroScience, 2025)
Aging is a complex biological process influenced by various factors, including genetic and environmental influences. In this study, we present BayesAge 2.0, an upgraded version of our maximum likelihood algorithm designed for predicting transcriptomic age (tAge) from RNA-seq data. Building on the original BayesAge framework, which was developed for epigenetic age prediction, BayesAge 2.0 integrates a Poisson distribution to model count-based gene expression data and employs LOWESS smoothing to capture nonlinear gene-age relationships. BayesAge 2.0 provides significant improvements over traditional linear models, such as Elastic Net regression. Specifically, it addresses issues of age bias in predictions, with minimal age-associated bias observed in residuals. Its computational efficiency further distinguishes it from traditional models, as reference construction and cross-validation are completed more quickly compared to Elastic Net regression, which requires extensive hyperparameter tuning. Overall, BayesAge 2.0 represents a step forward in tAge prediction, offering a robust, accurate, and efficient tool for aging research and biomarker development.

The effect of frailty on the relationship between cognition and depression symptoms in older people. A differential analysis by European regions - Marcelo de Maio Nascimento; Andreas Ihle; Élvio Rúbio Gouveia; Ricardo Hugo Gonzalez; Adilson Marques (GeroScience, 2025)

The independent and combined associations of nocturnal sleep duration, sleep midpoint, and sleep onset latency with global cognitive function in older Chinese adults - Xueyao Wu; Jiaqiang Liao; Xin Chen; Jinyu Xiao; Xinyang Dui; Tianpei Ma; Lin Hu; Xunying Zhao; Qian Bu; Mengyu Fan; Tao Zhang; Lu Long; et al. (GeroScience, 2025)

Resistance training protects the hippocampus and precuneus against atrophy and benefits white matter integrity in older adults with mild cognitive impairment - Isadora C. Ribeiro; Camila V. L. Teixeira; Thiago J. R. de Resende; Brunno M. de Campos; Gabriel B. Silva; Marco C. Uchida; Thamires N. C. Magalhães; Luciana R. Pimentel-Silva; Ítalo K. Aventurato; Brenda C. Gonçalves; Marjorie C. R. da Silva; Liara Rizzi; et al. (GeroScience, 2025)

Detecting early stages of Alzheimer’s disease using a web-based cognitive battery - Jordan R. Hoffmeister; Brady R. Robison; Christopher T. Copeland; Calin I. Prodan; Jim G. Scott; Jordan M. Glenn (GeroScience, 2024)

A brief report on biomarkers of cellular senescence associated with liver frailty and length of stay in liver transplantation - William C. Miller; Matthew J. Yousefzadeh; Jessica Fisher; Heidi Sarumi; Varvara Kirchner; Laura J. Niedernhofer; Timothy Pruett (GeroScience, 2024)

A machine learning approach identifies cellular senescence on transcriptome data of human cells in vitro - Shamsed Mahmud; Chen Zheng; Fernando E. Santiago; Lei Zhang; Paul D. Robbins; Xiao Dong (GeroScience, 2024)

Human brain aging is associated with dysregulation of cell type epigenetic identity - Hyeonsoo Jeong; Isabel Mendizabal; Soojin V. Yi (GeroScience, 2024)
Significant links between aging and DNA methylation are emerging from recent studies. On the one hand, DNA methylation undergoes changes with age, a process termed as epigenetic drift. On the other hand, DNA methylation serves as a readily accessible and accurate biomarker for aging. A key missing piece of information, however, is the molecular mechanisms underlying these processes and how they are related, if any. Addressing the limitations of previous research due to the limited number of investigated CpGs and the heterogeneous nature of tissue samples, here, we have examined DNA methylation of over 20 million CpGs across a broad age span in neurons and non-neuronal cells, primarily oligodendrocytes. We show that aging is a primary predictor of DNA methylation variation, surpassing the influence of factors such as sex and schizophrenia diagnosis, among others. On the genome-wide scale, epigenetic drift manifests as significant yet subtle trends that are influenced by the methylation level of individual CpGs. We reveal that CpGs that are highly differentiated between cell types are especially prone to age-associated DNA methylation alterations, leading to the divergence of epigenetic cell type identities as individuals age. On the other hand, CpGs that are included in commonly used epigenetic clocks tend to be those sites that are not highly cell type differentiated. Therefore, dysregulation of epigenetic cell type identities and current DNA epigenetic clocks represent distinct features of age-associated DNA methylation alterations.

Paroxetine promotes longevity via ser-7-dop-4-IIS axis in Caenorhabditis elegans - Yiming Zhou; Lijuan Chen; Meijing Wang; Yang Yang; Bin Hu; Guolin Li; Fang Wei (GeroScience, 2024)

R4Alz-R: a cutting-edge tool for spotting the very first and subtle signs of aging-related cognitive impairment with high accuracy - Eleni Poptsi; Despina Moraitou; Emmanouil Tsardoulias; Andreas L. Symeonidis; Magda Tsolaki (GeroScience, 2024)

Centenarians—the way to healthy vascular ageing and longevity: a review from VascAgeNet - Sabrina Summer; Maria Borrell-Pages; Rosa-Maria Bruno; Rachel E. Climie; Konstantina Dipla; Aysenur Dogan; Kseniia Eruslanova; Emil Fraenkel; Francesco Mattace-Raso; Christopher J. A. Pugh; Keith D. Rochfort; Mark Ross; et al. (GeroScience, 2024)
The prevalence of centenarians, people who lived 100 years and longer, is steadily growing in the last decades. This exceptional longevity is based on multifaceted processes influenced by a combination of intrinsic and extrinsic factors such as sex, (epi-)genetic factors, gut microbiota, cellular metabolism, exposure to oxidative stress, immune status, cardiovascular risk factors, environmental factors, and lifestyle behavior. Epidemiologically, the incidence rate of cardiovascular diseases is reduced in healthy centenarians along with late onset of age-related diseases compared with the general aged population. Understanding the mechanisms that affect vascular ageing in centenarians and the underlying factors could offer valuable insights for developing strategies to improve overall healthy life span in the elderly. This review discusses these key factors influencing vascular ageing and how their modulation could foster healthy longevity.

Abnormalities of resting-state EEG microstates in older adults with cognitive frailty - Yu Zhang; Yue Ma; Yu-Lin Gao; Hai-Chao Fu (GeroScience, 2024)

EEG brain networks modulation during sleep onset: the effects of aging - Francesca Miraglia; Alessia Cacciotti; Fabrizio Vecchio; Serena Scarpelli; Maurizio Gorgoni; Luigi De Gennaro; Paolo Maria Rossini (GeroScience, 2024)

Linking metabolic syndrome, cerebral small vessel disease, and cognitive health: insights from a subclinical population study using TriNetX - Jigar Gosalia; Jocelyn M. Delgado Spicuzza; Christine K. Bowlus; James A. Pawelczyk; David N. Proctor (GeroScience, 2024)

Association of the interaction between daily step counts and frailty with disability in older adults - Daiki Watanabe; Tsukasa Yoshida; Yuya Watanabe; Yosuke Yamada; Motohiko Miyachi; Misaka Kimura (GeroScience, 2024)
The differences in the association of objectively measured physical activity with disability between frail and non-frail older adults remain unclear. We (1) evaluated the dose-dependent relationship between daily steps and disability in older adults with and without frailty and (2) examined the interaction between steps and frailty status in relation to the risk of disability. This prospective study used data from 4065 adults aged ≥ 65 years from the Kyoto-Kameoka Study, Japan. The mean daily step count obtained using triaxial accelerometers across ≥ 4 days was recorded. Frailty was evaluated using the validated Kihon Checklist. Disability was identified using the long-term care insurance system’s nationally unified database, with data collected until November 30, 2016. Overall, 385 disabilities were recorded during a median follow-up period of 3.32 years (12,855 person-years). After adjusting for confounders, an inverse association was observed between daily step count and disability risk. The disability risk plateaued at 5,000–7,000 steps/day in non-frail people, whereas step counts showed an almost linear inverse relationship with disability risk in frail people. Low step counts (< 5,000 steps) in frail people were more strongly associated with disability risk than were high step counts (≥ 5,000 steps) in non-frail people. The additive interaction between steps and frailty was associated with the relative excess risk of disability in frail people with low step counts (p for interaction = 0.015). The relationship between daily steps and disability differs between older adults with and without frailty, and the adverse effects of frailty on disability risk depend on physical activity.

A unique inflammaging profile generated by T cells from people with obesity is metformin resistant - S. SantaCruz-Calvo; S. Saraswat; G. H. Kalantar; E. Zukowski; H. Marszalkowski; A. Javidan; F. Gholamrezaeinejad; L. P. Bharath; P. A. Kern; X. D. Zhang; B. S. Nikolajczyk (GeroScience, 2024)

Plasma extracellular vesicles carry immune system-related peptides that predict human longevity - Xin Zhang; Sisi Ma; Syeda Iffat Naz; Erik J. Soderblom; Constantin Aliferis; Virginia Byers Kraus (GeroScience, 2024)
Extracellular vesicles (EVs) play crucial roles in aging. In this National Institutes on Aging-funded study, we sought to identify circulating extracellular vesicle (EV) biomarkers indicative of longevity. The plasma EV proteome of 48 older adults (mean age 77.2 ± 1.7 years [range 72–80]; 50% female, 50% Black, 50% < 2-year survival, 50% ≥ 10-year survival) was analyzed by high-resolution mass spectrometry and flow cytometry. The ability of EV peptides to predict longevity was evaluated in discovery ( n = 32) and validation ( n = 16) datasets with areas under receiver operating characteristic curves (AUCs). Longevity-associated large EV (LEV) plasma subpopulations were mainly related to immune cells (HLA-ABC + , CD9 + , and CD31 + ) and muscle cells (MCAD + and RyR2 + ). Of 7960 identified plasma EV peptides (519 proteins), 46.4% were related to the immune system and 10.1% to muscle. Compared with short-lived older adults, 756 EV peptides (131 proteins) had a higher abundance, and 130 EV peptides (78 proteins) had a lower abundance in long-lived adults. Among longevity-associated peptides, 437 (58 proteins) were immune system related, and 12 (2 proteins) were muscle related. Using just three to five plasma EV peptides (mainly complement components C2-C6), we achieved high predictive accuracy for longevity (AUC range 0.91–1 in a hold-out validation dataset). Our findings suggest that immune cells produce longevity-associated plasma EVs and elucidate fundamental mechanisms regulating aging and longevity. EV longevity predictors suggest there may be merit in targeting complement pathways to extend lifespan, for instance, with any one of the multiple complement inhibitors currently available or in clinical development.

Biomarkers of cellular senescence and major health outcomes in older adults - Steven R. Cummings; Li-Yung Lui; Aversa Zaira; Theresa Mau; Roger A. Fielding; Elizabeth J. Atkinson; Sheena Patel; Nathan LeBrasseur (GeroScience, 2024)
The geroscience hypothesis proposes that underlying biological processes, such as the accumulation of senescent cells, have deleterious effects on multiple tissues and increase the risk of many chronic conditions with aging. Senescent cells produce heterogenous biomarkers, also called senescence-associated secretory phenotype (SASP). Circulating concentrations of senescence biomarkers may reflect an underlying burden of senescent cells in various tissues. Plasma levels of these proteins have been associated with increased mortality and poorer physical function. The associations of them with the incidence of major age-related conditions including heart failure, cardiovascular disease, stroke, and dementia, have not been studied. We measured 35 senescence biomarkers in baseline plasma samples from 1678 participants aged 70–79 years old in the longitudinal Health ABC cohort study. Clinical outcomes were ascertained and validated over an average 11.5 year follow-up. In models adjusted for age, sex, and race, higher levels of most of senescence biomarkers were associated with increased risk of all-cause mortality, mobility limitation, and heart failure. Several were also associated with an increased risk of coronary heart disease, stroke, and dementia. Very few were associated with the risk of cancer. Proteins that were selected by Lasso regression for each outcome that commonly included GDF15 and IL6, significantly improved the prediction of mortality, mobility limitation, and heart failure compared with age, sex, and race alone. These results indicate that levels of senescence biomarkers predict an increased risk of several age-related clinical outcomes and may identify individuals most likely to benefit from senotherapeutics.

The effectiveness of digital technology interventions for cognitive function in older adults: a systematic review and meta-analysis of randomized controlled trials - Chen Chen; Ning Huang; Ban Hu; Mingyu Zhang; Junliang Yuan; Jing Guo (GeroScience, 2024)

A complex systems approach to mosaic loss of the Y chromosome - Xihan Guo; Xueqin Dai (GeroScience, 2024)

Canagliflozin treatment prevents follicular exhaustion and attenuates hallmarks of ovarian aging in genetically heterogenous mice - José V. V. Isola; Subhasri Biswas; Hashan Jayarathne; Chase R. Hubbart; Jessica D. Hense; Satoshi Matsuzaki; Michael T. Kinter; Kenneth M. Humphries; Sarah R. Ocañas; Marianna Sadagurski; Michael B. Stout (GeroScience, 2024)

Downregulation of the NF-κB protein p65 is a shared phenotype among most anti-aging interventions - Ahmed M. Elmansi; Abraham Kassem; Rafael M. Castilla; Richard A. Miller (GeroScience, 2024)

A multi-stage feature selection method to improve classification of potential super-agers and cognitive decliners using structural brain MRI data—a UK biobank study - Parvin Mohammadiarvejeh; Mohammad Fili; Alice Dawson; Brandon S. Klinedinst; Qian Wang; Shannin Moody; Neil Barnett; Amy Pollpeter; Brittany Larsen; Tianqi Li; Sara A. Willette; Jonathan P. Mochel; et al. (GeroScience, 2024)
Cognitive aging is described as the age-related decline in areas such as memory, executive function, reasoning, and processing speed. Super-Agers, adults over 80 years old, have cognitive function performance comparable to middle-aged adults. To improve cognitive reserve and potentially decrease Alzheimer’s disease (AD) risk, it is essential to contrast changes in regional brain volumes between “Positive-Agers” who have superior cognitive performance compared to their age peers but are not 80 years old yet and aging adults who show cognitive decline (i.e., “Cognitive Decliners”). Using longitudinal cognitive tests over 7–9 years in UK Biobank, principal component analysis (PCA) was first applied to four cognitive domains to create a general cognition (GC) composite score. The GC score was then used to identify latent cognitive groups. Given cognitive groups as the target variable and structural magnetic resonance imaging (sMRI) data and demographics as predictors, we developed a multi-stage feature selection algorithm to identify the most important features. We then trained a Random Forest (RF) classifier on the final set of 54 selected sMRI and covariate predictors to distinguish between Positive-Agers and Cognitive Decliners. The RF model achieved an AUC of 73%. The top 6 features were age, education, brain total surface area, the area of pars orbitalis, mean intensity of the thalamus, and superior frontal gyrus surface area. Prediction of cognitive trajectory types using sMRI may improve our understanding of successful cognitive aging.

Circulating small extracellular vesicles as blood-based biomarkers of muscle health in aging nonhuman primates - Shalini Mishra; Ashish Kumar; Yangen He; Yixin Su; Sangeeta Singh; Mark F. Santos; Rakesh Singh; Jingyun Lee; Cristina M. Furdui; Carol A. Shively; Stephen B. Kritchevsky; Thomas C. Register; et al. (GeroScience, 2024)
Age-associated loss of muscle mass and function and subsequent mobility decline define poor health outcomes, reduced quality of life, and mortality risk. The rate and extent of aging-related muscle loss varies across older adults. It is challenging to understand the molecular pathogenesis of mobility decline, as anthropometric and imaging techniques, primarily used in muscle function assessment, do not offer much molecular information. Small extracellular vesicles (sEV) are lipid membrane-bound, nano-sized (≤ 200 nm) vesicles which carry a wide array of biomolecules as their cargo. sEV contain cell/tissue-specific signatures on their surface and can be isolated from biofluids. These properties pose sEV as a minimally invasive means to monitor the functional and biological health of difficult-to-access tissues, establishing them as a promising liquid biopsy tool. Here, we first isolated skeletal muscle-derived sEV (sEV SKM ) from the serum of vervet monkeys (16 to < 25 years old) using alpha sarcoglycan (SGCA) as a muscle-specific sEV surface marker. sEV SKM were extensively characterized for size, concentration, purity, and specificity. Further, sEV SKM isolated from young (11–15 years) and old (25–29 years) monkeys’ serum were characterized for oxidized proteins by mass spectrometry and miRNAs by small-RNAseq. Notably, the analysis of oxidized proteins indicated perturbation of metabolic pathways, actin cytoskeleton, muscle cytoskeleton regulation, and HIF-1 signaling in older monkeys. Furthermore, small-RNAseq analysis identified differential expression of several miRNAs regulating metabolic pathways, inflammation, and stress signaling. Altogether, these results suggest that it is feasible to isolate sEV SKM and use them to identify molecular biomarkers that reflect the physiological state of muscle tissue.

Differential proteomic profiles between cognitive frail and robust older adults from the MELoR cohort - Siong Meng Lim; Yee Ling Ng; Abu Bakar Abdul Majeed; Maw Pin Tan; Hui Min Khor; Shahrul Bahyah Kamaruzzaman; Kalavathy Ramasamy (GeroScience, 2024)

ADAM10-mediated β-klotho degradation: a key to FGF21 resistance in senescent vascular endothelial cells - Yuzhen Huang; Yucong Zhang; Ni Yang; Zonghao Qian; Ziwei Fang; Lang Zeng; Yi Huang; Han Li; Mandi Luo; Jinhua Yan; Lei Ruan; Cuntai Zhang; et al. (GeroScience, 2024)

Leaky gut in systemic inflammation: exploring the link between gastrointestinal disorders and age-related diseases - Jonathan Escalante; Olivia Artaiz; Shanti Diwakarla; Rachel M. McQuade (GeroScience, 2024)
Global average life expectancy has steadily increased over the last several decades and is projected to reach ~ 77 years by 2050. As it stands, the number of people > 60 years currently outnumbers children younger than 5 years, and by 2050, it is anticipated that the global population of people aged > 60 years will double, surpassing 2.1 billion. This demographic shift in our population is expected to have substantial consequences on health services globally due to the disease burden associated with aging. Osteoarthritis, chronic obstructive pulmonary disease, diabetes, cardiovascular disease, and cognitive decline associated with dementia are among the most common age-related diseases and contribute significantly to morbidity and mortality in the aged population. Many of these age-related diseases have been linked to chronic low-grade systemic inflammation which often accompanies aging. Gastrointestinal barrier dysfunction, also known as “leaky gut,” has been shown to contribute to systemic inflammation in several diseases including inflammatory bowel disease and irritable bowel syndrome, but its role in the development and/or progression of chronic low-grade systemic inflammation during aging is unclear. This review outlines current literature on the leaky gut in aging, how leaky gut might contribute to systemic inflammation, and the links between gastrointestinal inflammatory diseases and common age-related diseases to provide insight into a potential relationship between the intestinal barrier and inflammation.

Blood-based biomarkers for early frailty are sex-specific: validation of a combined in silico prediction and data-driven approach - Jelle C. B. C. de Jong; Martien P. M. Caspers; Remon Dulos; Jessica Snabel; Marjanne D. van der Hoek; Feike R. van der Leij; Robert Kleemann; Jaap Keijer; Arie G. Nieuwenhuizen; Anita M. van den Hoek; Lars Verschuren (GeroScience, 2024)
Frailty is characterized by loss of physical function and is preferably diagnosed at an early stage (e.g., during pre-frailty). Unfortunately, sensitive tools that can aid early detection are lacking. Blood-based biomarkers, reflecting pathophysiological adaptations before physical symptoms become apparent, could be such tools. We identified candidate biomarkers using a mechanism-based computational approach which integrates a priori defined database-derived clinical biomarkers and skeletal muscle transcriptome data. Identified candidate biomarkers were used as input for a sex-specific correlation analysis, using individual gene expression data from female ( n = 24) and male ( n = 28) older adults (all 75 + years, ranging from fit to pre-frail) and three frailty-related physical parameters. Male and female groups were matched based on age, BMI, and Fried frailty index. The best correlating candidate biomarkers were evaluated, and selected biomarkers were measured in serum. In females, myostatin and galectin-1 and, in males, cathepsin B and thrombospondin-4 serum levels were significantly different between the physically weakest and fittest participants (all p < 0.05). Logistic regression confirmed the added value of these biomarkers in conjunction with age and BMI to predict whether the subjects belonged to the weaker or fittest group (AUC = 0.80 in females and AUC = 0.83 in males). In conclusion, both in silico and in vivo analyses revealed the sex-specificity of candidate biomarkers, and we identified a selection of potential biomarkers which could be used in a biomarker panel for early detection of frailty. Further investigation is needed to confirm these leads for early detection of frailty.

Losartan attenuates sex-dependent hypertension, neuroinflammation, and cognitive impairment in the aging male sprague–dawley rat - Kayla M. Nist; Hannah Bard; Brannon McBride; Angela L. Capriglione; Jesse D. Moreira; David H. Farb; Richard D. Wainford (GeroScience, 2024)
The prevalence of hypertension increases with age and is the leading modifiable risk factor for cognitive impairment and dementia. At present, the neural mechanisms promoting hypertension across the lifespan are incompletely understood. Using the Sprague–Dawley (SD) rat as a model of normal aging, we hypothesized (1) blood brain barrier (BBB) disruption and neuroinflammation in the paraventricular nucleus (PVN) of the hypothalamus enhances sympathetic tone and contributes to age-dependent hypertension, (2) age-dependent hypertension is associated with cognitive impairment, and (3) lowering blood pressure in aged rats with established hypertension improves cognitive function. We found male, but not female, rats develop age-dependent hypertension with enhanced sympathetic tone, BBB disruption, and neuroinflammation in the PVN. Aged hypertensive male rats also showed impairments in recognition and spatial memory. Utilizing pharmacological interventions, blood pressure was lowered in male rats with established hypertension using either losartan (LOS) or hydrochlorothiazide. However, only losartan improved recognition memory. Further, LOS reduced BBB disruption, microglial activation, astrocyte reactivity, and proinflammatory cytokine expression in the PVN which we speculate contributes to a decrease in blood pressure. These data show SD rats develop age-dependent hypertension and cognitive impairment in a sex-dependent manner. However, not all antihypertensive agents improve cognitive function equally as only losartan, an angiotensin II type 1 receptor antagonist (AT1R) improved recognition memory. Thus, AT1R antagonists represent a potential therapeutic approach for treating cognitive decline in the aging population.

Cognitive frailty and functional disability in older adults: A 10-year prospective cohort study in Japan - Sanmei Chen; Tao Chen; Takanori Honda; Hiro Kishimoto; Yu Nofuji; Kenji Narazaki (GeroScience, 2024)
Cognitive frailty is considered a clinical entity associated with a high risk for adverse health outcomes. However, its clinical significance remains poorly understood. This study investigated the association between cognitive frailty and risk for functional disability among community-dwelling older adults. In total, 1,597 Japanese adults aged ≥ 65 years that were free of dementia and functional disability at baseline were prospectively followed for 10 years. Cognitive frailty was defined as the presence of both physical frailty (using Cardiovascular Health Study criteria) and cognitive impairment (Mini-Mental State Examination score < 26 points). Functional disability was identified using Japan’s Long-term Care Insurance System database. Cox proportional hazard models were used to estimate the hazard ratios (HR) for cognitive frailty on the risk for functional disability. Functional disability was identified in 488 participants during follow-up. A multiplicative interaction effect between cognitive impairment and physical frailty on the risk of disability was observed ( p = 0.045). Compared with the robust group, the multivariable-adjusted HRs (95% confidence interval) for functional disability were 3.70 (2.37‒5.77) for cognitive frailty, 2.51 (1.81‒3.47) for physical pre-frailty with cognitive impairment, 2.16 (1.42‒3.29) for cognitive impairment only, 1.95 (1.36‒2.80) for physical frailty only, and 1.94 (1.53‒2.46) for physical pre-frailty only. These associations remained after adjusting for the competing risk for death and in sensitivity analyses to minimize potential reverse causality. Cognitive frailty is associated with an increased risk for functional disability in community-dwelling older adults. Cognitive frailty may be a clinically important target for the prevention of functional disability.

Evaluating frailty assessment tools and biological frailty markers in C57BL/6 female mice - Laís R. Perazza; Christopher M. Bougher; LaDora V. Thompson (GeroScience, 2024)
Frailty is a complex condition characterized by a decline in multiple physiological systems, compromising an individual’s ability to maintain homeostasis. The onset and progression of frailty are linked to negative health outcomes such as disability, hospitalization, and mortality. To better understand frailty mechanisms, animal models have become valuable due to their accessibility to critical tissues and the ability to control variables. This study investigates frailty in female C57BL/6JN mice by comparing the two most widely accepted frailty assessment tools—the Physical Phenotype (PP) and the Frailty Index (FI). While FI relies on the accumulation of health deficits, PP focuses on functional physical performance. Our results suggest that these tools are complementary rather than interchangeable, each targeting distinct markers of frailty. To address the limitations of both, we propose a new combined assessment tool, the Vitality Phenotype (VP), which integrates physical performance and health deficits into a more comprehensive evaluation. We also explore the challenges in standardizing frailty cutoff values and the need for a reference group to enhance the accuracy of frailty identification. Lastly, we investigate the correlation between frailty criteria and biological markers, particularly bone mineral density (BMD), which shows a significant relationship with physical performance metrics such as grip strength and voluntary wheel activity, highlighting its potential role in frailty pathophysiology.

Establishment of primary and immortalized fibroblasts reveals resistance to cytotoxic agents and loss of necroptosis-inducing ability in long-lived Damaraland mole-rats - Yusuke Suzuki; Kanta Yamaguchi; Kaitlyn N. Lewis Hardell; Kurumi Ota; Taira Kamikado; Yoshimi Kawamura; Rochelle Buffenstein; Kaori Oka; Kyoko Miura (GeroScience, 2024)
The Damaraland mole-rat (DMR; Fukomys damarensis ) is a long-lived (~ 20 years) Bathyergid rodent that diverged 26 million years ago from its close relative, the naked mole-rat (NMR). While the properties of NMR cultured fibroblasts have been extensively studied and have revealed several unusual features of this cancer-resistant, long-lived species, comparative DMR studies are extremely limited. We optimized conditions for successfully culturing primary DMR skin fibroblasts and also established immortalized DMR cells using simian virus 40 early region expression. Like NMRs, DMR fibroblasts are more resistant than mice to various cytotoxins including heavy metals, DNA-damaging agents, oxidative stressors, and proteasome inhibitors. DMR genome sequencing analyses revealed the presence of premature stop codons in the master regulator genes of necroptosis, an inflammatory programmed cell death—receptor-interacting protein kinase 3 ( RIPK3 ) and mixed lineage kinase domain-like ( MLKL ), although these mutations have different locations to those found in the NMR. DMR cells, like NMR cells, did not show significantly increased cell death in response to necroptosis induction. Our data suggest that both Bathyergid species require species-specific cell culture conditions for optimized growth, display similar resistance to cytotoxins, and show loss-of-function mutations abrogating the ability to employ necroptosis. These shared traits may contribute to their evolved adaptations to their subterranean lifestyle and prolonged longevity. These convergent insights and valuable resource may be pertinent to biomedical research.

Effect of transcranial direct current stimulation with cognitive training on executive functions in healthy older adults: a secondary analysis from the ACT trial - Serkan Aksu; Aprinda Indahlastari; Andrew O’Shea; Michael Marsiske; Ronald Cohen; Gene E. Alexander; Steven T. DeKosky; Georg A. Hishaw; Yunfeng Dai; Samuel S. Wu; Adam J. Woods (GeroScience, 2024)

Exploring the global impact of obesity and diet on dementia burden: the role of national policies and sex differences - Xueshan Cao; Huiyuan Peng; Ziyi Hu; Chang Xu; Monan Ning; Mengge Zhou; Yuanqi Mi; Peixin Yu; Vince Fazekas-Pongor; David Major; Zoltan Ungvari; Monika Fekete; et al. (GeroScience, 2024)

Associations between MASLD, atrial fibrillation, cardiovascular events, mortality and aspirin use in older adults - Daniel Clayton-Chubb; Stuart K. Roberts; Ammar Majeed; Robyn L. Woods; Andrew M. Tonkin; Mark R. Nelson; Andrew T. Chan; Joanne Ryan; Cammie Tran; Alexander Hodge; John S. Lubel; Hans G. Schneider; et al. (GeroScience, 2024)

Life satisfaction and risk of dementia over 18 years: an analysis of the National Alzheimer's Coordinating Center dataset - Selin Karakose; Martina Luchetti; Yannick Stephan; Angelina R. Sutin; Antonio Terracciano (GeroScience, 2024)

Dysregulation of astrocytic Aquaporin-1 in the brains of oldest-old rhesus macaques: the NIA caloric restriction study - Opal Stayer-Wilburn; Donald I. Brown; Randy L. Woltjer; Sathya Srinivasan; Byung S. Park; Penny Shultz; Ana Vitantonio; Christina Dimovasili; Kelli L. Vaughan; Matthew F. Starost; Douglas Rosene; Julie A. Mattison; et al. (GeroScience, 2024)

Advancing prediction of age-related vascular cognitive impairment based on peripheral and retinal vascular health in a pilot study: a novel comprehensive assessment developed for a prospective workplace-based cohort (The Semmelweis Study) - Tamas Csipo; Agnes Lipecz; Peter Mukli; Anna Péterfi; Zsofia Szarvas; Anna Ungvari; Lamyae El Alaoui; Márton Sándor; Attila Kállai; Mónika Fekete; Gábor Á. Fülöp; Stefano Tarantini; et al. (GeroScience, 2024)
With a growing elderly population in the European Union, age-related diseases associated with unhealthy aging pose increasing public health challenges, including a loss of independence and heightened societal burdens. The Semmelweis Study, a prospective occupational cohort study in Hungary, seeks to identify determinants of unhealthy aging, focusing on the complex relationship between lifestyle, environmental, occupational factors, and the development of chronic age-associated diseases, including age-related vascular cognitive impairment (VCI). The primary objective of this pilot study was to establish a robust, high-throughput assessment methodology to comprehensively evaluate both peripheral and cerebrovascular health to provide a solid foundation for the forthcoming Semmelweis Study framework. The study involved 49 participants aged 23 to 87 years, and it assessed multi-domain cognitive performance through an automated battery of tests (CANTAB). Vascular health was comprehensively evaluated using laser speckle contrast imaging (LSCI), flow-mediated dilation (FMD), static and dynamic retinal vessel analysis (SVA, DVA), and measurements of vascular stiffness. The retinal microvasculature, which closely mirrors the cerebral circulation in anatomy, physiology, and pathophysiology, provided a unique window for examination. Optical imaging through SVA and DVA enables the identification of structural and functional changes in the central nervous system’s microcirculation, which are highly relevant to the pathogenesis of VCI. Subsequently, the collected measures were integrated into vascular health indices using principal component analysis (PCA) and the relationship to the age and cognitive status of study participants was explored. These comprehensive vascular health indices demonstrated a correlation not only with age but also with cognitive performance. This methodology holds promise for providing novel insights into the intricate interplay between vascular and cognitive health within the context of the Semmelweis Study.

Slowed epigenetic aging in Olympic champions compared to non-champions - Zsolt Radák; Dóra Aczél; Iván Fejes; Soroosh Mozaffaritabar; Gabor Pavlik; Zsolt Komka; László Balogh; Zsofia Babszki; Gergely Babszki; Erika Koltai; Kristen M. McGreevy; Juozas Gordevicius; et al. (GeroScience, 2024)
The lifestyle patterns of top athletes are highly disciplined, featuring strict exercise regimens, nutrition plans, and mental preparation, often beginning at a young age. Recently, it was shown that physically active individuals exhibit slowed epigenetic aging and better age-related outcomes. Here, we investigate whether the extreme intensity of physical activity of Olympic champions still has a beneficial effect on epigenetic aging. To test this hypothesis, we examined the epigenetic aging of 59 Hungarian Olympic champions and of the 332 control subjects, 205 were master rowers. We observed that Olympic champions exhibit slower epigenetic aging, applying seven state-of-the-art epigenetic aging clocks. Additionally, male champions who won any medal within the last 10 years showed slower epigenetic aging compared to other male champions, while female champions exhibited the opposite trend. We also found that wrestlers had higher age acceleration compared to gymnasts, fencers, and water polo players. We identified the top 20 genes that showed the most remarkable difference in promoter methylation between Olympic champions and non-champions. The hypo-methylated genes are involved in synaptic health, glycosylation, metal ion membrane transfer, and force generation . Most of the hyper-methylated genes were associated with cancer promotion. The data suggest that rigorous and long-term exercise from adolescence to adulthood has beneficial effects on epigenetic aging.

Plasma triacylglycerol length and saturation level mark healthy aging groups in humans - Weisha Li; Bauke V. Schomakers; Michel van Weeghel; Lotte Grevendonk; Frédéric M. Vaz; Gajja S. Salomons; Patrick Schrauwen; Joris Hoeks; Arwen W. Gao; Riekelt H. Houtkooper; Georges E. Janssens (GeroScience, 2024)

Expression of alpha smooth muscle actin decreases with ageing and increases upon lumen obstruction in mouse brain pericytes - Fanni Győri; Ádám Mészáros; Mónika Krecsmarik; Kinga Molnár; Cornel Balta; Anca Hermenean; Attila E. Farkas; István A. Krizbai; Imola Wilhelm (GeroScience, 2024)
Cerebral pericytes are mural cells covering brain microvessels, organized as ensheathing, mesh and thin-strand pericytes. These latter two, together called capillary pericytes, have low levels of alpha smooth muscle actin (α-SMA), regulating basal vascular tone and applying a slow influence on cerebral blood flow. Pericytes are subject to alterations in ageing which may be even more pronounced in age-related pathologies, including microinfarcts, which usually affect a large number of vessels in the ageing brain. We modelled this condition by injecting 10 µm-size microspheres into the circulation of mice resulting in the occlusion of capillaries covered by ensheathing and mesh pericytes. We observed that α-SMA and Acta2 , the gene encoding it, as well as TGF-β1/ Tgfb1 , the major regulator of α-SMA, decreased during ageing in cerebral microvessels. In the vicinity of the microspheres stalled in the capillaries, expression of α-SMA increased significantly in both ensheathing and especially in mesh pericytes, both in young (2 to 3 months of age) and old (24 months of age) mice. On the other hand, γ-actin was detected in endothelial cells, but not in pericytes, and decreased in microvessels of microsphere-containing hemispheres. Altogether, our data show that obstruction of cerebral microvessels increases α-SMA expression in pericytes in both age groups, but this does not compensate for the lower expression of the contractile protein in old animals. Increased α-SMA expression may lead to constriction of the obstructed vessels probably aggravating flow heterogeneity in the aged brain.

Evaluating the reproducibility of a deep learning algorithm for the prediction of retinal age - Jay Rodney Toby Zoellin; Ferhat Turgut; Ruiye Chen; Amr Saad; Samuel D. Giesser; Chiara Sommer; Viviane Guignard; Jonas Ihle; Marie-Louise Mono; Matthias D. Becker; Zhuoting Zhu; Gábor Márk Somfai (GeroScience, 2024)
Recently, a deep learning algorithm (DLA) has been developed to predict the chronological age from retinal images. The Retinal Age Gap (RAG), a deviation between predicted age from retinal images (Retinal Age, RA) and chronological age, correlates with mortality and age-related diseases. This study evaluated the reliability and accuracy of RA predictions and analyzed various factors that may influence them. We analyzed two groups of participants: Intravisit and Intervisit, both imaged by color fundus photography. RA was predicted using an established algorithm. The Intervisit group comprised 26 subjects, imaged in two sessions. The Intravisit group had 41 subjects, of whom each eye was photographed twice in one session. The mean absolute test–retest difference in predicted RA was 2.39 years for Intervisit and 2.13 years for Intravisit, with the latter showing higher prediction variability. The chronological age was predicted accurately from fundus photographs. Subsetting image pairs based on differential image quality reduced test–retest discrepancies by up to 50%, but mean image quality was not correlated with retest outcomes. Marked diurnal oscillations in RA predictions were observed, with a significant overestimation in the afternoon compared to the morning in the Intravisit cohort. The order of image acquisition across imaging sessions did not influence RA prediction and subjective age perception did not predict RAG. Inter-eye consistency exceeded 3 years. Our study is the first to explore the reliability of RA predictions. Consistent image quality enhances retest outcomes. The observed diurnal variations in RA predictions highlight the need for standardized imaging protocols, but RAG could soon be a reliable metric in clinical investigations.

Alzheimer’s Disease polygenic risk, the plasma proteome, and dementia incidence among UK older adults - May A. Beydoun; Hind A. Beydoun; Zhiguang Li; Yi-Han Hu; Nicole Noren Hooten; Jun Ding; Sharmin Hossain; Christian A. Maino Vieytes; Lenore J. Launer; Michele K. Evans; Alan B. Zonderman (GeroScience, 2024)
Alzheimer’s Disease (AD) is a complex polygenic neurodegenerative disorder. Its genetic risk’s relationship with all-cause dementia may be influenced by the plasma proteome. Up to 40,139 UK Biobank participants aged ≥ 50y at baseline assessment (2006–2010) were followed-up for ≤ 15 y for dementia incidence. Plasma proteomics were performed on a sub-sample of UK Biobank participants ( k = 1,463 plasma proteins). AD polygenic risk scores (PRS) were used as the primary exposure and Cox proportional hazards models were conducted to examine the AD PRS-dementia relationship. A four-way decomposition model then partitioned the total effect (TE) of AD PRS on dementia into an effect due to mediation only, an effect due to interaction only, neither or both. The study found that AD PRS tertiles significantly increased the risk for all-cause dementia, particularly among women. The study specifically found that AD PRS was associated with a 79% higher risk for all-cause dementia for each unit increase (HR = 1.79, 95% CI: 1.70–1.87, P < 0.001). Eighty-six plasma proteins were significantly predicted by AD PRS, including a positive association with PLA2G7, BRK1, the glial acidic fibrillary protein (GFAP), neurofilament light chain (NfL), and negative with TREM2. Both GFAP and NfL significantly interacted synergistically with AD PRS to increase all-dementia risk (> 10% of TE is pure interaction), while GFAP was also an important consistent mediator in the AD PRS-dementia relationship. In summary, we detected significant interactions of NfL and GFAP with AD PRS, in relation to dementia incidence, suggesting potential for personalized dementia prevention and management.

Serine metabolism in aging and age-related diseases - Shengshuai Shan; Jessica M. Hoffman (GeroScience, 2024)

Comparative lifespan and healthspan of nonhuman primate species common to biomedical research - Hillary F. Huber; Hannah C. Ainsworth; Ellen E. Quillen; Adam Salmon; Corinna Ross; Adinda D. Azhar; Karen Bales; Michele A. Basso; Kristine Coleman; Ricki Colman; Huda S. Darusman; William Hopkins; et al. (GeroScience, 2024)

DEAD-box RNA helicase DDX-23 mediates dietary restriction induced health span in Caenorhabditis elegans - Yi Xiao; Hongjiao Zhang; Xiaocong Li; Chao Han; Fang Liu (GeroScience, 2024)

Prevalence of dehydration in older hospitalized patients with oropharyngeal dysphagia - Paula Viñas; Pere Clavé; Noemí Tomsen (GeroScience, 2024)

Artificial intelligence improves risk prediction in cardiovascular disease - Achamyeleh Birhanu Teshale; Htet Lin Htun; Mor Vered; Alice J. Owen; Joanne Ryan; Andrew Tonkin; Rosanne Freak-Poli (GeroScience, 2024)

White matter lesions contribute to motor and non-motor disorders in Parkinson’s disease: a critical review - Yue-Qi Jiang; Qiu-Zhu Chen; Yang Yang; Cai-Xia Zang; Jing-Wei Ma; Jin-Rong Wang; Yi-Rong Dong; Ning Zhou; Xing Yang; Fang-Fang Li; Xiu-Qi Bao; Dan Zhang (GeroScience, 2024)

Cognitive aging and reserve factors in the Metropolit 1953 Danish male cohort - Mostafa Mehdipour Ghazi; Olalla Urdanibia-Centelles; Aftab Bakhtiari; Birgitte Fagerlund; Mark Bitsch Vestergaard; Henrik Bo Wiberg Larsson; Erik Lykke Mortensen; Merete Osler; Mads Nielsen; Krisztina Benedek; Martin Lauritzen (GeroScience, 2024)
Identifying early predictors of cognitive decline and at-risk individuals is essential for timely intervention and prevention of dementia. This study aimed to detect neurobiological changes and factors related to cognitive performance in the Metropolit 1953 Danish male birth cohort. We analyzed data from 582 participants, aged 57–68 years, using machine learning techniques to group cognitive trajectories into four clusters differentiating high- and low-performing groups. These clusters were then evaluated with MRI, EEG, and lifestyle/familial risk factors to identify predictors of cognitive decline. Low education and occupation, alcohol consumption, and type 2 diabetes were associated with lower cognitive performance. Declines in neocortical volume and increases in frontotemporal alpha and temporoparietal gamma activity preceded clinical symptoms of cognitive decline. Neocortical atrophy and disruptions in network activity were prominent in lower-performing groups, with higher education and IQ scores and a lower prevalence of lifestyle factors moderating cognitive decline.

A review on gut microbiota and miRNA crosstalk: implications for Alzheimer’s disease - Maruthu Pandian Ayyanar; Murali Vijayan (GeroScience, 2024)

Influence of individual’s age on the characteristics of brain effective connectivity - Nakisa Nourzadegan; Sepideh Baghernezhad; Mohammad Reza Daliri (GeroScience, 2024)

The Multi-State Epigenetic Pacemaker enables the identification of combinations of factors that influence DNA methylation - Colin Farrell; Keshiv Tandon; Roberto Ferrari; Kalsuda Lapborisuth; Rahil Modi; Sagi Snir; Matteo Pellegrini (GeroScience, 2024)
Epigenetic clocks, DNA methylation-based predictive models of chronological age, are often utilized to study aging associated biology. Despite their widespread use, these methods do not account for other factors that also contribute to the variability of DNA methylation data. For example, many CpG sites show strong sex-specific or cell-type-specific patterns that likely impact the predictions of epigenetic age. To overcome these limitations, we developed a multidimensional extension of the Epigenetic Pacemaker, the Multi-state Epigenetic Pacemaker (MSEPM). We show that the MSEPM is capable of accurately modeling multiple methylation-associated factors simultaneously, while also providing site-specific models that describe the per site relationship between methylation and these factors. We utilized the MSEPM with a large aggregate cohort of blood methylation data to construct models of the effects of age-, sex-, and cell-type heterogeneity on DNA methylation. We found that these models capture a large faction of the variability at thousands of DNA methylation sites. Moreover, this approach allows us to identify sites that are primarily affected by aging and no other factors. An analysis of these sites reveals that those that lose methylation over time are enriched for CTCF transcription factor chip peaks, while those that gain methylation over time are associated with bivalent promoters of genes that are not expressed in blood. These observations suggest mechanisms that underlie age-associated methylation changes and suggest that age-associated increases in methylation may not have strong functional consequences on cell states. In conclusion, the MSEPM is capable of accurately modeling multiple methylation-associated factors, and the models produced can illuminate site-specific combinations of factors that affect methylation dynamics.

Senescence cell signature associated with poor prognosis, epithelial–mesenchymal transition, solid histology, and spread through air spaces in lung adenocarcinoma - Young Wha Koh; Jae-Ho Han; Seokjin Haam; Hyun Woo Lee (GeroScience, 2024)

Correction to: Impaired brain ability of older adults to transit and persist to latent states with well‑organized structures at wakeful rest - Zijin Liu; Haishuo Xia; Antao Chen (GeroScience, 2024)

Analysis of six consecutive waves of ICU-admitted COVID-19 patients: key findings and insights from a Portuguese population - Cristiana P. Von Rekowski; Iola Pinto; Tiago A. H. Fonseca; Rúben Araújo; Cecília R. C. Calado; Luís Bento (GeroScience, 2024)
Identifying high-risk patients, particularly in intensive care units (ICUs), enhances treatment and reduces severe outcomes. Since the pandemic, numerous studies have examined COVID-19 patient profiles and factors linked to increased mortality. Despite six pandemic waves, to the best of our knowledge, there is no extensive comparative analysis of patients’ characteristics across these waves in Portugal. Thus, we aimed to analyze the demographic and clinical features of 1041 COVID-19 patients admitted to an ICU and their relationship with the different SARS-Cov-2 variants in Portugal. Additionally, we conducted an in-depth examination of factors contributing to early and late mortality by analyzing clinical data and laboratory results from the first 72 h of ICU admission. Our findings revealed a notable decline in ICU admissions due to COVID-19, with the highest mortality rates observed during the second and third waves. Furthermore, immunization could have significantly contributed to the reduction in the median age of ICU-admitted patients and the severity of their conditions. The factors contributing to early and late mortality differed. Age, wave number, D-dimers, and procalcitonin were independently associated with the risk of early death. As a measure of discriminative power for the derived multivariable model, an AUC of 0.825 ( p < 0.001; 95% CI, 0.719–0.931) was obtained. For late mortality, a model incorporating age, wave number, hematologic cancer, C-reactive protein, lactate dehydrogenase, and platelet counts resulted in an AUC of 0.795 ( p < 0.001; 95% CI, 0.759–0.831). These findings underscore the importance of conducting comprehensive analyses across pandemic waves to better understand the dynamics of COVID-19.

The impact of inactivation of the GH/IGF axis during aging on healthspan - Sher Bahadur Poudel; Ryan R. Ruff; Zhiming He; Manisha Dixit; Godze Yildirim; Hashan Jayarathne; Dulmalika Herath Manchanayake; Jelena Basta-Pljakic; Silvana Duran-Ortiz; Mitchell B. Schaffler; John J. Kopchick; Marianna Sadagurski; et al. (GeroScience, 2024)

Plasma proteomic signature of risk and prognosis of frailty in the UK Biobank - Jianhong Xu; Jingyun Liu; Junhan Tang; Jinhui Liao; Xiaojuan Liu; Michelle C. Odden; Chenkai Wu (GeroScience, 2024)

ACSL3 is a promising therapeutic target for alleviating anxiety and depression in Alzheimer’s disease - Celeste Yin-Chieh Wu; Yulan Zhang; Peyton Howard; Fang Huang; Reggie Hui-Chao Lee (GeroScience, 2024)
Alzheimer’s disease (AD), the leading cause of dementia, affects over 55 million people worldwide and is often accompanied by depression and anxiety. Both significantly impact patients’ quality of life and impose substantial societal and economic burdens on healthcare systems. Identifying the complex regulatory mechanisms that contribute to the psychological and emotional deficits in AD will provide promising therapeutic targets. Biosynthesis of omega-3 (ω3) and omega-6 fatty acids (ω6-FA) through long-chain acyl-CoA synthetases (ACSL) is crucial for cell function and survival. This is due to ω3/6-FA’s imperative role in modulating the plasma membrane, energy production, and inflammation. While ACSL dysfunction is known to cause heart, liver, and kidney diseases, the role of ACSL in pathological conditions in the central nervous system (e.g., depression and anxiety) remains largely unexplored. The impact of ACSLs on AD-related depression and anxiety was investigated in a mouse model of Alzheimer’s disease (3xTg-AD). ACSL3 levels were significantly reduced in the hippocampus of aged 3xTg-AD mice (via capillary-based immunoassay). This reduction in ACAL3 was closely associated with increased depression and anxiety-like behavior (via forced swim, tail suspension, elevated plus maze, and sucrose preference test). Upregulation of ACSL3 via adenovirus in aged 3xTg-AD mice led to increased protein levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor C (VEGF-C) (via brain histology, capillary-based immunoassay), resulting in alleviation of depression and anxiety symptoms. The present study highlights a novel neuroprotective role of ACSL3 in the brain. Targeting ACSL3 will offer an innovative approach for treating AD-related depression and anxiety.

Plasma proteomics-based brain aging signature and incident dementia risk - Minghao Kou; Hao Ma; Xuan Wang; Yoriko Heianza; Lu Qi (GeroScience, 2024)
Investigating brain-enriched proteins with machine learning methods may enable a brain-specific understanding of brain aging and provide insights into the molecular mechanisms and pathological pathways of dementia. The study aims to analyze associations of brain-specific plasma proteomic aging signature with risks of incident dementia. In 45,429 dementia-free UK Biobank participants at baseline, we generated a brain-specific biological age using 63 brain-enriched plasma proteins with machine learning methods. The brain age gap was estimated, and Cox proportional hazards models were used to study the association with incident all-cause dementia, Alzheimer’s disease (AD), and vascular dementia. Per-unit increment in the brain age gap z -score was associated with significantly higher risks of all-cause dementia (hazard ratio [95% confidence interval], 1.67 [1.56–1.79], P < 0.001), AD (1.85 [1.66–2.08], P < 0.001), and vascular dementia (1.86 [1.55–2.24], P < 0.001), respectively. Notably, 2.1% of the study population exhibited extreme old brain aging defined as brain age gap z -score > 2, correlating with over threefold increased risks of all-cause dementia and vascular dementia (3.42 [2.25–5.20], P < 0.001, and 3.41 [1.05–11.13], P = 0.042, respectively), and fourfold increased risk of AD (4.45 [2.32–8.54], P < 0.001). The associations were stronger among participants with healthier lifestyle factors (all P -interaction < 0.05). These findings were corroborated by magnetic resonance imaging assessments showing that a higher brain age gap aligns global pathophysiology of dementia, including global and regional atrophy in gray matter, and white matter lesions ( P < 0.001). The brain-specific proteomic age gap is a powerful biomarker of brain aging, indicative of dementia risk and neurodegeneration.

Functional and vascular neuroimaging in maritime pilots with long-term sleep disruption - Lara J. Mentink; Matthias J. P. van Osch; Leanne J. Bakker; Marcel G. M. Olde Rikkert; Christian F. Beckmann; Jurgen A. H. R. Claassen; Koen V. Haak (GeroScience, 2024)
The mechanism underlying the possible causal association between long-term sleep disruption and Alzheimer’s disease remains unclear Musiek et al. 2015. A hypothesised pathway through increased brain amyloid load was not confirmed in previous work in our cohort of maritime pilots with long-term work-related sleep disruption Thomas et al. Alzheimer’s Res Ther 2020;12:101. Here, using functional MRI, T2-FLAIR, and arterial spin labeling MRI scans, we explored alternative neuroimaging biomarkers related to both sleep disruption and AD: resting-state network co-activation and between-network connectivity of the default mode network (DMN), salience network (SAL) and frontoparietal network (FPN), vascular damage and cerebral blood flow (CBF). We acquired data of 16 maritime pilots (56 ± 2.3 years old) with work-related long-term sleep disruption (23 ± 4.8 working years) and 16 healthy controls (59 ± 3.3 years old), with normal sleep patterns (Pittsburgh Sleep Quality Index ≤ 5). Maritime pilots did not show altered co-activation in either the DMN, FPN, or SAL and no differences in between-network connectivity. We did not detect increased markers of vascular damage in maritime pilots, and additionally, maritime pilots did not show altered CBF-patterns compared to healthy controls. In summary, maritime pilots with long-term sleep disruption did not show neuroimaging markers indicative of preclinical AD compared to healthy controls. These findings do not resemble those of short-term sleep deprivation studies. This could be due to resiliency to sleep disruption or selection bias, as participants have already been exposed to and were able to deal with sleep disruption for multiple years, or to compensatory mechanisms Mentink et al. PLoS ONE. 2021;15(12):e0237622. This suggests the relationship between sleep disruption and AD is not as strong as previously implied in studies on short-term sleep deprivation, which would be beneficial for all shift workers suffering from work-related sleep disruptions.

Stay social, stay young: a bioanthropological outlook on the processes linking sociality and ageing - Vincenzo Iannuzzi; Nicolas Narboux-Nême; Andrea Lehoczki; Giovanni Levi; Cristina Giuliani (GeroScience, 2024)
In modern human societies, social interactions and pro-social behaviours are associated with better individual and collective health, reduced mortality, and increased longevity. Conversely, social isolation is a predictor of shorter lifespan. The biological processes through which sociality affects the ageing process, as well as healthspan and lifespan, are still poorly understood. Unveiling the physiological, neurological, genomic, epigenomic, and evolutionary mechanisms underlying the association between sociality and longevity may open new perspectives to understand how lifespan is determined in a broader socio/evolutionary outlook. Here we summarize evidence showing how social dynamics can shape the evolution of life history traits through physiological and genetic processes directly or indirectly related to ageing and lifespan. We start by reviewing theories of ageing that incorporate social interactions into their model. Then, we address the link between sociality and lifespan from two separate points of view: (i) considering evidences from comparative evolutionary biology and bioanthropology that demonstrates how sociality contributes to natural variation in lifespan over the course of human evolution and among different human groups in both pre-industrial and post-industrial society, and (ii) discussing the main physiological, neurological, genetic, and epigenetic molecular processes at the interface between sociality and ageing. We highlight that the exposure to chronic social stressors deregulates neurophysiological and immunological pathways and promotes accelerated ageing and thereby reducing lifespan. In conclusion, we describe how sociality and social dynamics are intimately embedded in human biology, influencing healthy ageing and lifespan, and we highlight the need to foster interdisciplinary approaches including social sciences, biological anthropology, human ecology, physiology, and genetics.

Cardioprotection and neurobehavioral impact of swimming training in ovariectomized rats - Alejandro Martín Ibañez; Joshua Godoy Coto; Valeria Romina Martínez; Alejandra del Milagro Yeves; Franco Juan Cruz Dolcetti; Sofía Cervellini; Lucía Echavarría; Jorge Omar Velez-Rueda; Juan Manuel Lofeudo; Enrique Leo Portiansky; María José Bellini; Ernesto Alejandro Aiello; et al. (GeroScience, 2024)

Centenarians of the Basque Country are resilient to cancer - Sara Cruces-Salguero; Igor Larrañaga; Javier Mar; Ander Matheu (GeroScience, 2024)
Cancer is one of the leading causes of death and its prevalence increases with age. While centenarians exhibit extreme longevity and potential to avoid or delay aging-related diseases, their response to cancer is still barely explored. Our study took advantage of the Electronic Health Records to retrospectively compare the severity of cancer in centenarians ( n = 649) and non-centenarians ( n = 62,753) in the Basque Country (province of Gipuzkoa), Spain, through analyzing all the recorded diagnoses throughout their lifetime. Descriptive statistics were applied to discern differences between the two population groups in terms of prevalence of tumor types, number of diagnoses, and treatments. Survival analysis was performed through Kaplan–Meier estimator. We found that centenarians had fewer cancer diagnoses (17.1%, n = 111) than non-centenarians (40.5%, n = 25,405), and notably avoided the most aggressive cancer types and did not develop metastasis. Furthermore, they barely had records of treatments or drugs and had extended survival both since the first and last diagnosis of cancer. These results suggest resilience of the centenarians against malignant cancers explaining, in part, their extended longevity.

The influence of a human macronutrient-matched diet on phenotypes in old mice - Mary A. Darrah; Abigail G. Longtine; Nathan T. Greenberg; Sophia A. Mahoney; Ravinandan Venkatasubramanian; Nicholas S. VanDongen; Julie A. Reisz; Angelo D’Alessandro; Douglas R. Seals; Yara Bernaldo de Quiros Miranda; Zachary S. Clayton (GeroScience, 2024)

The role of inflammation induced by necroptosis in the development of fibrosis and liver cancer in novel knockin mouse models fed a western diet - Ramasamy Selvarani; HoangVan Michelle Nguyen; Natesan Pazhanivel; Muthusamy Raman; Sunho Lee; Roman F. Wolf; Sathyaseelan S. Deepa; Arlan Richardson (GeroScience, 2024)
Non-resolving, chronic inflammation (inflammaging) is believed to play an important role in aging and age-related diseases. The goal of this study was to determine if inflammation induced by necroptosis arising from the liver plays a role in chronic liver disease (CLD) and liver cancer in mice fed a western diet (WD). Necroptosis was induced in liver using two knockin (KI) mouse models that overexpress genes involved in necroptosis (Ripk3 or Mlkl) specifically in liver (i.e., hRipk3-KI and hMlkl-KI mice). These mice and control mice (not overexpressing Ripk3 or Mlkl) were fed a WD (high in fat, sucrose, and cholesterol) starting at 2 months of age for 3, 6, and 12 months. Feeding the WD induced necroptosis in the control mice, which was further elevated in the hRipk3-KI and hMlkl-KI mice and was associated with a significant increase in inflammation in the livers of the hRipk3-KI and hMlkl-KI mice compared to control mice fed the WD. Overexpressing Ripk3 or Mlkl significantly increased steatosis and fibrosis compared to control mice fed the WD. Mice fed the WD for 12 months developed liver tumors (hepatocellular adenomas): 28% of the control mice developing tumors compared to 62% of the hRipk3-KI and hMlkl-KI mice. The hRipk3-KI and hMlkl-KI mice showed significantly more and larger tumor nodules. Our study provides the first direct evidence that inflammation induced by necroptosis arising from hepatocytes can lead to the progression of hepatic steatosis to fibrosis in obese mice that eventually results in an increased incidence in hepatocellular adenomas.

Physical activity and DNA methylation–based markers of ageing in 6208 middle-aged and older Australians: cross-sectional and longitudinal analyses - Haoxin Tina Zheng; Danmeng Lily Li; Makayla W. C. Lou; Allison M. Hodge; Melissa C. Southey; Graham G. Giles; Roger L. Milne; Brigid M. Lynch; Pierre-Antoine Dugué (GeroScience, 2024)
Epigenetic age quantifies biological age using DNA methylation information and is a potential pathway by which physical activity benefits general health. We aimed to assess the cross-sectional and longitudinal associations between physical activity and epigenetic age in middle-aged and older Australians. Blood DNA methylation data for 6208 participants (40% female) in the Melbourne Collaborative Cohort Study (MCCS) were available at baseline (1990–1994, mean age, 59 years) and, of those, for 1009 at follow-up (2003–2007, mean age, 69 years). Physical activity measurements (weighted scores at baseline and follow-up and total MET hours per week at follow-up) were calculated from self-reported questionnaire data. Five blood methylation–based markers of ageing ( PCGrimAge , PCPhenoAge , bAge , DNAmFitAge , and DunedinPACE ) and four fitness-related markers ( DNAmGaitspeed , DNAmGripmax , DNAmVO2max , and DNAmFEV1 ) were calculated and adjusted for age. Linear regression was used to examine the cross-sectional and longitudinal associations between physical activity and epigenetic age. Effect modification by age, sex, and BMI was assessed. At baseline, a standard deviation (SD) increment in physical activity was associated with 0.03-SD ( DNAmFitAge , 95%CI = 0.01, 0.06, P = 0.02) to 0.07-SD ( bAge , 95%CI = 0.04, 0.09, P = 2 × 10 −8 ) lower epigenetic age. These associations were attenuated after adjustment for other lifestyle variables. Only weak evidence was found for the longitudinal association ( N = 1009) of changes in physical activity and epigenetic age (e.g. DNAmFitAge : adjusted β = − 0.04, 95%CI = − 0.08, 0.01). The associations were not modified by age, sex, or BMI. In middle-aged and older Australians, higher levels of self-reported physical activity were associated with slightly lower epigenetic age.

Characterizing the oral and gastrointestinal microbiome associated with healthy aging: insights from long-lived populations in Northeastern China - Yue Ji; Hao Sun; Yingda Wang; Yanhui Li; Rennv Piao; Li Bu; Hui Xu (GeroScience, 2024)

The COVID-19 legacy: consequences for the human DNA methylome and therapeutic perspectives - Carlo Gaetano; Sandra Atlante; Michela Gottardi Zamperla; Veronica Barbi; Davide Gentilini; Barbara Illi; Marco Malavolta; Fabio Martelli; Antonella Farsetti (GeroScience, 2024)
The COVID-19 pandemic has left a lasting legacy on human health, extending beyond the acute phase of infection. This article explores the evidence suggesting that SARS-CoV-2 infection can induce persistent epigenetic modifications, particularly in DNA methylation patterns, with potential long-term consequences for individuals’ health and aging trajectories. The review discusses the potential of DNA methylation-based biomarkers, such as epigenetic clocks, to identify individuals at risk for accelerated aging and tailor personalized interventions. Integrating epigenetic clock analysis into clinical management could mark a new era of personalized treatment for COVID-19, possibly helping clinicians to understand patient susceptibility to severe outcomes and establish preventive strategies. Several valuable reviews address the role of epigenetics in infectious diseases, including the Sars-CoV-2 infection. However, this article provides an original overview of the current understanding of the epigenetic dimensions of COVID-19, offering insights into the long-term health implications of the pandemic. While acknowledging the limitations of current data, we emphasize the need for future research to unravel the precise mechanisms underlying COVID-19-induced epigenetic changes and to explore potential approaches to target these modifications. Graphical Abstract: Impact of SARS-CoV-2 infection on the epigenetic landscape and individual response Following SARS-CoV-2 infection, individuals may develop either a normal immune response or an aberrant one, such as a cytokine storm. Both scenarios can result in long-lasting consequences, known as “long COVID.” This condition can reshape the epigenetic landscape by altering DNA methylation patterns, contributing to the “epigenetic drift.” This drift, further influenced by various factors, can lead to changes in gene expression, immune functionality, and disease susceptibility. One significant consequence of the epigenetic drift is the acceleration of biological aging, which can profoundly impact personalized medical interventions. Created with BioRender.com.

Novel biomarkers of mitochondrial dysfunction in Long COVID patients - Titanilla Szögi; Barbara N. Borsos; Dejana Masic; Bence Radics; Zsolt Bella; Andrea Bánfi; Nóra Ördög; Csenge Zsiros; Ágnes Kiricsi; Gabriella Pankotai-Bodó; Ágnes Kovács; Dóra Paróczai; et al. (GeroScience, 2024)
Coronavirus disease 2019 (COVID-19) can lead to severe acute respiratory syndrome, and while most individuals recover within weeks, approximately 30–40% experience persistent symptoms collectively known as Long COVID, post-COVID-19 syndrome, or post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC). These enduring symptoms, including fatigue, respiratory difficulties, body pain, short-term memory loss, concentration issues, and sleep disturbances, can persist for months. According to recent studies, SARS-CoV-2 infection causes prolonged disruptions in mitochondrial function, significantly altering cellular energy metabolism. Our research employed transmission electron microscopy to reveal distinct mitochondrial structural abnormalities in Long COVID patients, notably including significant swelling, disrupted cristae, and an overall irregular morphology, which collectively indicates severe mitochondrial distress. We noted increased levels of superoxide dismutase 1 which signals oxidative stress and elevated autophagy-related 4B cysteine peptidase levels, indicating disruptions in mitophagy. Importantly, our analysis also identified reduced levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in these patients, serving as a novel biomarker for the condition. These findings underscore the crucial role of persistent mitochondrial dysfunction in the pathogenesis of Long COVID. Further exploration of the cellular and molecular mechanisms underlying post-viral mitochondrial dysfunction is critical, particularly to understand the roles of autoimmune reactions and the reactivation of latent viruses in perpetuating these conditions. This comprehensive understanding could pave the way for targeted therapeutic interventions designed to alleviate the chronic impacts of Long COVID. By utilizing circulating ccf-mtDNA and other novel mitochondrial biomarkers, we can enhance our diagnostic capabilities and improve the management of this complex syndrome.

Increased risk of falls in older adults with hearing loss and slow gait: results from the Otassha Study - Ryota Sakurai; Hisashi Kawai; Hiroyuki Suzuki; Susumu Ogawa; Hirohiko Hirano; Masayasu Ito; Kazushige Ihara; Shuichi Obuchi; Yoshinori Fujiwara (GeroScience, 2024)

The efficacy of cognitive stimulation, cognitive training, and cognitive rehabilitation for people living with dementia: a systematic review and meta-analysis - Alice Paggetti; Ylenia Druda; Francesco Sciancalepore; Francesco Della Gatta; Antonio Ancidoni; Nicoletta Locuratolo; Paola Piscopo; Luca Vignatelli; Luciano Sagliocca; Antonio Guaita; Piero Secreto; Andrea Stracciari; et al. (GeroScience, 2024)
Cognition-oriented treatments (COTs) are a group of non-pharmacological treatments aimed at maintaining or improving cognitive functioning. Specific recommendations on the use of these interventions in people living with dementia (PLwD) are included in the Italian Guideline on the Diagnosis and Treatment of Dementia and Mild Cognitive Impairment, developed by the Italian National Institute of Health. This systematic review and meta-analysis, based on the GRADE methodology, is part of the guideline. Considered outcomes included the cognitive functions, quality of life, and functional abilities of PLwD, taking into account disease severity, modality and system of delivery, and form of the intervention. The effectiveness of these interventions on caregivers’ outcomes was also assessed. Both group and individual cognitive stimulation were reported as effective in supporting cognitive functions in PLwD at any degree of severity. Individual cognitive training and group cognitive training were reported as effective in improving global cognitive functions in people with mild dementia. Cognitive rehabilitation appeared to be effective only in improving the functional abilities of people with mild dementia. Cognitive rehabilitation appeared to be the most effective in improving caregivers’ outcomes, with results suggesting a reduction in care burden. The observed differences in the effectiveness of these interventions in people with different disease severity can be explained by the intrinsic characteristics of each intervention. Despite the large number of available studies, a high clinical, statistical, and methodological heterogeneity was observed. More methodologically rigorous studies are needed to clarify the effectiveness of each protocol and modality of intervention.

Neurocognitive correlates of cerebral mitochondrial function and energy metabolism using phosphorus magnetic resonance spectroscopy in older adults - Francesca V. Lopez; Andrew O’Shea; Zhiguang Huo; Steven T. DeKosky; Theodore P. Trouard; Gene E. Alexander; Adam J. Woods; Dawn Bowers (GeroScience, 2024)

Plasma proteomics-based organ-specific aging for all-cause mortality and cause-specific mortality: a prospective cohort study - Renjia Zhao; Heyang Lu; Huangbo Yuan; Shuaizhou Chen; Kelin Xu; Tiejun Zhang; Zhenqiu Liu; Yanfeng Jiang; Chen Suo; Xingdong Chen (GeroScience, 2024)

Age-related increase in the excitability of mouse layer V pyramidal neurons in the primary motor cortex is accompanied by an increased persistent inward current - Jose A. Viteri; Nikolaus Bueschke; Joseph M. Santin; W. David Arnold (GeroScience, 2024)

White matter integrity and motor function: a link between cerebral myelination and longitudinal changes in gait speed in aging - Zhaoyuan Gong; Mary E. Faulkner; Mohammad A. B. S. Akhonda; Alex Guo; Jonghyun Bae; John P. Laporte; Sarah Church; Jarod D’Agostino; Jan Bergeron; Christopher M. Bergeron; Luigi Ferrucci; Mustapha Bouhrara (GeroScience, 2024)
Gait speed is a robust health biomarker in older adults, correlating with the risk of physical and cognitive impairments, including dementia. Myelination plays a crucial role in neurotransmission and consequently affects various functions, yet the connection between myelination and motor functions such as gait speed is not well understood. Understanding this link could offer insights into diagnosing and treating neurodegenerative diseases that impair mobility. This study analyzed 437 longitudinal observations from 138 cognitively unimpaired adults, aged 22 to 94 years, to investigate the relationship between myelin content and changes in gait speed over an average of 6.42 years. Myelin content was quantified using a novel multicomponent magnetic resonance relaxometry method, and both usual and rapid gait speeds (UGS, RGS) were measured following standard protocols. Adjusting for covariates, we found a significant fixed effect of myelin content on UGS and RGS. Longitudinally, lower myelin content was linked to a greater decline in UGS, particularly in brain regions associated with motor planning. These results suggest that changes in UGS may serve as a reliable marker of neurodegeneration, particularly in cognitively unimpaired adults. Interestingly, the relationship between myelin content and changes in RGS was only observed in a limited number of brain regions, although the reason for such local susceptibility remains unknown. These findings enhance our understanding of the critical role of myelination in gait performance in unimpaired adults and provide evidence of the interconnection between myelin content and motor function impairment.

Aging disrupts blood–brain and blood-spinal cord barrier homeostasis, but does not increase paracellular permeability - Mitchell J. Cummins; Ethan T. Cresswell; Renee J. Bevege; Doug W. Smith (GeroScience, 2024)
Blood-CNS barriers protect the CNS from circulating immune cells and damaging molecules. It is thought barrier integrity becomes disrupted with aging, contributing to impaired CNS function. Using genome-wide and targeted molecular approaches, we found aging affected expression of predominantly immune invasion and pericyte-related genes in CNS regions investigated, especially after middle age, with spinal cord being most impacted. We did not find significant perturbation of endothelial cell junction genes or proteins, nor were vascular density or pericyte coverage affected by aging. We evaluated barrier paracellular permeability using small molecular weight tracers, serum protein extravasation, CNS water content, and iron labelling measures. We found no evidence for age-related increased barrier permeability in any of these tests. We conclude that blood–brain (BBB) and blood-spinal cord barrier (BSCB) paracellular permeability does not increase with normal aging in mouse. Whilst expression changes were not associated with increased permeability, they may represent an age-related primed state whereby additional insults cause increased leakiness.

Clonal hematopoiesis in cardiovascular aging: Insights from the verona heart study - Katarzyna Malgorzata Kwiatkowska; Nicola Martinelli; Luca Bertamini; Sara De Fanti; Oliviero Olivieri; Claudia Sala; Gastone Castellani; Luciano Xumerle; Elisa Zago; Fabiana Busti; Cristina Giuliani; Paolo Garagnani; et al. (GeroScience, 2024)

Post-senescence reproductive rebound in Daphnia associated with reversal of age-related transcriptional changes - Ishaan Dua; A. Catherine Pearson; Rachael L. Lowman; Leonid Peshkin; Lev Y. Yampolsky (GeroScience, 2024)

Understanding perioperative risk determinants in carotid endarterectomy: the impact of compromised circle of Willis morphology on inter-hemispheric blood flow indices based on intraoperative internal carotid artery stump pulse pressure and backflow patterns - Zsófia Czinege; Ágnes Dóra Sándor; Dániel Gyürki; Andrea Varga; Tamás Csípő; Andrea Székely; Zoltán Ungvári; Péter Banga; Péter Sótonyi; Tamás Horváth (GeroScience, 2024)
Carotid artery stenosis (CAS) often requires surgical intervention through carotid endarterectomy (CEA) to prevent stroke. Accurate cerebrovascular risk assessments are crucial in CEA, as poor collateral circulation can lead to insufficient interhemispheric blood flow compensation, resulting in ischemic complications. Therefore, understanding perioperative risk determinants is vital. This study aims to determine the impact of compromised circle of Willis (CoW) morphology on inter-hemispheric blood flow, focusing on indices based on intraoperative internal carotid artery stump pulse pressure and backflow patterns. In 80 CAS patients who underwent CEA, preoperative CT angiography for CoW was conducted. Patients were categorized into five subgroups based on their CoW anatomy and three additional groups based on intraoperative internal carotid artery (ICA) stump backflow patterns evaluated by the surgeon. Continuous blood pressure signals, including systolic, diastolic, mean, and pulse pressure values, were recorded during the procedure. The relationship between CoW anatomical variants and the systolic and diastolic segments of the averaged pressure waveforms, particularly diastolic pressure decay, was analyzed. The correlation between CoW anatomy and stump backflow intensity was also examined. Significant variability in ICA stump backflow and pressure values was evident across CoW variants. Patients with compromised CoW morphology exhibited weaker backflow patterns and lower ICA stump pulse pressure values, consistent with impaired interhemispheric blood flow. Notably, ICA stump diastolic pressure decay was consistent across most CoW variant groups, indicating developed collateral circulation in cases with CoW anomalies. Thus, impaired CoW integrity is associated with compromised interhemispheric blood flow indices based on intraoperative ICA stump pulse pressure and backflow patterns during CEA. Integrating intraoperative pulse waveform analysis with preoperative CT angiography provides a more detailed assessment of cerebrovascular risk, guiding the selective use of shunts. This combined approach may improve surgical outcomes and patient safety by identifying patients at increased risk of perioperative neurological events due to CoW anomalies.

Telomere- and oxidative stress dynamics in Psittacidae species with different longevity trajectories - Angélica Domínguez-de-Barros; Inés Sifaoui; Roberto Dorta-Guerra; Jacob Lorenzo-Morales; Rafael Castro-Fuentes; Elizabeth Córdoba-Lanús (GeroScience, 2024)
Telomeres, conserved DNA sequences at chromosome ends, naturally shorten with age, exacerbated by external factors like environmental challenges and reproduction. Birds, particularly psittacine, are gaining prominence as new aging models over the years because of their unique characteristics. This study explores erythrocyte telomere length (TL) and oxidative stress markers in plasma of long- and short-lived captive birds of the order Psittaciformes over four years. Long-lived birds consistently exhibited longer TL than short-lived ones ( p = 0.012) but experienced a more pronounced TL shortening rate ( p < 0.001) than short-lived ones. Breeding individuals experienced increased TL shortening compared to non-reproductive counterparts in long-lived birds ( p = 0.008). Interestingly, long-lived birds showed a higher total antioxidant capacity than short-lived ones ( p < 0.001), which was also increased during breeding ( p = 0.026). A significant correlation was found between the telomere length shortening rate within the 4 years of study and the accumulated oxidative stress ( r = 0.426, p = 0.069) in short-lived birds. These findings shed light on TL and oxidative stress dynamics over time, revealing distinct patterns influenced by life-traits among longevity groups.

An explainable machine learning estimated biological age based on morphological parameters of the spine - Zi Xu; Yunsong Peng; Mudan Zhang; Rongpin Wang; Zhenlu Yang (GeroScience, 2024)

Impact of age-related hearing loss on decompensation of left DLPFC during speech perception in noise: a combined EEG-fNIRS study - Songjian Wang; Yi Liu; Nuonan Kou; Younuo Chen; Tong Liu; Yuan Wang; Shuo Wang (GeroScience, 2024)
Understanding speech-in-noise is a significant challenge for individuals with age-related hearing loss (ARHL). Evidence suggests that increased activity in the frontal cortex compensates for impaired speech perception in healthy aging older adults. However, whether older adults with ARHL still show preserved compensatory function and the specific neural regulatory mechanisms underlying such compensation remains largely unclear. Here, by utilizing a synchronized EEG-fNIRS test, we investigated the neural oscillatory characteristics of the theta band and synchronous hemodynamic changes in the frontal cortex during a speech recognition task in noise. The study included healthy older adults ( n = 26, aged 65.4 ± 2.8), those with mild hearing loss ( n = 26, aged 66.3 ± 3.8), and those with moderate to severe hearing loss ( n = 26, aged 67.5 ± 3.7). Results showed that, relative to healthy older adults, older adults with ARHL exhibited lower activation and weakened theta band neural oscillations in the left dorsolateral prefrontal cortex (DLPFC) under noisy conditions, and this decreased activity correlated with high-frequency hearing loss. Meanwhile, we found that the connectivity of the frontoparietal network was significantly reduced, which might depress the top-down articulatory prediction function affecting speech recognition performance in ARHL older adults. The results suggested that healthy aging older adults might exhibit compensatory attentional resource recruitment through a top-down auditory-motor integration mechanism. In comparison, older adults with ARHL reflected decompensation of the left DLPFC involving the frontoparietal integration network during speech recognition tasks in noise.

Complementary value of molecular, phenotypic, and functional aging biomarkers in dementia prediction - Andreas Engvig; Karl Trygve Kalleberg; Lars T. Westlye; Esten Høyland Leonardsen; Michael Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; William Jagust; John Q. Trojanowski; Arthur W. Toga; Laurel Beckett; et al. (GeroScience, 2024)
DNA methylation age (MA), brain age (BA), and frailty index (FI) are putative aging biomarkers linked to dementia risk. We investigated their relationship and combined potential for prediction of cognitive impairment and future dementia risk using the ADNI database. Of several MA algorithms, DunedinPACE and GrimAge2, associated with memory, were combined in a composite MA alongside BA and a data-driven FI in predictive analyses. Pairwise correlations between age- and sex-adjusted measures for MA (aMA), aBA, and aFI were low. FI outperformed BA and MA in all diagnostic tasks. A model including age, sex, and aFI achieved an area under the curve (AUC) of 0.94 for differentiating cognitively normal controls (CN) from dementia patients in a held-out test set. When combined with clinical biomarkers (apolipoprotein E ε4 allele count, memory, executive function), a model including aBA and aFI predicted 5-year dementia risk among MCI patients with an out-of-sample AUC of 0.88. In the prognostic model, BA and FI offered complementary value (both β s 0.50). The tested MAs did not improve predictions. Results were consistent across FI algorithms, with data-driven health deficit selection yielding the best performance. FI had a stronger adverse effect on prognosis in males, while BA’s impact was greater in females. Our findings highlight the complementary value of BA and FI in dementia prediction. The results support a multidimensional view of dementia, including an intertwined relationship between the biomarkers, sex, and prognosis. The tested MA’s limited contribution suggests caution in their use for individual risk assessment of dementia.

Identifying modifiable factors and their joint effect on frailty: a large population-based prospective cohort study - Ling-Zhi Ma; Yi-Jun Ge; Yi Zhang; Xi-Han Cui; Jian-Feng Feng; Wei Cheng; Lan Tan; Jin-Tai Yu (GeroScience, 2024)

Efficacy of swallowing rehabilitative therapies for adults with dysphagia: a network meta-analysis of randomized controlled trials - Chi-Li Lee; Kondwani Joseph Banda; Yu-Hao Chu; Doresses Liu; Chiu-Kuei Lee; Chien-Mei Sung; Hidayat Arifin; Kuei-Ru Chou (GeroScience, 2024)

Divergent regulation of long non-coding RNAs H19 and PURPL affects cell senescence in human dermal fibroblasts - Elena Frediani; Cecilia Anceschi; Jessica Ruzzolini; Sara Ristori; Alice Nerini; Anna Laurenzana; Anastasia Chillà; Claudia Elena Zoe Germiniani; Gabriella Fibbi; Mario Del Rosso; Alessandra Mocali; Marco Venturin; et al. (GeroScience, 2024)
Cellular senescence is a permanent cell growth arrest that occurs in response to various intrinsic and extrinsic stimuli and is associated with cellular and molecular changes. Long non-coding RNAs (lncRNAs) are key regulators of cellular senescence by affecting the expression of many important genes involved in senescence-associated pathways and processes. Here, we evaluated a panel of lncRNAs associated with senescence for their differential expression between young and senescent human dermal fibroblasts (NHDFs) and studied the effect of a known senomorphic compound, resveratrol, on the expression of lncRNAs in senescent NHDFs. As markers of senescence, we evaluated cell growth, senescence-associated (SA)-β-Gal staining, and the expression of p21, Lamin B1 and γH2AX. We found that H19 and PURPL were the most altered lncRNAs in replicative, in doxorubicin (DOXO) and ionising radiation (IR)-induced senescence models. We then investigated the function of H19 and PURPL in cell senescence by siRNA-mediated silencing in young and senescent fibroblasts, respectively. Our results showed that H19 knockdown reduced cell viability and induced cell senescence and autophagy of NHDFs through the regulation of the PI3K/AKT/mTOR pathway; conversely, PURPL silencing reversed senescence by reducing (SA)-β-Gal staining, recovering cell proliferation with an increase of S-phase cells, and reducing the p53-dependent DNA damage response. Overall, our data highlighted the role of H19 and PURPL in the senescent phenotype and suggested that these lncRNAs may have important implications in senescence-related diseases.

Increased 1H-NMR metabolomics-based health score associates with declined cognitive performance and functional independence in older adults at risk of cardiovascular disease - Michelle H. Zonneveld; Nour Al Kuhaili; Simon P. Mooijaart; P. Eline Slagboom; J. Wouter Jukema; Raymond Noordam; Stella Trompet (GeroScience, 2024)
The 1-HMR metabolomics-based MetaboHealth score, comprised of 14 serum metabolic markers, associates with disease-specific mortality, but it is unclear whether the score also reflects cognitive changes and functional impairment. We aimed to assess the associations between the MetaboHealth score with cognitive function and functional decline in older adults at increased cardiovascular risk. A total of 5292 older adults free of dementia at baseline with mean age 75.3 years (SD = 3.4) from the Prospective Study of Pravastatin in the Elderly (PROSPER). MetaboHealth score were measured at baseline, and cognitive function and functional independence were measured at baseline and every 3 months during up to 2.5 years follow-up. Cognitive function was assessed using the Stroop test (selective attention), the Letter Digit Coding test (LDCT) (processing speed), and the two versions of the Picture Learning test (delayed and immediate; memory). Two tests of functional independence were used: Barthel Index (BI) and instrumental activities at daily living (IADL). A higher MetaboHealth score was associated with worse cognitive function (in all domains) and with worse functional independence. For example, after full adjustments, a 1-SD higher MetaboHealth score was associated with 9.02 s (95%CI 7.29, 10.75) slower performance on the Stroop test and 2.79 (2.21, 3.26) less digits coded on the LDCT. During follow-up, 1-SD higher MetaboHealth score was associated with an additional decline of 0.53 s (0.23, 0.83) on the Stroop test and − 0.08 (− 0.11, − 0.06) points on the IADL. Metabolic disturbance, as reflected by an increased metabolomics-based health score, may mark future cognitive and functional decline.

Investigating the influence of the SIRT6 gene and alternative splicing on canine longevity: an in-depth bioinformatics analysis and experimental confirmation via NGS-based targeted sequencing - Özge Özmen; Gülin Köklü (GeroScience, 2024)

Correction to: The RESIST Senior Individuals Cohort: Design, participant characteristics and aims - Lennart Matthias Roesner; Manoj Kumar Gupta; Verena Kopfnagel; Nienke van Unen; Yvonne Kemmling; Jana‑Kristin Heise; Stephanie Castell; Xun Jiang; Lennart Riemann; Stephan Traidl; Berit Lange; Kurt‑Wolfram Sühs; et al. (GeroScience, 2024)

Sex differences in the association between skeletal muscle energetics and perceived physical fatigability: the Study of Muscle, Mobility and Aging (SOMMA) - Emma L. Gay; Paul M. Coen; Stephanie Harrison; Reagan E. Garcia; Yujia Qiao; Bret H. Goodpaster; Daniel E. Forman; Frederico G. S. Toledo; Giovanna Distefano; Philip A. Kramer; Sofhia V. Ramos; Anthony J. A. Molina; et al. (GeroScience, 2024)

Artemisiae Iwayomogii Herba mitigates excessive neuroinflammation and Aβ accumulation by regulating the pro-inflammatory response and autophagy-lysosomal pathway in microglia in 5xFAD mouse model of Alzheimer’s disease - In Gyoung Ju; Seungmin Lee; Hyeri Im; Jae Hoon Kim; Hyeyoon Eo; Myung Sook Oh (GeroScience, 2024)

Profiles of brain topology for dual-functional stability in old age - Sa Zhou; Mia Anthony; Ehsan Adeli; F. Vankee Lin (GeroScience, 2024)

Integrating aging biomarkers and immune function to predict kidney health: insights from the future of families and child wellbeing study - Saanie Sulleyx; Yan Zhou; Memory Ndanga; Abimbola Saka (GeroScience, 2024)

Senescence-related genes as prognostic indicators in breast cancer survival - Zoltan Ungvari; Anna Ungvari; Monika Fekete; Csaba Kiss; Balázs Győrffy (GeroScience, 2024)
Breast cancer is a leading cause of cancer-related mortality among women worldwide, particularly affecting those in their later years. As the incidence of breast cancer increases with age, understanding the biological mechanisms that link aging and cancer becomes crucial. Cellular senescence, a hallmark of aging, plays a dual role in cancer by inhibiting tumorigenesis while also contributing to tumor progression through the senescence-associated secretory phenotype (SASP). This study aims to investigate the prognostic significance of senescence-related genes in breast cancer. We utilized the SenMayo gene list, a comprehensive set of senescence-related genes, to analyze gene expression data from a large cohort of breast cancer samples. The data was sourced from the Kaplan–Meier plotter, an integrated database that compiles gene expression information from multiple independent cohorts. Cox proportional hazards regression and false discovery rate (FDR) corrections were employed to evaluate the correlation between gene expression and survival outcomes, aiming to establish a prognostic signature. Our findings demonstrate that higher expression levels of senescence-related genes are significantly associated with improved survival, while lower expression levels correlate with shorter survival outcomes. These results suggest that senescence-related pathways play a protective role in breast cancer, potentially serving as valuable prognostic indicators. The identification of a prognostic signature based on senescence-related genes underscores the importance of cellular senescence in breast cancer progression and survival. Our study highlights the potential of senescence-related biomarkers in enhancing patient stratification and informing treatment strategies, contributing to the growing body of literature on the intersection of aging and cancer.

Frailty, age, and treatment effect of surgical coronary revascularization in ischemic cardiomyopathy: a post hoc analysis of the STICHES trial - Lajjaben Patel; Matthew W. Segar; Vinayak Subramanian; Sumitabh Singh; Traci Betts; Nidhish Lokesh; Neil Keshvani; Kershaw Patel; Ambarish Pandey (GeroScience, 2024)

Alzheimer’s disease and other memory disorders in the age of AI: reflection and perspectives on the 120th anniversary of the birth of Dr. John von Neumann - Ferenc Deak (GeroScience, 2024)

Retraction Note: Improvement in Th1/Th2 immune homeostasis, antioxidative status and resistance to pathogenic E. coli on consumption of probiotic Lactobacillus rhamnosus fermented milk in aging mice - Rohit Sharma; Rajeev Kapila; Gulshan Dass; Suman Kapila (GeroScience, 2024)

Genomic instability and genetic heterogeneity in aging: insights from clonal hematopoiesis (CHIP), monoclonal gammopathy (MGUS), and monoclonal B-cell lymphocytosis (MBL) - Attila Kallai; Zoltan Ungvari; Mónika Fekete; Andrea B. Maier; Gabor Mikala; Hajnalka Andrikovics; Andrea Lehoczki (GeroScience, 2024)
Aging is a multifaceted process characterized by a gradual decline in physiological function and increased susceptibility to a range of chronic diseases. Among the molecular and cellular mechanisms driving aging, genomic instability is a fundamental hallmark, contributing to increased mutation load and genetic heterogeneity within cellular populations. This review explores the role of genomic instability and genetic heterogeneity in aging in the hematopoietic system, with a particular focus on clonal hematopoiesis of indeterminate potential (CHIP), monoclonal gammopathy of undetermined significance (MGUS), and monoclonal B-cell lymphocytosis (MBL) as biomarkers. CHIP involves the clonal expansion of hematopoietic stem cells with somatic mutations. In contrast, MGUS is characterized by the presence of clonal plasma cells producing monoclonal immunoglobulins, while MBL is characterized by clonal proliferation of B cells. These conditions are prevalent in the aging population and serve as measurable indicators of underlying genomic instability. Studying these entities offers valuable insights into the mechanisms by which somatic mutations accumulate and drive clonal evolution in the hematopoietic system, providing a deeper understanding of how aging impacts cellular and tissue homeostasis. In summary, the hematopoietic system serves as a powerful model for investigating the interplay between genomic instability and aging. Incorporating age-related hematological conditions into aging research, alongside other biomarkers such as epigenetic clocks, can enhance the precision and predictive power of biological age assessments. These biomarkers provide a comprehensive view of the aging process, facilitating the early detection of age-related diseases and hopefully enabling personalized healthcare strategies.

Gene and transcript expression patterns, coupled with isoform switching and long non-coding RNA dynamics in adipose tissue, underlie the longevity of Ames dwarf mice - Sebastian Cano-Besquet; Maiyon Park; Nadia Berkley; Michelle Wong; Sarah Ashiqueali; Sarah Noureddine; Adam Gesing; Augusto Schneider; Jeffrey Mason; Michal M. Masternak; Joseph M. Dhahbi (GeroScience, 2024)
Our study investigates gene expression in adipose tissue of Ames dwarf (df/df) mice, whose deficiency in growth hormone is linked to health and extended lifespan. Recognizing adipose tissue influence on metabolism, aging, and related diseases, we aim to understand its contribution to the health and longevity of df/df mice. We have identified gene and transcript expression patterns associated with critical biological functions, including metabolism, stress response, and resistance to cancer. Intriguingly, we identified genes that, despite maintaining unchanged expression levels, switch between different isoforms, impacting essential cellular functions such as tumor suppression, oncogenic activity, ATP transport, and lipid biosynthesis and storage. The isoform switching is associated with changes in protein domains, retention of introns, initiation of nonsense-mediated decay, and emergence of intrinsically disordered regions. Moreover, we detected various alternative splicing events that may drive these structural alterations. We also found changes in the expression of long non-coding RNAs (lncRNAs) that may be involved in the aging process and disease resistance by regulating crucial genes in survival and metabolism. Through weighted gene co-expression network analysis, we have linked four lncRNAs with 29 genes, which contribute to protein complexes such as the Mili-Tdrd1-Tdrd12 complex. Beyond safeguarding DNA integrity, this complex also has a wider impact on gene regulation, chromatin structure, and metabolic control. Our detailed investigation provides insight into the molecular foundations of the remarkable health and longevity of df/df mice, emphasizing the significance of adipose tissue in aging and identifying new avenues for health-promoting therapeutic strategies.

Associations between glycated haemoglobin and multi-modal imaging markers of early cardiac aging - Abigail C. C. Chng; Hong Chang Tan; Louis L. Y. Teo; Ru-San Tan; See Hooi Ewe; Shuang Leng; Xiao-Dan Zhao; Liang Zhong; Woon-Puay Koh; Jean-Paul Kovalik; Fei Gao; Angela S. Koh (GeroScience, 2024)

Association between cognitive reserve proxies and frailty phenotype: data from UK Biobank - Laura Lorenzo-López; Nuria Cibeira; Ali Hemadeh; Rocío López-López; Carlota Lema-Arranz; Ana Maseda; Natalia Fernández-Bertólez; Solange Costa; Eduardo Pásaro; Vanessa Valdiglesias; José C. Millán-Calenti; Blanca Laffon (GeroScience, 2024)

Broad immunogenicity to prior SARS-CoV-2 strains and JN.1 variant elicited by XBB.1.5 vaccination in nursing home residents - Yasin Abul; Clare Nugent; Igor Vishnepolskiy; Tiffany Wallace; Evan Dickerson; Laurel Holland; Iva Esparza; Mandi Winkis; Kazi Tanvee Wali; Philip A. Chan; Rosa R. Baier; Amy Recker; et al. (GeroScience, 2024)

Creating respiratory pathogen-free environments in healthcare and nursing-care settings: a comprehensive review - Attila Nagy; Aladár Czitrovszky; Andrea Lehoczki; Árpád Farkas; Péter Füri; János Osán; Veronika Groma; Szilvia Kugler; Adrienn Micsinai; Alpár Horváth; Zoltán Ungvári; Veronika Müller (GeroScience, 2024)
Hospital- and nursing-care-acquired infections are a growing problem worldwide, especially during epidemics, posing a significant threat to older adults in geriatric settings. Intense research during the COVID-19 pandemic highlighted the prominent role of aerosol transmission of pathogens. Aerosol particles can easily adsorb different airborne pathogens, carrying them for a long time. Understanding the dynamics of airborne pathogen transmission is essential for controlling the spread of many well-known pathogens, like the influenza virus, and emerging ones like SARS-CoV-2. Particles smaller than 50 to 100 µm remain airborne and significantly contribute to pathogen transmission. This review explores the journey of pathogen-carrying particles from formation in the airways, through airborne travel, to deposition in the lungs. The physicochemical properties of emitted particles depend on health status and emission modes, such as breathing, speaking, singing, coughing, sneezing, playing wind instruments, and medical interventions. After emission, sedimentation and evaporation primarily determine particle fate. Lung deposition of inhaled aerosol particles can be studied through in vivo, in vitro, or in silico methods. We discuss several numerical lung models, such as the Human Respiratory Tract Model, the LUng Dose Evaluation Program software (LUDEP), the Stochastic Lung Model, and the Computational Fluid Dynamics (CFD) techniques, and real-time or post-evaluation methods for detecting and characterizing these particles. Various air purification methods, particularly filtration, are reviewed for their effectiveness in healthcare settings. In the discussion, we analyze how this knowledge can help create environments with reduced PM2.5 and pathogen levels, enhancing safety in healthcare and nursing-care settings. This is particularly crucial for protecting older adults, who are more vulnerable to infections due to weaker immune systems and the higher prevalence of chronic conditions. By implementing effective airborne pathogen control measures, we can significantly improve health outcomes in geriatric settings.

DNA methylation drives hematopoietic stem cell aging phenotypes after proliferative stress - Hagai Yanai; Taylor McNeely; Saipriya Ayyar; Michael Leone; Le Zong; Bongsoo Park; Isabel Beerman (GeroScience, 2024)
Aging of hematopoietic stem cells (HSCs) is implicated in various aging phenotypes, including immune dysfunction, anemia, and malignancies. The role of HSC proliferation in driving these aging phenotypes, particularly under stress conditions, remains unclear. Therefore, we induced forced replications of HSCs in vivo by a cyclical treatment with low-dose fluorouracil (5FU) and examined the impact on HSC aging. Our findings show that proliferative stress induces several aging phenotypes, including altered leukocyte counts, decreased lymphoid progenitors, accumulation of HSCs with high expression of Slamf1, and reduced reconstitution potential, without affecting stem cell self-renewal capacity. The divisional history of HSCs was imprinted in the DNA methylome, consistent with functional decline. Specifically, DNA methylation changes included global hypermethylation in non-coding regions and similar frequencies of hypo- and hyper-methylation at promoter regions, particularly affecting genes targeted by the PRC2 complex. Importantly, initial forced replication promoted DNA damage repair accumulated with age, but continuous proliferative stress led to the accumulation of double-strand breaks, independent of functional decline. Overall, our results suggest that HSC proliferation can drive some aging phenotypes primarily through epigenetic mechanisms, including DNA methylation changes.

Apathy, gait slowness, and executive dysfunction (AGED) triad: opportunities to predict and delay dementia onset - Frederico Pieruccini-Faria; Vladimir Hachinski; Surim Son; Manuel Montero-Odasso (GeroScience, 2024)

Uncovering mediational pathways behind racial and socioeconomic disparities in brain volumes: insights from the UK Biobank study - May A. Beydoun; Hind A. Beydoun; Marie T. Fanelli-Kuczmarski; Yi-Han Hu; Danielle Shaked; Jordan Weiss; Shari R. Waldstein; Lenore J. Launer; Michele K. Evans; Alan B. Zonderman (GeroScience, 2024)
Mediation pathways explaining racial/ethnic and socioeconomic (SES) disparities in structural MRI markers of brain health remain underexplored. We examined racial/ethnic and SES disparities in sMRI markers and tested total, direct, and indirect effects through lifestyle, health-related, and cognition factors using a structural equations modeling approach among 36,184 UK Biobank participants aged 40–70 years at baseline assessment (47% men). Race (non-White vs. White) and lower SES-predicted poorer brain sMRI volumetric outcomes at follow-up, with racial/ethnic disparities in sMRI outcomes involving multiple pathways and SES playing a central role in those pathways. Mediational patterns differed across outcomes, with the SES-sMRI total effect being partially mediated for all outcomes. Over 20% of the total effect (TE) of race/ethnicity on WMH was explained by the indirect effect (IE), by a combination of different pathways going through SES, lifestyle, health-related, and cognition factors. This is in contrast to < 10% for total brain, gray matter (GM), white matter (WM), and frontal GM left/right. Another significant finding is that around 57% of the total effect for SES and the normalized white matter hyperintensity (WMH) was attributed to an indirect effect. This effect encompasses many pathways that involve lifestyle, health-related, and cognitive aspects. Aside from WMH, the percent of TE of SES mediated through various pathways ranged from ~ 5% for WM to > 15% up to 36% for most of the remaining sMRI outcomes, which are composed mainly of GM phenotypes. Race and SES were important determinants of brain volumetric outcomes, with partial mediation of racial/ethnic disparities through SES, lifestyle, health-related, and cognition factors.

Hyperactive mTORC1/4EBP1 signaling dysregulates proteostasis and accelerates cardiac aging - Weronika Zarzycka; Kamil A. Kobak; Catherine J. King; Frederick F. Peelor; Benjamin F. Miller; Ying Ann Chiao (GeroScience, 2024)

Overweight and obesity significantly increase colorectal cancer risk: a meta-analysis of 66 studies revealing a 25–57% elevation in risk - Zoltan Ungvari; Mónika Fekete; Peter Varga; Andrea Lehoczki; János Tibor Fekete; Anna Ungvari; Balázs Győrffy (GeroScience, 2024)
The incidence of colorectal cancer (CRC) has been steadily rising, and obesity has been identified as a significant risk factor. Numerous studies suggest a strong correlation between excess body weight and increased risk of CRC, but comprehensive quantification through pooled analysis remains limited. This study aims to systematically review and meta-analyze the existing literature to evaluate the association between obesity and CRC risk, considering variations across sex and study designs. A systematic literature search was conducted in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science to identify randomized controlled trials and human clinical trials from 1992 to 2024. Statistical analysis was performed using the https://metaanalysisonline.com web application using a random effects model to estimate the pooled hazard rates (HR). Forest plots, funnel plots, and Z-score plots were utilized to visualize results. We identified 52 clinical trials and 14 case–control studies, encompassing a total of 83,251,050 and 236,877 subjects, respectively. The pooled analysis indicated that obesity significantly increased the prevalence of CRC (HR = 1.36, 95% CI = 1.24–1.48, p < 0.01). This effect was consistent across sexes, with HRs of 1.57 (95% CI = 1.38–1.78, p = 0.01) for males and 1.25 (95% CI = 1.14–1.38, p < 0.01) for females. Case–control studies specifically showed an effect, but with marginal significance only (HR = 1.27, 95% CI = 0.98–1.65, p = 0.07). The Z-score plot indicated the need for additional analysis in the case–control group. A significant heterogeneity was observed across studies in all four settings. This meta-analysis provides robust evidence that obesity is a significant risk factor for colorectal cancer, with an overall hazard rate indicating a 36% increased risk. The effect is pronounced across both sexes, with males showing a slightly higher risk compared to females. Although case–control studies showed a weaker association, the overall trend supports the link between obesity and CRC. These results underscore the importance of public health interventions aimed at reducing obesity to potentially lower the risk of colorectal cancer.

Compensation versus deterioration across functional networks in amnestic mild cognitive impairment subtypes - Benxamín Varela-López; Montserrat Zurrón; Mónica Lindín; Fernando Díaz; Santiago Galdo-Alvarez (GeroScience, 2024)
Functional connectivity studies to detect neurophysiological correlates of amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer’s disease, have generated contradictory results in terms of compensation and deterioration, as most of the studies did not distinguish between the different aMCI subtypes: single-domain aMCI (sd-aMCI) and multiple-domain aMCI (md-aMCI). The present study aimed to characterize the neurophysiological correlates of aMCI subtypes by using resting-state functional magnetic resonance imaging. The study included sd-aMCI ( n = 29), md-aMCI ( n = 26), and control ( n = 30) participants. The data were subjected to independent component analysis (ICA) to explore the default mode network (DMN) and the fronto-parietal control network (FPCN). Additionally, seed-based and moderation analyses were conducted to investigate the connectivity of the medial temporal lobe and functional networks. aMCI subtypes presented differences in functional connectivity relative to the control group: sd-aMCI participants displayed increased FPCN connectivity and reduced connectivity between the posterior parahippocampal gyrus (PHG) and medial structures; md-aMCI participants exhibited lower FPCN connectivity, higher anterior PHG connectivity with frontal structures and lower posterior PHG connectivity with central-parietal and temporo-occipital areas. Additionally, md-aMCI participants showed higher posterior PHG connectivity with structures of the DMN than both control and sd-aMCI participants, potentially indicating more severe cognitive deficits. The results showed gradual and qualitative neurofunctional differences between the aMCI subgroups, suggesting the existence of compensatory (sd-aMCI) and deterioration (md-aMCI) mechanisms in functional networks, mainly originated in the DMN. The findings support consideration of the subgroups as different stages of MCI within the Alzheimer disease continuum.

Deletion of the stress response protein REDD1 prevents sodium iodate-induced RPE damage and photoreceptor loss - Sandeep M. Subrahmanian; Esma I. Yerlikaya; Siddharth Sunilkumar; Allyson L. Toro; Christopher M. McCurry; Stephanie L. Grillo; Alistair J. Barber; Jeffrey M. Sundstrom; Michael D. Dennis (GeroScience, 2024)
Age-related macular degeneration (AMD) is a leading cause of blindness in elderly populations, yet the molecular events that initiate the early retinal defects that lead to visual function deficits remain poorly understood. The studies here explored a role for the stress response protein Regulated in Development and DNA damage response 1 (REDD1) in the development of retinal pathology by using the oxidant stressor sodium iodate (NaIO 3 ) to model dry AMD in mice. REDD1 protein abundance was increased in the retinal pigmented epithelium (RPE) and retina of mice administered NaIO 3 . In wild-type REDD1 +/+ mice, reactive oxygen species (ROS) levels were robustly increased in the outer retinal layers 1 day after NaIO 3 administration, with focal areas of increased ROS seen throughout the outer retina after 7 days. In contrast with REDD1 +/+ mice, ROS levels were blunted in REDD1 −/− mice after NaIO 3 administration. REDD1 was also required for upregulated expression of pro-inflammatory factors in the RPE/retina and immune cell activation in the outer retina following NaIO 3 administration. In REDD1 +/+ mice, NaIO 3 reduced RPE65 and rhodopsin levels in the RPE and photoreceptor layers, respectively. Unlike REDD1 +/+ mice, REDD1 −/− mice did not exhibit disrupted RPE integrity, retinal degeneration, or photoreceptor thinning. Overall, REDD1 deletion was sufficient to prevent retinal oxidative stress, RPE damage, immune cell activation, and photoreceptor loss in response to NaIO 3 . The findings support a potential role for REDD1 in the development of retinal complications in the context of dry AMD.

Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome - Martina Vinicki; Tea Pribić; Frano Vučković; Azra Frkatović-Hodžić; Isaac Plaza-Andrades; Francisco Tinahones; Joseph Raffaele; José Carlos Fernández-García; Gordan Lauc (GeroScience, 2024)
With aging, the body’s ability to maintain regular functions declines, increasing susceptibility to age-related diseases. Therapeutic interventions targeting the underlying biological changes of aging hold promise for preventing or delaying multiple age-related diseases. Metformin, a drug commonly used for diabetes treatment, has emerged as a potential gerotherapeutic agent due to its established safety record and preclinical and clinical data on its anti-aging effects. Glycosylation, one of the most common and complex co- and post-translational protein modifications, plays a crucial role in regulating protein function and has been linked to aging and various diseases. Changes in immunoglobulin G (IgG) glycosylation patterns have been observed with age, and these alterations may serve as valuable biomarkers for disease predisposition, diagnosis, treatment monitoring, and overall health assessment. In this study, we analyzed the IgG glycosylation patterns of white men from Europe, aged 29–45 years, under treatment with metformin, testosterone, metformin plus testosterone, and placebo (trial registration number NCT02514629, 2013/07/04), and investigated the longitudinal changes in glycosylation over time. We observed statistically significant differences in the IgG glycome composition between participants on testosterone therapy and placebo, with decreased agalactosylation and increased galactosylation and sialylation. However, metformin therapy did not result in statistically significant changes in glycosylation patterns. These findings contribute to our understanding of the impact of therapeutic interventions on IgG glycosylation and confirm the value of IgG glycosylation as a significant biomarker, capable of assessing biological age using the GlycanAge index and providing insight into overall health compared to chronological age.

Impaired brain ability of older adults to transit and persist to latent states with well-organized structures at wakeful rest - Zijin Liu; Haishuo Xia; Antao Chen (GeroScience, 2024)

Aging enhances pro-atrogenic gene expression and skeletal muscle loss following respiratory syncytial virus infection - J. Sophie Sagawe; Verity I. P. Loake; Peter J. M. Openshaw; Paul Kemp; Fiona J. Culley (GeroScience, 2024)
Aging and many age-related health conditions are associated with skeletal muscle loss. Furthermore, older adults are more susceptible to severe respiratory infections, which can in turn lead to muscle wasting. The mechanisms by which respiratory viral infection can impact skeletal muscle in older adults are not well understood. We determined the effects of acute infection with respiratory syncytial virus (RSV) on the lung and skeletal muscle of aged mice. RSV infection caused more severe disease in aged mice with enhanced weight loss, reduced feeding, higher viral load, and greater airway inflammation. Aged but not young mice showed decreased leg muscle weight at the peak of illness and decreased size of leg muscle fibers. Aged mice increased muscle-specific expression of atrophy-promoting enzymes (Atrogin-1 and MuRF-1) and failed to increase the rate of muscle protein synthesis during RSV infection. In aged mice, the changes in Atrogin-1 and MuRF-1 gene expression in skeletal muscle correlated with IL-6 levels in the lungs. These findings indicate that RSV infection of aged mice provides a model for studying the diverse adverse systemic consequences of respiratory viral infections on health and wellbeing in older adults.

Association of a DASH diet and magnetoencephalography in dementia-free adults with different risk levels of Alzheimer’s disease - Alfredo Trabado-Fernández; Alejandra García-Colomo; Esther Cuadrado-Soto; África Peral-Suárez; María Dolores Salas-González; Ana María Lorenzo-Mora; Aránzazu Aparicio; María Luisa Delgado-Losada; Fernando Maestú-Unturbe; Ana M. López-Sobaler (GeroScience, 2024)

Purpose in life and grip strength: An individual-participant meta-analysis of 115,972 participants from 24 countries across four continents - Angelina R. Sutin; Martina Luchetti; Yannick Stephan; Norma Mansor; Tiia Kekäläinen; Antonio Terracciano (GeroScience, 2024)

A biological age based on common clinical markers predicts health trajectory and mortality risk in dogs - Sébastien Herzig; Alix Zollinger; Lorane Texari; James A. Holzwarth; Rondo P. Middleton; Yuanlong Pan; Pascal Steiner; Philipp Gut (GeroScience, 2024)
Predicting aging trajectories through biomarkers of biological aging can guide interventions that optimize healthy lifespan in humans and companion animals. Differences in physiology, genetics, nutrition, and lifestyle limit the generalization of such biomarkers and may therefore require species-specific algorithms. Here, we compared correlations of standard clinical blood parameters with survival probability in humans with those of the two most common mammalian companion animals, cats and dogs, and highlighted universal and species-specific relationships. Based on this comparative analysis, we generated and validated an algorithm that predicts biological age in canines using a longitudinal dataset with health records, blood count, and clinical chemistry from 829 dogs spanning over 12 years. Positive deviations of biological from chronological age (AgeDev) measured by this composite score significantly correlated with a decreased survival probability (hazard ratio = 1.75 per 1 year of AgeDev, p = 3.7e − 06). Importantly, in nearly half of the dogs whose biological age was accelerated by more than 1 year, none or only a single individual marker scored outside its respective reference range, suggesting practical applications for the detection of unfavorable health trajectories. Analyzing samples from a unique 14-year life-long diet restriction study, we show that restricted caloric intake lowers biological age, an effect that can be quantified at midlife years before a difference in survival is observed. Thus, a biological age clock based on clinical blood tests predicts the health trajectories of dogs for use in research and veterinary practice.

Inflammation and aging-related disease: A transdisciplinary inflammaging framework - Brian J. Andonian; Joseph A. Hippensteel; Katrina Abuabara; Eileen M. Boyle; James F. Colbert; Michael J. Devinney; Adam S. Faye; Bharati Kochar; Jiha Lee; Rachel Litke; Devika Nair; Sebastian E. Sattui; et al. (GeroScience, 2024)

A review of antioxidant strategies to improve reproduction in aging male broiler breeders - Sarallah Yarmohammadi Barbarestani; Firooz Samadi; Mojtaba Zaghari; Soroush Khademian; Zarbakht Ansari Pirsaraei; John P. Kastelic (GeroScience, 2024)

Nut consumption is associated with a lower risk of all-cause dementia in adults: a community-based cohort study from the UK Biobank - Bruno Bizzozero-Peroni; Valentina Díaz-Goñi; Nuria Beneit; Andreia Oliveira; Estela Jiménez-López; Vicente Martínez-Vizcaíno; Arthur Eumann Mesas (GeroScience, 2024)

Local molecular and connectomic contributions of tau-related neurodegeneration - Fardin Nabizadeh; Michael W. Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; William Jagust; John Q. Trojanowski; Arthur W. Toga; Laurel Beckett; Robert C. Green; Andrew J. Saykin; John Morris; et al. (GeroScience, 2024)

Differences in motor learning-related structural plasticity of layer 2/3 parvalbumin-positive interneurons of the young and aged motor cortex - Andrew M. Davidson; Hernán Mejía-Gómez; Bryn M. Wooten; Sharai Marqués; Michael Jacobowitz; Irene F. Ugidos; Ricardo Mostany (GeroScience, 2024)
Changes to neuronal connectivity are believed to be a key factor in cognitive impairments associated with normal aging. Because of its effect on activities of daily living, deficient motor control is a critical type of cognitive decline to understand. Diminished inhibitory networks in the cortex are implicated in such motor control deficits, pointing to the connectivity of inhibitory cortical interneurons as an important area for study. Here, we used chronic two-photon microscopy to track the structural plasticity of en passant boutons (EPBs) of parvalbumin-positive interneurons in the mouse motor cortex in the first longitudinal, in vivo study of inhibitory interneuron synapses in the context of aging. Young (3–5 months) and aged (23–28 months) mice underwent training on the accelerating rotarod to evoke motor learning-induced structural plasticity. Our analysis reveals that, in comparison with axons from young mice, those from aged mice have fewer EPBs at baseline that also tend to be larger in size. Aged axons also express learning-related structural plasticity—like new bouton stabilization and bouton enlargement—that is less persistent than that of young axons. This study reveals striking baseline differences in young and aged axon morphology as well as differences in the deployment of learning-related structural plasticity across axons.

Disruption of sleep macro- and microstructure in Alzheimer’s disease: overlaps between neuropsychology, neurophysiology, and neuroimaging - Anna Csilla Kegyes-Brassai; Robert Pierson-Bartel; Gergo Bolla; Anita Kamondi; Andras Attila Horvath (GeroScience, 2024)
Alzheimer’s disease (AD) is the leading cause of dementia, often associated with impaired sleep quality and disorganized sleep structure. This study aimed to characterize changes in sleep macrostructure and K-complex density in AD, in relation to neuropsychological performance and brain structural changes. We enrolled 30 AD and 30 healthy control participants, conducting neuropsychological exams, brain MRI, and one-night polysomnography. AD patients had significantly reduced total sleep time (TST), sleep efficiency, and relative durations of non-rapid eye movement (NREM) stages 2 (S2), 3 (S3), and rapid eye movement (REM) sleep ( p < 0.01). K-complex (KC) density during the entire sleep period and S2 ( p < 0.001) was significantly decreased in AD. We found strong correlations between global cognitive performance and relative S3 ( p < 0.001; r = 0.86) and REM durations ( p < 0.001; r = 0.87). TST and NREM stage 1 (S1) durations showed a moderate negative correlation with amygdaloid and hippocampal volumes ( p < 0.02; r = 0.51–0.55), while S3 and REM sleep had a moderate positive correlation with cingulate cortex volume ( p < 0.02; r = 0.45–0.61). KC density strongly correlated with global cognitive function ( p < 0.001; r = 0.66) and the thickness of the anterior cingulate cortex ( p < 0.05; r = 0.45–0.47). Our results indicate significant sleep organization changes in AD, paralleling cognitive decline. Decreased slow wave sleep and KCs are strongly associated with cingulate cortex atrophy. Since sleep changes are prominent in early AD, they may serve as prognostic markers or therapeutic targets.

Monoamine alterations in Alzheimer’s disease and their implications in comorbid neuropsychiatric symptoms - Shalini Saggu; Ava Bai; Mae Aida; Hasibur Rehman; Andrew Pless; Destany Ware; Ferenc Deak; Kai Jiao; Qin Wang (GeroScience, 2024)
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by relentless cognitive decline and the emergence of profoundly disruptive neuropsychiatric symptoms. As the disease progresses, it unveils a formidable array of neuropsychiatric manifestations, including debilitating depression, anxiety, agitation, and distressing episodes of psychosis. The intricate web of the monoaminergic system, governed by serotonin, dopamine, and norepinephrine, significantly influences our mood, cognition, and behavior. Emerging evidence suggests that dysregulation and degeneration of this system occur early in AD, leading to notable alterations in these critical neurotransmitters’ levels, metabolism, and receptor function. However, how the degeneration of monoaminergic neurons and subsequent compensatory changes contribute to the presentation of neuropsychiatric symptoms observed in Alzheimer’s disease remains elusive. This review synthesizes current findings on monoamine alterations in AD and explores how these changes contribute to the neuropsychiatric symptomatology of the disease. By elucidating the biological underpinnings of AD-related psychiatric symptoms, we aim to underscore the complexity and inform innovative approaches for treating neuropsychiatric symptoms in AD. Graphical Abstract [created With Biorender.com]

Deletion of absent in melanoma-2 (AIM2) drives bone marrow adipogenesis and impairs bone microarchitecture - Zhenwei Gong; Manisha Dixit; Zhiming He; Sher Bahadur Poudel; Gozde Yildirim; Shoshana Yakar; Radhika Muzumdar (GeroScience, 2024)

Interplay of education and DNA methylation age on cognitive impairment: insights from the Health and Retirement Study - Erin B. Ware; César Higgins Tejera; Herong Wang; Sean Harris; Jonah D. Fisher; Kelly M. Bakulski (GeroScience, 2024)
Few studies have assessed the association of educational attainment on dementia and cognitive impairment through DNA methylation age acceleration, while accommodating exposure-mediator interaction effects. We evaluated the mediation role of six epigenetic clocks with dementia, cognitive impairment non-dementia, and normal cognition, while accommodating exposure-mediator interaction effects. To understand the joint association of low education (≤12 years) and DNA methylation age acceleration (yes/no) in relation to cognitive impairment, we used weighted logistic regression, adjusting for chronological age, sex, race/ethnicity, and cell type composition. We performed four-way mediation and interaction decomposition analysis. Analyses were conducted on 2016 venous blood study participants from the Health and Retirement Study ( N = 3724). Both GrimAge acceleration (OR = 1.6 95%CI 1.3–2.1) and low educational attainment (OR = 2.4 95%CI 1.9–3.0) were associated with higher odds of cognitive impairment in a mutually adjusted logistic model. We found additive interaction associations between low education and GrimAge acceleration on dementia. We observed that 6–8% of the association of education on dementia was mediated through GrimAge acceleration. While mediation effects were small, the portion of the association of education on dementia due to additive interaction with GrimAge acceleration was between 23.6 and 29.2%. These results support the interplay of social disadvantage and biological aging processes on impaired cognition.

Large-scale genome-wide interaction analyses on multiple cardiometabolic risk factors to identify age-specific genetic risk factors - Linjun Ao; Diana van Heemst; Jiao Luo; Maris Teder-Laving; Reedik Mägi; Ruth Frikke-Schmidt; Ko Willems van Dijk; Raymond Noordam (GeroScience, 2024)
The genetic landscape of cardiometabolic risk factors has been explored extensively. However, insight in the effects of genetic variation on these risk factors over the life course is sparse. Here, we performed genome-wide interaction studies (GWIS) on different cardiometabolic risk factors to identify age-specific genetic risks. This study included 270,276 unrelated European-ancestry participants from the UK Biobank (54.2% women, a median age of 58 [interquartile range ( IQR ): 50, 63] years). GWIS models with interaction terms between genetic variants and age were performed on apolipoprotein B (ApoB), low-density lipoprotein-cholesterol (LDL-C), log-transformed triglycerides (TG), body mass index (BMI) and systolic blood pressure (SBP). Replication was subsequently performed in the Copenhagen General Population Study (CGPS) and the Estonian Biobank (EstBB). Multiple lead variants were identified to have genome-wide significant interactions with age ( P interaction < 1e − 08). In detail, rs429358 (tagging APOE4 ) was identified for ApoB ( P interaction = 9.0e − 14) and TG ( P interaction = 5.4e − 16). Three additional lead variants were identified for ApoB: rs11591147 (R46L in PCSK9 , P interaction = 3.9e − 09), rs34601365 (near APOB , P interaction = 8.4e − 09) and rs17248720 (near LDLR , P interaction = 2.0e − 09). Effect sizes of the identified lead variants were generally closer to the null with increasing age. No variant-age interactions were identified for LDL-C, SBP and BMI. The significant interactions of rs429358 with age on ApoB and TG were replicated in both CGPS and EstBB. The majority of genetic effects on cardiometabolic risk factors remain relatively constant over age, with the noted exceptions of specific genetic effects on ApoB and TG.

The resistance of domestic canine skin-derived fibroblasts to oxidative and non-oxidative chemical injury: implications of breed and body size - James M. Harper; Megan Hicks; Ana Gabriela Jiménez (GeroScience, 2024)

Mitochondrial DNA copy number associated dementia risk by somatic mutations and frailty - Qu Tian; David A. Zweibaum; Yong Qian; Richard F. Oppong; Luke C. Pilling; Francesco Casanova; Janice L. Atkins; David Melzer; Jun Ding; Luigi Ferrucci (GeroScience, 2024)
Mitochondrial dysfunction is linked to physical impairment and dementia. Mitochondrial DNA copy number (mtDNAcn) from blood may predict cognitive decline and dementia risk, but the effect of somatic mutations or frailty is unknown. We estimated mtDNAcn using fastMitoCalc and microheteroplasmies using mitoCaller , from Whole Genome Sequencing (WGS) data. In 189,566 participants free of dementia at study entry (mean age = 56 ± 8), we examined the association between mtDNAcn and subsequent dementia diagnosis using Cox regression. Cognition was assessed in a subset on average 8.9 years later. We examined the associations between mtDNAcn and cognitive measures using multivariable linear regression, adjusted for demographic factors, mtDNAcn-related parameters, and apolipoprotein E ε4 status. We further stratified by frailty and microheteroplasmies. Over an average follow-up of 13.2 years, 3533 participants developed dementia. Each SD higher mtDNAcn (16) was associated with 4.2% lower all-cause dementia hazard (HR = 0.958, p = 0.030), 6% lower non-AD dementia hazard (HR = 0.933, p = 0.022), and not-AD dementia hazard. The associations between mtDNAcn and all-cause dementia and non-AD dementia were stronger among those who were pre-frail or frail or with higher microheteroplasmies. Higher mtDNAcn was associated with higher DSST scores ( p = 0.036) and significant only among those with higher microheteroplasmies or frailty ( p = 0.029 and 0.048, respectively). mtDNAcn was also associated with delta TMT and paired associate learning only in pre-frail/frail participants ( p = 0.007 and 0.045, respectively). Higher WGS-based mtDNAcn in human blood is associated with lower dementia risk, specifically non-AD dementia, and specific cognitive function. The relationships appear stronger in high somatic mutations or frailty. Future studies are warranted to investigate biological underpinnings.

White matter lipid alterations during aging in the rhesus monkey brain - Christina Dimovasili; Ana T. Vitantonio; Bryce Conner; Kelli L. Vaughan; Julie A. Mattison; Douglas L. Rosene (GeroScience, 2024)

Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats - Robert V. Musci; Jordan D. Fuqua; Frederick F. Peelor; Hoang Van Michelle Nguyen; Arlan Richardson; Solbie Choi; Benjamin F. Miller; Jonathan Wanagat (GeroScience, 2024)
Mitochondrial genomic integrity is a key element of physiological processes and health. Changes in the half-life of the mitochondrial genome are implicated in the generation and accumulation of age-induced mitochondrial DNA (mtDNA) mutations, which are implicated in skeletal muscle aging and sarcopenia. There are conflicting data on the half-life of mtDNA, and there is limited information on how aging affects half-life in skeletal muscle. We hypothesized that skeletal muscle mtDNA synthesis rates would decrease with age in both female and male rats concomitant with changes in mtDNA integrity reflected in mtDNA copy number and mutation frequency. We measured mitochondrial genome half-life using stable isotope labeling over a period of 14 days and assessed mtDNA copy number and deletion mutation frequency using digital PCR in the quadriceps muscle of 9-month-old and 26-month-old male and female OKC-HET rats. We found a significant age-related increase in mtDNA half-life, from 132 days at 9 months to 216 days at 26 months of age in OKC-HET quadriceps. Concomitant with the increase in mtDNA half-life, we found an age-related increase in mtDNA deletion mutation frequency in both male and female rats. Notably, 26-month-old female rats had a lower mutation frequency than male rats, and there were no changes in mtDNA copy number with sex, age, or mitochondrial genotype. These data reveal several key findings: (1) mtDNA turnover in rat skeletal muscle decreases with age, (2) mtDNA half-lives in skeletal muscle are approximately an order of magnitude longer than what is reported for other tissues, and (3) muscle mtDNA turnover differs significantly from the turnover of other mitochondrial macromolecules including components of the mitochondrial nucleoid. These findings provide insight into the factors driving age-induced mtDNA mutation accumulation, which contribute to losses of mitochondrial genomic integrity and may play a role in skeletal muscle dysfunction.

Contributions and future potential of animal models for geroscience research on sensory systems - Arthur G. Fernandes; Alice C. Poirier; Carrie C. Veilleux; Amanda D. Melin (GeroScience, 2024)

Acquired hemophilia A as a disease of the elderly: A comprehensive review of epidemiology, pathogenesis, and novel therapy - Andrea Lehoczki; Mónika Fekete; Gábor Mikala; Imre Bodó (GeroScience, 2024)
Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder characterized by the development of neutralizing autoantibodies (inhibitors) against coagulation factor VIII (FVIII). This review provides an in-depth exploration of AHA, covering its epidemiology, pathogenesis, clinical presentation, diagnosis, complications, and treatment strategies, focusing on recent advancements. AHA can manifest in both men and women with no prior bleeding history. The annual incidence is estimated to be approximately 1 case per million individuals in the general population. The incidence increases significantly with age: the incidence among individuals aged 60 years or older is approximately 3 to 4 cases per million individuals per year. Typically, patients present with an acquired bleeding disorder that is characterized by an isolated, prolonged activated partial thromboplastin time stemming from FVIII deficiency. Diagnosis relies on the detection of neutralizing antibodies using the Nijmegen-modified Bethesda assay. Hemostatic control strategies involve bypassing agents like recombinant activated factor VII, activated prothrombin complex concentrate, and recombinant porcine FVIII for bleeding patients. Emicizumab, a novel bypassing agent, exhibits several potential advantages. In the realm of immunosuppressive treatment for inhibitor eradication, the CyDRi regimen emerged as a remarkable advancement, significantly enhancing the outlook for the management of AHA even in the elderly frail population.

Defining an ageing-related pathology, disease or syndrome: International Consensus Statement - Emma Short; Ian M. Adcock; Bilal Al-Sarireh; Ann Ager; Ramzi Ajjan; Naveed Akbar; Michael A. Akeroyd; Ghada Alsaleh; Ghada Al-Sharbatee; Kambiz Alavian; Winfried Amoaku; Julie Andersen; et al. (GeroScience, 2024)
Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased health span. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand and meet the healthcare, workforce, well-being and socioeconomic needs of ageing populations, whilst supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19, 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥ 70% for approval. The accepted criteria for an ageing-related pathology, disease or syndrome were (1) develops and/or progresses with increasing chronological age; (2) should be associated with, or contribute to, functional decline or an increased susceptibility to functional decline and (3) evidenced by studies in humans. Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.

Associations of nighttime sleep, midday napping, and physical activity with all-cause mortality in older adults: the Seniors-ENRICA cohorts - Miguel Angelo Duarte Junior; David Martinez-Gomez; Salud Pintos-Carrillo; Esther Lopez-Garcia; Fernando Rodríguez-Artalejo; Verónica Cabanas-Sánchez (GeroScience, 2024)

Resistance training suppresses accumulation of senescent fibro-adipogenic progenitors and senescence-associated secretory phenotype in aging rat skeletal muscle - Yung-Li Hung; Ayami Sato; Yuka Takino; Akihito Ishigami; Shuichi Machida (GeroScience, 2024)
Accumulation of senescent cells in tissues contributes to multiple aging-related pathologies. Senescent fibro-adipogenic progenitors (FAPs) contribute to aging-related muscle atrophy. Resistance training can help to maintain skeletal muscle mass, improve mobility, and reduce certain health risks commonly associated with aging. We investigated, using rat model, the impact of resistance training on FAPs in aging skeletal muscle, which remains unclear. Twenty-two-month-old female rats were divided into sedentary and training groups. The training group rodents were trained to climb a ladder while bearing a load for 20 training sessions over 2 months, after which, the flexor hallucis longus muscles were collected and analyzed. Senescent cells were identified using a senescence-associated β-galactosidase stain and p21 immunohistochemistry (IHC), and FAPs were identified using platelet-derived growth factor receptor alpha IHC. The results indicate that resistance training in rats prevented aging-associated skeletal muscle atrophy and suppressed M2 polarization of macrophages. The number of senescent cells was significantly reduced in the 24-month-old training group, with most of them being FAPs. Conversely, the number of senescent FAPs increased significantly in the 24-month-old sedentary group compared with that in the 18-month-old sedentary group. The number of senescent FAPs in the 24-month-old training group decreased significantly. Resistance training also suppressed the senescence-associated secretory phenotype (SASP). The killer T cell-specific marker, CD8α, was elevated in the skeletal muscles of the aging rats following resistance training, indicating upregulation of recognition and elimination of senescent cells. Overall, resistance training suppressed the accumulation of senescent FAPs and acquisition of SASP in aging skeletal muscles.

Dietary factors and DNA methylation-based markers of ageing in 5310 middle-aged and older Australian adults - Lachlan Cribb; Allison M. Hodge; Melissa C. Southey; Graham G. Giles; Roger L. Milne; Pierre-Antoine Dugué (GeroScience, 2024)
The role of nutrition in healthy ageing is acknowledged but details of optimal dietary composition are still uncertain. We aimed to investigate the cross-sectional associations between dietary exposures, including macronutrient composition, food groups, specific foods, and overall diet quality, with methylation-based markers of ageing. Blood DNA methylation data from 5310 participants (mean age 59 years) in the Melbourne Collaborative Cohort Study were used to calculate five methylation-based measures of ageing: PCGrimAge , PCPhenoAge , DunedinPACE , ZhangAge , TelomereAge . For a range of dietary exposures, we estimated (i) the ‘equal-mass substitution effect’, which quantifies the effect of adding the component of interest to the diet while keeping overall food mass constant, and (ii) the ‘total effect’, which quantifies the effect of adding the component of interest to the current diet. For ‘equal-mass substitution effects’, the strongest association for macronutrients was for fibre intake (e.g. DunedinPACE , per 12 g/day − 0.10 [standard deviations]; 95%CI − 0.15, − 0.05, p < 0.001). Associations were positive for protein (e.g. PCGrimAge , per 33 g/day 0.04; 95%CI 0.01–0.08, p = 0.005). For food groups, the evidence tended to be weak, though sugar-sweetened drinks showed positive associations, as did artificially-sweetened drinks (e.g. DunedinPACE , per 91 g/day 0.06, 95%CI 0.03–0.08, p < 0.001). ‘Total effect’ estimates were generally very similar. Scores reflecting overall diet quality suggested that healthier diets were associated with lower levels of ageing markers. High intakes of fibre and low intakes of protein and sweetened drinks, as well as overall healthy diets, showed the most consistent associations with lower methylation-based ageing in our study.

An antireductant approach ameliorates misfolded proinsulin-induced hyperglycemia and glucose intolerance in male Akita mice - Dwight A. L. Mattocks; Naidu B. Ommi; Virginia L. Malloy; Sailendra N. Nichenametla (GeroScience, 2024)
Protein folding in the endoplasmic reticulum (ER) requires a high ratio of oxidized to reduced glutathione (GSSG/rGSH). Since the GSSG/rGSH depends on total glutathione (tGSH = GSSG + rGSH) levels, we hypothesized that limiting GSH biosynthesis will ameliorate protein misfolding by enhancing the ER oxidative milieu. As a proof-of-concept, we used DL-buthionine-(S,R)-sulfoximine (BSO) to inhibit GSH biosynthesis in Akita mice, which are prone to proinsulin misfolding. We conducted a 2-week intervention to investigate if BSO was safe and a 6-week intervention to find its effect on glucose intolerance. In both cohorts, male heterozygous Akita (AK) and wild-type (WT) mice were continuously administered 15 mM BSO. No adverse effects were observed on body weight, food intake, and water intake in either cohort. Unaltered levels of plasma aspartate and alanine aminotransferases, and cystatin-C, indicate that BSO was safe. BSO-induced decreases in tGSH were tissue-dependent with maximal effects in the kidneys, where it altered the expression of genes associated with GSH biosynthesis, redox status, and proteostasis. BSO treatment decreased random blood glucose levels to 80% and 67% of levels in untreated mice in short-term and long-term cohorts, respectively, and 6-h fasting blood glucose to 82% and 74% ﻿of levels in untreated mice, respectively. BSO also improved glucose tolerance by 37% in AK mice in the long-term cohort, without affecting insulin tolerance. Neither glucose tolerance nor insulin tolerance were affected in WT. Data indicate that BSO might treat misfolded proinsulin-induced glucose intolerance. Future studies should investigate the effect of BSO on proinsulin misfolding and if it improves glucose intolerance in individuals with Mutant Insulin Diabetes of Youth. Graphical abstract 1) Male heterozygous C57BL/6-Ins2 Akita /J (AK) mice suffer from misfolded proinsulin-induced glucose intolerance . (a) Proinsulin misfolding occurs due to a genetic mutation in Ins2 gene that substitutes Cys with Tyr, (b) Due to heterozygosity, AK mice produce both wild-type and mutated proinsulin, (c) Mutated proinsulin forms aggregates with itself and with the bystander native proinsulin, (d) Proinsulin aggregation results in lower functional insulin, and (e) AK mice suffer from impaired glucose tolerance. 2) Treating mice with BSO improved glucose tolerance. (a) Mice were treated with continuous administration of 15 mM DL -buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione biosynthesis (b), BSO treatment increased the renal mRNA quantity of several genes involved in glutathione biosynthesis, glutathione redox status, and proteostasis, (c) we hypothesize that BSO-induced changes in cellular redox status and gene expression ameliorates proinsulin aggregation and increases the functional insulin levels in β-cells, and (d) BSO treatment significantly improved glucose intolerance in AK mice. Note: AUC - Area under the curve, GCL -γ-g-glutamylcysteine ligase, GS - Gluatthione synthetase.

Calorie restriction increases the sensitivity of progeroid Ercc1Δ/− mice to acute (neuro)inflammation - V. A. Reitsema; L. Schreuder; E. Gerrits; B. J. L. Eggen; M. Goris; J. D. Laman; S. E. de Rooij; E. M. Wesseling; H. R. Bouma; R. H. Henning (GeroScience, 2024)
Hospitalized elderly patients frequently suffer from delirium, especially in the context of sepsis-associated encephalopathy. Current treatments of delirium are merely symptomatic. Calorie restriction (CR) is both a promising strategy to protect against sepsis and has beneficial effects on aging-induced neurodegeneration. In this study, we investigated whether six weeks of 30% CR had protective effects on lipopolysaccharide (LPS) induced (neuro)inflammation in wild-type (WT) and progeroid mice deficient in the DNA excision-repair gene Ercc1 ( Ercc1 Δ /− ). While CR did not affect the LPS-induced inflammatory response in WT mice, CR exaggerated the peripheral inflammatory response in Ercc1 Δ/ − mice, as evidenced by an increase of pro-inflammatory serum cytokines (TNF-α, IL-1β, and IFN-γ) and kidney injury marker Ngal. Neuroinflammatory effects were assessed by RNA-sequencing of isolated microglia. Similarly, CR did not affect microglia gene expression in WT mice, but increased neuroinflammation-associated gene expression in Ercc1 Δ/ − mice. In conclusion, CR increases the peripheral and brain inflammatory response of Ercc1 Δ/ − mice to a systemic inflammatory stimulus.

Age-related breakdown in networks of inter-muscular coordination - Sergi Garcia-Retortillo; Óscar Abenza; Fidanka Vasileva; Natàlia Balagué; Robert Hristovski; Andrew Wells; Jason Fanning; Jeff Kattula; Plamen Ch. Ivanov (GeroScience, 2024)

Systemic low-dose anti-fibrotic treatment attenuates ovarian aging in the mouse - Farners Amargant; Carol Magalhaes; Michele T. Pritchard; Francesca E. Duncan (GeroScience, 2024)

Multiscale neural dynamics in sleep transition volatility across age scales: a multimodal EEG-EMG-EOG analysis of temazepam effects - Parikshat Sirpal; William A. Sikora; Hazem H. Refai (GeroScience, 2024)
Recent advances in computational modeling techniques have facilitated a more nuanced understanding of sleep neural dynamics across the lifespan. In this study, we tensorize multiscale multimodal electroencephalogram (EEG), electromyogram (EMG), and electrooculogram (EOG) signals and apply Generalized Autoregressive Conditional Heteroskedasticity (GARCH) modeling to quantify interactions between age scales and the use of pharmacological sleep aids on sleep stage transitions. Our cohort consists of 22 subjects in a crossover design study, where each subject received both a sleep aid and a placebo in different sessions. To understand these effects across the lifespan, three evenly distributed age groups were formed: 18–29, 30–49, and 50–66 years. The methodological framework implemented here employs tensor-based machine learning techniques to compute continuous wavelet transform time–frequency features and utilizes a GARCH model to quantify sleep signal volatility across age scales. Support Vector Machines are used for feature ranking, and our analysis captures interactions between signal entropy, age, and sleep aid status across frequency bands, sleep transitions, and sleep stages. GARCH model results reveal statistically significant volatility clustering in EEG, EMG, and EOG signals, particularly during transitions between REM and non-REM sleep. Notably, volatility was higher in the 50–66 age group compared to the 18–29 age group, with marked fluctuations during transitions from deep sleep to REM sleep (standard deviation of 0.35 in the older group vs. 0.30 in the 18–29 age group, p < 0.05). Statistical comparisons of volatility across frequency bands, age scales, and sleep stages highlight significant differences attributable to sleep aid use. Mean conditional volatility parameterization of the GARCH model reveals directional influences, with a causality index of 0.75 from frontal to occipital regions during REM sleep transition periods. Our methodological framework identifies distinct neural behavior patterns across age groups associated with each sleep stage and transition, offering insights into the development of targeted interventions for sleep regularity across the lifespan.

Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer’s disease - Michelle M. Sonsalla; Reji Babygirija; Madeline Johnson; Samuel Cai; Mari Cole; Chung-Yang Yeh; Isaac Grunow; Yang Liu; Diana Vertein; Mariah F. Calubag; Michaela E. Trautman; Cara L. Green; et al. (GeroScience, 2024)

The vasoprotective role of IGF-1 signaling in the cerebral microcirculation: prevention of cerebral microhemorrhages in aging - Levente Stankovics; Anna Ungvari; Mónika Fekete; Adam Nyul-Toth; Peter Mukli; Roland Patai; Boglarka Csik; Rafal Gulej; Shannon Conley; Anna Csiszar; Peter Toth (GeroScience, 2024)
Aging is closely associated with various cerebrovascular pathologies that significantly impact brain function, with cerebral small vessel disease (CSVD) being a major contributor to cognitive decline in the elderly. Consequences of CSVD include cerebral microhemorrhages (CMH), which are small intracerebral bleeds resulting from the rupture of microvessels. CMHs are prevalent in aging populations, affecting approximately 50% of individuals over 80, and are linked to increased risks of vascular cognitive impairment and dementia (VCID). Hypertension is a primary risk factor for CMHs. Vascular smooth muscle cells (VSMCs) adapt to hypertension by undergoing hypertrophy and producing extracellular matrix (ECM) components, which reinforce vessel walls. Myogenic autoregulation, which involves pressure-induced constriction, helps prevent excessive pressure from damaging the vulnerable microvasculature. However, aging impairs these adaptive mechanisms, weakening vessel walls and increasing susceptibility to damage. Insulin-like Growth Factor 1 (IGF-1) is crucial for vascular health, promoting VSMC hypertrophy, ECM production, and maintaining normal myogenic protection. IGF-1 also prevents microvascular senescence, reduces reactive oxygen species (ROS) production, and regulates matrix metalloproteinase (MMP) activity, which is vital for ECM remodeling and stabilization. IGF-1 deficiency, common in aging, compromises these protective mechanisms, increasing the risk of CMHs. This review explores the vasoprotective role of IGF-1 signaling in the cerebral microcirculation and its implications for preventing hypertension-induced CMHs in aging. Understanding and addressing the decline in IGF-1 signaling with age are crucial for maintaining cerebrovascular health and preventing hypertension-related vascular injuries in the aging population.

Fixel-based and tensor-derived white matter abnormalities in relation to memory impairment and neurocognitive disorders - Charly Hugo Alexandre Billaud; Junhong Yu (GeroScience, 2024)

Comprehensive analysis of molecular, physiological, and functional biomarkers of aging with neurological diseases using Mendelian randomization - Yume Imahori; Chenxi Qin; Bowen Tang; Sara Hägg (GeroScience, 2024)
An increasing burden of neurological diseases (NDs) has been a public health challenge in an aging society. Age, especially biological age, is the most important risk factor for NDs. Identification of biomarkers of aging to capture NDs might lead to a better understanding of the underlying mechanisms of pathological brain aging and the implementation of effective intervention. We conducted a comprehensive two-sample Mendelian Randomization (MR) study to investigate the association between various biomarkers of aging and three leading causes of NDs: Alzheimer’s disease (AD), vascular dementia (VaD), and ischemic stroke. Publicly available GWAS summary statistics on people from European ancestry were obtained for six molecular biomarkers, two physiological biomarkers, and eight functional biomarkers, and three NDs. Genetic variants serving as instrumental variables (IVs) were identified for each biomarker. The MR analysis included inverse variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO. We found that short telomere length and decrease in appendicular lean mass were associated with an increased risk for AD (OR IVW = 1.12 per 1SD decrease, 95% confidence interval 1.02–1.22, and OR IVW = 1.11, 1.06–1.16, respectively), whereas high frailty index showed a protective effect for AD. Accelerated BioAge appeared to be associated with increased risk for ischemic stroke (OR IVW = 1.3 per year in BioAge acceleration, 95% CI 1.19–1.41). Our findings implied a causal association of short telomere length and a decrease in appendicular lean mass with an increased risk for AD, while BioAge appeared to be a good biomarker for ischemic stroke. Further studies are needed to validate these associations and explore underlying mechanisms.

Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer’s disease mouse model via enhancing neurotrophic and synaptic signaling - Hash Brown Taha; Allison Birnbaum; Ian Matthews; Karel Aceituno; Jocelyne Leon; Max Thorwald; Jose Godoy-Lugo; Constanza J. Cortes (GeroScience, 2024)
Skeletal muscle regulates central nervous system (CNS) function and health, activating the muscle-to-brain axis through the secretion of skeletal muscle-originating factors (“myokines”) with neuroprotective properties. However, the precise mechanisms underlying these benefits in the context of Alzheimer’s disease (AD) remain poorly understood. To investigate muscle-to-brain axis signaling in response to amyloid β (Aβ)-induced toxicity, we generated 5xFAD transgenic female mice with enhanced skeletal muscle function (5xFAD;cTFEB;HSACre) at prodromal (4-months old) and late (8-months old) symptomatic stages. Skeletal muscle TFEB overexpression reduced Aβ plaque accumulation in the cortex and hippocampus at both ages and rescued behavioral neurocognitive deficits in 8-month-old 5xFAD mice. These changes were associated with transcriptional and protein remodeling of neurotrophic signaling and synaptic integrity, partially due to the CNS-targeting myokine prosaposin (PSAP). Our findings implicate the muscle-to-brain axis as a novel neuroprotective pathway against amyloid pathogenesis in AD.

Coffee consumption, cancer, and healthy aging: epidemiological evidence and underlying mechanisms - Setor K. Kunutsor; Andrea Lehoczki; Jari A. Laukkanen (GeroScience, 2024)

Association of adherence to the EAT-Lancet diet with risk of dementia according to social economic status: a prospective cohort in UK Biobank - Wanying Zhao; Qian Chen; Qi Zhang; Siqi Li; Jiaqi Zhao; Wanlan Chen; Jialu Yang; Min Xia; Yan Liu (GeroScience, 2024)

Impact of healthcare system strain on the implementation of ICU sedation practices and encephalopathy burden during the early COVID-19 pandemic - Jeffrey R. Clark; Ayush Batra; Robert A. Tessier; Kasey Greathouse; Dan Dickson; Abeer Ammar; Brandon Hamm; Lisa J. Rosenthal; Theresa Lombardo; Igor J. Koralnik; Lesli E. Skolarus; Clara J. Schroedl; et al. (GeroScience, 2024)

Active longevity and aging: dissecting the impacts of physical and sedentary behaviors on longevity and age acceleration - Ting Yu Lu; Jiao Wang; Chao Qiang Jiang; Ya Li Jin; Kar Keung Cheng; Tai Hing Lam; Wei Sen Zhang; Lin Xu (GeroScience, 2024)
Background To examine the associations of physical activity (PA) and sedentary behavior (SB) with longevity and age acceleration (AA) using observational and Mendelian randomization (MR) studies, and quantify the mediating effects of lipids. Methods In Guangzhou Biobank Cohort Study (GBCS), PA and SB were assessed by the Chinese Version of the International Physical Activity Questionnaire. Longevity was defined as participants whose age at follow-up or at death was at or above the 90th age percentile. AA was defined as the residual resulting from a linear model that regressed phenotypic age against chronological age. Linear regression and Poisson regression with robust error variance were used to assess the associations of total and specific PA in different intensities, and SB with AA and longevity, yielding βs or relative risks (RRs) and 95% confidence intervals (CIs). Two-sample MR was conducted to examine the causal effects. Mediation analysis was used to assess the mediating effects of lipids. Results Of 20,924 participants aged 50 + years in GBCS, during an average follow-up of 15.0 years, compared with low PA, moderate and high PA were associated with higher likelihood of longevity (RR (95% CI): 1.56 (1.16, 2.11), 1.66 (1.24, 2.21), respectively), and also cross-sectionally associated with lower AA (β (95% CI): -1.43 (-2.41, -0.45), -2.09 (-3.06, -1.11) years, respectively). Higher levels of moderate PA (MPA) were associated with higher likelihood of longevity and lower AA, whereas vigorous PA (VPA) showed opposite effects. The association of PA with longevity observed in GBCS was mediated by low-density lipoprotein cholesterol (LDL-C) by 8.23% (95% CI: 3.58–39.61%), while the association with AA was mediated through LDL-C, triglycerides and total cholesterol by 5.13% (3.94–7.30%), 7.81% (5.98–11.17%), and 3.37% (2.59–4.80%), respectively. Additionally, in two-sample MR, SB was positively associated with AA (β (95% CI): 1.02 (0.67, 1.36) years). Conclusions PA showed protective effects on longevity and AA, with the effects being partly mediated through lipids. Conversely, SB had a detrimental impact on AA. MPA was associated with higher likelihood of longevity and reduced AA, whereas VPA showed adverse effects. Our findings reinforce the recommendation of “sit less and move more” to promote healthy longevity, and highlight the potential risks associated with VPA in the elderly.

Effect of aging and exercise on hTERT expression in thymus tissue of hTERT transgenic bacterial artificial chromosome mice - Jeongjin J. Kim; Alexander Ahn; Jeffrey Y. Ying; Jesse Pollens-Voigt; Andrew T. Ludlow (GeroScience, 2024)

Resistance training improves cardiac function in older women: a randomized controlled trial - Ricardo J. Rodrigues; Paolo M. Cunha; João P. Nunes; Lauro C. Vianna; Patrícia C. Brum; Danilo S. Bocalini; Andrei C. Sposito; Luis C. Miguita Junior; Max D. Oliveira; Elaine Batistella; Rodrigo R. Fernandes; Paulo S. Junior; et al. (GeroScience, 2024)

Do people reach 100 by surviving, delaying, or avoiding diseases? A life course comparison of centenarians and non-centenarians from the same birth cohorts - Yuge Zhang; Shunsuke Murata; Katharina Schmidt-Mende; Marcus Ebeling; Karin Modig (GeroScience, 2024)
Centenarians are perceived as pioneers of longevity, possessing the secrets to surpassing age 100. It remains unclear whether they achieve this by surviving, delaying, or avoiding diseases to a greater extent than their shorter-lived peers. This register-based study encompassed all individuals aged 60 and older, born between 1912 and 1922 in Stockholm County, Sweden ( N = 170,787). Using historical data, individuals were prospectively followed from 1972 to 2022 and stratified by their age at death. Age-specific incidence rates and remaining lifetime risk from age 60 were calculated for stroke, myocardial infarction, hip fracture, and various cancers (including colorectal, breast, and prostate), and compared between those who survived to age 100 and their shorter-lived counterparts. Centenarians had lower age-specific incidence rates for almost all diseases and ages. Despite longer life spans, their lifetime risks for all diseases except hip fracture were lower than those of non-centenarians. This suggests that centenarians delay, and even avoid, many of the major age-related diseases rather than surviving them to a higher extent. The findings that centenarians not only exhibit lower disease rates at younger ages compared to their shorter-lived peers but throughout their lives challenge the notion that longer life span inevitably leads to higher disease rates or a simple shift of diseases to older ages.

Association between self-reported difficulty in chewing or swallowing and frailty in older adults: A retrospective cohort study - So Sato; Yusuke Sasabuchi; Akira Okada; Hideo Yasunaga (GeroScience, 2024)
Oral frailty can contribute to physical and mental health disorders. Previous research has shown an association between frailty and self-reported difficulty in chewing or swallowing. However, their combined assessment has obscured their specific impact on frailty-related outcomes. To investigate the independent associations between difficulty in chewing or swallowing and 1-year frailty outcomes, while also examining their interactions. This retrospective cohort study utilized the DeSC database to identify older adults aged ≥ 75 years who underwent health checkups between April 2014 and November 2022. Multivariate Cox regression analyses were conducted to assess the association between self-reported difficulty in chewing or swallowing and outcomes, including hospitalization due to aspiration pneumonia, all-cause hospitalization, and all-cause mortality within 1 year. Interactions between chewing and swallowing difficulties were also evaluated. Among 359,111 older adults, 39.0% reported oral function difficulties. Swallowing difficulty alone lacked significant outcome association. However, chewing difficulty alone was significantly associated with higher risks of hospitalization due to aspiration pneumonia (hazard ratio (HR), 1.35; 95% confidence interval (CI), 1.15–1.58; P < 0.001), all-cause hospitalization (HR, 1.08; 95% CI, 1.05–1.11; P < 0.001), and all-cause mortality (HR, 1.28; 95% CI, 1.14–1.44; P < 0.001) compared with no self-reported difficulty. A significant positive interaction between self-reported difficulty in chewing and swallowing was observed for all-cause mortality (P = 0.009). Self-reported difficulty in chewing was significantly associated with higher risks of hospitalization due to aspiration pneumonia, all-cause hospitalization, and all-cause mortality among older adults. Chewing and swallowing difficulties showed a synergistic effect, significantly increasing all-cause mortality risk.

The effect of cognitive reserve on the cognitive connectome in healthy ageing - Annegret Habich; Eloy Garcia-Cabello; Chiara Abbatantuono; Lissett Gonzalez-Burgos; Paolo Taurisano; Thomas Dierks; José Barroso; Daniel Ferreira (GeroScience, 2024)
During ageing, different cognitive functions decline at different rates. Additionally, cognitive reserve may influence inter-individual variability in age-related cognitive decline. These complex relationships can be studied by constructing a so-called cognitive connectome and characterising it with advanced graph-theoretical network analyses. This study examined the effect of cognitive reserve on the cognitive connectome across age. A total of 334 cognitively healthy participants were stratified into early middle age (37–50 years; n = 110), late middle age (51–64 years; n = 106), and elderly (65–78 years; n = 118) groups. Within each age group, individuals were subdivided into high and low cognitive reserve. For each subgroup, a cognitive connectome was constructed based on correlations between 47 cognitive variables. Applying graph theory, different global network measures were compared between the groups. Graph-theoretical network analyses revealed that individuals with high cognitive reserve were characterized by a stable cognitive connectome across age groups. High cognitive reserve groups only differed in modularity. In contrast, individuals with low cognitive reserve showed a marked reconfiguration of cognitive connectomes across age groups with differences extending over a variety of network measures including network strength, global efficiency, modularity, and small-worldness. Our results suggest a stabilizing effect of cognitive reserve on the cognitive connectome. Gaining further insights into these findings and underlying mechanisms will contribute to our understanding of age-related cognitive decline and guide the development of strategies to preserve cognitive function in ageing.

Resting-state neural dynamics changes in older adults with post-COVID syndrome and the modulatory effect of cognitive training and sex - Boglárka Nagy; Andrea B. Protzner; Balázs Czigler; Zsófia Anna Gaál (GeroScience, 2024)
Post-COVID syndrome manifests with numerous neurological and cognitive symptoms, the precise origins of which are still not fully understood. As females and older adults are more susceptible to developing this condition, our study aimed to investigate how post-COVID syndrome alters intrinsic brain dynamics in older adults and whether biological sex and cognitive training might modulate these effects, with a specific focus on older females. The participants, aged between 60 and 75 years, were divided into three experimental groups: healthy old female, post-COVID old female and post-COVID old male. They underwent an adaptive task-switching training protocol. We analysed multiscale entropy and spectral power density of resting-state EEG data collected before and after the training to assess neural signal complexity and oscillatory power, respectively. We found no difference between post-COVID females and males before training, indicating that post-COVID similarly affected both sexes. However, cognitive training was effective only in post-COVID females and not in males, by modulating local neural processing capacity. This improvement was further evidenced by comparing healthy and post-COVID females, wherein the latter group showed increased finer timescale entropy (1–30 ms) and higher frequency band power (11–40 Hz) before training, but these differences disappeared following cognitive training. Our results suggest that in older adults with post-COVID syndrome, there is a pronounced shift from more global to local neural processing, potentially contributing to accelerated neural aging in this condition. However, cognitive training seems to offer a promising intervention method for modulating these changes in brain dynamics, especially among females.

Critical gap in practice—lack of attention to falls and possible fall-related post-concussion symptoms in older adults and individuals with neurodegenerative disease - Goldin Joghataie; Sabrina Hundal; Asma Mushtaque; Charles H. Tator; M. Carmela Tartaglia (GeroScience, 2024)

Human herpesvirus reactivation and its potential role in the pathogenesis of post-acute sequelae of SARS-CoV-2 infection - Zsófia Gáspár; Bálint Gergely Szabó; Andrea Ceglédi; Botond Lakatos (GeroScience, 2024)
The emergence of SARS-CoV-2 has precipitated a global pandemic with substantial long-term health implications, including the condition known as post-acute sequelae of SARS-CoV-2 infection (PASC), commonly referred to as Long COVID. PASC is marked by persistent symptoms such as fatigue, neurological issues, and autonomic dysfunction that persist for months beyond the acute phase of COVID-19. This review examines the potential role of herpesvirus reactivation, specifically Epstein-Barr virus (EBV) and cytomegalovirus (CMV), in the pathogenesis of PASC. Elevated antibody titers and specific T cell responses suggest recent herpesvirus reactivation in some PASC patients, although viremia is not consistently detected. SARS-CoV-2 exhibits endothelial trophism, directly affecting the vascular endothelium and contributing to microvascular pathologies. These pathologies are significant in PASC, where microvascular dysfunction may underlie various chronic symptoms. Similarly, herpesviruses like CMV also exhibit endothelial trophism, which may exacerbate endothelial damage when reactivated. Evidence suggests that EBV and CMV reactivation could indirectly contribute to the immune dysregulation, immunosenescence, and autoimmune responses observed in PASC. Additionally, EBV may play a role in the genesis of neurological symptoms through creating mitochondrial dysfunction, though direct confirmation remains elusive. The reviewed evidence suggests that while herpesviruses may not play a direct role in the pathogenesis of PASC, their potential indirect effects, especially in the context of endothelial involvement, warrant further investigation.

Effects of a 6-month dual-task, power-based exercise program on cognitive function, neurological and inflammatory markers in older adults: secondary analysis of a cluster randomised controlled trial - Jamie L. Tait; Rachel L. Duckham; Timo Rantalainen; Catherine M. Milte; Luana C. Main; Caryl A. Nowson; Kerrie M. Sanders; Dennis R. Taaffe; Keith D. Hill; Gavin Abbott; Robin M. Daly (GeroScience, 2024)
Functional power-based exercise training can improve physical performance in older adults and cognitive training can improve measures of cognition, but their combined effects on cognition and related risk factors (neurological and inflammatory markers) remains uncertain. This 6-month cluster randomised controlled trial evaluated the effectiveness of dual-task functional power training (DT-FPT) on cognition and circulating neurological and inflammatory markers in older adults at increased falls risk, and whether intervention responses varied by apolipoprotein-E (ApoE) and brain derived neurotrophic factor (BDNF) polymorphisms. Three hundred residents aged ≥ 65 years at increased falls risk residing in 22 independent-living retirement communities, were randomised by village, to DT-FPT (n = 156, 11 villages) involving a multi-component power-based training program performed simultaneously with cognitive and/or motor tasks (45–60 min, 2/week), or a usual care control (CON) group (n = 144, 11 villages). Cognition (computerized CogState battery), inflammatory cytokines, BDNF, insulin-like growth factor-1, vascular endothelial growth factor, amyloid β (1–40) and (1–42) were assessed at baseline and 6-months. Overall, 233 (78%) participants completed the intervention and adherence averaged 50.1%. DT-FPT led to a net 0.18–0.20 SD benefit versus CON in psychomotor ability/attention and reaction time/attention (both P < 0.05). There were no significant intervention effects on circulating markers, except for a net 10.5% benefit in amyloid β (1–40) in DT-FPT versus CON (P < 0.05). Responses were not influenced by APOE or BDNF genotype. In conclusion, DT-FPT in older adults at increased falls risk can provide some cognitive benefits, but these were not related to corresponding changes in inflammatory or neurological markers or influenced by genotype. Australian New Zealand Clinical Trials Registry (ACTRN12613001161718). http://www.anzctr.org.au/ This project was funded by a grant from the National Health and Medical Research Council (NHMRC) Project (APP1046267).

Gait Speed Reserve in the general population-based ‘Good Aging in Skåne’ cohort study—distribution and associated factors - Beata Lindholm; Rani Basna; Henrik Ekström; Sölve Elmståhl; Arkadiusz Siennicki-Lantz (GeroScience, 2024)
Gait Speed Reserve (GSR) expresses a difference between fast and comfortable gait speed and may have an impact on everyday functioning. It was also hypothesized as a useful proxy measure of physiological reserve. However, height-normalizing values of GSR and its associated factors have not been evaluated in a general population of older adults. Therefore, we aimed to investigate the distribution of height-normalized GSR (HN-GSR) in an elderly population-based cohort from urban and rural areas ( n = 4342) aged 60–93 years and evaluate associated physiological and lifestyle factors. Using linear mixed models, we identified gender and nine modifiable factors as significantly associated with HN-GSR across four age groups. Better handgrip strength, cognition and standing balance, higher physical activity level, larger calf circumference, and less smoking had positive associations with HN-GSR, while female gender, more leg pain, higher weight and, alcohol consumption had opposite effects. The Marginal R2 imply that this model explained 26% of the variance in HN-GSR. Physical activity and handgrip strength varied across age groups in impact on HN-GSR. The differences were however comparatively minor. In this large cohort study of older adults, we proposed for the first time that factors associated with HN-GSR represented multi-domain features that are in line with previous findings reported for GSR. Measuring HN-GSR/GSR may help clinicians identify early physiological impairments or unhealthy lifestyle habits, especially among older women, and may also have safety implications in daily life. Further work is needed to find out if measuring HN-GSR/GSR may be useful in identifying adverse health outcomes and overall physiological reserve.

Electrical brain networks before and after transcranial pulsed shockwave stimulation in Alzheimer’s patients - Lars Wojtecki; Celine Cont; Natalie Stute; Anastasia Galli; Christina Schulte; Carlos Trenado (GeroScience, 2024)
Alzheimer’s disease (AD) is a neurodegenerative disorder that dramatically affects cognitive abilities and represents the most common cause of dementia. Currently, pharmacological interventions represent the main treatment to deal with the symptoms of AD; however, alternative approaches are readily sought. Transcranial pulse stimulation (TPS) is an emerging non-invasive neuromodulation technique that uses short, repetitive shockwaves with the potential to provide a wide range of vascular, metabolic, and neurotrophic changes and that has recently been shown to improve cognitive abilities in AD. This exploratory study aims to gain insight into the neurophysiological effect of one session of TPS in AD as reflected in electroencephalographic measures, e.g., spectral power, coherence, Tsallis entropy (TE), and cross-frequency coupling (cfc). We document changes in power (frontal and occipital), coherence (frontal, occipital and temporal), and TE (temporal and frontal) as well as changes in cfc (parietal-frontal, parietal-temporal, frontal–temporal). Our results emphasize the role of electroencephalographic measures as prospective markers for the neurophysiological effect of TPS.

Sleep onset time as a mediator in the association between screen exposure and aging: a cross-sectional study - Senlin Lin; Meng Gao; Juzhao Zhang; Yuting Wu; Tao Yu; Yajun Peng; Yingnan Jia; Haidong Zou; Lina Lu; Deshang Li; Yingyan Ma (GeroScience, 2024)
Excessive screen exposure has become a significant health concern. This study investigates the impact of screen time on aging in middle-aged and elderly populations. Healthy working adults over 45 years old in Shanghai, China, underwent general and ocular examinations. Questionnaires collected demographics, medical history, and screen exposure details. Aging was assessed using the retinal age gap, defined as the difference between the retinal age predicted by deep learning algorithms based on fundus images and chronological age. Pathway analysis tested the mediation effect of sleep duration and onset time on the relationship between screen usage and retinal age gap. The retinal age gap increased with longer screen exposure, from 0.49 ± 3.51 years in the lowest tertile to 5.13 ± 4.96 years in the highest tertile (Jonckheere-Terpstra test, p < 0.001). Each additional hour of screen exposure accelerated the retinal age gap by 0.087 years (95% CI, 0.027, 0.148, p = 0.005) in the fully adjusted linear model. Sleep onset time mediated the impact of screen usage on the retinal age gap (indirect effect, β = 0.11; 95% CI 0.04–0.24). The impact of screen usage in a light-off environment on the retinal age gap was fully mediated by sleep onset time (indirect effect, β = 0.22; 95% CI 0.07–0.38), with the proportion being 100%. Our study identified a correlation between excessive screen time and a wider retinal age gap in middle-aged and elderly individuals, likely due to delayed sleep onset. To mitigate the adverse effects on the retina and aging, it is important to limit screen usage and avoid screens before bedtime.

Two-month ketogenic diet alters systemic and brain metabolism in middle-aged female mice - Kirsten J. Roslund; Jon J. Ramsey; Jennifer M. Rutkowsky; Zeyu Zhou; Carolyn M. Slupsky (GeroScience, 2024)
The ketogenic diet (KD) is a very low-carbohydrate, high-fat diet that reduces glucose catabolism and enhances β-oxidation and ketogenesis. While research in female rodents is limited, research in male rodents suggests that ketogenic interventions initiated at midlife may slow age-related cognitive decline, as well as preserve muscle mass and physical function later in life. This study aimed to investigate the effects of a KD on global metabolic changes in middle-aged females to inform potential mechanisms behind the anti-aging effects of this diet in an understudied sex. Targeted 1 H-NMR metabolomics was conducted on serum, the liver, the kidney, and the gastrocnemius muscle, as well as the cortex and the hippocampal brain regions in 16-month-old female mice after a 2-month KD. Analysis of the serum and liver metabolome revealed that the 2-month KD resulted in increased concentrations of fatty acid catabolism metabolites, as well as system-wide elevations in ketones, consistent with the ketogenic phenotype. Metabolites involved in the glucose-alanine cycle were altered in the gastrocnemius muscle, serum and the liver. Other tissue-specific alterations were detected, including distinct effects on hepatic and renal one-carbon metabolism, as well as region specific differences in metabolism across hippocampal and cortical parts of the brain. Alterations to hippocampal metabolites involved in myelinogenesis could relate to the potential beneficial effects of a KD on memory.

Neuroanatomical and clinical factors predicting future cognitive impairment - Phoebe Imms; Nikhil N. Chaudhari; Nahian F. Chowdhury; Haoqing Wang; Xiaokun Yu; Anar Amgalan; Andrei Irimia (GeroScience, 2024)
Identifying cognitively normal (CN) older adults who will convert to cognitive impairment (CI) due to Alzheimer’s disease is crucial for early intervention. Clinical and neuroimaging measures were acquired from 301 CN adults who converted to CI within 15 years of baseline, and 294 who did not. Regional volumes and brain age measures were extracted from T 1 -weighted magnetic resonance images. Linear discriminant analysis compared non-converters’ characteristics against those of short-, mid-, and long-term converters. Conversion was associated with clinical measures such as hearing impairment and self-reported memory decline. Converters’ brain volumes were smaller than non-converters’ across 48 frontal, temporal, and subcortical structures. Brain age measures of 12 structures were correlated with shorter times to conversion. Conversion prediction accuracy increased from 81.5% to 90.5% as time to conversion decreased. Proximity to CI conversion is foreshadowed by anatomic features of brain aging that enhance the accuracy of predicting conversion.

Age-related alterations in vortex veins on indocyanine green angiography - Chen-Xi Cai; Shan-Shan Yu; Xiao-Mei Xiong; Bing-Qian Liu; Zhen-Qiang Lin; Qiang Wang; Jin-Li Cui; Ze-Hao Liu; Tao Li; Lin Lu; Ying Lin (GeroScience, 2024)
To determine age-related alterations in vortex veins in healthy subjects. A total of 228 healthy subjects (aged 4 to 86 years) were recruited and divided into four groups (G1, <21 years; G2, 21–40 years; G3, 41–60 years; and G4, 61–86 years). The clinical characteristics of the participants were recorded, and parameters including the number of vortex vein roots (NVVR), the central vortex vein diameter (CVVD), the mean root area of the vortex vein (MRAVV), and the weighted mean of the thickest branch diameter (WMTBD) were obtained by marking the vortex veins on indocyanine green angiography (ICGA). The NVVR in the age group over 60 years old was significantly lower than that in other age groups ( P < 0.05). The CVVD, MRAVV, and WMTBD of all age groups increased with increasing age ( P < 0.05). The NVVR was unevenly distributed among the quadrants ( P < 0.001). The proportions of type four vortex veins (complete systems including ampulla) and anastomotic branches of the vortex veins were significantly increased in elderly participants over 50 years of age ( P < 0.05). Subfoveal choroidal thickness was significantly correlated with age, NVVR, CVVD and MRAVV ( P < 0.05). This is the first study to reveal age-related alterations in vortex veins on ICGA in a healthy population. Aging may lead to partial vortex occlusion and residual vortex dilation. As age increases, anastomotic branches increasingly appear between the originally independent vortex veins. Translational relevance: Aging may lead to partial vortex occlusion and residual vortex dilation.

Sarcopenia and the management of spinal disease in the elderly - Alexander R. Evans; Lonnie Smith; Joshua Bakhsheshian; David B. Anderson; James M. Elliott; Hakeem J. Shakir; Zachary A. Smith (GeroScience, 2024)

The RESIST Senior Individuals Cohort: Design, participant characteristics and aims - Lennart Matthias Roesner; Manoj Kumar Gupta; Verena Kopfnagel; Nienke van Unen; Yvonne Kemmling; Jana-Kristin Heise; Stephanie Castell; Xun Jiang; Lennart Riemann; Stephan Traidl; Berit Lange; Kurt-Wolfram Sühs; et al. (GeroScience, 2024)
The number of older adults worldwide is growing exponentially. However, while living longer, older individuals are more susceptible to both non-infectious and infectious diseases, at least in part due to alterations of the immune system. Here, we report on a prospective cohort study investigating the influence of age on immune responses and susceptibility to infection. The RESIST Senior Individuals (SI) cohort was established as a general population cohort with a focus on the elderly, enrolling an age- and sex-stratified sample of 650 individuals ( n = 100 20-39y, n = 550 61-94y, 2019–2023, Hannover, Germany). It includes clinical, demographic, and lifestyle data and also extensive biomaterial sampling. Initial insights indicate that the SI cohort exhibits characteristics of the aging immune system and the associated susceptibility to infection, thereby providing a suitable platform for the decoding of age-related alterations of the immune system and unraveling the molecular mechanisms underlying the impaired immune responsiveness in aging populations by exploring comprehensive, unbiased multi-omics datasets.

The role of atrial fibrillation in vascular cognitive impairment and dementia: epidemiology, pathophysiology, and preventive strategies - Mónika Fekete; Eric M. Liotta; Tihamer Molnar; Gábor A. Fülöp; Andrea Lehoczki (GeroScience, 2024)
The aging population in Europe faces a substantial burden from dementia, with vascular cognitive impairment and dementia (VCID) being a preventable cause. Atrial fibrillation (AF), a common cardiac arrhythmia, increases the risk of VCID through mechanisms such as thromboembolism, cerebral hypoperfusion, and inflammation. This review explores the epidemiology, pathophysiology, and preventive strategies for AF-related VCID. Epidemiological data indicate that AF prevalence rises with age, affecting up to 12% of individuals over 80. Neuroimaging studies reveal chronic brain changes in AF patients, including strokes, lacunar strokes, white matter hyperintensities (WMHs), and cerebral microbleeds (CMHs), while cognitive assessments show impairments in memory, executive function, and attention. The COVID-19 pandemic has exacerbated the underdiagnosis of AF, leading to an increase in undiagnosed strokes and cognitive impairment. Many elderly individuals did not seek medical care due to fear of exposure, resulting in delayed diagnoses. Additionally, reduced family supervision during the pandemic contributed to missed opportunities for early detection of AF and related complications. Emerging evidence suggests that long COVID may also elevate the risk of AF, further complicating the management of this condition. This review underscores the importance of early detection and comprehensive management of AF to mitigate cognitive decline. Preventive measures, including public awareness campaigns, patient education, and the use of smart devices for early detection, are crucial. Anticoagulation therapy, rate and rhythm control, and addressing comorbid conditions are essential therapeutic strategies. Recognizing and addressing the cardiovascular and cognitive impacts of AF, especially in the context of the COVID-19 pandemic, is essential for advancing public health.

What is normal age-related thigh muscle composition among 45- to 84-year-old adults from the UK Biobank study - David B. Anderson; Aaron J. Beach; Lingxiao Chen; Henry J. Feng; Marnee J. McKay; Zachary A. Smith; Kenneth A. Weber; Evert Onno Wesselink; James M. Elliott (GeroScience, 2024)
A loss of skeletal muscle mass and an increase in intramuscular fat are known to occur as we enter middle and older age, but the expected changes or normative values have remained unknown. The primary reason for this is that imaging studies are difficult and expensive to conduct, and consequently, the sample sizes have remained small. The development of the UK Biobank which provides access to a large magnetic resonance imaging (MRI) data set of more than 50,000 participants provides an opportunity to finally address this question of normative values for each age group. The study’s primary aim was to determine the age-related changes in thigh muscle composition (e.g., thigh fat-free muscle volume and intramuscular fat) between the ages of 45 and 84 years. The second aim was to analyse associations between thigh fat-free muscle volume and intramuscular fat with lifestyle behaviours (smoking, alcohol consumption, and physical activity), leg pain, and bone mineral density. Fifty thousand three hundred thirty-two participants were included in the study. Total fat-free thigh muscle declined between the ages of 45 and 84 years, while intramuscular fat of the thigh continued to increase. The changes were stable between these age groups. The mean volume of fat-free muscle ranged from 11.16 (SD: 1.40) to 13.26 L (SD: 1.85) in adult males and 7.60 (SD: 0.97) to 8.80 L (SD 1.29) in females between the ages of 45 and 84 years. For intramuscular fat, the change among women was from 6.94% (SD: 1.59) in the 45 to 54 years age bracket to 8.83% (SD: 1.92) in the 75 to 84 age bracket, while for men, it was 5.83% (SD: 1.30) in the 45 to 54 age bracket to 7.85% (SD 1.89) in the 75 to 84 age bracket. The total fat-free muscle volume and intramuscular fat percentage provided can be used for the purpose of reference standards or normative values for adults in the age groups provided. Fat-free muscle and intramuscular fat were found to be associated with a range of health, activity, and leg pain outcomes, and these should be investigated in a follow-up longitudinal imaging study.

Impact of Helicobacter pylori eradication on age-specific risk of incident dementia in patients with peptic ulcer disease: a nationwide population-based cohort study - Dong Woo Kang; Jung-Won Lee; Man Young Park; Sung-Hwan Kim; Yoo Hyun Um; Sheng-Min Wang; Chang Uk Lee; Hyun Kook Lim (GeroScience, 2024)
The impact of peptic ulcer disease (PUD) and Helicobacter pylori ( H. pylori ) eradication therapy on dementia risk in high H. pylori prevalence populations remains uncertain. This study investigates the relationship between PUD, H. pylori eradication, and dementia risk, including Alzheimer’s disease (AD), in an elderly South Korean cohort, considering age and eradication timing. Data from the Korean National Health Insurance Service (2002–2015) for individuals aged 55–79 were analyzed. Participants were divided based on PUD and H. pylori therapy status. Propensity score matching was used to evaluate dementia incidence and hazard ratios over 5 and 10 years, alongside the timing of eradication therapy. PUD is linked to higher dementia risk at 5 and 10 years, more for overall dementia than AD, with eradication status not significantly altering the risk. Age-specific analysis showed increased AD risk in the 60s and 70s age groups. Late eradication therapy is correlated with a higher dementia risk. PUD is a risk factor for dementia in elderly South Koreans, particularly with delayed H. pylori therapy. The findings emphasize timely H. pylori management and its potential role in neurodegenerative disease prevention.

Sex-specific clinical and neurobiological correlates of fatigue in older adults - Marco Toccaceli Blasi; Alba Rosa Alfano; Martina Salzillo; Simona Buscarnera; Valeria Raparelli; Matteo Cesari; Giuseppe Bruno; Marco Canevelli (GeroScience, 2024)
Fatigue is a common and distressful symptom in older people and has been associated with adverse health outcomes. Nevertheless, its sex-specific pathophysiological underpinnings and clinical correlates have been scarcely investigated. We aimed to comprehensively explore the clinical and neurobiological determinants of fatigue in cognitively unimpaired older adults. A sex-stratified analysis was conducted to look for differences in the clinical expression of fatigue among women and men. Data on cognitively normal individuals were gathered from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 2 study. Fatigue was defined based on self-report at baseline. For each participant, information on sociodemographics, comorbidities, mood, cognitive performance, frailty, and biomarkers of brain pathology was collected. Logistic regression models, stratified by sex, were conducted to explore the factors associated with fatigue. Among the 291 participants selected, 44 subjects (15.1% of the total sample) self-reported fatigue at baseline. Subjects reporting fatigue were more likely women, had higher frailty degrees, and more severe depressive symptoms than those without fatigue. Moreover, they tended to have lower MRI hippocampus volumes. Among women, those reporting fatigue exhibited higher frailty levels, worse depression, and lower MRI hippocampus volumes relative to those without fatigue. Higher frailty degrees were also observed in men reporting vs. non-reporting fatigue. In the adjusted logistic regression model, more severe depression (OR 1.64, 95% CI 1.18–2.28; p < 0.01) and lower MRI hippocampus volumes (OR 0.41, 95% CI 0.19–0.90; p = 0.03) resulted independently associated with fatigue in women, while higher frailty degrees (OR 3.10, 95% CI 1.27–7.54 per 0.1 increase in a 39-item Frailty index; p = 0.01) in men. Fatigue is a complex symptom with a sex-specific pattern of clinical and neurobiological correlates. A better understanding of the underlying mechanisms of these associations is warranted to develop sex-informed approaches for personalized treatments.

Sport and longevity: an observational study of international athletes - Abdullah Altulea; Martijn G. S. Rutten; Lex B. Verdijk; Marco Demaria (GeroScience, 2024)
The human lifespan is influenced by various factors, with physical activity being a significant contributor. Despite the clear benefit of exercise on health and longevity, the association between different types of sports and lifespan is yet to be considered. Accordingly, we aimed to study this association in a large international cohort of former athletes using a robust linear regression model. We collected data on athletes from public sources, accumulating a total of 95,210 observations, 95.5% of which were accounted for by males. The dataset represented athletes born between 1862 and 2002 from 183 countries across 44 sports disciplines. We calculated the change in lifespan by measuring the difference in age between athletes and the corresponding reference populations, while accounting for variations caused by sex, year of death, and country. The results revealed that various sports impacted lifespan differently, with male athletes being more likely to experience benefits from sports than female athletes. Among male athletes, pole vaulting and gymnastics were linked to the highest extension in lifespan (8.4 years, 95% CI [6.8, 9.9] and 8.2 years, 95% CI [7.4, 9], respectively), while volleyball and sumo wrestling were the most negatively associated with lifespan (− 5.4 years, 95% CI [− 7, − 3.8]; − 9.8 years, 95% CI [− 11, − 8.6], respectively). The association between lifespan and popular team sports in males was positive for cricket, rowing, baseball, water polo, Australian rules, hurling, lacrosse, field hockey, minimal for rugby, canoeing and kayaking, basketball, gridiron football, and football (soccer), and negative for handball and volleyball. Racquet sports (i.e., tennis and badminton) exhibited a consistent and positive association in both male and female athletes, as shown by an extended lifespan of up to 5.7 years in males (95% CI [5, 6.5]) and 2.8 years in females (95% CI [1.8, 3.9]). Although lacking conclusive evidence, we theorize that the observed results may be attributed to the aerobic and anaerobic characteristics of each sport, with mixed sports yielding the maximum benefits for the lifespan. While results from female athletes should be cautiously interpreted, our study highlights the complex interplay between sports and lifespan and contributes to the growing body of knowledge on the multifaceted relationship between physical activity and human longevity. Graphical Abstract

Discriminative ability of instrumented cognitive-motor assessments to distinguish fallers from non-fallers - Julia Seinsche; Elena Kyprianou; Eling D. de Bruin; Enrico Saibene; Francesco Rizzo; Ilaria Carpinella; Lisa Lutz; Maurizio Ferrarin; Riccardo Villa; Savvina Chrysostomou; Sotiria Moza; Eleftheria Giannouli (GeroScience, 2024)
In older populations, sensitive fall risk assessment tools are important to timely intervene and prevent falls. Instrumented assessments have shown to be superior to standardized fall risk assessments such as the Timed Up and Go Test (TUG) and should capture both motor and cognitive functions. Therefore, the aim was to test novel instrumented assessments with and without a cognitive component. One hundred thirty-seven older adults aged 73.1 ± 7.3 years, 38 categorized as fallers and 99 as non-fallers, conducted five instrumented assessments on the Dividat Senso, a pressure sensitive stepping platform, and three standardized geriatric assessments (TUG, TUG-dual task, 30-s Sit-to-Stand Test (STS)). T -tests were applied to compare the test performance of fallers versus non-fallers. Furthermore, logistic regression analyses and area under the curve (AUC) analyses were performed. Statistically significant differences between fallers and non-fallers were found in the Go/No-Go test ( p = .001, d = .72), the TUG ( p = .014, d = .48), and the STS ( p = .008, d = .51). Only the Go/No-Go test contributed significantly to all regression models. Significant AUC values were found for the Reaction Time Test (RTT) (AUC = .628, p = .023), Go/No-Go (AUC = .673, p = .002), TUG (AUC = .642, p = .012), and STS (AUC = .690, p = .001). The Go/No-Go test measuring inhibition showed the best discriminative ability suggesting added value of instrumented assessments with a cognitive component for clinical fall risk assessment in relatively healthy older adults. The study should be extended with a frailer population, in which TUG and the other instrumented assessments are possibly good predictors as well.

Senolytic intervention improves cognition, metabolism, and adiposity in female APPNL−F/NL−F mice - Yimin Fang; Mackenzie R. Peck; Kathleen Quinn; Jenelle E. Chapman; David Medina; Samuel A. McFadden; Andrzej Bartke; Erin R. Hascup; Kevin N. Hascup (GeroScience, 2024)
Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer’s disease (AD). The APP NL−F/NL−F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue and the hippocampus before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APP NL−F/NL−F mice. Thus, 4-month-old male and female APP NL−F/NL−F mice were treated monthly with vehicle, 5 mg/kg dasatinib + 50 mg/kg quercetin, or 100 mg/kg fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + quercetin treatment in female APP NL−F/NL−F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-β (Aβ) 42 and senescence-associated-β-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APP NL−F/NL−F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine. Graphical Abstract

Non-invasive myocardial work as an independent predictor of postprocedural NT-proBNP in elderly patients undergoing transcatheter aortic valve replacement - Zsuzsanna Ladányi; Tímea Bálint; Alexandra Fábián; Adrienn Ujvári; Tímea Katalin Turschl; Dávid Nagy; Éva Straub; Csaba Fejér; Endre Zima; Astrid Apor; Anikó Ilona Nagy; Tímea Szigethi; et al. (GeroScience, 2024)
Aortic stenosis has become the most prevalent valvular disease with increasing life expectancy and the ageing of the population, representing a significant clinical burden for health care providers. Its treatment has been revolutionized by transcatheter aortic valve replacement (TAVR) as a safe and minimally invasive option for elderly patients. Left ventricular (LV) functional measurement is of particular importance before TAVR, however, increased afterload significantly influences the conventional echocardiographic parameters. Non-invasive myocardial work examines myocardial deformation in the context of instantaneous LV pressure, thus, it might be a more reliable measure of LV function. Accordingly, we aimed to study non-invasive myocardial work and its relationship with functional outcome following TAVR. We enrolled 90 TAVR candidates (80 [75–84] years; 44% female). Using echocardiography, we quantified ejection fraction (EF), global longitudinal strain (GLS), global myocardial work index (GWI) and global constructive work (GCW) before and 12 months after the procedure. Serum NT-proBNP levels were also measured. EF did not change (52.6 ± 13.1 vs. 54.2 ± 10.5%; p = 0.199), while GLS increased (-13.5 ± 4.6 vs. -15.2 ± 3.8%; p < 0.001). GWI decreased (1913 ± 799 vs. 1654 ± 613 mmHg%; p < 0.001) and so did GCW (2365 ± 851 vs. 2177 ± 652 mmHg%; p = 0.018). History of atrial fibrillation (AF) (β = 0.349) and preprocedural GCW (β = -0.238) were independent predictors of postprocedural NT-proBNP ( p < 0.001). GLS, GWI and GCW changed after TAVR while there was no alteration in EF. The preprocedural GCW and history of AF were independent predictors of postprocedural NT-proBNP. Accordingly, myocardial work indices may help patient selection and the prediction of the functional outcome in this population.

Identifying sources of bias when testing three available algorithms for quantifying white matter lesions: BIANCA, LPA and LGA - Tatiana Miller; Nora Bittner; Susanne Moebus; Svenja Caspers (GeroScience, 2024)
Brain magnetic resonance imaging frequently reveals white matter lesions (WMLs) in older adults. They are often associated with cognitive impairment and risk of dementia. Given the continuous search for the optimal segmentation algorithm, we broke down this question by exploring whether the output of algorithms frequently used might be biased by the presence of different influencing factors. We studied the impact of age, sex, blood glucose levels, diabetes, systolic blood pressure and hypertension on automatic WML segmentation algorithms. We evaluated three widely used algorithms (BIANCA, LPA and LGA) using the population-based 1000BRAINS cohort ( N = 1166, aged 18–87, 523 females, 643 males). We analysed two main aspects. Firstly, we examined whether training data (TD) characteristics influenced WML estimations, assessing the impact of relevant factors in the TD. Secondly, algorithm’s output and performance within selected subgroups defined by these factors were assessed. Results revealed that BIANCA’s WML estimations are influenced by the characteristics present in the TD. LPA and LGA consistently provided lower WML estimations compared to BIANCA’s output when tested on participants under 67 years of age without risk cardiovascular factors. Notably, LPA and LGA showed reduced accuracy for these participants. However, LPA and LGA showed better performance for older participants presenting cardiovascular risk factors. Results suggest that incorporating comprehensive cohort factors like diverse age, sex and participants with and without hypertension in the TD could enhance WML-based analyses and mitigate potential sources of bias. LPA and LGA are a fast and valid option for older participants with cardiovascular risk factors.

Anti-aging interventions in geriatric mice: insights into the timing of treatment, benefits, and limitations - Marco Malavolta (GeroScience, 2024)

Right anterior insula ASL hypoperfusion as a diagnostic biomarker of prodromal and mild dementia with Lewy bodies: preliminary evidence using a Bayesian approach - Golda Gommel; Ludovic Jeanjean-Dormegny; Clément de Crespin de Billy; Olivier Mainberger; Augustin Moreau; Alexandre Obrecht; Rémi Vernet; Ilia Humbert; Benoit Schorr; Candice Muller; Catherine Demuynck; Paulo Loureiro de Sousa; et al. (GeroScience, 2024)

Gonadal status modulates large elastic artery stiffness in healthy middle-aged and older men - Lyndsey E. DuBose; Matthew C. Babcock; Wendy M. Kohrt; Brian L. Stauffer; Kerry L. Hildreth; Jacob Walker; Matthew K. Armstrong; Kerrie L. Moreau (GeroScience, 2024)

A pilot study evaluating dosing tolerability of 17α-estradiol in male common marmosets (Callithrix jacchus) - Roshini Sathiaseelan; Jose V. V. Isola; Roberto Santín-Márquez; Daniel Adekunbi; Michal Fornalik; Adam B. Salmon; Michael B. Stout (GeroScience, 2024)

Characterizing dog cognitive aging using spontaneous problem-solving measures: development of a battery of tests from the Dog Aging Project - Stephanie H. Hargrave; Emily E. Bray; Stephanie McGrath; Gene E. Alexander; Theadora A. Block; Naomi Chao; Martin Darvas; Laura E. L. C. Douglas; Janet Galante; Brenda S. Kennedy; Breonna Kusick; Julie A. Moreno; et al. (GeroScience, 2024)

Beat-to-beat blood pressure variability, hippocampal atrophy, and memory impairment in older adults - Trevor Lohman; Isabel Sible; Allison C. Engstrom; Arunima Kapoor; Fatemah Shenasa; Elizabeth Head; Lorena Sordo; John Paul M. Alitin; Aimee Gaubert; Amy Nguyen; Kathleen E. Rodgers; David Bradford; et al. (GeroScience, 2024)
Visit-to-visit blood pressure variability (BPV) predicts age-related hippocampal atrophy, neurodegeneration, and memory decline in older adults. Beat-to-beat BPV may represent a more reliable and efficient tool for prospective risk assessment, but it is unknown whether beat-to-beat BPV is similarly associated with hippocampal neurodegeneration, or with plasma markers of neuroaxonal/neuroglial injury. Independently living older adults without a history of dementia, stroke, or other major neurological disorders were recruited from the community ( N = 104; age = 69.5 ± 6.7 (range 55–89); 63% female). Participants underwent continuous blood pressure monitoring, brain MRI, venipuncture, and cognitive testing over two visits. Hippocampal volumes, plasma neurofilament light, and glial fibrillary acidic protein levels were assessed. Beat-to-beat BPV was quantified as systolic blood pressure average real variability during 7-min of supine continuous blood pressure monitoring. The cross-sectional relationship between beat-to-beat BPV and hippocampal volumes, cognitive domain measures, and plasma biomarkers was assessed using multiple linear regression with adjustment for demographic covariates, vascular risk factors, and average systolic blood pressure. Elevated beat-to-beat BPV was associated with decreased left hippocampal volume ( P = .008), increased plasma concentration of glial fibrillary acidic protein ( P = .006), and decreased memory composite score ( P = .02), independent of age, sex, average systolic blood pressure, total intracranial volume, and vascular risk factor burden. In summary, beat-to-beat BPV is independently associated with decreased left hippocampal volume, increased neuroglial injury, and worse memory ability. Findings are consistent with prior studies examining visit-to-visit BPV and suggest beat-to-beat BPV may be a useful marker of hemodynamic brain injury in older adults.

Judith Campisi (1948–2024): tribute and personal memory - Steven N. Austad (GeroScience, 2024)

From data to decisions: AI and functional connectivity for diagnosis, prognosis, and recovery prediction in stroke - Alessia Cacciotti; Chiara Pappalettera; Francesca Miraglia; Claudia Carrarini; Cristiano Pecchioli; Paolo Maria Rossini; Fabrizio Vecchio (GeroScience, 2024)

Adherence to the Mediterranean diet and its protective effects against colorectal cancer: a meta-analysis of 26 studies with 2,217,404 participants - Zoltan Ungvari; Mónika Fekete; János Tibor Fekete; Giuseppe Grosso; Anna Ungvari; Balázs Győrffy (GeroScience, 2024)
Colorectal cancer (CRC) is a major global health concern and represents a significant public health challenge in Hungary, where it exhibits some of the highest morbidity and mortality rates in the European Union. The Mediterranean diet has been suggested to reduce the incidence of CRC, but comprehensive evidence from diverse study designs is needed to substantiate this effect. A systematic literature search was conducted in PubMed, ClinicalTrials.gov, CENTRAL, and the Web of Science to identify randomized controlled trials and human clinical trials from 2008 to 2024 to identify relevant studies. Statistical analysis was performed using the https://metaanalysisonline.com web application using a random effects model to estimate the pooled hazard rates (HRs). Forest plots, funnel plots, and Z -score plots were utilized to visualize results. We identified 15 clinical trials and 9 case–control studies, encompassing a total of 2,217,404 subjects. The pooled analysis indicated that adherence to the Mediterranean diet significantly reduced the prevalence of CRC (HR = 0.84, 95% CI = 0.78–0.91, p < 0.01). This protective effect was consistent across sexes, with HRs of 0.85 (95% CI = 0.75–0.97, p = 0.01) for males and 0.88 (95% CI = 0.79–0.99, p = 0.03) for females. Case–control studies specifically showed a substantial effect (HR = 0.51, 95% CI = 0.38–0.68, p < 0.01). Notable heterogeneity was observed across studies, yet the a priori information size was substantially below the cumulative sample size, ensuring sufficient data for reliable conclusions. The findings from this meta-analysis reinforce the protective role of the Mediterranean diet against CRC. The results of this meta-analysis will inform dietary interventions designed to mitigate CRC risk, which are conducted within the framework of the Semmelweis Study, an ongoing comprehensive cohort study at Semmelweis University, designed to explore the multifaceted causes of unhealthy aging in Hungary. These interventions aim to explore the practical application of Mediterranean dietary patterns in reducing CRC incidence among the Hungarian population.

No association between markers of systemic inflammation and endothelial dysfunction with Alzheimer’s disease progression: a longitudinal study - Arne van Setten; Jeroen F. Uleman; René J. F. Melis; Brian Lawlor; Niels P. Riksen; Jurgen A. H. R. Claassen; Rianne A. A. de Heus; Ricardo Segurado; Sean Kennelly; Marcel G. M. Olde Rikkert; Robert Howard; Florence Pasquier; et al. (GeroScience, 2024)
Introduction Systemic inflammation and endothelial dysfunction are potentially modifiable factors implicated in Alzheimer’s disease (AD), which offer potential therapeutic targets to slow disease progression. Methods We investigated the relationship between baseline circulating levels of inflammatory (TNF-α, IL-1ß) and endothelial cell markers (VCAM-1, ICAM-1, E-selectin) and 18-month cognitive decline (ADAS-cog12) in 266 mild-to-moderate AD patients from the NILVAD study. We employed individual growth models to examine associations, potential mediation, and interaction effects while adjusting for confounders. Results The average increase in ADAS-cog12 scores over all patients was 8.1 points in 18 months. No significant association was found between the markers and the rate of cognitive decline. Mediation analysis revealed no mediating role for endothelial cell markers, and interaction effects were not observed. Discussion Our results do not support the role of systemic inflammation or endothelial dysfunction in progression in persons with AD.

Age-associated proteins explain the role of medial temporal lobe networks in Alzheimer’s disease - Adam Turnbull; Yejin Kim; Kai Zhang; Xiaoqian Jiang; Zihuai He; Victor W. Henderson; F. Vankee Lin (GeroScience, 2024)

The untapped potential of cold water therapy as part of a lifestyle intervention for promoting healthy aging - Setor K. Kunutsor; Andrea Lehoczki; Jari A. Laukkanen (GeroScience, 2024)