Aging is associated with intestinal dysbiosis, a condition characterized by diminished microbial biodiversity and inflammation. This leads to increased vulnerability to extraintestinal manifestations such as autoimmune, metabolic, and neurodegenerative conditions thereby accelerating mortality. As such, modulation of the gut microbiome is a promising way to extend healthspan. In this study, we explore the effects of fecal microbiota transplant (FMT) from long-living Ames dwarf donors to their normal littermates, and vice versa, on the recipient gut microbiota and liver transcriptome. Importantly, our previous studies highlight differences between the microbiome of Ames dwarf mice relative to their normal siblings, potentially contributing to their extended lifespan and remarkable healthspan. Our findings demonstrate that FMT from Ames dwarf mice to normal mice significantly alters the recipient’s gut microbiota, potentially reprogramming bacterial functions related to healthy aging, and changes the liver transcriptome, indicating improved metabolic health. Particularly, the microbiome of Ames dwarf mice, characterized by a higher abundance of beneficial bacterial families such as Peptococcaceae, Oscillospiraceae, and Lachnospiraceae, appears to play a crucial role in modulating these effects. Alongside, our mRNA sequencing and RT-PCR validation reveals that FMT may contribute to the significant downregulation of p21, Elovl3, and Insig2, genes involved with cellular senescence and liver metabolic pathways. Our data suggest a regulatory axis exists between the gut and liver, highlighting the potential of microbiome-targeted therapies in promoting healthy aging. Future research should focus on functional validation of altered microbial communities and explore the underlying biomolecular pathways that confer geroprotection.
Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1c levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.
Ageing individuals often experience cognitive decline and intrinsic functional connectivity (FC) changes. Psychological resilience, a personality trait that reflects the capacity to adapt and cope with age-related challenges, plays a key role in mitigating cognitive decline. In this study involving 101 older adults, we investigated how psychological resilience influences cognitive decline measured by processing speed. Particularly, we obtained resting-state functional magnetic resonance imaging (fMRI) to assess how intrinsic FC, represented by degree centrality, modulates the relationship between resilience and processing speed. Our results indicated while psychological resilience positively predicted processing speed, this relationship was mainly driven by education. Additionally, the degree centrality of both thalamus and caudate negatively correlated with processing speed and resilience. Notably, the degree centrality of both thalamus and caudate significantly mediated the relationship between resilience and processing speed. These findings suggest that psychological resilience could protect against age-related cognitive decline via its influence on FC in the thalamus and caudate, highlighting these areas as potential intervention targets for reducing cognitive decline in ageing people.
This randomized controlled trial compared the effects of home-based exercise, with or without cognitive training, on cognition and physical function in individuals aged 50 years and older with stable CVD during the COVID-19 pandemic. 122 patients (67.3 ± 7.9 years, 71% men) with stable CVD (77% coronary heart disease) were randomly assigned (1:1) to (1) Home-based physical exercise alone, or (2) Home-based physical exercise combined with cognitive training. Cognition (executive functions (primary outcome), processing speed, episodic memory, and working memory) and physical functions were assessed remotely at baseline, 3 months, and 6 months. Adjusted mean changes from baseline to 3 months and 6 months for executive functions, episodic memory, working memory, sit-to-stand test, gait speed, and timed up-and-go test were significant in the overall sample (p < 0.05). Furthermore, executive functions, episodic memory, sit-to-stand test, and timed up-and-go performances were significantly improved at 6 months in both groups when analyzed separately although no group differences were observed. Mean exercise dose differed significantly between the 2 groups: 1413 vs 953 METs.min−1 week−1 respectively for the exercise and combined group (p < 0.01). Mean cognitive training duration was 25.6 ± 16.6 min.week−1 for the combined intervention group. Results remained unchanged after accounting for the exercise dose. In adults affected by CVD, a remote combined intervention integrating sequential cognitive and exercise training yields comparable enhancements in executive function, episodic memory, and physical performances compared to exercise training alone. ClinicalTrials.gov: NCT04661189.
Dysregulated solutes are linked to cancer progression, with associated carriers being potential targets for prognosis and treatment. Androgen deprivation therapy (ADT) is essential for prostate cancer (PCa) progression, but secondary resistance often leads to androgen-independent tumor growth, necessitating new prognostic biomarkers. Transcriptome-based datasets identify SLC25A29, an arginine carrier, as upregulated in PCa, correlating with metastatic features and serving as a high-risk prognostic factor, particularly in castration-resistant prostate cancer (CRPC). Molecular simulations indicate that SLC25A29-mediated pathways contribute to mitochondrial metabolism and redox homeostasis, implicating POLD1 regulation and suggesting a link to ferroptosis. Further analysis reveals that SLC25A29 may transactivate POLD1 via E2F1, as shown by RNA-seq profiling of E2F1 knockdown in CRPC-related cells, which demonstrated reduced POLD1 expression. Clinical and cellular studies confirm that SLC25A29, E2F1, and POLD1 levels positively correlate with pathological features, with their downstream effectors serving as prognosis signatures. The SLC25A29/E2F1/POLD1 axis is associated with neuroendocrine PCa (NEPC) development, indicating its role in response to androgen receptor inhibition. Downregulation of E2F1 not only decreases POLD1 levels but also reduces NEPC-related markers. These findings support the SLC25A29/E2F1/POLD1 axis as a prognostic tool for CRPC and NEPC, and targeting E2F1 may offer a therapeutic strategy to disrupt SLC25A29-mediated PCa progression.
Through systematic bioinformatic analysis and molecular simulation models, this study elucidates the molecular mechanisms underlying prostate cancer’s tolerance to androgen deprivation therapy (ADT). Our findings propose that the upregulation of SLC25A29 leads to the transactivation of POLD1 via E2F1. This pathway mitigates redox stress and maintains mitochondrial function, thereby contributing to the progression of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). The axis involving SLC25A29, E2F1, and POLD1 emerges as a promising prognostic signature in prostate cancer.
In an era marked by a rapidly aging global population, delving into the intricate neurophysiological changes that accompany the aging process assumes paramount importance. This narrative review offers a comprehensive exploration of the intricate relationship between electromagnetic neuromodulation and electroencephalography (EEG) within the context of aging. Moreover, it showed the promising landscape of non-invasive neuromodulation techniques, encompassing established methodologies like transcranial magnetic stimulation (TMS) and transcranial direct and alternating current stimulation (tDCS/tACS). These modalities are analyzed for their potential to shape EEG marks in the aging population. These associations not only could broaden our understanding of the aging brain but could also suggest exciting scenarios for therapeutic interventions and cognitive enhancement among the elderly. Consequently, the comprehension of these mechanisms emerges as a critical key player for the development of precisely tailored interventions, aimed at mitigating age-associated cognitive decline and supporting robust brain health in the elderly.
The current study examined cross-sectional and longitudinal associations between nocturia and frailty in a cohort of men and women aged 60 years and older, as evidence on this topic was lacking. We analyzed baseline and follow-up data (n = 1671) from the Berlin Aging Study II (BASE-II), a prospective longitudinal cohort study focusing on the factors associated with "healthy" vs. "unhealthy" aging. Self-reported nocturia was dichotomized into < / ≥ 2 micturitions per night, and frailty was assessed using the Fried frailty phenotype. Covariables were identified a priori based on a review of the existing literature. At baseline, 70.2% of the participants were robust, 28.9% were pre-frail, and 0.9% were frail; 254 participants (23.6%) had self-reported nocturia. In longitudinal analyses, the prevalence and incidence of frailty at follow-up significantly increased when nocturia was present at baseline. Over a median follow-up of 7.1 years, there were 41 incident frailty cases (IR 5.6, 95%-CI 3.9-7.2 per 1000 person-years). After adjusting for age, sex, morbidity burden, and baseline frailty status, baseline nocturia was associated with a 2.23-fold increased risk (95%-CI 1.17-4.18) of frailty at follow-up. Nocturia is associated with an increased risk of developing or progressing in frailty in older adults, and may serve as an early clinical marker for the progression of frailty.
Executive functions (EFs), encompassing inhibition, shifting, and updating as three fundamental subdomains, are typically characterized by a unity/diversity construct. However, given the dedifferentiation trend observed in aging, it remains controversial whether the construct of EFs in older adults becomes unidimensional or maintains unity/diversity. This study aims to explore and validate the construct of EFs in older adults. At the behavioral level, we conducted confirmatory factor analysis on data from 222 older adults who completed six tasks specifically targeting inhibition, shifting, and updating. One unidimensional model and six unity/diversity models of EFs were evaluated. Our results indicated that the EFs of older adults demonstrated greater congruence with the unity/diversity construct. At neural level, thirty older adults completed three thematically consistent fMRI tasks, targeting three subdomains of EFs respectively. Multivariate pattern analysis showed that rostromedial prefrontal cortex robustly showed similar neural representation across different tasks (unity). Meanwhile, the three EF domains were encoded by distinct global neural representation and the lateral prefrontal cortex play a crucial role in classification (diversity). These findings underscore the unity/diversity framework of EFs in older adults and offer important insights for designing interventions aimed at improving EFs in this population.
Dietary restriction (DR) is widely considered to be one of the most potent approaches to extend healthy lifespan across various species, yet it has become increasingly apparent that DR-mediated longevity is influenced by biological and non-biological factors. We propose that current priorities in the field should include understanding the relative contributions of these factors to elucidate the mechanisms underlying the beneficial effects of DR. Our work conducted in two laboratories represents an attempt to unify DR protocols in Drosophila and to investigate the stochastic effects of DR. Across 64 pairs of survival data (DR/ad libitum, or AL), we find that DR does not universally extend lifespan. Specifically, we observed that DR conferred a significant lifespan extension in only 26.7% (17/64) of pairs. Our pooled data show that the overall lifespan difference between DR and AL groups is statistically significant, but the median lifespan increase under DR (7.1%) is small. The effects of DR were overshadowed by stochastic factors and genotype. Future research efforts directed toward gaining a comprehensive understanding of DR-dependent mechanisms should focus on unraveling the interactions between genetic and environmental factors. This is essential for developing personalized healthspan-extending interventions and optimizing dietary recommendations for individual genetic profiles.
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