|
GeroScience : Official Journal of the American Aging Association (AGE)
Number of Followers: 8  Hybrid journal (It can contain Open Access articles)ISSN (Print) 2509-2715 - ISSN (Online) 2509-2723 Published by Springer-Verlag  [2469 journals]
|
- Task-based functional connectivity of the Useful Field of View (UFOV) fMRI
task-
Free pre-print version: Loading...
Abstract: Abstract Declines in processing speed performance occur in aging and are a critical marker of functional independence in older adults. Numerous studies suggest that Useful Field of View (UFOV) training may ameliorate cognitive decline in older adults. Despite its efficacy, little is known about the neural correlates of this task. The current study is the first to investigate the coherence of functional connectivity during UFOV task completion. A total of 336 participants completed the UFOV task while undergoing task-based functional magnetic resonance imaging (fMRI). Ten spherical regions of interest (ROIs), selected a priori, were created based on regions with the greatest peak BOLD activation patterns in the UFOV fMRI task and regions that have been shown to significantly relate to UFOV fMRI task performance. We used a weighted ROI-to-ROI connectivity analysis to model task-specific functional connectivity strength between these a priori selected ROIs. We found that our UFOV fMRI network was functionally connected during task performance and was significantly associated to UFOV fMRI task performance. Within-network connectivity of the UFOV fMRI network showed comparable or better predictive power in accounting for UFOV accuracy compared to 7 resting state networks, delineated by Yeo and colleagues. Finally, we demonstrate that the within-network connectivity of UFOV fMRI task accounted for scores on a measure of “near transfer”, the Double Decision task, better than the aforementioned resting state networks. Our data elucidate functional connectivity patterns of the UFOV fMRI task. This may assist in future targeted interventions that aim to improve synchronicity within the UFOV fMRI network.
PubDate: 2022-08-11
-
- Lipidomics profiling of biological aging in American Indians: the Strong
Heart Family Study-
Free pre-print version: Loading...
Abstract: Abstract Telomeres shorten with age and shorter leukocyte telomere length (LTL) has been associated with various age-related diseases. Thus, LTL has been considered a biomarker of biological aging. Dyslipidemia is an established risk factor for most age-related metabolic disorders. However, little is known about the relationship between LTL and dyslipidemia. Lipidomics is a new biochemical technique that can simultaneously identify and quantify hundreds to thousands of small molecular lipid species. In a large population comprising 1843 well-characterized American Indians in the Strong Heart Family Study, we examined the lipidomic profile of biological aging assessed by LTL. Briefly, LTL was quantified by qPCR. Fasting plasma lipids were quantified by untargeted liquid chromatography–mass spectrometry. Lipids associated with LTL were identified by elastic net modeling. Of 1542 molecular lipids identified (518 known, 1024 unknown), 174 lipids (36 knowns) were significantly associated with LTL, independent of chronological age, sex, BMI, hypertension, diabetes status, smoking status, bulk HDL-C, and LDL-C. These findings suggest that altered lipid metabolism is associated with biological aging and provide novel insights that may enhance our understanding of the relationship between dyslipidemia, biological aging, and age-related diseases in American Indians.
PubDate: 2022-08-11
-
- Metabolic and molecular responses of human patellar tendon to concentric-
and eccentric-type exercise in youth and older age-
Free pre-print version: Loading...
Abstract: Abstract Exercise training can induce adaptive changes to tendon tissue both structurally and mechanically; however, the underlying compositional changes that contribute to these alterations remain uncertain in humans, particularly in the context of the ageing tendon. The aims of the present study were to determine the molecular changes with ageing in patellar tendons in humans, as well as the responses to exercise and exercise type (eccentric (ECC) and concentric (CON)) in young and old patellar tendon. Healthy younger males (age 23.5 ± 6.1 years; n = 27) and older males (age 68.5 ± 1.9 years; n = 27) undertook 8 weeks of CON or ECC training (3 times per week; at 60% of 1 repetition maximum (1RM)) or no training. Subjects consumed D2O throughout the protocol and tendon biopsies were collected after 4 and 8 weeks for measurement of fractional synthetic rates (FSR) of tendon protein synthesis and gene expression. There were increases in tendon protein synthesis following 4 weeks of CON and ECC training (P < 0.01; main effect by ANOVA), with no differences observed between young and old males, or training type. At the transcriptional level however, ECC in young adults generally induced greater responses of collagen and extracellular matrix-related genes than CON, while older individuals had reduced gene expression responses to training. Different training types did not appear to induce differential tendon responses in terms of protein synthesis, and while tendons from older adults exhibited different transcriptional responses to younger individuals, protein turnover changes with training were similar for both age groups.
PubDate: 2022-08-11
-
- High-throughput sequencing analysis of nuclear-encoded mitochondrial genes
reveals a genetic signature of human longevity-
Free pre-print version: Loading...
Abstract: Abstract Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity.
PubDate: 2022-08-10
-
- DNA methylation trajectories and accelerated epigenetic aging in incident
type 2 diabetes-
Free pre-print version: Loading...
Abstract: Abstract DNA methylation (DNAm) patterns across the genome changes during aging and development of complex diseases including type 2 diabetes (T2D). Our study aimed to estimate DNAm trajectories of CpG sites associated with T2D, epigenetic age (DNAmAge), and age acceleration based on four epigenetic clocks (GrimAge, Hannum, Horvath, phenoAge) in the period 10 years prior to and up to T2D onset. In this nested case–control study within Doetinchem Cohort Study, we included 132 incident T2D cases and 132 age- and sex-matched controls. DNAm was measured in blood using the Illumina Infinium Methylation EPIC array. From 107 CpG sites associated with T2D, 10 CpG sites (9%) showed different slopes of DNAm trajectories over time (p < 0.05) and an additional 8 CpG sites (8%) showed significant differences in DNAm levels (at least 1%, p-value per time point < 0.05) at all three time points with nearly parallel trajectories between incident T2D cases and controls. In controls, age acceleration levels were negative (slower epigenetic aging), while in incident T2D cases, levels were positive, suggesting accelerated aging in the case group. We showed that DNAm levels at specific CpG sites, up to 10 years before T2D onset, are different between incident T2D cases and healthy controls and distinct patterns of clinical traits over time may have an impact on those DNAm profiles. Up to 10 years before T2D diagnosis, cases manifested accelerated epigenetic aging. Markers of biological aging including age acceleration estimates based on Horvath need further investigation to assess their utility for predicting age-related diseases including T2D.
PubDate: 2022-08-10
-
- Aging compromises oligodendrocyte precursor cell maturation and efficient
remyelination in the monkey brain-
Free pre-print version: Loading...
Abstract: Abstract Age-associated cognitive decline is common among otherwise healthy elderly people, even in the absence of Alzheimer’s disease and neuron loss. Instead, white matter loss and myelin damage are strongly associated with cognitive decline. Myelin is subject to lifelong oxidative stress that damages the myelin sheath, which is repaired by cells of the oligodendrocyte lineage. This process is mediated by oligodendrocyte precursor cells (OPCs) that sense the damage and respond by proliferating locally and migrating to the region, where they differentiate into mature myelinating oligodendrocytes. In aging, extensive myelin damage, in combination with inefficient remyelination, leads to chronically damaged myelin and loss of efficient neuronal conduction. This study used the rhesus monkey model of normal aging to examine how myelin regeneration capacity is affected by age. Results show that older subjects have reduced numbers of new BCAS1 + myelinating oligodendrocytes, which are newly formed cells, and that this reduction is associated with poorer cognitive performance. Interestingly, this does not result from limited proliferation of progenitor OPCs. Instead, the transcription factor NKX2.2, which regulates OPCs differentiation, is significantly decreased in aged OPCs. This suggests that these OPCs have a diminished potential for differentiation into mature oligodendrocytes. In addition, mature oligodendrocytes have reduced RNA expression of two essential myelin protein markers, MBP and PLP. These data collectively suggest that in the normal aging brain, there is a reduction in regenerative OPCs as well as myelin production that impairs the capacity for remyelination.
PubDate: 2022-08-05
-
- Unbiased proteomic analysis of extracellular vesicles secreted by
senescent human vascular smooth muscle cells reveals their ability to
modulate immune cell functions-
Free pre-print version: Loading...
Abstract: Abstract Atherosclerosis, a common age-related disease, is characterized by intense immunological activity. Atherosclerotic plaque is composed of endothelial cells, vascular smooth muscle cells (VSMCs), lipids and immune cells infiltrating from the blood. During progression of the disease, VSMCs undergo senescence within the plaque and secrete SASP (senescence-associated secretory phenotype) factors that can actively modulate plaque microenvironment. We demonstrated that senescent VSMCs secrete increased number of extracellular vesicles (senEVs). Based on unbiased proteomic analysis of VMSC-derived EVs and of the soluble fraction of SASP (sSASP), more than 900 proteins were identified in each of SASP compartments. Comparison of the composition of VMSC-derived EVs with the SASP atlas revealed several proteins, including Serpin Family F Member 1 (SERPINF1) and Thrombospondin 1 (THBS1), as commonly upregulated components of EVs secreted by senescent VSMCs and fibroblasts. Among soluble SASP factors, only Growth Differentiation Factor 15 (GDF15) was universally increased in the secretome of senescent VSMCs, fibroblasts, and epithelial cells. Bioinformatics analysis of EV proteins distinguished functionally organized protein networks involved in immune cell function regulation. Accordingly, EVs released by senescent VSMCs induced secretion of IL-17, INFγ, and IL-10 by T cells and of TNFα produced by monocytes. Moreover senEVs influenced differentiation of monocytes favoring mix M1/M2 polarization with proinflammatory characteristics. Altogether, our studies provide a complex, unbiased analysis of VSMC SASP and prove that EVs derived from senescent VSMCs influence the cytokine milieu by modulating immune cell activity. Our results strengthen the role of senescent cells as an important inducer of inflammation in atherosclerosis.
PubDate: 2022-07-28
-
- GH deficiency confers protective advantages against Alzheimer’s disease
through rescued miRNA expression profile in APP/PS1 mice-
Free pre-print version: Loading...
Abstract: Abstract Alzheimer’s disease (AD) is the most common form of dementia, affecting approximately 6.5 million Americans age 65 or older. AD is characterized by increased cognitive impairment and treatment options available provide minimal disease attenuation. Additionally, diagnostic methods for AD are not conclusive with definitive diagnoses requiring postmortem brain evaluations. Therefore, miRNAs, a class of small, non-coding RNAs, have garnered attention for their ability to regulate a variety of mRNAs and their potential to serve as both therapeutic targets and biomarkers of AD. Several miRNAs have already been implicated with AD and have been found to directly target genes associated with AD pathology. The APP/PS1 mice is an AD model that expresses the human mutated form of the amyloid precursor protein (APP) and presenilin-1 (PS1) genes. In a previous study, it was identified that crossing long-living growth hormone (GH)-deficient Ames dwarf (df/df) mice with APP/PS1 mice provided protection from AD through a reduction in IGF-1, amyloid-β (Aβ) deposition, and gliosis. Hence, we hypothesized that changes in the expression of miRNAs associated with AD mediated such benefits. To test this hypothesis, we sequenced miRNAs in hippocampi of df/df, wild type (+ / +), df/ + /APP/PS1 (phenotypically normal APP/PS1), and df/df/APP/PS1 mice. Results of this study demonstrated significantly upregulated and downregulated miRNAs between df/df/APP/PS1 and df/ + /APP/PS1 mice that suggest the df/df mutation provides protection from AD progression. Additionally, changes in miRNA expression with age were identified in both df/df and wild-type mice as well as df/df/APP/PS1 and APP/PS1 mice, with predictive functional roles in the Pi3k-AKT/mTOR/FOXO pathways potentially contributing to disease pathogenesis.
PubDate: 2022-07-28
-
- Hypothalamic microstructure and function are related to body mass, but not
mental or cognitive abilities across the adult lifespan-
Free pre-print version: Loading...
Abstract: Abstract Physical, mental, and cognitive resources are essential for healthy aging. Aging impacts on the structural integrity of various brain regions, including the hippocampus. Even though recent rodent studies hint towards a critical role of the hypothalamus, there is limited evidence on functional consequences of age-related changes of this region in humans. Given its central role in metabolic regulation and affective processing and its connections to the hippocampus, it is plausible that hypothalamic integrity and connectivity are associated with functional age-related decline. We used data of n = 369 participants (18–88 years) from the Cambridge Centre for Ageing and Neuroscience repository to determine functional impacts of potential changes in hypothalamic microstructure across the lifespan. First, we identified age-related changes in microstructure as a function of physical, mental, and cognitive health and compared those findings to changes in hippocampal microstructure. Second, we investigated the relationship of hypothalamic microstructure and resting-state functional connectivity and related those changes to age as well as physical health. Our results showed that hypothalamic microstructure is not affected by depressive symptoms (mental health), cognitive performance (cognitive health), and comparatively stable across the lifespan, but affected by body mass (physical health). Furthermore, body mass changes connectivity to limbic regions including the hippocampus, amygdala, and nucleus accumbens, suggesting functional alterations in the metabolic and reward systems. Our results demonstrate that hypothalamic structure and function are affected by body mass, focused on neural density and dispersion, but not inflammation. Still, observed effect sizes were small, encouraging detailed investigations of individual hypothalamic subunits.
PubDate: 2022-07-27
-
- Effect of simultaneous exercise and cognitive training on executive
functions, baroreflex sensitivity, and pre-frontal cortex oxygenation in
healthy older adults: a pilot study-
Free pre-print version: Loading...
Abstract: Abstract Aging is characterized by cognitive decline affecting daily functioning. To manage this socio-economic challenge, several non-pharmacological methods such as physical, cognitive, and combined training are proposed. Although there is an important interest in this subject, the literature is still heterogeneous. The superiority of simultaneous training compared to passive control and physical training alone seems clear but very few studies compared simultaneous training to cognitive training alone. The aim of this pilot study was to investigate the effect of simultaneous exercise and cognitive training on several cognitive domains in healthy older adults, in comparison with either training alone. Thirty-five healthy older adults were randomized into one of three experimental groups: exercise training, cognitive training, and simultaneous exercise and cognitive training. The protocol involved two 30-min sessions per week for 24 weeks. Cognitive performance in several domains, pre-frontal cortex oxygenation, and baroreflex sensitivity were assessed before and after the intervention. All groups improved executive performance, including flexibility or working memory. We found a group by time interaction for inhibition cost (F(2,28) = 6.44; p < 0.01) and baroreflex sensitivity during controlled breathing (F(2,25) = 4.22; p = 0.01), the magnitude of improvement of each variable being associated (r = -0.39; p = 0.03). We also found a decrease in left and right pre-frontal cortex oxygenation in all groups during the trail making test B. A simultaneous exercise and cognitive training are more efficient than either training alone to improve executive function and baroreflex sensitivity. The results of this study may have important clinical repercussions by allowing to optimize the interventions designed to maintain the physical and cognitive health of older adults.
PubDate: 2022-07-26
-
- Age-related decline in circulating IGF-1 associates with impaired
neurovascular coupling responses in older adults-
Free pre-print version: Loading...
Abstract: Abstract Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) to the increased oxygen and energy requirements of active brain regions via neurovascular coupling (NVC) contributes to the genesis of age-related cognitive impairment. Aging is associated with marked deficiency in the vasoprotective hormone insulin-like growth factor-1 (IGF-1). Preclinical studies on animal models of aging suggest that circulating IGF-1 deficiency is causally linked to impairment of NVC responses. The present study was designed to test the hypotheses that decreases in circulating IGF-1 levels in older adults also predict the magnitude of age-related decline of NVC responses. In a single-center cross-sectional study, we enrolled healthy young (n = 31, 11 female, 20 male, mean age: 28.4 + / − 4.2 years) and aged volunteers (n = 32, 18 female, 14 male, mean age: 67.9 + / − 4.1 years). Serum IGF-1 level, basal CBF (phase contrast magnetic resonance imaging (MRI)), and NVC responses during the trail making task (with transcranial Doppler sonography) were assessed. We found that circulating IGF-1 levels were significantly decreased with age and associated with decreased basal CBF. Age-related decline in IGF-1 levels predicted the magnitude of age-related decline in NVC responses. In conclusion, our study provides additional evidence in support of the concept that age-related circulating IGF-1 deficiency contributes to neurovascular aging, impairing CBF and functional hyperemia in older adults.
PubDate: 2022-07-23
-
- Different patterns of excess all-cause mortality by age and sex in Hungary
during the 2nd and 3rd waves of the COVID-19 pandemic-
Free pre-print version: Loading...
Abstract: Abstract It is well accepted that COVID-19-related mortality shows a strong age dependency. However, temporal changes in the age distribution of excess relative mortality between waves of the pandemic are less frequently investigated. We aimed to assess excess absolute mortality and the age-distribution of all-cause mortality during the second and third waves of the COVID-19 pandemic in Hungary compared to the same periods of non-pandemic years. Rate ratios for excess all-cause mortality with 95% confidence intervals and the number of excess deaths for the second (week 41 of 2020 through week 4 of 2021) and third waves (weeks 7–21 of 2021) of the COVID pandemic for the whole of Hungary compared to the same periods of the pre-pandemic years were estimated for 10-year age strata using Poisson regression. Altogether, 9771 (95% CI: 9554–9988) excess deaths were recorded during the second wave of the pandemic, while it was lower, 8143 (95% CI: 7953–8333) during the third wave. During the second wave, relative mortality peaked for ages 65–74 and 75–84 (RR 1.37, 95%CI 1.33–1.41, RR 1.38, 95%CI 1.34–1.42). Conversely, during the third wave, relative mortality peaked for ages 35–44 (RR 1.43, 95%CI 1.33–1.55), while those ≥65 had substantially lower relative risks compared to the second wave. The reduced relative mortality among the elderly during the third wave is likely a consequence of the rapidly increasing vaccination coverage of the elderly coinciding with the third wave. The hugely increased relative mortality of those 35–44 could point to non-biological causes, such as less stringent adherence to non-pharmaceutical measures in this population.
PubDate: 2022-07-22
-
- Circulating cell-free DNA in health and disease — the relationship to
health behaviours, ageing phenotypes and metabolomics-
Free pre-print version: Loading...
Abstract: Abstract Circulating cell-free DNA (cf-DNA) has emerged as a promising biomarker of ageing, tissue damage and cellular stress. However, less is known about health behaviours, ageing phenotypes and metabolic processes that lead to elevated cf-DNA levels. We sought to analyse the relationship of circulating cf-DNA level to age, sex, smoking, physical activity, vegetable consumption, ageing phenotypes (physical functioning, the number of diseases, frailty) and an extensive panel of biomarkers including blood and urine metabolites and inflammatory markers in three human cohorts (N = 5385; 17–82 years). The relationships were assessed using correlation statistics, and linear and penalised regressions (the Lasso), also stratified by sex. cf-DNA levels were significantly higher in men than in women, and especially in middle-aged men and women who smoke, and in older more frail individuals. Correlation statistics of biomarker data showed that cf-DNA level was higher with elevated inflammation (C-reactive protein, interleukin-6), and higher levels of homocysteine, and proportion of red blood cells and lower levels of ascorbic acid. Inflammation (C-reactive protein, glycoprotein acetylation), amino acids (isoleucine, leucine, tyrosine), and ketogenesis (3-hydroxybutyrate) were included in the cf-DNA level-related biomarker profiles in at least two of the cohorts. In conclusion, circulating cf-DNA level is different by sex, and related to health behaviour, health decline and metabolic processes common in health and disease. These results can inform future studies where epidemiological and biological pathways of cf-DNA are to be analysed in details, and for studies evaluating cf-DNA as a potential clinical marker.
PubDate: 2022-07-21
-
- Aging alters antiviral signaling pathways resulting in functional
impairment in innate immunity in response to pattern recognition receptor
agonists-
Free pre-print version: Loading...
Abstract: The progressive impairment of immunity to pathogens and vaccines with aging is a significant public health problem as the world population shifts to an increased percentage of older adults (> 65). We have previously demonstrated that cells obtained from older volunteers have delayed and defective induction of type I interferons and T cell and B cell helper cytokines in response to TLR ligands when compared to those from adult subjects. However, the underlying intracellular mechanisms are not well described. Herein, we studied two critical pathways important in the production of type I interferon (IFN), the interferon response factor 7 (pIRF7), and TANK-binding kinase (pTBK-1). We show a decrease in pIRF7 and pTBK-1 in cross-priming dendritic cells (cDC1s), CD4+ T cell priming DCs (cDC2s), and CD14dimCD16+ vascular patrolling monocytes from older adults (n = 11) following stimulation with pathway-specific agonists in comparison with young individuals (n = 11). The decrease in these key antiviral pathway proteins correlates with decreased phagocytosis, suggesting impaired function in Overall, our findings describe molecular mechanisms which explain the innate functional impairment in older adults and thus could inform us of novel approaches to restore these defects. Graphical abstract
PubDate: 2022-07-18
-
- Continent-wide evolutionary trends of emerging SARS-CoV-2 variants:
dynamic profiles from Alpha to Omicron-
Free pre-print version: Loading...
Abstract: Abstract The ongoing SARS-CoV-2 evolution process has generated several variants due to its continuous mutations, making pandemics more critical. The present study illustrates SARS-CoV-2 evolution and its emerging mutations in five directions. First, the significant mutations in the genome and S-glycoprotein were analyzed in different variants. Three linear models were developed with the regression line to depict the mutational load for S-glycoprotein, total genome excluding S-glycoprotein, and whole genome. Second, the continent-wide evolution of SARS-CoV-2 and its variants with their clades and divergence were evaluated. It showed the region-wise evolution of the SARS-CoV-2 variants and their clustering event. The major clades for each variant were identified. One example is clade 21K, a major clade of the Omicron variant. Third, lineage dynamics and comparison between SARS-CoV-2 lineages across different countries are also illustrated, demonstrating dominant variants in various countries over time. Fourth, gene-wise mutation patterns and genetic variability of SARS-CoV-2 variants across various countries are illustrated. High mutation patterns were found in the ORF10, ORF6, S, and low mutation pattern E genes. Finally, emerging AA point mutations (T478K, L452R, N501Y, S477N, E484A, Q498R, and Y505H), their frequencies, and country-wise occurrence were identified, and the highest event of two mutations (T478K and L452R) was observed.
PubDate: 2022-07-13
-
- Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on
the Alzheimer’s disease risk-
Free pre-print version: Loading...
Abstract: Abstract The mechanisms of incomplete penetrance of risk-modifying impacts of apolipoprotein E (APOE) ε2 and ε4 alleles on Alzheimer’s disease (AD) have not been fully understood. We performed genome-wide analysis of differences in linkage disequilibrium (LD) patterns between 6,136 AD-affected and 10,555 AD-unaffected subjects from five independent studies to explore whether the association of the APOE ε2 allele (encoded by rs7412 polymorphism) and ε4 allele (encoded by rs429358 polymorphism) with AD was modulated by autosomal polymorphisms. The LD analysis identified 24 (mostly inter-chromosomal) and 57 (primarily intra-chromosomal) autosomal polymorphisms with significant differences in LD with either rs7412 or rs429358, respectively, between AD-affected and AD-unaffected subjects, indicating their potential modulatory roles. Our Cox regression analysis showed that minor alleles of four inter-chromosomal and ten intra-chromosomal polymorphisms exerted significant modulating effects on the ε2- and ε4-associated AD risks, respectively, and identified ε2-independent (rs2884183 polymorphism, 11q22.3) and ε4-independent (rs483082 polymorphism, 19q13.32) associations with AD. Our functional analysis highlighted ε2- and/or ε4-linked processes affecting the lipid and lipoprotein metabolism and cell junction organization which may contribute to AD pathogenesis. These findings provide insights into the ε2- and ε4-associated mechanisms of AD pathogenesis, underlying their incomplete penetrance.
PubDate: 2022-07-09
-
- Evidence for preserved insulin responsiveness in the aging rat brain
-
Free pre-print version: Loading...
Abstract: Abstract Insulin appears to exert salutary effects in the central nervous system (CNS). Thus, brain insulin resistance has been proposed to play a role in brain aging and dementia but is conceptually complex and unlikely to fit classic definitions established in peripheral tissues. Thus, we sought to characterize brain insulin responsiveness in young (4–5 months) and old (24 months) FBN male rats using a diverse set of assays to determine the extent to which insulin effects in the CNS are impaired with age. When performing hyperinsulinemic-euglycemic clamps in rats, intracerebroventricular (ICV) infusion of insulin in old animals improved peripheral insulin sensitivity by nearly two-fold over old controls and comparable to young rats, suggesting preservation of this insulin-triggered response in aging per se (p < 0.05). We next used an imaging-based approach by comparing ICV vehicle versus insulin and performed resting state functional magnetic resonance imaging (rs-fMRI) to evaluate age- and insulin-related changes in network connectivity within the default mode network. In aging, lower connectivity between the mesial temporal (MT) region and other areas, as well as reduced MT signal complexity, was observed in old rats, which correlated with greater cognitive deficits in old. Despite these stark differences, ICV insulin failed to elicit any significant alteration to the BOLD signal in young rats, while a significant deviation of the BOLD signal was observed in older animals, characterized by augmentation in regions of the septal nucleus and hypothalamus, and reduction in thalamus and nucleus accumbens. In contrast, ex vivo stimulation of hippocampus with 10 nM insulin revealed increased Akt activation in young (p < 0.05), but not old rats. Despite similar circulating levels of insulin and IGF-1, cerebrospinal fluid concentrations of these ligands were reduced with age. Thus, these data highlight the complexity of capturing brain insulin action and demonstrate preserved or heightened brain responses to insulin with age, despite dampened canonical signaling, thereby suggesting impaired CNS input of these ligands may be a feature of reduced brain insulin action, providing further rationale for CNS replacement strategies.
PubDate: 2022-07-08
-
- Biomarkers of aging in real life: three questions on aging and the
comprehensive geriatric assessment-
Free pre-print version: Loading...
Abstract: Abstract Measuring intrinsic, biological age is a central question in medicine, which scientists have been trying to answer for decades. Age manifests itself differently in different individuals, and chronological age often does not reflect such heterogeneity of health and function. We discuss here the value of measuring age and aging using the comprehensive geriatric assessment (CGA), cornerstone of geriatric medicine, and operationalized assessment tools for prognosis. Specifically, we review the benefits of employing the multidimensional prognostic index (MPI), which collects information about eight domains relevant for the global assessment of the older person (functional and cognitive status, nutrition, mobility and risk of pressure sores, multi-morbidity, polypharmacy, and co-habitation), in the evaluation of the functional status, and in the prediction of health outcomes for older adults. Further integration of biological markers of aging into multidimensional prognostic tools is warranted, as well as actions which could facilitate prognostic assessments for older persons in all healthcare settings.
PubDate: 2022-07-07
-
- Brain age estimation reveals older adults’ accelerated senescence
after traumatic brain injury-
Free pre-print version: Loading...
Abstract: Abstract Adults aged 60 and over are most vulnerable to mild traumatic brain injury (mTBI). Nevertheless, the extent to which chronological age (CA) at injury affects TBI-related brain aging is unknown. This study applies Gaussian process regression to T1-weighted magnetic resonance images (MRIs) acquired within \(\sim\) 7 days and again \(\sim\) 6 months after a single mTBI sustained by 133 participants aged 20–83 (CA \(\mu \pm \sigma\) = 42.6 ± 17 years; 51 females). Brain BAs are estimated, modeled, and compared as a function of sex and CA at injury using a statistical model selection procedure. On average, the brains of older adults age by 15.3 ± 6.9 years after mTBI, whereas those of younger adults age only by 1.8 ± 5.6 years, a significant difference (Welch’s t32 = − 9.17, p ≃ 9.47 × 10−11). For an adult aged \(\sim\) 30 to \(\sim\) 60, the expected amount of TBI-related brain aging is \(\sim\) 3 years greater than in an individual younger by a decade. For an individual over \(\sim\) 60, the respective amount is \(\sim\) 7 years. Despite no significant sex differences in brain aging (Welch’s t108 = 0.78, p > 0.78), the statistical test is underpowered. BAs estimated at acute baseline versus chronic follow-up do not differ significantly (t264 = 0.41, p > 0.66, power = 80%), suggesting negligible TBI-related brain aging during the chronic stage of TBI despite accelerated aging during the acute stage. Our results indicate that a single mTBI sustained after age \(\sim\) 60 involves approximately \(\sim\) 10 years of premature and lasting brain aging, which is MRI detectable as early as \(\sim\) 7 days post-injury.
PubDate: 2022-07-06
-
- Which components of the Mediterranean diet are associated with
dementia' A UK Biobank cohort study-
Free pre-print version: Loading...
Abstract: Abstract Cohort studies suggest that the Mediterranean diet is associated with better global cognition in older adults, slower cognitive decline and lower risk of dementia. However, little is known about the relative contribution of each component of the Mediterranean diet to dementia risk or whether the diet’s effects are due to one or more specific food components. We aimed to examine whether Mediterranean diet components are associated with all-cause dementia risk in the UK BioBank cohort. Participants joined the UK Biobank study from 2006 to 2010 and were followed until December 2020. 249,511 participants, who were at least 55 years old, without dementia at baseline were included. We used self-reported consumption of food groups, considered part of the Mediterranean diet including fruit, vegetables, processed meat, unprocessed red meat and unprocessed poultry, fish, cheese, wholegrains. Incident dementia was ascertained through electronic linkage to primary care records, hospital and mortality records or self-report. In this study with a total follow-up of 2,868,824 person-years (median 11.4), after adjusting for all covariates and other food groups, moderate fish consumption of between 2.0 and 3.9 times a week was associated with decreased risk of dementia (HR 0.84, 95%CI 0.71–0.98) compared to no consumption. Additionally, fruit consumption of between 1.0 and 1.9 servings a day was associated with reduced dementia risk (HR 0.85, 95%CI 0.74–0.99) compared to no consumption. No other Mediterranean diet components were associated with dementia risk suggesting that fish consumption may drive the beneficial effects seen from the Mediterranean diet. Further study of potential mechanisms and diet-based intervention trials are needed to establish this.
PubDate: 2022-07-06
-
