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[Effects of smoking on brain aging: II. Brain atrophy and smoking--a quantitative study with computed tomography].
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Epigenetic drift and LINE-1 activation in aging brain: Implications for neurodegenerative disease.
Brain aging and age-associated neurological diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), are largely attributed to epigenetic drift which is characterized by the gradual accumulation of alterations in neural cell methylation patterns over time. These methylation changes are particularly evident in transposable element (TE)-derived sequences such as Long interspersed element-1 (LINE-1) which comprises approximately 17% of the human genome. During aging, LINE-1 elements gradually lose their methylation, as well as the regulatory safeguard mechanisms that usually keep them inactive. This repression loss can lead to LINE-1 reactivation, contributing to harmful effects including genomic instability, neuroinflammation, and more. Together these findings indicate that impaired epigenetic maintenance, especially in repetitive genome regions, plays a key role in biological aging of neurons and glial cells. In this narrative review, we discuss the methylation dynamics and regulatory mechanisms of LINE-1 retrotransposons, their activation processes during aging, and contribution to age-associated neurological diseases. We also highlight the potential of targeting LINE-1 methylation to restore methylation homeostasis, epigenetic stability and delay brain aging.
Correlation of extracellular vesicle Alu RNA with brain aging and neuronal injury: a potential biomarker for brain aging.
BACKGROUND: Extracellular vesicles (EVs) are promising biomarkers for neurodegeneration. Alu elements are retrotransposons increasingly expressed with age and may be involved in aging-related diseases. OBJECTIVE: To determine the potential of Alu RNA in plasma-derived EVs as a biomarker for brain aging and neuronal injury. METHODS: EVs were isolated from plasma samples across different age groups. EV Alu RNA levels were measured and their associations with biomarkers of brain aging, including plasma neurofilament light chain (NfL), plasma amyloid-beta (Aβ42 and Aβ40), and plasma phosphorylated tau (p-Tau181), were analyzed. RESULTS: EV Alu RNA levels were increased significantly with age and were strongly correlated with plasma NfL, suggesting a strong association between EV Alu RNA and neuronal injury. Significant correlations were also found between EV Alu RNA and plasma amyloid-beta levels, while no significant association was observed with tau pathology. CONCLUSIONS: EV Alu RNA levels are elevated with age and associated with neuronal injury, highlighting their potential as a novel, non-invasive biomarker for brain aging and neurodegeneration.
Multivariate data analysis in biochemistry: a new integrative approach to metabolic control in brain aging.
The principal component analysis (PCA) allows to obtain a quantitative measure of the state of metabolism as a whole. In this paper we applied this method to the study of energy metabolism during aging process and of the effect of a drug (Acetyl-1-carnitine, ALCAR) on the aging brain.
Drugs and the aging brain.
The aging brain is more sensitive to the potentially deleterious effects of drugs used to treat common geriatric disorders. The atypical presentation of medical conditions can lead to inaccurate diagnoses and inappropriate drug prescribing. Working from a knowledge of general principles of geriatric pharmacokinetics and pharmacodynamics, the clinician will be better attuned to the problems of prescribing for the elderly, so as to maximize beneficial therapeutic effects without compromising mental function.
Functions of the ageing brain from physiological ageing to dementia.
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[Age of the brain, age factor of the organism].
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Serotonergic ligand binding in aging brain of experimental animals.
Although the use of aging experimental animals for studying serotonergic neuronal changes is limited because of species differences, cholinergic neuronal deterioration does appear to be a feature common to mammalian aging brains. In the present study, a recently introduced experimental animal, Suncus murinus (house musk shrew, an insectivore classified as being at the stem of the mammalian phylogenic tree) which in certain physiological characteristics is more closely related to the primate than is the rat, was used as an experimental animal model for serotonergic neuronal deterioration in aging brain. We examined the changes in binding to the membrane fraction of aging brain cortex of the experimental animals Suncus and Fischer rat of the serotonergic ligands, 5-HT, imipramine, and 8-OH-DPAT. Morphological study of the brain stem including the Nucleus raphae by immunohistochemical staining demonstrated that in Suncus all the serotonergic ligands had decreasing affinity to the membrane of aging brain; binding of 8-OH-DPAT and imipramine decreased to a greater extent than that of 5-HT. In contrast, the aging rat brain showed no appreciable change in the binding of serotonergic ligands.
Optics-free spatial genomics for mapping mammalian brain aging by IRISeq.
Spatial transcriptomics has emerged as a transformative approach for in situ mapping of cellular heterogeneity and interactions, yet existing methods often compromise throughput, cost and tissue coverage. Here we introduce Imaging Reconstruction using Indexed Sequencing (IRISeq): an optics-free, cost-effective platform that leverages spatial interaction mapping by indexed sequencing to profile tissues at adjustable sizes and resolutions (5-50 µm). We applied IRISeq to map gene expression across more than 70 coronal sections from both adult and aged mouse brains, including wild-type and two lymphocyte-deficient models (Rag1 and Prkdc mutants) and generated more than 460,000 spatial transcriptome profiles. Our integrated analysis with 783,264 single-cell transcriptomes revealed region-specific aging signatures that are lymphocyte dependent, notably a downregulation of interferon signaling and inflammation in ventricular regions upon lymphocyte depletion, alongside mutant-specific upregulation of senescence pathways. Furthermore, lymphocyte deficiency was linked to preserved abundance of ependymal cells that line the brain's ventricles and to distinct microglial state dynamics, highlighting a key role for lymphocytes in driving inflammatory processes during brain aging. Overall, IRISeq provides a high-throughput and cost-effective solution for spatially resolved transcriptomic profiling, opening new avenues for elucidating region-specific cellular mechanisms underlying aging and identifying potential therapeutic targets to preserve brain homeostasis.
Joint Effects of Long-Term Obesity and Genetic Susceptibility on Sex-Specific Brain Aging.
OBJECTIVE: This study aimed to examine the associations of longitudinal obesity trajectories and polygenic risk with sex-specific brain aging. METHODS: We analyzed 35,092 UK Biobank participants (16,484 males and 18,608 females). Sex-specific XGBoost models estimated multimodal brain age. We derived 16-year longitudinal obesity trajectories from repeatedly collected anthropometric measurements. Polygenic risk scores were constructed based on 55 independent genetic loci. Multivariable logistic regression examined associations of obesity trajectories and genetic risk with brain age acceleration. RESULTS: A total of 8198 (49.73%) males and 9089 (48.84%) females had accelerated brain aging. High genetic risk significantly increased brain age acceleration odds (males: OR = 1.39; females: OR = 1.34). Crucially, the high-stable obesity trajectory exerted a stronger effect in males (OR = 1.90, 95% CI: 1.64-2.21) than in females (OR = 1.25, 95% CI: 1.12-1.40), with the joint presence of high genetic risk and high-stable obesity amplifying risk to an OR of 2.78 in males and 1.57 in females. Conversely, shifting from obesity to non-obesity reduced risk by 30% in males and 18% in females. CONCLUSIONS: These findings underscore long-term obesity as a critical, sex-dimorphic driver of accelerated brain aging, and midlife weight management offers robust neuroprotection even in genetically susceptible individuals.
Changes in the aging brain as they affect psychotropics: a review.
This article reviews a number of neuroanatomic and neurochemical changes that occur in the brain with aging, and focuses specifically on those that may affect the response to psychotropic drugs. We hope to increase physicians' awareness of these "central," or brain, changes, that occur with aging when prescribing and monitoring psychotropic use, since the traditional emphasis in prescribing for the elderly has rested with the review of pharmacokinetic, or "peripheral" organ changes.
SIRT1 in brain aging: molecular mechanisms and therapeutic potential of pharmacological and natural modulators.
Aging is a multifactorial process affects different tissues and organs and is modulated by genetic and environmental factors. In aging, the frequency of DNA repair errors and genomic instability are augmented. Depletion of endogenous antioxidant capacity during aging promotes the development of oxidative stress which triggers oxidative stress-induced DNA injury. Brain aging is manifested by cognitive impairment and memory disorders. Development of neuronal senescence is the major pathway in the progression of brain aging. Silent information regulator sirtuin 1 (SIRT1) is a class III histone deacetylase plays a critical role in genomic stability during aging. SIRT1 is highly expressed in specific brain regions involved in energy expenditure and metabolic activity that is necessary for brain development and control of brain senescence. Therefore, SIRT1 may have neuroprotective effects against brain aging and related neurodegenerative diseases. This narrative review aims to critically evaluate the role of SIRT1 in brain aging and to summarize current evidence on compounds that directly or indirectly modulate SIRT1 activity, with a focus on their mechanistic pathways and potential therapeutic implications. Findings of the present review highlighted that SIRT1 activators such as resveratrol, metformin and statins have neuroprotective effects against brain aging by regulating inflammatory and oxidative stress disorders through modulation of downstream signaling pathways.
Nuclear magnetic resonance imaging in the aging brain.
43 patients aged over 55 years with different clinical diagnoses but with the common aspect of impairment of the cognitive functions underwent a 0.5 Tesla magnetic resonance imaging (MRI) investigation in order to obtain further information about the pathological causes underlying the clinical syndromes. The occurrence of white matter signal alterations (periventricular lucency) and of multifocal ischemic areas represented the most frequent and atypical finding. Independently of the clinical focal symptomatology, these data might well represent a marker of a diffuse tissue sufferance due to a chronic mild cerebral hypoperfusion. The incidence of similar findings in 'normal' elderly subjects must be assessed before giving them a definite relevance in the evaluation of the pathological aging.
Genetic evidence links hypertension to accelerated brain aging.
Hypertension affects one-third of adults and is a major comorbidity of neurocognitive disorders. The causal relationship, shared genetic architecture, and upstream mechanisms linking hypertension to brain aging remain unclear. Hypertension GWAS datasets from MVP and FinnGen R12 were meta-analyzed as the exposure, and a European-ancestry brain age gap (BAG) GWAS derived from the UK Biobank and LIFE-Adult cohorts was used as the outcome. MR and GSMR assessed causality. LDSC, HDL, and S-LDSC estimated genetic correlation. Four TWAS methods (MAGMA, FUSION, JTI-PrediXcan, FOCUS) mapped associations to genes, followed by SMR for causal validation and PoPS for prioritization. GSMAP with spatial transcriptomics characterized regional and cell-type enrichment. Hypertension and brain aging were genetically correlated, and MR and GSMR analyses suggested a causal effect of hypertension on increased brain age gap. TWAS identified 15 shared Hypertension-BAG genes, 10 supported by SMR. PoPS prioritized TRIM47 as the core gene. Shared signals were enriched in meninges, fiber tracts, cortical layer 1, and CA1 stratum lacunosum/radiatum, with cell-type enrichment in meninges, smooth muscle cells, oligodendrocytes, and astrocyte subtypes. Hypertension is genetically correlated with, and shows evidence of a causal effect on, accelerated brain aging. TRIM47 is a core gene bridging hypertension and BAG. GSMAP-based spatial enrichment provides a hypothesis-generating framework for understanding vascular, meningeal, and myelin-related pathways linking hypertension to increased brain age gap.
An endocrine hypothesis of brain aging and studies on brain-endocrine correlations and monosynaptic neurophysiology during aging.
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Imaging of the aging brain. Part I. Normal findings.
A thorough knowledge of the normal changes that occur in the brain with age is critical before abnormal findings are analyzed. Magnetic resonance (MR) imaging improves the ability to distinguish normal and abnormal findings in the brain. The major changes that may occur in elderly individuals without neurologic deficits include enlargement of the ventricles, cortical sulci, and vermian subarachnoid spaces; multifocal areas of hyperintensity in the white matter and basal ganglia; a progressive prominence of hypointensity on T2-weighted images of the putamen, almost equal to that of the globus pallidus; an increase in the oxygen extraction ratio with normal or mildly decreased neuron metabolism; arteriosclerosis in large and small arteries and amyloid angiopathy in leptomeningeal cortical vessels; and decreased dopamine receptor binding in the corpus striatum. Since approximately half of the elderly population exhibits only negligible brain alterations, MR imaging may facilitate the distinction between usual (no neurologic dysfunction) and successful (no brain or vascular changes) aging.
Animal models of brain ageing and dementia.
Six animal models of human brain ageing or of age-related diseases, especially Alzheimer's disease, are evaluated. Special emphasis is laid on comparing the neuropathological symptoms found in aged human brains or in Alzheimer patients, with the neuronal symptoms induced experimentally by the different treatments described here. For each model, the experimental methods for induction of the neuropathological symptoms (lipofuscin accumulation, senile plaques, neurofibrillary degeneration, etc.) and for their identification are discussed. In addition, the behavioral significance of each animal model is evaluated in the content of its meaning for cognitive alterations in senescence or in dementia.