Premature Brain Aging Research Articles

Longitudinal analysis of astrocyte-derived protein levels in the blood of drug-naive and relapsed patients with schizophrenia

The potential influence of astrocytes on neuronal circuitry and psychotic symptoms in schizophrenia have recently been highlighted. Human postmortem studies have observed reduced astrocyte numbers in schizophrenia, but whether this pathology is present at disease onset or accumulates progressively with further psychotic episodes remains unclear.Therefore, we analyzed serum levels of the astrocyte-derived proteins glial fibrillary acidic protein (GFAP) and fatty acid-binding protein 7 (FABP7) in acutely ill first-episode (n=60) and relapsed (n=34) schizophrenia patients compared to 94 matched controls. Measurements were taken before and 6 weeks after antipsychotic treatment. We found significantly lower levels of GFAP (p<0.001) and FABP7 (p<0.001) in patients compared to controls, with no significant differences between first-episode and relapsed patients or changes after treatment. FABP7 negatively correlated with age in controls (r=-0.319, p=0.002), but not in patients (r=-0.251, p=0.015). In contrast, GFAP showed no correlation with age.Our findings suggest that lowered GFAP and FABP7 may serve as trait markers of astrocyte pathology in schizophrenia, even prior to antipsychotic treatment. The absent correlation between FABP7 and age in schizophrenia patients, contrary to controls may be related to premature brain aging in schizophrenia. Long-term studies are needed to explore the relationship between chronic disease and astrocyte pathology in schizophrenia.

Association between large neutral amino acids and white matter hyperintensities in middle-aged adults at varying metabolic risk.

This investigation delves into the interplay between large neutral amino acids (LNAA) and metabolic syndrome (MetS) in midlife adults, examining their collective influence on brain structure. While LNAA, such as tryptophan and phenylalanine, are known to bolster cognition in youth, these relationships often reverse later in life. Our study hypothesized an earlier reversal of these benefits in middle-aged adults with MetS, potentially signaling premature brain aging. Eighty participants between 40-61years underwent MetS component quantification, LNAA measurement via high-performance liquid chromatography, and brain imaging to evaluate white matter hyperintensities (WMH) volume and medial temporal lobe (MTL) cortical thickness. Our linear regression analyses, adjusting for sex, age, and education, revealed that phenylalanine levels moderated the relationship between MetS and WMH volume (F(6, 69) = 3.134, p < 0.05, R2 = 0.214), suggesting the brain impact of MetS may be partly due to phenylalanine catabolism byproducts. LNAA metabolites did not significantly modulate the MetS-MTL cortical thickness relationship. These findings suggest that better understanding of the role of phenylalanine in the pathogenesis of cerebrovascular disease in midlife may be essential to developing early interventions to protect cognitive health. Further research is crucial to elucidate the longitudinal influence of LNAA and MetS on brain health, thereby informing strategies to mitigate cognitive decline.

Gestational diabetes mellitus, not obesity, triggers postpartum brain inflammation and premature aging in Sprague-Dawley rats

Previous studies showed that women with gestational diabetes mellitus (GDM) are susceptible to cognitive dysfunction. We investigated the effects of GDM on brain pathologies and premature brain aging in rats. Seven-week-old female Sprague-Dawley rats were fed a normal diet (ND) or a high-fat diet (HFD) after two weeks of acclimatization. On pregnancy day 0, HFD-treated rats received streptozotocin (GDM group) or vehicle (Obese mothers). ND-treated rats received vehicle (ND-control mothers). On postpartum day 21, brains and blood were collected. The GDM group showed increased inflammatory and premature aging markers, mitochondrial changes, and compensatory increases in the blood–brain barrier and synaptic proteins in the prefrontal cortex and hippocampus. GDM triggers maternal brain inflammation and premature aging, suggesting compensatory mechanisms may protect against these effects.

Regional brain aging: premature aging of the domain general system predicts aphasia severity

Premature brain aging is associated with poorer cognitive reserve and lower resilience to injury. When there are focal brain lesions, brain regions may age at different rates within the same individual. Therefore, we hypothesize that reduced gray matter volume within specific brain systems commonly associated with language recovery may be important for long-term aphasia severity. Here we show that individuals with stroke aphasia have a premature brain aging in intact regions of the lesioned hemisphere. In left domain-general regions, premature brain aging, gray matter volume, lesion volume and age were all significant predictors of aphasia severity. Increased brain age following a stroke is driven by the lesioned hemisphere. The relationship between brain age in left domain-general regions and aphasia severity suggests that degradation is possible to specific brain regions and isolated aging matters for behavior.

Exploring the link between tooth loss, cognitive function, andbrain wellness in the context of healthy aging.

The aim of this study was to evaluate the utility of using MRI-derived tooth count, an indirect and nonspecific indicator of oral/periodontal health, and brain age gap (BAG), an MRI-based measure of premature brain aging, in predicting cognition in a population of otherwise healthy adults. This retrospective study utilized data from 329 participants from the University of South Carolina's Aging Brain Cohort Repository. Participants underwent neuropsychological testing including the Montreal Cognitive Assessment (MoCA), completed an oral/periodontal health questionnaire, and submitted to high-resolution structural MRI imaging. The study compared variability on cognitive scores (MoCA) accounted for by MRI-derived BAG, MRI-derived total tooth count, and self-reported oral/periodontal health. We report a significant positive correlation between the total number of teeth and MoCA total scores after controlling for age, sex, and race, indicating a robust relationship between tooth count and cognition, r(208) = .233, p < .001. In a subsample of participants identified as being at risk for MCI (MoCA <= 25, N = 36) inclusion of MRI-based tooth count resulted in an R2 change of .192 (H0 = 0.138 → H1 = 0.330), F(1,31) = 8.86, p = .006. Notably, inclusion of BAG, a valid and reliable measure of overall brain health, did not significantly improve prediction of MoCA scores in similar linear regression models. Our data support the idea that inclusion of MRI-based total tooth count may enhance the ability to predict clinically meaningful differences in cognitive abilities in healthy adults. This study contributes to the growing body of evidence linking oral/periodontal health with cognitive function.

Aged HIV-1 Tg26 Transgenic Mice display Vascular Dysfunction with No Alterations in Neurocognitive Function or Cerebral Blood Flow

Although combination antiretroviral therapy (cART) has markedly reduced HIV mortality and increased life expectancy, people living with HIV (PLWH) develop premature cognitive and brain aging, classified as HIV-associated neurocognitive disorder (HAND). Vascular dysfunction and expression of HIV-derived proteins have independently been associated with cognitive impairment without causality being established. Thus, we investigated the role of HIV viral proteins in endothelial dysfunction and cognitive impairment in an aged mouse model of HIV. We used 18-month-old Tg26 mice and their wild-type littermate controls. Tg26 mice express 7 out of the 9 HIV viral proteins under the control of the long-term repeat promoter and have previously been shown to exhibit signs of cognitive impairment at eight months of age. Conduction of concentration-response curves to acetylcholine in mesenteric arteries using wire myography revealed impaired endothelium-dependent relaxation in Tg26 mice compared to WT mice. Measurements of brain perfusion with arterial spin labeling magnetic resonance imaging showed no differences in the whole brain and hippocampal cerebral blood flow. In addition, there were no changes in the hippocampus volume, which has been reported to be reduced with cognitive impairments. Two methods were employed to assess the cognitive abilities of the mice: Morris water maze (MWM) and the IntelliCage system. MWM requires human handling while the IntelliCage system is fully automated enabling the testing of mouse cognitive function during their active period and independently of human handling. Tg26 and WT mice underwent ten days of MWM testing and eight days of IntelliCage testing to assess spatial learning and memory. Tg26 mice showed no significant differences in latency to platform, distance swam to platform, or swim velocity when compared to their WT littermates. The IntelliCage results showed no differences in total visits, total visits with nose pokes, or total licks during the reversal learning period. Additionally, there were no significant differences in percent side error or place error indicating that cognitive function is not impaired in Tg26 mice. The Y-maze test further showed no differences in spontaneous alteration, a measure of spatial working memory. Altogether, our data shows that although 18-month-old female Tg26 mice develop endothelial dysfunction, they display no alterations in cerebral blood flow and no cognitive impairment indicating that systemic viral protein expression and vascular dysfunction might minimally contribute to neurocognitive impairment in HIV. R01HL130301 &amp; R01HL155265 (E.J.B). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Early childhood malnutrition impairs adult resting brain function using near-infrared spectroscopy.

Early childhood malnutrition affects 200+ million children under 5 years of age worldwide and is associated with persistent cognitive, behavioral and psychiatric impairments in adulthood. However, very few studies have investigated the long-term effects of childhood protein-energy malnutrition (PEM) on brain function using a functional hemodynamic brain imaging technique. This study aims to investigate functional brain network alterations using near infrared spectroscopy (NIRS) in adults, aged 45-51 years, from the Barbados Nutrition Study (BNS) who suffered from a single episode of malnutrition restricted to their first year of life (n = 26) and controls (n = 29). A total of 55 individuals from the BNS cohort underwent NIRS recording at rest. Using functional connectivity and permutation analysis, we found patterns of increased Pearson's correlation with a specific vulnerability of the frontal cortex in the PEM group (ps < 0.05). Using a graph theoretical approach, mixed ANCOVAs showed increased segregation (ps = 0.0303 and 0.0441) and decreased integration (p = 0.0498) in previously malnourished participants compared to healthy controls. These results can be interpreted as a compensatory mechanism to preserve cognitive functions, that could also be related to premature or pathological brain aging. To our knowledge, this study is the first NIRS neuroimaging study revealing brain function alterations in middle adulthood following early childhood malnutrition limited to the first year of life.

Dietary Marine Oils Selectively Decrease Obesogenic Diet-Derived Carbonylation in Proteins Involved in ATP Homeostasis and Glutamate Metabolism in the Rat Cerebellum.

The regular intake of diets high in saturated fat and sugars increases oxidative stress and has been linked to cognitive decline and premature brain aging. The cerebellum is highly vulnerable to oxidative stress and thus, obesogenic diets might be particularly detrimental to this tissue. However, the precise molecular mechanisms behind obesity-related brain damage are still not clear. Since protein carbonylation, a biomarker of oxidative stress, influences protein functions and is involved in metabolic control, the current investigation addressed the effect of long-term high-fat and high-sucrose diet intake on the cerebellum of Sprague-Dawley rats by deciphering the changes caused in the carbonylated proteome. The antioxidant effects of fish oil supplementation on cerebellar carbonylated proteins were also investigated. Lipid peroxidation products and carbonylated proteins were identified and quantified using immunoassays and 2D-LC-MS/MS in the cerebellum. After 21 weeks of nutritional intervention, the obesogenic diet selectively increased carbonylation of the proteins that participate in ATP homeostasis and glutamate metabolism in the cerebellum. Moreover, the data demonstrated that fish oil supplementation restrained carbonylation of the main protein targets oxidatively damaged by the obesogenic diet, and additionally protected against carbonylation of several other proteins involved in amino acid biosynthesis and neurotransmission. Therefore, dietary interventions with fish oils could help the cerebellum to be more resilient to oxidative damage. The results could shed some light on the effect of high-fat and high-sucrose diets on redox homeostasis in the cerebellum and boost the development of antioxidant-based nutritional interventions to improve cerebellum health.

Metformin and dietary restriction pathway are associated with neuroprotection in Alzheimer’s disease context. A key role for glial autophagy

AbstractBackgroundThe global rise of type 2 diabetes and obesity prevalence has elicited a great interest in understanding how changes in metabolic function lead to premature brain aging. The inflammation and insulin resistance interplay represent a potential target to prevent neurodegeneration.MethodWe evaluated the effect of the antidiabetic drug metformin‐considered a dietary restriction (DR) mimetic‐ on patients enrolled in ADNI, an observational and longitudinal study including patients from all around the world. We employed data from patients diagnosed with mild cognitive impairment (MCI) due to AD and we performed a principal component analysis focusing on biomarkers associated to AD measured in cerebrospinal fluid.We analyzed memory performance and hippocampal alterations in a model of AD, the PDAPP‐J20 transgenic mouse (Tg) and evaluated the effects of a periodic DR protocol (3 cycles of 40% DR for 5 days and ad libitum diet for 9 days).ResultMCI metformin‐treated patients were characterized as subjects with a better CSF biomarkers profile than the mean population of MCI patients (p&lt;0.05). Control subjects and T2D patients were paired by age, gender, ApoE allele and education, defining three groups: MCI, MCI+T2D and MCI+T2D+metformin. We evaluated the effect of T2D and metformin treatment employing the PACC score and composites defined from standardized ADNI variables to evaluate the memory/learning function. We found that MCI+T2D patients have a worse cognitive performance than MCI patients (p&lt;0.01), but this effect was absent in MCI+T2D+metformin patients. These cognitive variations were associated with changes in cortical thickness and hippocampal volume (p&lt;0.001). Our study shows a beneficial effect of metformin treatment on cognitive performance, CSF biomarkers profile and neuroanatomical measures in MCI due to AD patients.We observed cognitive impairment, low adult neurogenesis and progressive Aβ deposition in the hippocampus of Tg mice. Periodic DR was associated to cognitive improvement, increased hippocampal neurogenesis, and reduced hippocampal amyloid load; we found that autophagy is modulated in Tg mice with a high proportion of LC3/Aβ colocalizing in astrocytes, probably contributing to the reduction in amyloid plaques associated to DR.ConclusionOur data suggest that metformin and DR may be potential interventions to promote healthy aging and prevent dementia.

Fish oil supplementation counteracts the effect of high-fat and high-sucrose diets on the carbonylated proteome in the rat cerebral cortex

High daily intake of saturated fats and refined carbohydrates, which often leads to obesity and overweight, has been associated with cognitive impairment, premature brain aging and the aggravation of neurodegenerative diseases. Although the molecular pathology of obesity-related brain damage is not fully understood, the increased levels of oxidative stress induced by the diet seem to be definitively involved. Being protein carbonylation determinant for protein activity and function and a main consequence of oxidative stress, this study aims to investigate the effect of the long-term high-fat and sucrose diet intake on carbonylated proteome of the cerebral cortex of Sprague-Dawley rats. To achieve this goal, the study identified and quantified the carbonylated proteins and lipid peroxidation products in the cortex, and correlated them with biometrical, biochemical and other redox status parameters. Results demonstrated that the obesogenic diet selectively increased oxidative damage of specific proteins that participate in fundamental pathways for brain function, i.e. energy production, glucose metabolism and neurotransmission. This study also evaluated the antioxidant properties of fish oil to counteract diet-induced brain oxidative damage. Fish oil supplementation demonstrated a stronger capacity to modulate carbonylated proteome in the brain cortex. Data indicated that fish oils did not just decrease carbonylation of proteins affected by the obesogenic diet, but also decreased the oxidative damage of other proteins participating in the same metabolic functions, reinforcing the beneficial effect of the supplement on those pathways. The results could help contribute to the development of successful nutritional-based interventions to prevent cognitive decline and promote brain health.

Lower socioeconomic status is associated with premature brain aging

BackgroundPremature age-related brain changes may be influenced by physical health factors. Lower socioeconomic status (SES) is often associated with poorer physical health. In this study, we aimed to investigate the relationship between SES and premature brain aging. MethodsBrain age was estimated from T1-weighted images using BrainAgeR in 217 participants from the ABC@UofSC Repository. The difference between brain and chronological age (BrainGAP) was calculated. Multiple regression models were used to predict BrainGAP with age, SES, body mass index, diabetes, hypertension, sex, race, and education as predictors. SES was calculated from size-adjusted household income and the cost of living. ResultsFifty-five participants (25.35%) had greater brain age than chronological age (premature brain aging). Multiple regression models revealed that age, sex, and SES were significant predictors of BrainGAP with lower SES associated with greater BrainGAP (premature brain aging). ConclusionsThis study demonstrates that lower SES is an independent contributor to premature brain aging. This may provide additional insight into the mechanisms associated with brain health, cognition, and resilience to neurological injury.

254. Altered Structural Covariance Network Patterns in Young Adults With High Polygenic Risk for Premature Brain Aging

254. Altered Structural Covariance Network Patterns in Young Adults With High Polygenic Risk for Premature Brain Aging

HIV-1 gp120 protein promotes HAND through the calcineurin pathway activation

For over two decades, highly active antiretroviral therapy (HAART) was able to help prolong the life expectancy of people living with HIV-1 (PLWH) and eliminate the virus to an undetectable level. However, an increased prevalence of HIV- associated neurocognitive disorders (HAND) was observed. These symptoms range from neuronal dysfunction to cell death. Among the markers of neuronal deregulation, we cite the alteration of synaptic plasticity and neuronal communications. Clinically, these dysfunctions led to neurocognitive disorders such as learning alteration and loss of spatial memory, which promote premature brain aging even in HAART-treated patients. In support of these observations, we showed that the gp120 protein deregulates miR-499-5p and its downstream target, the calcineurin (CaN) protein. The gp120 protein also promotes the accumulation of calcium (Ca2+) and reactive oxygen species (ROS) inside the neurons leading to the activation of CaN and the inhibition of miR-499-5p. gp120 protein also caused mitochondrial fragmentation and changes in shape and size. The use of mimic miR-499 restored mitochondrial functions, appearance, and size. These results demonstrated the additional effect of the gp120 protein on neurons through the miR-499-5p/calcineurin pathway.

Theaflavin-3,3′-digallate ameliorates learning and memory impairments in mice with premature brain aging induced by D-galactose

Age-related neurodegenerative diseases accompanied by learning and memory deficits are growing in prevalence due to population aging. Cellular oxidative stress is a common pathomechanism in multiple age-related disorders, and various antioxidants have demonstrated therapeutic efficacy in patients or animal models. Many plants and plant extracts possess potent antioxidant activity, but the compounds responsible are frequently unknown. Identification and evaluation of these phytochemicals is necessary for optimal targeted therapy. A recent study identified theaflavin-3,3′-digallate (TFDG) as the most potent among a large series of phytochemical antioxidants. Here we examined if TFDG can mitigate learning and memory impairments in the D-galactose model of age-related neurodegeneration. Experimental mice were injected subcutaneously with D-galactose (120 mg/kg) for 56 days. In treatment groups, different doses of TFDG were administered daily by gavage starting on day 29 of D-galactose injection. Model mice exhibited poor learning and memory in the novel object recognition and Y-maze tests, reduced brain/body mass ratio, increased brain glutamate concentration and acetylcholinesterase activity, decreased brain acetylcholine concentration, and lower choline acetyltransferase, glutaminase, and glutamine synthetase activities. Activities of antioxidant enzymes glutathione peroxidase and superoxide dismutase were also reduced, while the concentration of malondialdehyde, a lipid peroxidation product, was elevated. Further, antioxidant genes Nrf2, Prx2, Gsh-px1, and Sod1 were downregulated in brain. Each one of these changes was dose-dependently reversed by TFDG. TFDG is an effective antioxidant response inducer and neuroprotectant that can restore normal neurotransmitter metabolism and ameliorate learning and memory dysfunction in the D-galactose model of age-related cognitive decline.

Premature aging in co‐occurring Alcohol Use Disorder and Post‐Traumatic Stress Disorder from a functional connectome perspective

AbstractBackgroundPost‐Traumatic Stress Disorder (PTSD) and Alcohol Use Disorder (AUD) may be associated with premature brain aging which increases the risk for Alzheimer’s Disease and Related Dementias (ADRD). While each disorder alone has been studied as a risk factor for ADRD, few studies have examined premature brain aging in co‐occurring PTSD/AUD. It is important to know whether co‐occurring PTSD/AUD may amplify ADRD risk. Consequently, the present study tested the hypothesis that, relative to healthy controls (HC), PTSD/AUD would show more pronounced premature brain aging than AUD alone.MethodA functional connectome approach was used to develop a model of healthy brain aging. The graph‐theory measure eigenvector centrality was calculated from resting state fMRI scans in 60 mid‐life HC (HC‐mid; mean age=56.9), 69 older adult HC (HC‐older; mean age = 74.1), 36 AUD (mean age=54.4), and 30 PTSD/AUD participants (mean age=55.7). AUD and PTSD/AUD diagnoses were determined by a structured clinical interview. Connectome node features that were most predictive of age in HC‐mid and HC‐older were used in predictive modeling with bootstrap aggregation. These features were from multiple cortical areas and resting state networks. The healthy aging model was transferred to the AUD and PTSD/AUD groups to estimate brain age. Estimated ages in AUD and PTSD/AUD were compared to the predicted age in HC‐mid and HC‐older using generalized linear mixed modeling (GLMM).ResultPredictive modeling in HC yielded an aggregate model with 49.5% accuracy in predicting age (p &lt; .0001), with some network features showing increases in eigenvector centrality with age and others showing decreases. After model transfer and correcting for age estimation bias, the GLMM yielded a main effect of diagnostic group (Wald c23=141.6, p &lt; .0001). Predicted age for PTSD/AUD was significantly higher (M=61.0) than HC‐mid (M=57.2; p=.048) but predicted age for AUD (M=59.9) was not different from HC‐mid (p=.133). HC‐older predicted age (M=74.1) was different from all other groups (p &lt; .0001).ConclusionIn this preliminary analysis, premature brain aging in PTSD/AUD was more pronounced than in AUD alone which may suggest greater vulnerability to AD‐like neurodegenerative processes that are manifest at the level of large‐scale network connectivity.

Language Fluency and Premature Brain Aging

AbstractBackgroundAge‐related changes in the brain are often associated with general cognitive decline. Cognitive aging affects the ability to produce spoken language, with older adults experiencing increased difficulties in word‐finding1 and verbal fluency2,3. Neurodegenerative diseases such as Alzheimer’s disease are often attributed to an acceleration of typical aging processes (i.e., premature aging). Accelerated age‐related atrophy is present in mild cognitive impairment4,5 and premature brain aging may contribute to declining cognitive skills6,7. A recent study demonstrated that the disparity between chronological age and brain age (based on measures of cortical integrity) is a good predictor of early cognitive impairment8. Our aim was to extend these findings by investigating the role of brain age in overall cognition as well as language in particular.MethodParticipants included 216 healthy controls (age range 20–79) from the Aging Brain Cohort at the University of South Carolina9. Structural T1‐weighted MRI scans were collected, and participants completed the Montreal Cognitive Assessment (MoCA10). Brain age was calculated based on T1‐weighted structural data using the BrainAgeR analysis pipeline (github.com/james‐cole/brainageR). A brain age gap estimate (BrainAGE)11 was calculated as the difference between brain age and chronological age. This was used as the primary measure of advanced/delayed brain health, where positive values represent premature brain aging.ResultEstimated brain age differences ranged from 22 years younger to 14 years older than chronological age. Pearson correlations revealed a negative correlation between MoCA total score and chronological age (r(209) = ‐0.41, p&lt;0.001), but not in partial correlations using BrainAGE, accounting for chronological age (r(207) = ‐0.003, p = 0.48.). Regarding our language measure (words generated during the MoCA fluency task), we observed a negative correlation with BrainAGE, corrected for chronological age (r(208) = ‐0.133, p = 0.03), but no correlation with chronological age (r(210) = ‐0.04, p = 0.58).ConclusionOur data support the hypothesis that differences between chronological and brain age are related to cognition and language, and highlight the utility/importance of brain age in understanding cognitive impairment. Interestingly, findings suggest that there may be a particularly strong relationship between the brain age gap estimation and MRI‐based measure of brain aging and language in particular.

White matter hyperintensity load is associated with premature brain aging.

Brain age is an MRI-derived estimate of brain tissue loss that has a similar pattern to aging-related atrophy. White matter hyperintensities (WMHs) are neuroimaging markers of small vessel disease and may represent subtle signs of brain compromise. We tested the hypothesis that WMHs are independently associated with premature brain age in an original aging cohort. Brain age was calculated using machine-learning on whole-brain tissue estimates from T1-weighted images using the BrainAgeR analysis pipeline in 166 healthy adult participants. WMHs were manually delineated on FLAIR images. WMH load was defined as the cumulative volume of WMHs. A positive difference between estimated brain age and chronological age (BrainGAP) was used as a measure of premature brain aging. Then, partial Pearson correlations between BrainGAP and volume of WMHs were calculated (accounting for chronological age). Brain and chronological age were strongly correlated (r(163)=0.932, p<0.001). There was significant negative correlation between BrainGAP scores and chronological age (r(163)=-0.244, p<0.001) indicating that younger participants had higher BrainGAP (premature brain aging). Chronological age also showed a positive correlation with WMH load (r(163)=0.506, p<0.001) indicating older participants had increased WMH load. Controlling for chronological age, there was a statistically significant relationship between premature brain aging and WMHs load (r(163)=0.216, p=0.003). Each additional year in brain age beyond chronological age corresponded to an additional 1.1mm3 in WMH load. WMHs are an independent factor associated with premature brain aging. This finding underscores the impact of white matter disease on global brain integrity and progressive age-like brain atrophy.

Disruption of Mitochondrial-associated ER membranes by HIV-1 tat protein contributes to premature brain aging.

Mitochondrial-associated ER membranes (MAMs) control many cellular functions, including calcium and lipid exchange, intracellular trafficking, and mitochondrial biogenesis. The disruption of these functions contributes to neurocognitive disorders, such as spatial memory impairment and premature brain aging. Using neuronal cells, we demonstrated that HIV-1 Tat protein deregulates the mitochondria. To determine the mechanisms, we used a neuronal cell line and showed that Tat-induced changes in expression and interactions of both MAM-associated proteins and MAM tethering proteins. The addition of HIV-1 Tat protein alters expression levels of PTPIP51 and VAPB proteins in the MAM fraction but not the whole cell. Phosphorylation of PTPIP51 protein regulates its subcellular localization and function. We demonstrated that the Tat protein promotes PTPIP51 phosphorylation on tyrosine residues and prevents its binding to VAPB. Treatment of the cells with a kinase inhibitor restores the PTPIP51-VAPB interaction and overcomes the effect of Tat. These results suggest that Tat disrupts the MAM, through the induction of PTPIP51 phosphorylation, leading to ROS accumulation, mitochondrial stress, and altered movement. Hence, we concluded that interfering in the MAM-associated cellular pathways contributes to spatial memory impairment and premature brain aging often observed in HIV-1-infected patients.

Brain age estimation reveals older adults' accelerated senescence after traumatic brain injury.

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 [Formula: see text]7days and again [Formula: see text]6months after a single mTBI sustained by 133 participants aged 20-83 (CA [Formula: see text]= 42.6 ± 17years; 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 ± 6.9years after mTBI, whereas those of younger adults age only by 1.8 ± 5.6years, a significant difference (Welch's t32 = - 9.17, p ≃ 9.47 × 10-11). For an adult aged [Formula: see text]30 to [Formula: see text]60, the expected amount of TBI-related brain aging is [Formula: see text]3years greater than in an individual younger by a decade. For an individual over [Formula: see text]60, the respective amount is [Formula: see text]7years. 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 [Formula: see text]60 involves approximately [Formula: see text]10years of premature and lasting brain aging, which is MRI detectable as early as [Formula: see text]7days post-injury.

Dose‐dependent relationship between social drinking and brain aging

Low-level alcohol consumption is commonly perceived as being inconsequential or even beneficial for overall health, with some reports suggesting that it may protect against dementia or cardiovascular risks. However, these potential benefits do not preclude the concurrent possibility of negative health outcomes related to alcohol consumption. To examine whether casual, non-heavy drinking is associated with premature brain aging, we utilized the Brain-Age Regression Analysis and Computational Utility Software package to predict brain age in a community sample of adults [n = 240, mean age 35.1 (±10.7) years, 48% male, 49% African American]. Accelerated brain aging was operationalized as the difference between predicted and chronological age (“brain age gap”). Multiple regression analysis revealed a significant association between previous 90-day alcohol consumption and brain age gap (β = 0.014, p = 0.023). We replicated these results in an independent cohort [n = 231 adults, mean age 34.3 (±11.1) years, 55% male, 28% African American: β = 0.014, p = 0.002]. Our results suggest that even low-level alcohol consumption is associated with premature brain aging. The clinical significance of these findings remains to be investigated.