GeroScience最新文献

The ovary is one of the first organs in humans to exhibit age-related functional impairments. As an organ composed of diverse heterogeneous cell types, the ovary exhibits cell-type-specific changes during the aging process, ultimately leading to a decline in female fertility. Investigating the molecular mechanisms of ovarian aging is crucial for understanding age-related fertility dysfunction in females. In this study, we combine scRNA-seq and scATAC-seq from mouse young/aged ovaries to characterize molecular features during ovarian aging. Using the single-cell multi-omic data, we revealed the cell-type-specific transcriptional changes during the aging process in seven major ovarian cell types and identified the cis/trans-regulatory elements governing these transcriptional changes. Specifically, we uncovered the transcriptional alterations of TGF-beta signaling in mesenchymal cells and endoplasmic reticulum stress in granulosa cells of aged mouse ovaries and further identified the potential corresponding cis/trans-regulatory elements. These molecular alterations may contribute to aging-induced functional impairments in mouse ovaries. In summary, this work provides transcriptome and chromatin accessibility landscape of ovarian aging in mice, which serve as a resource for identifying the cell-type-specific molecular mechanisms underlying ovarian aging, aiding in the identification of potential diagnostic biomarkers and treatment strategies.

Chronic, low-grade inflammation is a hallmark of aging and various age-related diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The prevalence of metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of MASLD, increases with age and contributes to morbidity and mortality among the elderly. This study investigates the role of necroptosis, a programmed cell death pathway that promotes inflammation, in liver inflammaging and age-associated MASLD by utilizing genetic ablation models of two key necroptosis proteins, Mlkl or Ripk3. The absence of Mlkl or Ripk3 significantly reduced liver inflammation, steatosis, and fibrosis in aged male mice, supporting the role of necroptosis in age-associated MASLD. Additionally, Mlkl or Ripk3 deletion impacted other non-necroptotic cellular processes that drive inflammation and MASLD, such as cellular senescence, apoptosis, and autophagy in aged liver. Levels of plasma TNFα and IL6, key proinflammatory cytokines associated with inflammaging, are reduced in Mlkl^−/− or Ripk3^−/− aged mice, supporting a systemic effect of necroptosis inhibition on inflammation. Proteomic analysis of liver tissues emphasizes the critical role of lipid and immune regulatory processes in maintaining liver homeostasis when Mlkl or Ripk3 is absent in aging liver. While Mlkl deletion did not affect the lifespan of mice, Ripk3 deletion shortened it. Additionally, Mlkl deficiency improved insulin sensitivity, whereas Ripk3 deficiency exacerbated glucose intolerance in aged mice. Thus, selective inhibition of Mlkl, not Ripk3, represents a potential therapeutic avenue for mitigating age-related liver disease and enhancing metabolic outcomes in the elderly.

Several progeroid syndromes’ causative mutations have been linked to epigenetic age acceleration as measured via several epigenetic clocks. At the same time, several protective variants have also been discovered that can reduce the risk of developing certain age-related disorders. However, the impact of these protective variants on epigenetic aging has not been well elucidated. Our research, which involved screening over 14,669 healthy individuals enrolled in the Qatar BioBank (QBB) and sequenced by the Qatar Genome Project (QGP), identified individuals carrying protective variants against age-related disorders, including Alzheimer’s disease (AD), type 2 diabetes (T2D), and atherosclerosis. In this study, we measured methylation levels in blood DNA using the EPIC v2 arrays. In addition, epigenetic age was calculated using various epigenetic clocks. Our analysis revealed that the APOE*E2 protective variant reduces the rate of GrimAge epigenetic aging when compared to individuals with the APOE4 AD risk allele. Furthermore, our differential DNA methylation analysis discovered the association of the PCSK9 protective variant with specific biological processes related to immune function and the cardiovascular system. In conclusion, APOE*E2 protective variants have a positive impact on epigenetic aging, while PCSK9 protective variants have a significant effect on DNA methylation signatures. Further studies are needed to better understand the underlying mechanisms by which protective variants influence epigenetic aging, particularly the role of APOE*E2 protective variants in biological aging. Furthermore, additional research is required to fully uncover the processes that might enable specific targeted therapies to mimic the effects of beneficial mutations, such as LOF variants in PCSK9, in reducing the risk of geriatric disorders.

Alzheimer’s disease (AD) can be identified through biomarkers of amyloid (A) and tau (T) pathology. Frailty, a measure of biological aging, could impact the association between AD neuropathology and its clinical manifestation. We aimed to investigate the relationship between frailty and AD biomarkers among people with mild cognitive impairment (MCI) attending a university memory clinic. Data were collected from a cohort of patients with MCI at the Memory Center of Geneva University Hospital (Switzerland). Frailty was assessed using a 35-item Frailty Index (FI). A and T positivity were determined through amyloid and tau PET or CSF analysis. Participants were divided into two subgroups: (i) A + T + (both amyloid and tau positive) and (ii) E/N (either A + or T + , neither A + nor T +), including all other combinations of A/T status. We first explored the correlation between FI, age, and education. Demographics, FI scores, and neuropsychological test results were then compared between these two groups. Logistic regression models, adjusted for age, sex, and education were used to examine the association between FI and AT positivity. One hundred twenty patients were included. FI was positively correlated with age and inversely with education. A + T + patients exhibited lower FI scores compared to E/N participants (0.13 ± 0.10 vs. 0.15 ± 0.08, p = 0.01). Logistic regressions found a negative association between FI and A + T + (OR 0.6, 95% CI 0.32–0.90; p = 0.02). Frailty is associated with a lower likelihood of AD biomarker positivity in patients with MCI. Frailty might reflect alternative pathophysiological mechanisms contributing to cognitive impairment.

Current European Stroke Organisation (ESO) guidelines recommend extended time window reperfusion therapies (4.5–9 h for thrombolysis, 6–24 h for thrombectomy) based on advanced imaging. However, the workload and clinical benefit of this strategy on a population basis are not known. To determine the caseload, treatment rates, and outcomes in the extended as compared to the standard time windows. All consecutive ischaemic stroke patients within 24 h of last known well between 1st March 2021 and 28th February 2022 were included in a prospective single-centre study. Treatment eligibility in the extended time windows or wake-up strokes recognized within 4 h was based on current ESO guideline criteria using MRI DWI-PWI or DWI-FLAIR mismatch. MRI was only available during working hours (8–20 h); otherwise, CT/CTA was used. Clinical outcome in treated patients was assessed at three months. Among the 777 admitted patients, 252 (32.4%) had MRI. The thrombolysis rate was 119/304 (39.1%) in standard and 14/231 (6.1%) in the extended time window. The thrombectomy rate was 34/386 (8.8%) in standard and 15/391 (3.8%) in the extended time window. Independent clinical outcomes (mRS ≤ 2) were not statistically different in early and late-treated patients both for thrombolysis (48% vs. 28.6%, p = 0.25) and thrombectomy (38.4% vs. 33.3%, p = 0.99). Even with a limited availability of advanced imaging extending therapeutic time windows resulted in an 11.7% increase in thrombolysis and a 44% increase in thrombectomy with comparable clinical outcomes in early and late-treated patients at the price of a twofold burden in clinical and advanced imaging screening.

There is a growing interest in developing drugs with a general geroprotective effect, aimed at slowing down aging. Several compounds have been shown to increase the lifespan and reduce the incidence of age-related diseases in model organisms. Translating these results is challenging, due to the long lifespan of humans. To address this, we propose using a battery of medical imaging protocols that allow for assessments of age-related processes known to precede disease onset. These protocols, based on magnetic resonance imaging, positron emission-, computed-, and optical coherence tomography, are already in use in drug development and are available at most modern hospitals. Here, we outline how an informed use of these techniques allows for detecting changes in the accumulation of age-related pathologies in a diverse set of physiological systems. This in vivo imaging battery enables efficient screening of candidate geroprotective compounds in early phase clinical trials, within reasonable trial durations.

There is growing interest in studying vascular contributions to cognitive impairment and dementia (VCID) and developing biomarkers to identify at-risk individuals. A combination of biofluid and neuroimaging markers may better profile early stage VCID than individual measures. Here, we tested this possibility focusing on plasma levels of S100 calcium-binding protein B (S100B), which has been linked with blood–brain-barrier (BBB) integrity, and neuroimaging measures assessing BBB function (water exchange rate across the BBB (k_w)) and cerebral small vessel disease (white matter hyperintensities (WMHs)). A total of 74 older adults without dementia had plasma samples collected and underwent cognitive assessment. A subsample had neuroimaging data including diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) for assessment of BBB k_w and T2-weighted fluid-attenuated inversion recovery (FLAIR) for quantification of WMHs. Results indicated that higher plasma S100B levels were associated with poorer episodic memory performance (β = − .031, SE = .008, p < .001). Moreover, significant interactions were observed between plasma S100B levels and parietal lobe BBB k_w (interaction β = .095, SE = .042, p = .028) and between plasma S100B levels and deep WMH volume (interaction β = − .025, SE = .009, p = .007) for episodic memory. Individuals with the poorest memory performance showed both high plasma S100B and either low BBB k_w in the parietal lobe or increased deep WMH burden. Taken together, our results provide support for the combined use of biofluid and neuroimaging markers in the study of VCID.

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.