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One of the basic questions in the aging field is whether there is a fundamental difference between the aging of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-aging Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at an early age was observed, indicating its involvement in normal aging of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal aging. adeno-associated virus delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan. These findings demonstrate the complexity of aging in mammals and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan., (© The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.)

Brain aging is a multifactorial process that includes a reduction in the biological and metabolic activity of individuals. Oxidative stress and inflammatory processes are characteristic of brain aging. Given the current problems, the need arises to implement new therapeutic approaches. Polyoxidovanadates (POV), as well as curcumin, have stood out for their participation in a variety of biological activities. This work aimed to evaluate the coupling of metavanadate and curcumin (Cuma-MV) on learning, memory, redox balance, neuroinflammation, and cell death in the hippocampal region (CA1 and CA3) and dentate gyrus (DG) of aged rats. Rats 18 months old were administered a daily dose of curcumin (Cuma), sodium metavanadate (MV), or Cuma-MV for two months. The results demonstrated that administration of Cuma-MV for 60 days in aged rats improved short- and long-term recognition memory, decreased reactive oxygen species, and substantially improved lipoperoxidation in the hippocampus. Furthermore, the activity of superoxide dismutase and catalase increased in animals treated with Cuma-MV. It is important to highlight that the treatment with Cuma-MV exhibited a significantly greater effect than the treatments with MV or Cuma in all the parameters evaluated. Finally, we conclude that Cuma-MV represents a potential therapeutic option in the prevention and treatment of cognitive decline associated with aging., (© 2025 Wiley Periodicals LLC.)

As the organism ages, there is a decline in effective energy supply, and this retards the ability to elaborate new proteins. The consequences of this are especially marked in the gradual decline in brain function. The senescence of cells and their constituent organelles is ultimately the cause of aging of the entire nervous system. What is less immediately obvious is that brain aging is also accompanied by the failure of catabolic events that lead to the removal of non-functional cells and ineffective subcellular components. The removal of non-working cellular and subcellular elements within the brain is essential in order to allow the appearance of fresh cells and organelles with a full range of capacities. Thus, the maintenance of operative mechanisms for the dispersal of failed tissue components is important, and its diminished capacity with aging is a significant contributory factor to the onset and progression of age-related neurological disorder. This report discusses the mechanisms underlying autophagy and phagocytosis and how these can be adversely modulated as aging proceeds. The means by which the effective recycling of cellular components may be reinstated in the aged brain are considered.

Background: Brain aging is a complex process that involves functional alterations in multiple subnetworks and brain regions. However, most previous studies investigating aging-related functional connectivity (FC) changes using resting-state functional magnetic resonance images (rs-fMRIs) have primarily focused on the linear correlation between brain subnetworks, ignoring the nonlinear casual properties of fMRI signals., Methods: We introduced the neural Granger causality technique to investigate the sex-dependent nonlinear Granger connectivity (NGC) during aging on a publicly available dataset of 227 healthy participants acquired cross-sectionally in Leipzig, Germany., Results: Our findings indicate that brain aging may cause widespread declines in NGC at both regional and subnetwork scales. These findings exhibit high reproducibility across different network sparsities, demonstrating the efficacy of static and dynamic analysis strategies. Females exhibit greater heterogeneity and reduced stability in NGC compared to males during aging, especially the NGC between the visual network and other subnetworks. Besides, NGC strengths can well reflect the individual cognitive function, which may therefore work as a sensitive metric in cognition-related experiments for individual-scale or group-scale mechanism understanding., Conclusion: These findings indicate that NGC analysis is a potent tool for identifying sex-dependent brain aging patterns. Our results offer valuable perspectives that could substantially enhance the understanding of sex differences in neurological diseases in the future, especially in degenerative disorders., Competing Interests: Declaration of competing interest The authors confirm that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Age-related cognitive decline and dementia are significant manifestations of brain aging. As the elderly population grows rapidly, the health and socio-economic impacts of cognitive dysfunction have become increasingly significant. Although clinical treatment of dementia has faced considerable challenges over the past few decades, with limited breakthroughs in slowing its progression, there has been substantial progress in understanding the molecular mechanisms and hallmarks of age-related dementia (ARD). This progress brings new hope for the intervention and treatment of this disease. In this review, we categorize the latest findings in ARD biomarkers into four stages based on disease progression: Healthy brain, pre-clinical, mild cognitive impairment, and dementia. We then systematically summarize the most promising therapeutic approaches to prevent or slow ARD at four levels: Genome and epigenome, organelle, cell, and organ and organism. We emphasize the importance of early prevention and detection, along with the implementation of combined treatments as multimodal intervention strategies, to address brain aging and ARD in the future., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The current study aimed to evaluate the preventive effects of urolithin C (Uro C), a gut microbial metabolite of ellagitannins on D-galactose (D-gal)-induced brain damage during the aging process and to elucidate the underlying mechanisms. In our study, the protective effect of Uro C on D-gal-induced BV2 microglia cell-mediated neuroinflammation damage in primary cortical neurons in vitro was confirmed. The results in an aging model in vivo induced by D-gal demonstrated that Uro C prevented D-gal-induced memory impairment, long-term potentiation (LTP) damage, and synaptic dysfunction through behavioral, electrophysiological, and histological examinations. Additionally, amyloidogenesis was observed in the central nervous system. The findings indicated that Uro C exhibited a preventive effect on the D-gal-induced elevation of β-amyloid (1-42 specific) (Aβ 1-42 ) accumulation, APP levels, ABCE1 levels, and the equilibrium of the cholinergic system in the aging mouse brain. Moreover, Uro C demonstrated downregulation of D-gal-induced glial overactivation through inhibition of the MAPK/NF-kB pathway. This resulted in the regulation of inflammatory mediators and cytokines, including iNOS, IL-6, IL-1β, and TNF-ɑ, in the mouse brain and BV2 microglial cells. Taken together, our results suggested that Uro C treatment could effectively mitigate the D-gal-induced memory impairment and amyloidogenesis, and the underlying mechanism might be tightly related to the improvement of neuroinflammation by suppressing the MAPK/NF-kB pathway, indicating Uro C might be an alternative and promising agent for the treatment of aging and age-associated brain diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Impaired cardiac function is associated with cognitive impairment and brain imaging features of aging. Cardiac arrhythmias, including atrial fibrillation, are implicated in clinical and subclinical brain injuries. Even in the absence of a clinical diagnosis, subclinical or prodromal substrates of arrhythmias, including an abnormally long or short P-wave duration (PWD), a measure associated with atrial abnormalities, have been associated with stroke and cognitive decline. However, the extent to which PWD has subclinical influences on overall aging patterns of the brain is not clearly understood., Methods and Results: Here, using neuroimaging and ECG data from the UK Biobank, we use a novel regional "brain age" method to identify the brain aging networks associated with abnormal PWD. We find associations between short PWD and accelerated brain aging in the sensorimotor, frontoparietal, ventral attention, and dorsal attention networks, even in the absence of overt cardiac diseases., Conclusions: These findings contribute to our understanding of the relationship between PWD and structural brain aging. This work emphasizes the need for continued study designs that consider brain-based outcomes related to abnormally short PWD.

Background: Aging of the brain is a major contributor to the onset and progression of neurodegenerative diseases. Conventional treatments for these diseases are often limited by significant side effects and a lack of efficacy in halting disease progression. Ginsenoside compound K (CK), a bioactive secondary metabolite derived from ginseng, has shown promise because of its potent antioxidant properties., Purpose: This study aimed to elucidate the molecular mechanisms underlying the impact of CK on brain senescence, with a particular focus on its role in modulating oxidative stress and related signaling pathways., Methods: We employed a d-galactose (D-gal)-induced PC-12 senescent cell model and a mouse brain aging model to explore the antioxidant properties of CK in the context of brain aging. The effects of CK on mitochondrial dysfunction associated with brain aging were assessed using immunofluorescence and western blotting techniques. The potential molecular mechanisms by CK influences brain aging were investigated using transcriptomic analysis and western blotting. Additionally, CK's regulatory effect on apoptosis signal-regulating kinase 1 (ASK1) was validated by molecular docking, microscale thermophoresis, and small interfering RNA transfection., Results: Our findings demonstrate that CK effectively alleviates cognitive decline associated with brain aging. CK reduces the number of senescent cells, alleviates neuronal damage, and enhances the activity of key antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Additionally, CK restores mitochondrial function and upregulated the expression of solute carrier family 7 member 11 and glutathione peroxidase 4, thereby inhibiting ferroptosis. Furthermore, CK targets ASK1 and suppresses the hyperphosphorylation of MAPK kinase 7 (MKK7) and c-Jun N-terminal kinase (JNK). This suppression promotes the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), effectively reducing ferroptosis and oxidative damage linked to brain aging., Conclusion: In summary, our research demonstrates that CK effectively delays brain aging by inhibiting the ASK1-MKK7-JNK signaling pathway, enhancing nuclear Nrf2 expression, and suppressing the ferroptosis response. These findings highlight CK as a promising therapeutic agent for slowing brain aging and alleviating neurodegenerative diseases., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

In recent decades, entropy measures have gained prominence in neuroscience due to the nonlinear behaviour exhibited by neural systems. This rationale justifies the application of methods from the theory of nonlinear dynamics to cerebral activity, aiming to detect and quantify its variability more effectively. In the context of electroencephalogram (EEG) signals, entropy analysis offers valuable insights into the complexity and irregularity of electromagnetic brain activity. By moving beyond linear analyses, entropy measures provide a deeper understanding of neural dynamics, particularly pertinent in elucidating the mechanisms underlying brain aging and various acute/chronic-progressive neurological disorders. Indeed, various pathologies can disrupt nonlinear structuring in neural activity, which may remain undetected by linear methods such as power spectral analysis. Consequently, the utilization of nonlinear tools, including entropy analysis, becomes crucial for capturing these alterations. To establish the relevance of entropy analysis and its potential to discern between physiological and pathological conditions, this review discusses its diverse applications in studying healthy brain aging and neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Various entropy parameters, such as approximate entropy (ApEn), sample entropy (SampEn), multiscale entropy (MSE), and permutation entropy (PermEn), are analysed within this context. By quantifying the complexity and irregularity of EEG signals, entropy analysis may serve as a valuable biomarker for early diagnosis, treatment monitoring, and disease management. Such insights offer clinicians crucial information for devising personalized treatment and rehabilitation plans tailored to individual patients., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Aging is an inevitable law of the process of life during which many physiological functions change. Brain aging is an important mechanism in the occurrence and development of degenerative diseases of the central nervous system. β-Hydroxybutyrate (BHBA) is a water-soluble, endogenous small-molecule ketone that can cross the blood-brain barrier and induce neuroprotective effects. This study aimed to investigate the effects of BHBA on D-galactose (D-gal) induced aging in mice and its underlying mechanisms using in vitro and in vivo experiments. These results indicated that D-gal-induced senescence, oxidative stress, and inflammatory responses were inhibited by BHBA, and autophagy was promoted by BHBA. Mechanistically, we explored the role of metastasis-associated antigen-1 (MTA1) in D-gal-induced damaged in HT22 cells using small interfering RNA (siRNA). The results demonstrated that the expression of MTA1 was significantly increased by BHBA, which attenuated D-gal-induced aging, oxidative stress, and inflammatory responses, and promoted autophagy through the upregulation of MTA1. In conclusion, MTA1 may be a novel target for treating aging caused by neurological damage. BHBA improves brain aging by activating the MTA1 pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Drosophila NF-κB transcription factor Dif has been well known for its function in innate immunity, and recent study also reveals its role in neuronal cells. However, the underlying mechanisms of Dif in the brain remain elusive. In this study, we aim to investigate the function of Dif in Drosophila brain development and how Dif regulates structure and plasticity of the brain to affect aging and behaviors. Based on the analysis of differentially expressed genes, we identified key genes associated with cell division, development and aging in the brain of Dif 1 loss of function mutant. In Dif 1 larvae, we found that the metamorphosis and brain development were delayed, and cell division was decreased. In Dif 1 adults, the number of neuron cells was reduced in the brain, the lifespan and locomotor activity were decreased, protein markers associated with aging-related neurodegenerative diseases in the brain were altered in abundance or activity. Our results indicated that Dif plays a crucial role in brain plasticity and neurogenesis, dysfunction of Dif delays larval brain development and impacts proliferation of neuronal cells, resulting in aging adult brain by regulating expression of key genes in multiple signaling pathways involved in cell division, neurogenesis and aging., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2024 Elsevier B.V. All rights reserved.)

White matter (WM) development has been studied extensively, but most studies used cross-sectional data, and to the best of our knowledge, none of them considered the possible effects of biological (vs. chronological) age. Therefore, we conducted a longitudinal multimodal study of WM development and studied changes in fractional anisotropy (FA) in the different WM tracts and their relationship with cortical thickness-based measures of brain aging in young adulthood. A total of 105 participants from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort underwent magnetic resonance imaging (MRI) at the age of 23-24, and the age of 28-30 years. At both time points, FA in the different WM tracts was extracted using the JHU atlas, and brain age gap estimate (BrainAGE) was calculated using the Neuroanatomical Age Prediction using R (NAPR) model based on cortical thickness maps. Changes in FA and the speed of cortical brain aging were calculated as the difference between the respective variables in the late vs. early 20s. We demonstrated tract-specific increases as well as decreases in FA, which indicate that the WM microstructure continues to develop in the third decade of life. Moreover, the significant interaction between the speed of cortical brain aging, tract, and sex on mean FA revealed that a greater speed of cortical brain aging in young adulthood predicted greater decreases in FA in the bilateral cingulum and left superior longitudinal fasciculus in young adult men. Overall, these changes in FA in the WM tracts in young adulthood point out the protracted development of WM microstructure, particularly in men., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Oxidative stress-induced neuronal apoptosis is primarily involved in brain aging and impaired hippocampal neurogenesis. Long-term D-galactose administration increases oxidative stress related to brain aging. Chrysin, a subtype of flavonoids, exhibits neuroprotective effects, particularly its antioxidant properties. To elucidate the neuroprotection of chrysin on neuronal apoptosis and an impaired hippocampal neurogenesis relevant to oxidative damage in D-galactose-induced brain aging, male Sprague Dawley rats were allocated into vehicle control, D-galactose, chrysin, and cotreated rats. The rats received their respective treatments daily for 8 weeks. The reactions of scavenging enzymes, protein regulating endogenous antioxidant defense, and anti-apoptotic protein expression were significantly reduced in the hippocampus and prefrontal cortex of the animals receiving D-galactose. Conversely, product of oxidative damage and apoptotic protein expressions were significantly elevated in both cortical areas of the D-galactose group. In hippocampal neurogenesis, significant upregulation of cell cycle arrest and decrease in differentiated protein expression were detected after D-galactose administration. Nevertheless, chrysin supplementation significantly mitigated all negative effects in animals receiving D-galactose. This study demonstrates that chrysin likely attenuates brain aging induced by D-galactose by enhancing scavenging enzyme activities and reducing oxidative stress, neuronal apoptosis, and the impaired hippocampal neurogenesis., (© 2024. The Author(s).)

Brain aging is compared between Cercopithecinae (macaques and baboons), non-human Hominidae (chimpanzees, orangutans, and gorillas), and their close relative, humans. β-amyloid deposition in the form of senile plaques (SPs) and cerebral β-amyloid angiopathy (CAA) is a frequent neuropathological change in non-human primate brain aging. SPs are usually diffuse, whereas SPs with dystrophic neurites are rare. Tau pathology, if present, appears later, and it is generally mild or moderate, with rare exceptions in rhesus macaques and chimpanzees. Behavior and cognitive impairment are usually mild or moderate in aged non-human primates. In contrast, human brain aging is characterized by early tau pathology manifested as neurofibrillary tangles (NFTs), composed of paired helical filaments (PHFs), progressing from the entorhinal cortex, hippocampus, temporal cortex, and limbic system to other brain regions. β-amyloid pathology appears decades later, involves the neocortex, and progresses to the paleocortex, diencephalon, brain stem, and cerebellum. SPs with dystrophic neurites containing PHFs and CAA are common. Cognitive impairment and dementia of Alzheimer's type occur in about 1-5% of humans aged 65 and about 25% aged 85. In addition, other proteinopathies, such as limbic-predominant TDP-43 encephalopathy, amygdala-predominant Lewy body disease, and argyrophilic grain disease, primarily affecting the archicortex, paleocortex, and amygdala, are common in aged humans but non-existent in non-human primates. These observations show that human brain aging differs from brain aging in non-human primates, and humans constitute the exception among primates in terms of severity and extent of brain aging damage.

Purpose: Brain aging is a complex and heterogeneous process characterized by both structural and functional decline. This study aimed to establish a novel deep learning (DL) method for predicting brain age by utilizing structural and metabolic imaging data., Methods: The dataset comprised participants from both the Universal Medical Imaging Diagnostic Center (UMIDC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). The former recruited 395 normal control (NC) subjects, while the latter included 438 NC subjects, 51 mild cognitive impairment (MCI) subjects, and 56 Alzheimer's disease (AD) subjects. We developed a novel dual-pathway, 3D simple fully convolutional network (Dual-SFCNeXt) to estimate brain age using [ 18 F]fluorodeoxyglucose positron emission tomography ([ 18 F]FDG PET) and structural magnetic resonance imaging (sMRI) images of NC subjects as input. Several prevailing DL models were trained and tested using either MRI or PET data for comparison. Model accuracies were evaluated using mean absolute error (MAE) and Pearson's correlation coefficient (r). Brain age gap (BAG), deviations of brain age from chronologic age, was correlated with cognitive assessments in MCI and AD subjects., Results: Both PET- and MRI-based models achieved high prediction accuracy. The leading model was the SFCNeXt (the single-pathway version) for PET (MAE = 2.92, r = 0.96) and MRI (MAE = 3.23, r = 0.95) on all samples. By integrating both PET and MRI images, the Dual-SFCNeXt demonstrated significantly improved accuracy (MAE = 2.37, r = 0.97) compared to all single-modality models. Significantly higher BAG was observed in both the AD (P < 0.0001) and MCI (P < 0.0001) groups compared to the NC group. BAG correlated significantly with Mini-Mental State Examination (MMSE) scores (r=-0.390 for AD, r=-0.436 for MCI) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores (r = 0.333 for AD, r = 0.372 for MCI)., Conclusion: The integration of [ 18 F]FDG PET with structural MRI enhances the accuracy of brain age prediction, potentially introducing a new avenue for related multimodal brain age prediction studies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

As an important biomarker of neural aging, the brain age reflects the integrity and health of the human brain. Accurate prediction of brain age could help to understand the underlying mechanism of neural aging. In this study, a cross-stratified ensemble learning algorithm with staking strategy was proposed to obtain brain age and the derived predicted age difference (PAD) using T1-weighted magnetic resonance imaging (MRI) data. The approach was characterized as by implementing two modules: one was three base learners of 3D-DenseNet, 3D-ResNeXt, 3D-Inception-v4; another was 14 secondary learners of liner regressions. To evaluate performance, our method was compared with single base learners, regular ensemble learning algorithms, and state-of-the-art (SOTA) methods. The results demonstrated that our proposed model outperformed others models, with three metrics of mean absolute error (MAE), root mean-squared error (RMSE), and coefficient of determination (R 2 ) of 2.9405 years, 3.9458 years, and 0.9597, respectively. Furthermore, there existed significant differences in PAD among the three groups of normal control (NC), mild cognitive impairment (MCI) and Alzheimer's disease (AD), with an increased trend across NC, MCI, and AD. It was concluded that the proposed algorithm could be effectively used in computing brain aging and PAD, and offering potential for early diagnosis and assessment of normal brain aging and AD., Competing Interests: Declaration of competing interest The authors declare no conflicts of interests., (Copyright © 2024. Published by Elsevier Inc.)

Neuroinflammation is a feature of both neurodegenerative disease and normal brain aging. The roles of type I interferon (IFN-I) in the aged brain are incompletely understood. A recent article by Roy et al. reveals pervasive IFN-I activity in normal mouse brain aging, and highlights the importance of microglial IFN-I signaling in neuroinflammation., Competing Interests: Declaration of interests The authors declare no competing interests in relation to this work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Age-related cerebromicrovascular changes, including blood-brain barrier (BBB) disruption and microvascular rarefaction, play a significant role in the development of vascular cognitive impairment (VCI) and neurodegenerative diseases. Utilizing the unique model of heterochronic parabiosis, which involves surgically joining young and old animals, we investigated the influence of systemic factors on these vascular changes. Our study employed heterochronic parabiosis to explore the effects of young and aged systemic environments on cerebromicrovascular aging in mice. We evaluated microvascular density and BBB integrity in parabiotic pairs equipped with chronic cranial windows, using intravital two-photon imaging techniques. Our results indicate that short-term exposure to young systemic factors leads to both functional and structural rejuvenation of cerebral microcirculation. Notably, we observed a marked decrease in capillary density and an increase in BBB permeability to fluorescent tracers in the cortices of aged mice undergoing isochronic parabiosis (20-month-old C57BL/6 mice [A-(A)]; 6 weeks of parabiosis), compared to young isochronic parabionts (6-month-old, [Y-(Y)]). However, aged heterochronic parabionts (A-(Y)) exposed to young blood exhibited a significant increase in cortical capillary density and restoration of BBB integrity. In contrast, young mice exposed to old blood from aged parabionts (Y-(A)) rapidly developed cerebromicrovascular aging traits, evidenced by reduced capillary density and increased BBB permeability. These findings underscore the profound impact of systemic factors in regulating cerebromicrovascular aging. The rejuvenation observed in the endothelium, following exposure to young blood, suggests the existence of anti-geronic elements that counteract microvascular aging. Conversely, pro-geronic factors in aged blood appear to accelerate cerebromicrovascular aging. Further research is needed to assess whether the rejuvenating effects of young blood factors could extend to other age-related cerebromicrovascular pathologies, such as microvascular amyloid deposition and increased microvascular fragility., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Brain aging is characterized by several structural, biochemical and molecular changes which can vary among different individuals and can be influenced by genetic, environmental and lifestyle factors. Accumulation of protein aggregates, altered neurotransmitter composition, low-grade chronic inflammation and prolonged oxidative stress have been shown to contribute to brain tissue damage. Among key metabolic byproducts, advanced glycation end products (AGEs), formed endogenously through non-enzymatic reactions or acquired directly from the diet or other exogenous sources, have been detected to accumulate in brain tissue, exerting detrimental effects on cellular structure and function, contributing to neurodegeneration and cognitive decline. Upon binding to signal transduction receptor RAGE, AGEs can initiate pro-inflammatory pathways, exacerbate oxidative stress and neuroinflammation, thus impairing neuronal function and cognition. AGE-RAGE signaling induces programmed cell death, disrupts the blood-brain barrier and promotes protein aggregation, further compromising brain health. In this review, we investigate the intricate relationship between the AGE-RAGE pathway and brain aging in order to detect affected molecules and potential targets for intervention. Reduction of AGE deposition in brain tissue either through novel pharmacological therapeutics, dietary modifications, and lifestyle changes, shows a great promise in mitigating cognitive decline associated with brain aging., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aging is a natural and inevitable process of organisms. With the intensification of population aging, research on aging has become a hot topic of global attention. The most obvious manifestation of human aging is the aging of brain function, which has been linked to the development of neurodegenerative diseases. In this study, COP-22, a mono-carbonyl curcumin derivative, was evaluated for its anti-aging ability, especially its ability to resist brain aging induced by D-galactose (D-gal) in mice. For brain protection, COP-22 could resist D-gal-induced oxidative stress by increasing the activity of antioxidative defense enzymes and enhancing antioxidant capacity in the brain tissue; COP-22 could improve the dysfunction of the cholinergic system by decreasing the increased activity of acetylcholinesterase and increasing the reduced content of acetylcholine induced by D-gal; and COP-22 could protect nerve cells of the brain. Further, western blot was used to determine related proteins of the brain. We found that COP-22 could effectively protect against brain injury (SIRT1, p53, p21, and p16) by inhibiting oxidative stress (Nrf2 and HO-1), inflammation (IL-6 and TNF-α), and apoptosis (Bax and caspase-3) in D-gal-induced aging mice. Additionally, COP-22 demonstrated the ability to reduce oxidative stress in serum and liver caused by D-gal, as well as relieve the damages in the liver and kidney induced by D-gal. These results indicated that COP-22 had potential anti-aging activity and could be used in the therapy of aging and aging-associated diseases like Alzheimer disease., (© 2024. The Author(s).)

There has been extensive evidence that aging affects human brain function. However, there is no complete picture of what brain functional changes are mostly related to normal aging and how aging affects brain function similarly and differently between males and females. Based on resting-state brain functional connectivity (FC) of 25,582 healthy participants (13,373 females) aged 49-76 years from the UK Biobank project, we employ deep learning with explainable AI to discover primary FCs related to progressive aging and reveal similarity and difference between females and males in brain aging. Using a nested cross-validation scheme, we conduct 4200 deep learning models to classify all paired age groups on the main data for females and males separately and then extract gender-common and gender-specific aging-related FCs. Next, we validate those FCs using additional 21,000 classifiers on the independent data. Our results support that aging results in reduced brain functional interactions for both females and males, primarily relating to the positive connectivity within the same functional domain and the negative connectivity between different functional domains. Regions linked to cognitive control show the most significant age-related changes in both genders. Unique aging effects in males and females mainly involve the interaction between cognitive control and the default mode, vision, auditory, and frontoparietal domains. Results also indicate females exhibit faster brain functional changes than males. Overall, our study provides new evidence about common and unique patterns of brain aging in females and males., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

The field of aging biology, which aims to extend healthy lifespans and prevent age-related diseases, has turned its focus to the Callithrix jacchus (common marmoset) to understand the aging process better. This study utilized magnetic resonance imaging (MRI) to non-invasively analyze the brains of 216 marmosets, investigating age-related changes in brain structure; the relationship between body weight and brain volume; and potential differences between males and females. The key findings revealed that, similar to humans, Callithrix jacchus experiences a reduction in total intracranial volume, cortex, subcortex, thalamus, and cingulate volumes as they age, highlighting site-dependent changes in brain tissue. Notably, the study also uncovered sex differences in cerebellar volume. These insights into the structural connectivity and volumetric changes in the marmoset brain throughout aging contribute to accumulating valuable knowledge in the field, promising to inform future aging research and interventions for enhancing healthspan., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Machine learning can be used to create "biologic clocks" that predict age. However, organs, tissues, and biofluids may age at different rates from the organism as a whole. We sought to understand how cerebrospinal fluid (CSF) changes with age to inform the development of brain aging-related disease mechanisms and identify potential anti-aging therapeutic targets. Several epigenetic clocks exist based on plasma and neuronal tissues; however, plasma may not reflect brain aging specifically and tissue-based clocks require samples that are difficult to obtain from living participants. To address these problems, we developed a machine learning clock that uses CSF proteomics to predict the chronological age of individuals with a 0.79 Pearson correlation and mean estimated error (MAE) of 4.30 years in our validation cohort. Additionally, we analyzed proteins highly weighted by the algorithm to gain insights into changes in CSF and uncover novel insights into brain aging. We also demonstrate a novel method to create a minimal protein clock that uses just 109 protein features from the original clock to achieve a similar accuracy (0.75 correlation, MAE 5.41). Finally, we demonstrate that our clock identifies novel proteins that are highly predictive of age in interactions with other proteins, but do not directly correlate with chronological age themselves. In conclusion, we propose that our CSF protein aging clock can identify novel proteins that influence the rate of aging of the central nervous system (CNS), in a manner that would not be identifiable by examining their individual relationships with age., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Observational studies suggest an association between sarcopenia-related traits and brain aging, but whether this association reflects a causal relationship remains unclear. This study aims to employ Mendelian randomization (MR) methods to investigate the causal impact of sarcopenia-related traits on brain aging., Methods: This study presents a comprehensive analysis of genome-wide association study (GWAS) summary data associated with sarcopenia-related traits. The data were derived from a large-scale cohort, encompassing measures such as grip strength, lean body mass, and walking pace. Measurements of brain aging were obtained from neuroimaging genetics, utilizing meta-analysis (ENIGMA) to combine magnetic resonance imaging (MRI) data from 33,992 participants. The primary methodology employed in this analysis was the inverse-variance-weighted method (IVW). Additionally, sensitivity analyses were conducted, to assess heterogeneity and pleiotropy., Result: Appendicular lean mass(ALM) is negatively correlated with Pallidum aging; Whole body fat-free mass shows a negative correlation with Amygdala aging; Leg fat-free mass (left) and Leg fat-free mass (right) are negatively correlated with Pallidum aging; Usual walking pace is positively correlated with Nucleus Accumbens aging. Cerebellum WM aging is negatively correlated with Leg fat-free mass (left) and Leg fat-free mass (right); Hippocampus aging is negatively correlated with Hand grip strength (left) and Hand grip strength (right). Ventricles aging is positively correlated with Usual walking pace; Nucleus Accumbens aging is positively correlated with Leg fat-free mass (left) and Leg fat-free mass (right); Putamen aging is positively correlated with ALM., Conclusion: Our study confirms that reduced muscle mass speeds up brain aging. Walking too fast raises the risk of brain aging, while maintaining or increasing appendicular lean mass, overall muscle mass, and muscle mass in both legs lowers the risk of brain aging., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Alzheimer's disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi-morbidities of human aging. We previously demonstrated that, in comparison to the PigmEnTed (PET) guinea pig strain which models "typical" brain aging, the Hartley strain develops hallmarks of AD like aging humans. Hartleys also exhibit age-related impairments in cartilage and skeletal muscle. Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age-related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain., Methods: Therefore, we assessed hippocampal mitochondrial respiration in 5- and 12-month Hartley and PET guinea pigs using high-resolution respirometry., Results: At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age., Conclusions: Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression., (© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Brain biological age, which measures the aging process in the brain using neuroimaging data, has been used to assess advanced brain aging in neurodegenerative diseases, including Parkinson disease (PD). However, assuming that whole brain degeneration is uniform may not be sufficient for assessing the complex neurodegenerative processes in PD. In this study we constructed a multiscale brain age prediction models based on structural MRI of 1240 healthy participants. To assess the brain aging patterns using the brain age prediction model, 93 PD patients and 91 healthy controls matching for sex and age were included. We found increased global and regional brain age in PD patients. The advanced aging regions were predominantly noted in the frontal and temporal cortices, limbic system, basal ganglia, thalamus, and cerebellum. Furthermore, region-level rather than global brain age in PD patients was associated with disease severity. Our multiscale brain age prediction model could aid in the development of objective image-based biomarkers to detect advanced brain aging in neurodegenerative diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Patients with major depressive disorder (MDD) can present with altered brain structure and deficits in cognitive function similar to those seen in aging. However, the interaction between age-related brain changes and brain development in MDD remains understudied. In a cohort of adolescents and adults with and without MDD, we assessed brain aging differences and associations through a newly developed tool that quantifies normative neurodevelopmental trajectories., Methods: A total of 304 participants with MDD and 236 control participants without depression were recruited and scanned from 3 studies under the Canadian Biomarker Integration Network for Depression. Volumetric data were used to generate brain centile scores, which were examined for 1) differences between participants with MDD and control participants; 2) differences between individuals with versus without severe childhood maltreatment; and 3) correlations with depressive symptom severity, neurocognitive assessment domains, and escitalopram treatment response., Results: Brain centiles were significantly lower in the MDD group than in the control group. Brain centile was also significantly correlated with working memory in the control group but not the MDD group. No significant associations were observed between depression severity or antidepressant treatment response and brain centiles. Likewise, childhood maltreatment history did not significantly affect brain centiles., Conclusions: Consistent with previous work on machine learning models that predict brain age, brain centile scores differed in people diagnosed with MDD, and MDD was associated with differential relationships between centile scores and working memory. The results support the notion of atypical development and aging in MDD, with implications for neurocognitive deficits associated with aging-related cognitive function., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Human brain aging is characterized by the production and deposition of β-amyloid (Aβ) in the form of senile plaques and cerebral amyloid angiopathy and the intracellular accumulation of hyper-phosphorylated tau (Hp-tau) to form neurofibrillary tangles (NFTs) and dystrophic neurites of senile plaques. The process progresses for years and eventually manifests as cognitive impairment and dementia in a subgroup of aged individuals. Aβ is produced and deposited first in the neocortex in most aged mammals, including humans; it is usually not accompanied by altered behavior and cognitive impairment. Hp-tau is less frequent than Aβ pathology, and NFTs are rare in most mammals. In contrast, NFTs are familiar from middle age onward in humans; NFTs first appear in the paleocortex and selected brain stem nuclei. NFTs precede for decades or years Aβ deposition and correlate with dementia in about 5% of individuals at the age of 65 and 25% at the age of 85. Based on these comparative data, (a) Aβ deposition is the most common Alzheimer's disease neuropathological change (ADNC) in the brain of aged mammals; (b) Hp-tau is less common, and NFTs are rare in most aged mammals; however, NFTs are the principal cytoskeletal pathology in aged humans; (c) NFT in aged humans starts in selected nuclei of the brain stem and paleocortical brain regions progressing to the most parts of the neocortex and other regions of the telencephalon; (d) human brain aging is unique among mammalian species due to the early appearance and dramatic progression of NFTs from middle age onward, matching with cognitive impairment and dementia in advanced cases; (e) neither mammalian nor human brain aging supports the concept of the amyloid cascade hypothesis.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

The notion of notable anatomical, biochemical, and behavioral distinctions within male and female brains has been a contentious topic of interest within the scientific community over several decades. Advancements in neuroimaging and molecular biological techniques have increasingly elucidated common mechanisms characterizing brain aging while also revealing disparities between sexes in these processes. Variations in cognitive functions; susceptibility to and progression of neurodegenerative conditions, notably Alzheimer's and Parkinson's diseases; and notable disparities in life expectancy between sexes, underscore the significance of evaluating aging within the framework of gender differences. This comprehensive review surveys contemporary literature on the restructuring of brain structures and fundamental processes unfolding in the aging brain at cellular and molecular levels, with a focus on gender distinctions. Additionally, the review delves into age-related cognitive alterations, exploring factors influencing the acceleration or deceleration of aging, with particular attention to estrogen's hormonal support of the central nervous system.

Aging is a multifaceted and progressive physiological change of the organism categorized by the accumulation of deteriorating processes, which ultimately compromise the biological functions. The objective of this study was to investigate the anti-aging potential of berberine (BBR) in D-galactose (D-Gal) induced aging in rat models. In this study, male Wistar rats were divided into four groups: The control group was given only vehicle, the BBR group was treated with berberine orally, the D-Gal group was treated with D-galactose subcutaneously and the BBR + D-Gal group was treated with D-galactose and berberine simultaneously. D-galactose exposure elevated the pro-oxidants such as malondialdehyde (MDA) level, protein carbonyl and advanced oxidation protein products (AOPP) in the brain. It decreased the anti-oxidants such as reduced glutathione (GSH) and ferric reducing antioxidant potential (FRAP) in the brain. D-galactose treatment also reduced the mitochondrial complexes (I, II, III and IV) activities and elevated the inflammatory markers such as interleukine-6 (IL-6), tumor necrosis factor- α (TNF-α) and C-reactive protein (CRP). The mRNA expressions of IL-6 and TNF-α in the brain were upregulated following D-galactose exposure. Berberine co-treatment in D-galactose induced aging rat model prevented the alteration of pro-oxidant and anti-oxidant in the brain. Berberine treatment restored the mitochondrial complex activities in the brain and also normalized the inflammatory markers. Based on these findings we conclude that berberine treatment has the potential to mitigate brain aging in rats via stabilizing the redox equilibrium and neuroinflammation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

During aging, the brain is subject to greater oxidative stress (OS), which is thought to play a critical role in cognitive impairment. Glutathione (GSH), as a major antioxidant in the brain, can be used to combat OS. However, how brain GSH levels vary with age and their associations with cognitive function is unclear. In this study, we combined point-resolved spectroscopy and edited spectroscopy sequences to investigate extended and closed forms GSH levels in the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and occipital cortex (OC) of 276 healthy participants (extended form, 166 females, age range 20-70 years) and 15 healthy participants (closed form, 7 females, age range 26-56 years), and examined their relationships with age and cognitive function. The results revealed decreased extended form GSH levels with age in the PCC among 276 participants. Notably, the timecourse of extended form GSH level changes in the PCC and ACC differed between males and females. Additionally, positive correlations were observed between extended form GSH levels in the PCC and OC and visuospatial memory. Additionally, a decreased trend of closed form GSH levels with age was also observed in the PCC among 15 participants. Taken together, these findings enhance our understanding of the brain both closed and extended form GSH time course during normal aging and associations with sex and memory, which is an essential first step for understanding the neurochemical underpinnings of healthy aging., Competing Interests: Declaration of competing interest None to disclose, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aging may lead to low-level chronic inflammation that increases the susceptibility to age-related conditions, including memory impairment and progressive loss of brain volume. As brain health is essential to promoting healthspan and lifespan, it is vital to understand age-related changes in the immune system and central nervous system (CNS) that drive normal brain aging. However, the relative importance, mechanistic interrelationships, and hierarchical order of such changes and their impact on normal brain aging remain to be clarified. Here, we synthesize accumulating evidence that age-related DNA damage and cellular senescence in the immune system and CNS contribute to the escalation of neuroinflammation and cognitive decline during normal brain aging. Targeting cellular senescence and immune modulation may provide a logical rationale for developing new treatment options to restore immune homeostasis and counteract age-related brain dysfunction and diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in the field of chronobiology. A plethora of new data demonstrates melatonin to be a very powerful molecule, being a potent ROS/RNS scavenger with anti-inflammatory, immunoregulatory, and oncostatic properties. Melatonin and its metabolites exert multiple beneficial effects in cutaneous and systemic aging. This review is focused on the neuroprotective role of melatonin during aging. Melatonin has an anti-aging capacity, retarding the rate of healthy brain aging and the development of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process. Melatonin could also be implicated in the treatment of neurodegenerative conditions, by modifying their characteristic low-grade neuroinflammation. It can either prevent the initiation of inflammatory responses or attenuate the ongoing inflammation. Drawing on the current knowledge, this review discusses the potential benefits of melatonin supplementation in preventing and managing cognitive impairment and neurodegenerative diseases.

Mitochondrial cristae, infoldings of the mitochondrial inner membrane, undergo aberrant changes in their architecture with age. However, the underlying molecular mechanisms and their contribution to brain aging are largely elusive. Here, we observe an age-dependent accumulation of Glu-5'tsRNA-CTC, a transfer-RNA-derived small RNA (tsRNA), derived from nuclear-encoded tRNA Glu in the mitochondria of glutaminergic neurons. Mitochondrial Glu-5'tsRNA-CTC disrupts the binding of mt-tRNA Leu and leucyl-tRNA synthetase2 (LaRs2), impairing mt-tRNA Leu aminoacylation and mitochondria-encoded protein translation. Mitochondrial translation defects disrupt cristae organization, leading to damaged glutaminase (GLS)-dependent glutamate formation and reduced synaptosomal glutamate levels. Moreover, reduction of Glu-5'tsRNA-CTC protects aged brains from age-related defects in mitochondrial cristae organization, glutamate metabolism, synaptic structures, and memory. Thus, beyond illustrating a physiological role for normal mitochondrial cristae ultrastructure in maintaining glutamate levels, our study defines a pathological role for tsRNAs in brain aging and age-related memory decline., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sensory impairment and brain atrophy is common among older adults, increasing the risk of dementia. Yet, the degree to which multiple co-occurring sensory impairments (MSI across vision, proprioception, vestibular function, olfactory, and hearing) are associated with brain morphometry remain unexplored. Data were from 208 cognitively unimpaired participants (mean age 72 ± 10 years; 59% women) enrolled in the Baltimore Longitudinal Study of Aging. Multiple linear regression models were used to estimate cross-sectional associations between MSI and regional brain imaging volumes. For each additional sensory impairment, there were associated lower orbitofrontal gyrus and entorhinal cortex volumes but higher caudate and putamen volumes. Participants with MSI had lower mean volumes in the superior frontal gyrus, orbitofrontal gyrus, superior parietal lobe, and precuneus compared to participants with < 2 impairments. While MSI was largely associated with lower brain volumes, our results suggest the possibility that MSI was associated with higher basal ganglia volumes. Longitudinal analyses are needed to evaluate the temporality and directionality of these associations., (© 2024. The Author(s).)

Senile plaques, mainly diffuse, and cerebral amyloid-β (Aβ) angiopathy are prevalent in the aging brain of non-human primates, from lemurs to non-human Hominidae. Aβ but not hyper-phosphorylated tau (HPtau) pathology is the common nominator proteinopathy of non-human primate brain aging. The abundance of Aβ in the aging primate brain is well tolerated, and the impact on cognitive functions is usually limited to particular tasks. In contrast, human brain aging is characterized by the early appearance of HPtau pathology, mainly forming neurofibrillary tangles, dystrophic neurites of neuritic plaques, and neuropil threads, preceding Aβ deposits by several decades and by its severity progressing from selected nuclei of the brain stem, entorhinal cortex, and hippocampus to the limbic system, neocortex, and other brain regions. Neurofibrillary tangles correlate with cognitive impairment and dementia in advanced cases. Aβ pathology is linked in humans to altered membrane protein and lipid composition, particularly involving lipid rafts. Although similar membrane alterations are unknown in non-human primates, membrane senescence is postulated to cause the activated β-amyloidogenic pathway, and Aβ pathology is the prevailing signature of non-human and human primate brain aging.

Research during the last two decades has shown that the brain undergoes continuous changes throughout life, with substantial heterogeneity in age trajectories between regions. Especially, temporal and prefrontal cortices show large changes, and these correlate modestly with changes in the corresponding cognitive abilities such as episodic memory and executive function. Changes seen in normal aging overlap with changes seen in neurodegenerative conditions such as Alzheimer's disease; differences between what reflects normal aging vs. a disease-related change are often blurry. This calls for a dimensional view on cognitive decline in aging, where clear-cut distinctions between normality and pathology cannot be always drawn. Although much progress has been made in describing typical patterns of age-related changes in the brain, identifying risk and protective factors, and mapping cognitive correlates, there are still limits to our knowledge that should be addressed by future research. We need more longitudinal studies following the same participants over longer time intervals with cognitive testing and brain imaging, and an increased focus on the representativeness vs. selection bias in neuroimaging research of aging., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: Genetic and epigenetic changes, oxidative stress and inflammation influence the rate of aging, which diseases, lifestyle and environmental factors can further accelerate. In accelerated aging (AA), the biological age exceeds the chronological age., Objective: The objective of this study is to reappraise the AA concept critically, considering its weaknesses and limitations., Methods: We reviewed more than 300 recent articles dealing with the physiology of brain aging and neurodegeneration pathophysiology., Results: (1) Application of the AA concept to individual organs outside the brain is challenging as organs of different systems age at different rates. (2) There is a need to consider the deceleration of aging due to the potential use of the individual structure-functional reserves. The latter can be restored by pharmacological and/or cognitive therapy, environment, etc. (3) The AA concept lacks both standardised terminology and methodology. (4) Changes in specific molecular biomarkers (MBM) reflect aging-related processes; however, numerous MBM candidates should be validated to consolidate the AA theory. (5) The exact nature of many potential causal factors, biological outcomes and interactions between the former and the latter remain largely unclear., Conclusions: Although AA is commonly recognised as a perspective theory, it still suffers from a number of gaps and limitations that assume the necessity for an updated AA concept.

Lipids are essential components of brain structure and shown to affect brain function. Previous studies have shown that aging men undergo greater brain atrophy than women, but whether the associations between lipids and brain atrophy differ by sex is unclear. We examined sex differences in the associations between circulating lipids by liquid chromatography-tandem mass spectrometry and the progression of MRI-derived brain atrophy index Spatial Patterns of Atrophy for Recognition of Brain Aging (SPARE-BA) over an average of 4.7 (SD = 2.3) years in 214 men and 261 women aged 60 or older who were initially cognitively normal using multivariable linear regression, adjusted for age, race, education, and baseline SPARE-BA. We found significant sex interactions for beta-oxidation rate, short-chain acylcarnitines, long-chain ceramides, and very long-chain triglycerides. Lower beta-oxidation rate and short-chain acylcarnitines in women and higher long-chain ceramides and very long-chain triglycerides in men were associated with faster increases in SPARE-BA (accelerated brain aging). Circulating lipid profiles of accelerated brain aging are sex-specific and vary by lipid classes and structure. Mechanisms underlying these sex-specific lipid profiles of brain aging warrant further investigation., (Published by Elsevier Inc.)

The brain undergoes many changes at pathological and functional levels in healthy aging. This study employed a longitudinal and multimodal imaging dataset from the OASIS-3 study (n = 300) and explored possible relationships between amyloid beta (Aβ) accumulation and functional brain organization over time in healthy aging. We used positron emission tomography (PET) with Pittsburgh compound-B (PIB) to quantify the Aβ accumulation in the brain and resting-state functional MRI (rs-fMRI) to measure functional connectivity (FC) among brain regions. Each participant had at least 2 to 3 follow-up visits. A linear mixed-effect model was used to examine longitudinal changes of Aβ accumulation and FC throughout the whole brain. We found that the limbic and frontoparietal networks had a greater annual Aβ accumulation and a slower decline in FC in aging. Additionally, the amount of the Aβ deposition in the amygdala network at baseline slowed down the decline in its FC in aging. Furthermore, the functional connectivity of the limbic, default mode network (DMN), and frontoparietal networks accelerated the Aβ propagation across their functionally highly connected regions. The functional connectivity of the somatomotor and visual networks accelerated the Aβ propagation across the brain regions in the limbic, frontoparietal, and DMN networks. These findings suggested that the slower decline in the functional connectivity of the functional hubs may compensate for their greater Aβ accumulation in aging. The Aβ propagation from one brain region to the other may depend on their functional connectivity strength., Competing Interests: Declaration of Competing Interest No author has competing interest., (Copyright © 2023. Published by Elsevier Inc.)

The neutrophil-to-lymphocyte ratio (NLR) is a trans-prognostic biomarker of physiologic stress and inflammation linked to muscle weakness in older adults. Generation of grip force coincides with sustained activity in the primary sensorimotor cortex (SM1). The current study investigates whether whole-brain functional connectivity, that is, degree centrality (CD) of SM1 relates to grip strength and whether both functional measures are predicted by advancing age as a function of the NLR. A structural regression model investigated the main and interactive effects of age and NLR on grip strength and CD of SM1 in 589 adults aged 21-85 years (M = 45.87, SD = 18.06). The model including the entire sample had a good fit (χ 2(4) = 1.63, p = .804). In individuals aged 50 years and older, age predicted lower grip strength and SM1 CD as a function of increasing NLR. In a model stratified by sex, the effect of age, NLR, and their interaction on grip strength are significant for older men but not older women. Analyses support CD of SM1 at rest as a neural biomarker of grip strength. Grip and its neural underpinnings decrease with advancing age and increasing NLR in mid to late life. Age-related decrements in grip strength and functional connectivity of brain regions involved in the generation of dynamic grip appear to be accelerated as a function of systemic physiological stress and inflammation, particularly in older men., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The brain's functional architecture and organization undergo continual development and modification throughout adolescence. While it is well known that multiple factors govern brain maturation, the constantly evolving patterns of time-resolved functional connectivity are still unclear and understudied. We systematically evaluated over 47,000 youth and adult brains to bridge this gap, highlighting replicable time-resolved developmental and aging functional brain patterns. The largest difference between the two life stages was captured in a brain state that indicated coherent strengthening and modularization of functional coupling within the auditory, visual, and motor subdomains, supplemented by anticorrelation with other subdomains in adults. This distinctive pattern, which we replicated in independent data, was consistently less modular or absent in children and presented a negative association with age in adults, thus indicating an overall inverted U-shaped trajectory. This indicates greater synchrony, strengthening, modularization, and integration of the brain's functional connections beyond adolescence, and gradual decline of this pattern during the healthy aging process. We also found evidence that the developmental changes may also bring along a departure from the canonical static functional connectivity pattern in favor of more efficient and modularized utilization of the vast brain interconnections. State-based statistical summary measures presented robust and significant group differences that also showed significant age-related associations. The findings reported in this article support the idea of gradual developmental and aging brain state adaptation processes in different phases of life and warrant future research via lifespan studies to further authenticate the projected time-resolved brain state trajectories., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: Brain structure and function change with age. Both educational attainments, a proxy for cognitive reserve, and intracranial volume (ICV), a proxy for brain reserve, could contribute to resilience against degenerative change in the brain with aging. Whether the effect of educational attainment on regional brain volume in adults is mediated by ICV is yet unclear. We aimed to investigate the direct and indirect effects (mediated through ICV) of education in early life on regional brain volume in later life., Materials and Method: We investigated the association between ICV and education level and regional brain volume in adults using magnetic resonance imaging scans of 1,731 individuals from multicenter studies. The mediation effect of ICV was analyzed to determine the association between educational attainment at an earlier age and regional brain volume in adults., Results: Our results showed that the effect of education on regional brain volume was significantly mediated by ICV in both men and women. The indirect (mediated via ICV) effect of education on brain volume amounted to 75% of the total effect in the hippocampus (p < 0.001) and 100% in the frontal and insular gray matter (p < 0.001)., Conclusion: Our study demonstrated that the association between educational attainment in early life and regional brain volume in later life was largely mediated by ICV. Attention should be given to the effect of educational attainment and ICV on regional brain size in adults as a measurable resilience effect in brain aging., Competing Interests: Declaration of Competing Interest Authors RK, ML, and DK were employed by NEUROPHET INC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: The volume of the hippocampus and its subfields is known to be affected by aging, disease, and physical training. In regard to training, the differential effects of aerobic exercise and dance training on the subfield volume suggest that balance function may be involved. However, the relationship between balance function and the volume of the hippocampus and its subfields remains unclear., Methods: Subjects were 30 cognitively intact individuals. They underwent balance tests, cognitive tests and structural MRI scans. The balance index measured was the index of postural stability (IPS) under a visual block condition and/or a proprioception block condition. MR images acquired using a 3-tesla system and three-dimensional T1-weighted images were segmented in the hippocampal subfield with Freesurfer 6.0.0. The relationship between the IPS and hippocampal volume was evaluated., Results: A positive correlation was observed only between the IPS closed eyes/soft surface condition and whole hippocampal volume ratio. In the subfields, positive correlations were found between the IPS and molecular layer of the hippocampus, granule cell layer of the dentate gyrus (GC-ML-DG), and cornu ammonis areas (CA)3 and CA4. These correlations were stronger under the closed eyes/soft surface condition than under the other conditions., Conclusions: A correlation between balance function and the volume of the hippocampus and subfields was found in healthy elderly subjects. The balance function may be involved in the volume of the whole hippocampus and specific subfields. The IPS closed eyes/soft surface condition is considered to reflect vestibular function. Thus, IPS may be useful in evaluations of the relationship between the vestibular system function via the hippocampus and balance., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

The diversity and complex organization of cells in the brain have hindered systematic characterization of age-related changes in its cellular and molecular architecture, limiting our ability to understand the mechanisms underlying its functional decline during aging. Here, we generated a high-resolution cell atlas of brain aging within the frontal cortex and striatum using spatially resolved single-cell transcriptomics and quantified changes in gene expression and spatial organization of major cell types in these regions over the mouse lifespan. We observed substantially more pronounced changes in cell state, gene expression, and spatial organization of non-neuronal cells over neurons. Our data revealed molecular and spatial signatures of glial and immune cell activation during aging, particularly enriched in the subcortical white matter, and identified both similarities and notable differences in cell-activation patterns induced by aging and systemic inflammatory challenge. These results provide critical insights into age-related decline and inflammation in the brain., Competing Interests: Declaration of interests X.Z. is an inventor of patents applied for by Harvard University related MERFISH, a co-founder and consultant of Vizgen, Inc., and a member of the Cell advisory board., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The current evidence on the association of leukocyte telomere length (LTL) with age-related structural and cognitive changes in the brain is mixed. Herein conforming to PRISMA 2020 guidelines, we performed a systematic review and meta-analysis using data from 27 observational studies in non-demented individuals. We used effect size and p-value based meta-analysis methods considering marked heterogeneity among studies. We found that the longer LTL was associated with higher brain volume (β = 0.43, 95%CI: 0.36-0.50%, p = 0.008, N = 1102) and with higher global cognition (β = 0.01; 95%CI: 0.00-0.02, p = 0.03, N = 19609) by effect size based meta-analysis and with brain volume, hippocampal volume, global cognition, cognitive domains of attention/speed as well as executive functions by p-value based meta-analysis. No significant association of LTL with brain white matter hyperintensities was detected. Furthermore, the evidence strongly suggests a subgroup-specific canonical effect of telomeres, notably in older individuals and females. In conclusion, we provide meta-analytic evidence on the beneficial effect of telomeres on brain structure as well as cognition and advocate for a beneficial subgroup-specific effect that warrants further attention., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Brain age is a neuroimaging-based biomarker of aging. This study examined whether the difference between brain age and chronological age (brain-PAD) is associated with cognitive function at baseline and longitudinally. Participants were relatively healthy, predominantly white community-dwelling older adults (n = 531, aged ≥70 years), with high educational attainment (61% ≥12 years) and socioeconomic status (59% ≥75th percentile). Brain age was estimated from T1-weighted magnetic resonance images using an algorithm by Cole et al., 2018. After controlling for age, gender, education, depression and body mass index, brain-PAD was negatively associated with psychomotor speed (Symbol Digit Modalities Test) at baseline (Bonferroni p < 0.006), but was not associated with baseline verbal fluency (Controlled Oral Word Association Test), delayed recall (Hopkins Learning Test Revised), or general cognitive status (Mini-Mental State Examination). Baseline brain-PAD was not associated with 3-year change in cognition (Bonferroni p > 0.006). These findings indicate that even in relatively healthy older people, accelerated brain aging is associated with worse psychomotor speed, but future longitudinal research into changes in brain-PAD is needed., (Copyright © 2021. Published by Elsevier Inc.)