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The suprachiasmatic nucleus (SCN) in the hypothalamus regulates circadian timing system (CTS) by co-ordinating peripheral tissue clocks and extra-SCN oscillators in the brain. Aging disrupts the CTS, impairing physiological functions and reducing antioxidant defences, which contribute to neurodegeneration. The brain is vulnerable to oxidative damage due to its high metabolic activity, oxygen consumption, and levels of iron and lipids. Antioxidant enzymes, such as catalase (CAT), glutathione S-transferase (GST), superoxide dismutase (SOD), and lipid peroxidation (LPO), help against oxidative damage. In this study, we examined the temporal patterns of these antioxidant stress indicators in the SCN and extra-SCN brain regions (frontal cortex, cerebellum, and hippocampus) at various time points in male Wistar rats 3, 12, and 24 months. The rhythmicity of GST and LPO levels persisted across brain regions with aging, while CAT rhythmicity was lost in the SCN and hippocampus of older rats. SOD rhythmicity persisted in cortex, cerebellum, and hippocampus but was lost in the SCN. The daily rhythm parameters of CAT were affected most significantly, followed by SOD, GST, and LPO. Our findings demonstrate that aging leads to desynchronization of oxidative stress indicators potentially contributing to neurodegeneration and circadian dysfunction with varying effects across different brain tissues., Competing Interests: Declarations Conflict of interest Authors declare they have no conflict., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Brain structure, oxygenation and perfusion are important factors in aging. Coupling between regional cerebral oxygen consumption and perfusion also reflects functions of neurovascular unit (NVU). Their trajectories and sex differences during normal aging important for clinical interpretation are still not well defined. In this study, we aim to investigate the relationship between brain structure, functions and age, and exam the sex disparities., Method: A total of 137 healthy subjects between 20∼69 years old were enrolled with conventional MRI, structural three-dimensional T 1 -weighted imaging (3D-T 1 WI), 3D multi-echo gradient echo sequence (3D-mGRE), and 3D pseudo-continuous arterial spin labeling (3D-pCASL). Oxygen extraction fraction (OEF) and cerebral blood flow (CBF) were respectively reconstructed from 3D-mGRE and 3D-pCASL images. Cerebral metabolic rate of oxygen (CMRO 2 ) were calculated as follows: CMRO 2 =CBF·OEF·[H] a , [H] a =7.377 μmol/mL. Brains were segmented into global gray matter (GM), global white matter (WM), and 148 cortical subregions. OEF, CBF, CMRO 2 , and volumes of GM/WM relative to intracranial volumes (rel&#95;GM/rel&#95;WM) were compared between males and females. Generalized additive models were used to evaluate the aging trajectories of brain structure and functions. The coupling between OEF and CBF was analyzed by correlation analysis. P or P FDR < 0.05 was considered statistically significant., Results: Females had larger rel&#95;GM, higher CMRO 2 and CBF of GM/WM than males (P < 0.05). With control of sex, CBF of GM significantly declined between 20 and 32 years, CMRO 2 of GM declined subsequently from 33 to 41 years and rel&#95;GM decreased significantly at all ages (R 2 = 0.27, P < 0.001; R 2 = 0.17, P < 0.001; R 2 = 0.52, P < 0.001). In subregion analysis, CBF declined dispersedly while CMRO 2 declined widely across most subregions of the cortex during aging. Robust negative coupling between OEF and CBF was found in most of the subregions (r range = -0.12∼-0.48, P FDR < 0.05)., Conclusion: The sex disparities, age trajectories of brain structure and functions as well as the coupling of NVU in healthy individuals provide insights into normal aging which are potential targets for study of pathological conditions., Competing Interests: Declaration of competing interest I have nothing to declare., (Copyright © 2024. Published by Elsevier Inc.)

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.)

Aging involves complex processes that impact the structure, function, and metabolism of the human brain. Declines in both structural and functional integrity along with reduced local inhibitory tone in the motor areas, as indicated by reduced γ-aminobutyric acid (GABA) levels, are often associated with compromised motor performance in elderly adults. Using multimodal neuroimaging techniques including magnetic resonance spectroscopy (MRS), diffusion magnetic resonance imaging (MRI), functional MRI as well as transcranial magnetic stimulation to assess short-interval intracortical inhibition (SICI), this study explores whether these age-related changes can be mitigated by motor learning. The investigation focused on the effects of long-term balance learning (3 months) on intracortical inhibition, metabolism, structural, and functional connectivity in the cortical sensorimotor network among an elderly cohort. We found that after 3 months of balance learning, subjects significantly improved balance performance, upregulated sensorimotor cortical GABA levels and ventral sensorimotor network functional connectivity (VSN-FC) compared to a passive control group. Furthermore, correlation analysis suggested a positive association between baseline VSN-FC and balance performance, between baseline VSN-FC and SICI, and between improvements in balance performance and upregulation in SICI in the training group, though these correlations did not survive the false discovery rate correction. These findings demonstrate that balance learning has the potential to counteract aging-related decline in functional connectivity and cortical inhibition on the "tonic" (MRS) and "functional" (SICI) level and shed new light on the close interplay between the GABAergic system, functional connectivity, and behavior., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Alzheimer's disease (AD) and its associated pathology have been primarily identified in humans, who have relatively large brains and long lifespans. To expand what is known about aging and neurodegeneration across mammalian species, we characterized amyloid-beta (Aβ) and tau lesions in five species of aged felids (n = 9; cheetah, clouded leopard, African lion, serval, Siberian tiger). We performed immunohistochemistry to detect Aβ40 and Aβ42 in plaques and vessels and hyperphosphorylated tau in the temporal lobe gyrus sylvius and in the CA1 and CA3 subfields of the hippocampus. We also quantified the densities and morphological types of microglia expressing IBA1. We found that diffuse Aβ42 plaques, but not dense-core plaques, were present more frequently in the temporal cortex and tended to be more common than Aβ40 plaques across species. Conversely, vascular Aβ was labeled more consistently with Aβ40 for each species on average. Although all individuals showed some degree of Aβ40 and/or Aβ42 immunoreactivity, only the cheetahs and clouded leopards exhibited intraneuronal hyperphosphorylated tau (i.e., pretangles), which was more common in the hippocampus. Reactive, intermediate microglia were significantly associated with total Aβ40 vessel area and pretangle load in the hippocampus. This study demonstrates the co-occurrence of Aβ and tau pathology in two felid species, cheetahs and clouded leopards. Overall, these results provide an initial view of the manifestation of Aβ and tau pathology in aged, large-brained felids, which can be compared with markers of neurodegeneration across different taxa, including domestic cats, nonhuman primates, and humans., (© 2024 Wiley Periodicals LLC.)

Background: Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer's disease (AD)., Methods: Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42-85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n = 291), resilient in both (n = 260) or advanced in one/resilient in the other (n = 163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task)., Findings: Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits., Interpretation: The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life., Funding: The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests TB has received investigator-initiated research awards from the NIH, the Alzheimer’s Association, the Foundation at Barnes-Jewish Hospital, Siemens Healthineers, Hyperfine and Avid Radiopharmaceuticals (a wholly-owned subsidiary of Eli Lilly and Company). She participates as a site investigator in clinical trials sponsored by Eli Lilly and Company, Biogen, Eisai, Jaansen, and Roche. She has served as a paid and unpaid consultant to Eisai, Siemens, Biogen, Janssen, Hyperfine, Merck Lilly, and Bristol-Myers Squibb. JCM has served as a paid consultant to the Barcelona Brain Research Center and the Native Alzheimer Disease-related Resource Center in Minority Aging Research. He also received payments for presentations at the AAIM meeting, Longer Life Foundation and the International Brain Health Symposium. JCM has received travel support to attend meetings including: AAIM, DIAN, AD/PD, ATRI/ADNI, ADRC, ADC, the International conference on Health Aging & Biomarkers and the International Brain Health Symposium. He has served on the advisory board for the Cure Alzheimer’s Fund and LEADS at Indiana University. IMN has received payments from Premier, Inc for participating in an advisory board, from Peerview for an educational talk, and from Subtle Medical, Inc for consulting. DW has served as a paid consultant to Qynapse, Beckman Coulter and Eli Lilly. He also received grants from the NIH and Biogen paid to his institution and received travel support from the Alzheimer's Association. SR is an NIA IRP employee and has served on the advisory board of Dementia Platforms, UK, the Canadian Consortium on Neurodegeneration in Aging and the Adult Aging Brain Connectome. She has received travel support from the McKnight Foundation to attend an annual meeting., (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.)

Preservation of brain health is a worldwide priority. The traditional view is that the major threats to the ageing brain lie within the brain itself. Consequently, therapeutic approaches have focused on protecting the brain from these presumably intrinsic pathogenic processes. However, an increasing body of evidence has unveiled a previously under-recognized contribution of peripheral organs to brain dysfunction and damage. Thus, in addition to the well-known impact of diseases of the heart and endocrine glands on the brain, accumulating data suggest that dysfunction of other organs, such as gut, liver, kidney and lung, substantially affects the development and clinical manifestation of age-related brain pathologies. In this Review, a framework is provided to indicate how organ dysfunction can alter brain homeostasis and promote neurodegeneration, with a focus on dementia. We delineate the associations of subclinical dysfunction in specific organs with dementia risk and provide suggestions for public health promotion and clinical management., (© 2024. Springer Nature Limited.)

Introduction: Transposable element (TE) dysregulation is associated with neuroinflammation in Alzheimer's disease (AD) brains. Yet, TE quantitative trait loci (teQTL) have not been well characterized in human aged brains with AD., Methods: We leveraged large-scale bulk and single-cell RNA sequencing, whole-genome sequencing (WGS), and xQTL from three human AD brain biobanks to characterize TE expression dysregulation and experimentally validate AD-associated TEs using CRISPR interference (CRISPRi) assays in human induced pluripotent stem cell (iPSC)-derived neurons., Results: We identified 26,188 genome-wide significant TE expression QTLs (teQTLs) in human aged brains. Subsequent colocalization analysis of teQTLs with AD genetic loci identified AD-associated teQTLs and linked locus TEs. Using CRISPRi assays, we pinpointed a neuron-specific suppressive role of the activated short interspersed nuclear element (SINE; chr11:47608036-47608220) on expression of C1QTNF4 via reducing neuroinflammation in human iPSC-derived neurons., Discussion: We identified widespread TE dysregulation in human AD brains and teQTLs offer a complementary analytic approach to identify likely AD risk genes., Highlights: Widespread transposable element (TE) dysregulations are observed in human aging brains with degrees of neuropathology, apolipoprotein E (APOE) genotypes, and neuroinflammation in Alzheimer's disease (AD). A catalog of TE quantitative trait loci (teQTLs) in human aging brains was created using matched RNA sequencing and whole-genome sequencing data. CRISPR interference assays reveal that an upregulated intergenic TE from the MIR family (chr11: 47608036-47608220) suppresses expression of its nearest anti-inflammatory gene C1QTNF4 in human induced pluripotent stem cell-derived neurons., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Ageing is characterised by a progressive increase in systemic inflammation and especially neuroinflammation. Neuroinflammation is associated with altered brain states that affect behaviour, such as an increased level of anxiety with a concomitant decline in cognitive abilities. Although multiple factors play a role in the development of neuroinflammation, microglia have emerged as a crucial target. Microglia are the only macrophage population in the CNS parenchyma that plays a crucial role in maintaining homeostasis and in the immune response, which depends on the activation and subsequent deactivation of microglia. Therefore, microglial dysfunction has a major impact on neuroinflammation. The gut microbiota has been shown to significantly influence microglia from birth to adulthood in terms of development, proliferation, and function. Diet is a key modulating factor that influences the composition of the gut microbiota, along with prebiotics that support the growth of beneficial gut bacteria. Although the role of diet in neuroinflammation and behaviour has been well established, its relationship with microglia functionality is less explored. This article establishes a link between diet, animal behaviour and the functionality of microglia. The results of this research stem from experiments on mouse behaviour, i.e., memory, anxiety, and studies on microglia functionality, i.e., cytochemistry (phagocytosis, cellular senescence, and ROS assays), gene expression and protein quantification. In addition, shotgun sequencing was performed to identify specific bacterial families that may play a crucial role in the brain function. The results showed negative effects of long-term consumption of a high fat diet on ageing mice, epitomised by increased body weight, glucose intolerance, anxiety, cognitive impairment and microglia dysfunction compared to ageing mice on a control diet. These effects were a consequence of the changes in gut microbiota modulated by the diet. However, by adding the prebiotics fructo- and galacto-oligosaccharides, we were able to mitigate the deleterious effects of a long-term high-fat diet., 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 Author(s). Published by Elsevier Inc. All rights reserved.)

Background: During aging, both the brain and the immune system undergo a progressive impairment of physiological functions. Microglia, the immunocompetent cells of the central nervous system, shift towards a chronic mild inflammatory state that impacts brain homeostasis. Extracellular vesicles (EVs) released by microglia transport packages of molecular information that mirror the inflammatory status of donor cells and modulate the inflammatory phenotype of recipient microglia and other cell types., Results: We demonstrated that intranasal administration of EVs derived from microglial-like BV2 cells to late adult mice (16-20 months of age) shifts microglia toward a "juvenile" morphology affecting their inflammatory profile. Mice treated with BV2-derived EVs have a reduction of anxiety-like behavior and an increased spatial learning, with sex-dependent differences. Further, BV2-derived EVs increased neuronal plasticity both in male and female mice. These findings suggest the involvement of microglial cells in vesicles-mediated anti-aging effect., Conclusions: Our data indicate that BV2-derived EVs could represent a resource to slow down age-dependent inflammation in the mouse brain., 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.)

In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin's influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin's effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging., Competing Interests: Declaration of interests J.C.I.B., S.H., C.R.E., P.R., and A.H. are employees of Altos Labs. S.H. is a founder of the non-profit Epigenetic Clock Development Foundation, which has licensed several of his patents from UC Regents and distributes the mammalian methylation array., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.

The actin cytoskeleton is a key determinant of cell structure and homeostasis. However, possible tissue-specific changes to actin dynamics during aging, notably brain aging, are not understood. Here, we show that there is an age-related increase in filamentous actin (F-actin) in Drosophila brains, which is counteracted by prolongevity interventions. Critically, decreasing F-actin levels in aging neurons prevents age-onset cognitive decline and extends organismal healthspan. Mechanistically, we show that autophagy, a recycling process required for neuronal homeostasis, is disabled upon actin dysregulation in the aged brain. Remarkably, disrupting actin polymerization in aged animals with cytoskeletal drugs restores brain autophagy to youthful levels and reverses cellular hallmarks of brain aging. Finally, reducing F-actin levels in aging neurons slows brain aging and promotes healthspan in an autophagy-dependent manner. Our data identify excess actin polymerization as a hallmark of brain aging, which can be targeted to reverse brain aging phenotypes and prolong healthspan., (© 2024. The Author(s).)

Aging represents a natural and unavoidable phenomenon in organisms. With the acceleration of population aging, investigations into aging have garnered widespread global interest. One of the most striking aspects of human aging is the decline in brain function, a phenomenon intricately tied to the onset of neurodegenerative conditions. This study aimed to assess the impact of a fish hydrolysate, rich in low-molecular-weight peptides and n-3 LC-PUFAs, on cognitive function, inflammatory response, and oxidative stress via the AGE-RAGE axis in a mouse model of accelerated aging. This model induces cognitive decline and biochemical alterations akin to those observed during natural aging. The findings revealed that fish hydrolysate exhibited a protective effect against cognitive impairment induced by D-galactose. This effect was associated with increased protein expression of SOD1 and decreased genetic expression of IL-6 and advanced glycation end products (AGE). Consequently, within the realm of preventive and personalized nutrition, fish hydrolysate emerges as a promising avenue for mitigating age-related declines in memory function., Competing Interests: Céline Lucas, Véronique Pallet, Corinne Joffre and Anne-Laure Dinel report no disclosures. Abyss Ingredients funds Camille Mougin, Mathilde Chataigner, and Elodie Bouvret. Mathilde Chataigner: employee of Abyss Ingredients; Elodie Bouvret: employee of Abyss Ingredients. This work is part of a collaborative project named Optimyss which has been funded by the National Agency of Research (ANR France) and Abyss Ingredients in the context of national French project “Plan de relance”. Mathilde Chataigner and Elodie Bouvret work for Abyss Ingredients and provide the fish hydrolysate, described in the patent number FR3099339(B1) in which Mathilde Chataigner is cited as an inventor; Camile Mougin was recruited for this specific research program by NutriNeuro. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Mougin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aging, an inevitable physiological process leading to a progressive decline in bodily functions, has been an abundantly researched domain with studies attempting to slow it down and reduce its debilitating effects. Investigations into the cellular and molecular pathways associated with aging have allowed the formulation of therapeutic strategies. Of these, caloric restriction (CR) has been implicated for its role in promoting healthy aging by modulating key molecular targets like Insulin/IGF-1, mTOR, and sirtuins. However, CR requires dedication and commitment to a strict regimen which poses a difficulty in maintaining consistency. To maneuver around cumbersome diets, Caloric Restriction Mimetics (CRMs) have emerged as promising alternatives by mimicking the beneficial effects of CR. This review elucidates the molecular foundations enabling CRMs like rapamycin, metformin, resveratrol, spermidine, and many more to function as suitable anti-aging molecules. Moreover, it explores clinical trials (retrieved from the clinicaltrials.gov database) aimed at demonstrating the efficacy of CRMs as effective candidates against age-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease., (© 2024. The Author(s).)

Researchers implementing non-invasive neuroimaging have reported distinct load-dependent brain activity patterns in older adults compared with younger adults. Although findings are mixed, these age-related patterns are often associated with compensatory mechanisms of cognitive decline even in the absence of direct comparisons between brain activity and cognitive performance. This study investigated the effects of cognitive load on brain-behavior relationships in younger and older adults using a data-driven, multivariate partial least squares (PLS) analysis of functional near-infrared spectroscopy (fNIRS) data. We measured bilateral prefrontal brain activity in 31 older and 27 younger adults while they performed single and dual 2-back tasks. Behavioral PLS analysis was used to determine relationships between performance metrics (reaction time and error rate) and brain oxygenation (HbO) and deoxygenation (HbR) patterns across groups and task loads. Results revealed significant age-group differences in brain-behavior relationships. In younger adults, increased brain activity (i.e., increased HbO and decreased HbR) was associated with faster reaction times and better accuracy in the single task, indicating sufficient neural capacity. Conversely, older adults showed a negative correlation between HbR and error rates in the single task; however, in the dual task, they demonstrated a positive relationship between HbO and performance, indicative of compensatory mechanisms under the higher cognitive load. Overall, older adults' showed relationships with either HbR or HbO, but not both, indicating that the robustness of the relationship between brain activity and behavior varies across task load conditions. Our PLS approach revealed distinct load-dependent brain activity between age groups, providing further insight into neurocognitive aging patterns, such as compensatory mechanisms, by emphasizing the variability and complexity of brain-behavior relationships. Our findings also highlight the importance of considering task complexity and cognitive demands in interpreting age-related brain activity patterns., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gonzalez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

One key limitation in developing effective treatments for neurodegenerative diseases is the lack of models accurately mimicking the complex physiopathology of the human disease. Humans accumulate with age the pigment neuromelanin inside neurons that synthesize catecholamines. Neurons reaching the highest neuromelanin levels preferentially degenerate in Parkinson's, Alzheimer's and apparently healthy aging individuals. However, this brain pigment is not taken into consideration in current animal models because common laboratory species, such as rodents, do not produce neuromelanin. Here we generate a tissue-specific transgenic mouse, termed tgNM, that mimics the human age-dependent brain-wide distribution of neuromelanin within catecholaminergic regions, based on the constitutive catecholamine-specific expression of human melanin-producing enzyme tyrosinase. We show that, in parallel to progressive human-like neuromelanin pigmentation, these animals display age-related neuronal dysfunction and degeneration affecting numerous brain circuits and body tissues, linked to motor and non-motor deficits, reminiscent of early neurodegenerative stages. This model could help explore new research avenues in brain aging and neurodegeneration., (© 2024. The Author(s).)

Exogenous gaseous formaldehyde (FA) is recognized as a significant indoor air pollutant due to its chemical reactivity and documented mutagenic and carcinogenic properties, particularly in its capacity to damage DNA and impact human health. Despite increasing attention on the adverse effects of exogenous FA on human health, the potential detrimental effects of endogenous FA in the brain have been largely neglected in current research. Endogenous FA have been observed to accumulate in the aging brain due to dysregulation in the expression and activity of enzymes involved in FA metabolism. Surprisingly, excessive FA have been implicated in the development of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and brain cancers. Notably, FA has the ability to not only initiate DNA double strand breaks but also induce the formation of crosslinks of DNA-DNA, DNA-RNA, and DNA-protein, which further exacerbate the progression of these brain diseases. However, recent research has identified that FA-resistant gene exonuclease-1 (EXO1) and FA scavengers can potentially mitigate FA toxicity, offering a promising strategy for mitigating or repairing FA-induced DNA damage. The present review offers novel insights into the impact of FA metabolism on brain ageing and the contribution of FA-damaged DNA to the progression of neurological disorders., (© 2024. The Author(s).)

Background: Microglia (MG) are myeloid cells of the central nervous system that support homeostasis and instigate neuroinflammation in pathologies. Single-cell RNA sequencing (scRNA-seq) revealed the functional heterogeneity of MG in mouse brains. Microglia are self-renewing cells and inhibition of colony-stimulating factor 1 receptor (CSF1R) signaling depletes microglia which rapidly repopulate. The functions of repopulated microglia are poorly known., Methods: We combined scRNA-seq, bulk RNA-seq, immunofluorescence, and confocal imaging to study the functionalities and morphology of repopulated microglia., Results: A CSRF1R inhibitor (BLZ-945) depleted microglia within 21 days and a number of microglia was fully restored within 7 days, as confirmed by TMEM119 staining and flow cytometry. ScRNA-seq and computational analyses demonstrate that repopulated microglia originated from preexisting progenitors and reconstituted functional clusters but upregulated inflammatory genes. Percentages of proliferating, immature microglia displaying inflammatory gene expression increased in aging mice. Morphometric analysis of MG cell body and branching revealed a distinct morphology of repopulated MG, particularly in brains of old mice. We demonstrate that with aging some repopulated MG fail to reach the homeostatic phenotype. These differences may contribute to the deterioration of MG protective functions with age., (© 2024. The Author(s).)

Using Phosphorus Magnetic Resonance Spectroscopy ( 31 P MRS), we examined five metabolites associated with brain energy cycle, and cellular membrane production and degradation in 11 brain regions of 48 children (age 6-15), and 80 middle-aged and older adults (age 52-87). Levels of phosphomonoesters (PMEs) and phosphodiesters (PDEs), gamma plus alpha adenosine triphosphate (γαATP), phosphocreatine (PCr) and inorganic phosphate (Pi), were residualized on the total amplitude value. PMEs were greater in children compared to adults, whereas PDEs showed the opposite age difference. Higher γαATP and lower Pi were found in children compared to adults. The age group differences were particularly salient in the association cortices and anterior white matter. Among children, age correlated negatively with PMEs and positively with PDEs in association cortices. Compared to children, adults had lower intracellular pH. The results suggest reduction in membrane synthesis and increase in membrane degradation in adolescents and to a greater degree in adults compared to younger children. Concomitant reduction in γαATP and increase in Pi are consistent with reduced energy consumption in adolescents and further drop in middle-aged and older adults, although it is impossible to distinguish declines in energy supply from reduced demand due to shrinking neuropil, without longitudinal studies., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Aging involves seemingly paradoxical changes in energy metabolism. Molecular damage accumulation increases cellular energy expenditure, yet whole-body energy expenditure remains stable or decreases with age. We resolve this apparent contradiction by positioning the brain as the mediator and broker in the organismal energy economy. As somatic tissues accumulate damage over time, costly intracellular stress responses are activated, causing aging or senescent cells to secrete cytokines that convey increased cellular energy demand (hypermetabolism) to the brain. To conserve energy in the face of a shrinking energy budget, the brain deploys energy conservation responses, which suppress low-priority processes, producing fatigue, physical inactivity, blunted sensory capacities, immune alterations and endocrine 'deficits'. We term this cascade the brain-body energy conservation (BEC) model of aging. The BEC outlines (1) the energetic cost of cellular aging, (2) how brain perception of senescence-associated hypermetabolism may drive the phenotypic manifestations of aging and (3) energetic principles underlying the modifiability of aging trajectories by stressors and geroscience interventions., (© 2024. Springer Nature America, Inc.)

Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence to proliferation in the adult mammalian brain. Functional decline of NSCs results in the decreased production of new neurons and defective regeneration following injury during ageing 1-4 . Several genetic interventions have been found to ameliorate old brain function 5-8 , but systematic functional testing of genes in old NSCs-and more generally in old cells-has not been done. Here we develop in vitro and in vivo high-throughput CRISPR-Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice. Our genome-wide screens in primary cultures of young and old NSCs uncovered more than 300 gene knockouts that specifically restore the activation of old NSCs. The top gene knockouts are involved in cilium organization and glucose import. We also establish a scalable CRISPR-Cas9 screening platform in vivo, which identified 24 gene knockouts that boost NSC activation and the production of new neurons in old brains. Notably, the knockout of Slc2a4, which encodes the GLUT4 glucose transporter, is a top intervention that improves the function of old NSCs. Glucose uptake increases in NSCs during ageing, and transient glucose starvation restores the ability of old NSCs to activate. Thus, an increase in glucose uptake may contribute to the decline in NSC activation with age. Our work provides scalable platforms to systematically identify genetic interventions that boost the function of old NSCs, including in vivo, with important implications for countering regenerative decline during ageing., (© 2024. The Author(s).)

This study aims to compare the efficacy of 5-alpha-reductase inhibitors (5ARIs) on anxiety and depression between long-term and short-term treatment followed by withdrawal in d-galactose (Dgal)-induced senescent male rats. Thirty-two, 8-week-old, male Wistar rats were divided into two groups: control rats and Dgal-treated rats (150 mg/kg/day; subcutaneously) for 18 weeks. At week 13, Dgal-treated rats were subdivided into three subgroups: (1) vehicle (DgV), (2) long-term treatment with 5ARIs, Finasteride 5 mg/kg/day, per oral for 6 weeks (DgF), (3) short-term treatment with 5ARIs, Finasteride 5 mg/kg/day, per oral for 2 weeks followed by a 4-week withdrawal period (DgW). Anxiety and depression were assessed using the elevated-plus maze (EPM) and splash test (ST). Blood was collected for biochemical analysis. After euthanasia, the brains were removed to examine brain inflammation, oxidative stress, neuroactive steroids, brain metabolites, and brain senescent markers. We found that DgV rats exhibited metabolic disturbance with a reduced preference index of the EPM, and grooming duration in ST. Increased brain neurotoxic metabolites, along with increased brain inflammation/oxidative stress, and reduced microglia complexity were observed in the DgV rats. Both therapeutic approaches improved metabolic parameters and preference index in the open arm of EPM in Dgal-treated rats, while grooming duration and microglia complexity were increased only in DgF rats. Our results indicate that Fin reduces depression-like and anxiety-like behaviors by reducing brain inflammation, oxidative stress, and brain senescent. In conclusion, long-term treatment with 5ARIs is more effective in alleviating depression than short-term treatment followed by withdrawal in Dgal-induced early senescent male rats., (© 2024 Wiley Periodicals LLC.)

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.)

Luteolin is an essential natural polyphenol found in a variety of plants. Numerous studies have supported its protective role in neurodegenerative diseases, yet the research for its therapeutic utility in D-galactose (D-gal)-induced brain ageing is still lacking. In this study, the potential neuroprotective impact of luteolin against D-gal-induced brain ageing was explored. Forty rats were randomly divided into four groups: control, luteolin, D-gal, and luteolin-administered D-gal groups. All groups were subjected to behavioural, cholinergic function, and hippocampal mitochondrial respiration assessments. Hippocampal oxidative, neuro-inflammatory, senescence and apoptotic indicators were detected. Gene expressions of SIRT1, BDNF, and RAGE were assessed. Hippocampal histopathological studies, along with GFAP and Ki67 immunoreactivity, were performed. Our results demonstrated that luteolin effectively alleviated D-gal-induced cognitive impairment and reversed cholinergic abnormalities. Furthermore, luteolin administration substantially mitigated hippocampus oxidative stress, mitochondrial dysfunction, neuro-inflammation, and senescence triggered by D-gal. Additionally, luteolin treatment considerably attenuated neuronal apoptosis and upregulated hippocampal SIRT1 mRNA expression. In conclusion, our findings revealed that luteolin administration attenuated D-gal-evoked brain senescence, improving mitochondrial function and enhancing hippocampal neuroregeneration in an ageing rat model through its antioxidant, senolytic, anti-inflammatory, and anti-apoptotic impacts, possibly due to upregulation of SIRT1. Luteolin could be a promising therapeutic modality for brain aging-associated abnormalities., (© 2024. The Author(s).)

Iron deposition and myelin loss are observed in the brain with aging, and iron accumulation is suggested to be involved in myelin damage. However, the exact mechanism of iron deposition with aging remains unclear. This study was aimed to determine whether expanded visceral adipose tissue contributes to iron deposition and myelin loss by inducing hepcidin in the brains of aged male mice. Compared with young adult mice, levels of hepcidin in the brain, epididymal adipose tissue, and circulation were increased in aged mice, which had expanded visceral adipose tissue with inflammation. An increase in expressions of ferritin, an indicator of intracellular iron status, was accompanied by decreased levels of proteins related to myelin sheath in the brains of aged mice. These age-related changes in the brain were improved by visceral fat removal. In addition, IL-6 level, activation of microglia/macrophages, and nuclear translocation of phosphorylated Smad1/5 (pSmad1/5) inducing hepcidin expression were reduced in the brains of aged mice after visceral fat removal, accompanied by decreases of pSmad1/5- and ferritin-positive microglia/macrophages and mature oligodendrocytes. These findings indicate that visceral adiposity contributes to hepcidin-mediated iron deposition and myelin loss with inflammation in the aged brain. Our results support the importance of preventing visceral adiposity for maintaining brain health in older individuals., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Emerging evidence shows that disrupted gut microbiota-bile acid (BA) axis is critically involved in the development of neurodegenerative diseases. However, the alterations in spatial distribution of BAs among different brain regions that command important functions during aging and their exact roles in aging-related neurodegenerative diseases are poorly understood. Here, we analyzed the BA profiles in cerebral cortex, hippocampus, and hypothalamus of young and natural aging mice of both sexes. The results showed that aging altered brain BA profiles sex- and region- dependently, in which TβMCA was consistently elevated in aging mice of both sexes, particularly in the hippocampus and hypothalamus. Furthermore, we found that aging accumulated-TβMCA stimulated microglia inflammation in vitro and shortened the lifespan of C. elegans, as well as behavioral impairment and neuroinflammation in mice. In addition, metagenomic analysis suggested that the accumulation of brain TβMCA during aging was partially attributed to reduction in BSH-carrying bacteria. Finally, rejuvenation of gut microbiota by co-housing aged mice with young mice restored brain BA homeostasis and improved neurological dysfunctions in natural aging mice. In conclusion, our current study highlighted the potential of improving aging-related neuro-impairment by targeting gut microbiota-brain BA axis., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The debate surrounding nature versus nurture remains a central question in neuroscience, psychology, and in psychiatry, holding implications for both aging processes and the etiology of mental illness. Epigenetics can serve as a bridge between genetic predisposition and environmental influences, thus offering a potential avenue for addressing these questions. Epigenetic clocks, in particular, offer a theoretical framework for measuring biological age based on DNA methylation signatures, enabling the identification of disparities between biological and chronological age. This structured review seeks to consolidate current knowledge regarding the relationship between mental disorders and epigenetic age within the brain. Through a comprehensive literature search encompassing databases such as EBSCO, PubMed, and ClinicalTrials.gov, relevant studies were identified and analyzed. Studies that met inclusion criteria were scrutinized, focusing on those with large sample sizes, analyses of both brain tissue and blood samples, investigation of frontal cortex markers, and a specific emphasis on schizophrenia and depressive disorders. Our review revealed a paucity of significant findings, yet notable insights emerged from studies meeting specific criteria. Studies characterized by extensive sample sizes, analysis of brain tissue and blood samples, assessment of frontal cortex markers, and a focus on schizophrenia and depressive disorders yielded particularly noteworthy results. Despite the limited number of significant findings, these studies shed light on the complex interplay between epigenetic aging and mental illness. While the current body of literature on epigenetic aging in mental disorders presents limited significant findings, it underscores the importance of further research in this area. Future studies should prioritize large sample sizes, comprehensive analyses of brain tissue and blood samples, exploration of specific brain regions such as the frontal cortex, and a focus on key mental disorders. Such endeavors will contribute to a deeper understanding of the relationship between epigenetic aging and mental illness, potentially informing novel diagnostic and therapeutic approaches., (© 2024. The Author(s).)

Introduction: Abdominal adipose tissue (AT) mass has adverse effects on the brain. This study aimed to investigate the effect of glucose uptake by abdominal AT on brain aging., Methods: Three-hundred twenty-five participants underwent total-body positron emission tomography scan. Brain age was estimated in an independent test set (n = 98) using a support vector regression model that was built using a training set (n = 227). Effects of abdominal subcutaneous and visceral AT (SAT/VAT) glucose uptake on brain age delta were evaluated using linear regression., Results: Higher VAT glucose uptake was linked to negative brain age delta across all subgroups. Higher SAT glucose uptake was associated with negative brain age delta in lean individuals. In contrast, increased SAT glucose uptake demonstrated positive trends with brain age delta in female and overweight/obese participants., Discussion: Increased glucose uptake of the abdominal VAT has positive influences on the brain, while SAT may not have such influences, except for lean individuals., Highlights: Higher glucose uptake of the visceral adipose tissue was linked to decelerated brain aging. Higher glucose uptake of the subcutaneous adipose tissue (SAT) was associated with negative brain age delta in lean individuals. Faster brain aging was associated with increased glucose uptake of the SAT in female and overweight and obese individuals., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Neurodegenerative disorders, including Dementia, Parkinson's disease, various Vision disorders, Multiple sclerosis, and transsynaptic degenerative changes represent a significant challenge in aging populations. This editorial synthesizes and discusses recent advancements in understanding the genetic and environmental factors contributing to these diseases. Central to these advancements is the role of neuroinflammation and oxidative stress, which exacerbate neuronal damage and accelerate disease progression. Emerging research underscores the significance of mitochondrial dysfunction and protein aggregation in neurodegenerative pathology, highlighting shared mechanisms across various disorders. Innovative therapeutic strategies, including gene therapy, CRISPR-Cas technology, and the use of naturally occurring antioxidant molecules, are being investigated to target and manage these conditions. Additionally, lifestyle interventions such as exercise and healthy diet have shown promise in enhancing brain plasticity and reducing neuroinflammation. Advances in neuroimaging and biomarker discovery are necessary to improve early diagnosis, while clinical and preclinical studies are essential for the translation of these novel treatments. This edition aims to bridge the gap between molecular mechanisms and therapeutic applications, offering insights into potential interventions to mitigate the impact of neurodegenerative diseases. By establishing a deeper understanding of these complex processes, we aim to move closer to effective prevention and treatment strategies, ultimately improving the quality of life for those affected by neurodegenerative disorders.

Low aerobic capacity is strongly associated with all-cause mortality and risk for Alzheimer's disease (AD). Individuals with early dementia and AD have lower aerobic capacity compared to age-matched controls. The mechanism by which aerobic capacity influences AD risk is unknown but is likely mediated by sexual dimorphism and tissue-level differences in mitochondrial energetics. Here, we used rats selectively bred for large differences in intrinsic aerobic exercise capacity. Brain tissue from 18-month and 24-month-old female and male low-capacity runner (LCR) and high-capacity runner (HCR) rats were analyzed for markers of mitochondrial function and AD-associated pathologies. LCR rats, irrespective of sex, exhibited a greater increase in brain amyloid beta (Aβ 42 ) and tau hyperphosphorylation (pTau thr181 /total tau) with aging. In female LCR rats, brain mitochondrial respiration at states 3, 4, and FCCP-induced uncoupling, when stimulated with pyruvate/malate, was reduced at 18 and 24 months, leading to lower ATP-linked mitochondrial respiration compared to mitochondria from HCR rats. Male LCR rats also showed reduced complex II-stimulated mitochondrial respiration (succinate + rotenone) at 24 months compared to HCR rats. Differences in mitochondrial respiration were associated with tau hyperphosphorylation and Aβ42 alterations in both HCR and LCR strains. Proteomic analysis unveiled a distinct difference in the mitochondrial proteome, wherein female LCR rats displayed diminished mitochondrial translation and oxidative phosphorylation (OXPHOS) proteins at 18 months compared to female HCR rats. Conversely, male LCR rats exhibited increased OXPHOS protein abundance but reduced tricarboxylic acid (TCA) cycle proteins compared to male HCR rats. These findings underscore a robust association between intrinsic aerobic exercise capacity, brain mitochondrial function, and AD pathologies during aging., (© 2024. The Author(s).)

To better assess the pathology of neurodegenerative disorders and the efficacy of neuroprotective interventions, it is necessary to develop biomarkers that can accurately capture age-related biological changes in the human brain. Brain serotonin 2A receptors (5-HT2AR) show a particularly profound age-related decline and are also reduced in neurodegenerative disorders, such as Alzheimer's disease. This study investigates whether the decline in 5-HT2AR binding, measured in vivo using positron emission tomography (PET), can be used as a biomarker for brain aging. Specifically, we aim to (1) predict brain age using 5-HT2AR binding outcomes, (2) compare 5-HT2AR-based predictions of brain age to predictions based on gray matter (GM) volume, as determined with structural magnetic resonance imaging (MRI), and (3) investigate whether combining 5-HT2AR and GM volume data improves prediction. We used PET and MR images from 209 healthy individuals aged between 18 and 85 years (mean = 38, std = 18) and estimated 5-HT2AR binding and GM volume for 14 cortical and subcortical regions. Different machine learning algorithms were applied to predict chronological age based on 5-HT2AR binding, GM volume, and the combined measures. The mean absolute error (MAE) and a cross-validation approach were used for evaluation and model comparison. We find that both the cerebral 5-HT2AR binding (mean MAE = 6.63 years, std = 0.74 years) and GM volume (mean MAE = 6.95 years, std = 0.83 years) predict chronological age accurately. Combining the two measures improves the prediction further (mean MAE = 5.54 years, std = 0.68). In conclusion, 5-HT2AR binding measured using PET might be useful for improving the quantification of a biomarker for brain aging., (© 2024. The Author(s).)

Progress made by the medical community in increasing lifespans comes with the costs of increasing the incidence and prevalence of age-related diseases, neurodegenerative ones included. Aging is associated with a series of morphological changes at the tissue and cellular levels in the brain, as well as impairments in signaling pathways and gene transcription, which lead to synaptic dysfunction and cognitive decline. Although we are not able to pinpoint the exact differences between healthy aging and neurodegeneration, research increasingly highlights the involvement of neuroinflammation and chronic systemic inflammation (inflammaging) in the development of age-associated impairments via a series of pathogenic cascades, triggered by dysfunctions of the circadian clock, gut dysbiosis, immunosenescence, or impaired cholinergic signaling. In addition, gender differences in the susceptibility and course of neurodegeneration that appear to be mediated by glial cells emphasize the need for future research in this area and an individualized therapeutic approach. Although rejuvenation research is still in its very early infancy, accumulated knowledge on the various signaling pathways involved in promoting cellular senescence opens the perspective of interfering with these pathways and preventing or delaying senescence.

Normal aging, though lacking widespread neurodegeneration, is nevertheless characterized by cognitive impairment in learning, memory, and executive function. The aged brain is spared from neuron loss, but white matter is lost and damage to myelin sheaths accumulates. This myelin damage is strongly associated with cognitive impairment. Although the cause of the myelin damage is not known, microglia dysregulation is a likely contributor. Immunologic proteins interact with microglial receptors to modulate microglia-mediated phagocytosis, which mediates myelin damage clearance and turn-over. Two such proteins, "eat me" signal C1q and "don't eat me" signal CD47, act in opposition with microglia. Both C1q and CD47 have been implicated in Multiple Sclerosis, a demyelinating disease, but whether they play a role in age-related myelin pathology is currently unknown. The present study investigates C1q and CD47 in relation to age-related myelin degeneration using multilabel immunofluorescence, RNAscope, and confocal microscopy in the cingulum bundle of male and female rhesus monkeys across the lifespan. Our findings showed significant age-related elevation in C1q localized to myelin basic protein, and this increase is associated with more severe cognitive impairment. In contrast, CD47 localization to myelin decreased in middle age and oligodendrocyte expression of CD47 RNA decreased with age. Lastly, microglia reactivity increased with age in association with the changes in C1q and CD47. Together, these results suggest disruption in the balance of "eat me" and "don't eat me" signals during normal aging, biasing microglia toward increased reactivity and phagocytosis of myelin, resulting in cognitive deficits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 DeVries, Dimovasili, Medalla, Moore and Rosene.)

Background and Objectives: The aging population is growing faster than all other demographic strata. With older age comes a greater risk of health conditions such as obesity and high blood pressure (BP). These cardiometabolic risk factors (CMRs) exhibit prominent sex differences in midlife and aging, yet their influence on brain health in females vs males is largely unexplored. In this study, we investigated sex differences in relationships between BP, body mass index (BMI), and brain age over time and tested for interactions with APOE ε4 genotype ( APOE4 ), a known genetic risk factor of Alzheimer disease., Methods: The sample included participants from 2 United Kingdom-based longitudinal birth cohorts, the Lothian Birth Cohort (1936) and Insight 46 (1946). Participants with MRI data from at least 1 time point were included to evaluate sex differences in associations between CMRs and brain age. The open-access software package brainageR 2.1 was used to estimate brain age for each participant. Linear mixed-effects models were used to assess the relationships between brain age, BMI, BP, and APOE4 status (i.e., carrier vs noncarrier) in males and females over time., Results: The combined sample comprised 1,120 participants (48% female) with a mean age (SD) of 73 (0.72) years in the Lothian Birth Cohort and 71 (0.68) years in Insight 46 at the time point 1 assessment. Approximately 30% of participants were APOE4 carriers. Higher systolic and diastolic BP was significantly associated with older brain age in females only (β = 0.43-0.56, p < 0.05). Among males, higher BMI was associated with older brain age across time points and APOE4 groups (β = 0.72-0.77, p < 0.05). In females, higher BMI was linked to older brain age among APOE4 noncarriers (β = 0.68-0.99, p < 0.05), whereas higher BMI was linked to younger brain age among carriers, particularly at the last time point (β = -1.75, p < 0.05)., Discussion: This study indicates sex-dependent and time-dependent relationships between CMRs, APOE4 status, and brain age. Our findings highlight the necessity of sex-stratified analyses to elucidate the role of CMRs in individual aging trajectories, providing a basis for developing personalized preventive interventions.

Sodium serves as one of the primary cations in the central nervous system, playing a crucial role in maintaining normal brain function. In this study, we investigated alterations in sodium concentrations in the brain and/or cerebrospinal fluid across multiple models, including an aging model, a stroke model, a nitroglycerin (NTG)-induced rat migraine model, a familial hemiplegic migraine type 2 (FHM2) mouse model, and a transgenic mouse model of Alzheimer's disease (AD). Our results reveal that older rats exhibited higher sodium concentrations in cerebrospinal fluid (CSF), plasma, and various brain regions compared to their younger counterparts. Additionally, findings from the stroke model demonstrated a significant increase in sodium in the ischemic/reperfused region, accompanied by a decrease in potassium and an elevated sodium/potassium ratio. However, we did not detect significant changes in sodium in the NTG-induced rat migraine model or the FHM2 mouse model. Furthermore, AD transgenic mice showed no significant differences in sodium levels compared to wild-type mice in CSF, plasma, or the hippocampus. These results underscore the nuanced regulation of sodium homeostasis in various neurological conditions and aging, providing valuable insights into potential mechanisms underlying these alterations., (© 2024. The Author(s).)

Cell type-specific gene signatures in an aged brain imply biological links to age-related disorders.

Cognitive flexibility represents the capacity to switch among different mental schemes, providing an adaptive advantage to a changing environment. The neural underpinnings of this executive function have been deeply studied in humans through fMRI, showing that the left inferior frontal cortex (IFC) and the left inferior parietal lobule (IPL) are crucial. Here, we investigated the inhibitory-excitatory balance in these regions by means of γ-aminobutyric acid (GABA+) and glutamate + glutamine (Glx), measured with magnetic resonance spectroscopy, during a cognitive flexibility task and its relationship with the performance level and the local task-induced blood oxygenation level-dependent (BOLD) response in 40 young (18-35 years; 26 female) and 40 older (18-35 years; 21 female) human adults. As the IFC and the IPL are richly connected regions, we also examined whole-brain effects associated with their local metabolic activity. Results did not show absolute metabolic modulations associated with flexibility performance, but the performance level was related to the direction of metabolic modulation in the IPL with opposite patterns in young and older individuals. The individual inhibitory-excitatory balance modulation showed an inverse relationship with the local BOLD response in the IPL. Finally, the modulation of inhibitory-excitatory balance in IPL was related to whole-brain effects only in older individuals. These findings show disparities in the metabolic mechanisms underlying cognitive flexibility in young and older adults and their association with the performance level and BOLD response. Such metabolic differences are likely to play a role in executive functioning during aging and specifically in cognitive flexibility., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Effective cognitive performance often requires the allocation of additional neural resources (i.e. blood-oxygen-level-dependent [BOLD] activation) as task demands increase, and this demand-related modulation is affected by amyloid-beta deposition and normal aging. The present study investigated these complex relationships between amyloid, modulation, and cognitive function (i.e. fluid ability). Participants from the Dallas Lifespan Brain Study (DLBS, n = 252, ages 50-89) completed a semantic judgment task during functional magnetic resonance imaging (fMRI) where the judgments differed in classification difficulty. Amyloid burden was assessed via positron emission tomography (PET) using 18F-florbetapir. A quadratic relationship between amyloid standardized value uptake ratios (SUVRs) and BOLD modulation was observed such that modulation was weaker in those with moderately elevated SUVRs (e.g. just reaching amyloid-positivity), whereas those with very high SUVRs (e.g. SUVR > 1.5) showed strong modulation. Greater modulation was related to better fluid ability, and this relationship was strongest in younger participants and those with lower amyloid burden. These results support the theory that effective demand-related modulation contributes to healthy cognitive aging, especially in the transition from middle age to older adulthood, whereas high modulation may be dysfunctional in those with substantial amyloid deposition., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Glucose-dependent insulinotropic polypeptide (GIP), a 42-aminoacid hormone, exerts multifaceted effects in physiology, most notably in metabolism, obesity, and inflammation. Its significance extends to neuroprotection, promoting neuronal proliferation, maintaining physiological homeostasis, and inhibiting cell death, all of which play a crucial role in the context of neurodegenerative diseases. Through intricate signaling pathways involving its cognate receptor (GIPR), a member of the G protein-coupled receptors, GIP maintains cellular homeostasis and regulates a defense system against ferroptosis, an essential process in aging. Our study, utilizing GIP-overexpressing mice and in vitro cell model, elucidates the pivotal role of GIP in preserving neuronal integrity and combating age-related damage, primarily through the Epac/Rap1 pathway. These findings shed light on the potential of GIP as a therapeutic target for the pathogenesis of ferroptosis in neurodegenerative diseases and aging. [BMB Reports 2024; 57(9): 417-423].

Aging is characterized by the decline in many of the individual's capabilities. It has been recognized that the brain undergoes structural and functional changes during aging that are occasionally associated with the development of neurodegenerative diseases. In this sense, altered glutamatergic neurotransmission, which involves the release, binding, reuptake, and degradation of glutamate (Glu) in the brain, has been widely studied in physiological and pathophysiological aging. In particular, changes in glutamatergic neurotransmission are exacerbated during neurodegenerative diseases and are associated with cognitive impairment, characterized by difficulties in memory, learning, concentration, and decision-making. Thus, in the present manuscript, we aim to highlight the relevance of glutamatergic neurotransmission during cognitive impairment to develop novel strategies to prevent, ameliorate, or delay cognitive decline. To achieve this goal, we provide a comprehensive review of the changes reported in glutamatergic neurotransmission components, such as Glu transporters and receptors during physiological aging and in the most studied neurodegenerative diseases. Finally, we describe the current therapeutic strategies developed to target glutamatergic neurotransmission., (Copyright © 2024. Published by Elsevier Inc.)

BBB dysfunction during aging is characterized by an increase in its permeability and phenotypic alterations of brain endothelial cells (BECs) including dysregulation of tight junction's expression. Here we have investigated the role of BEC senescence in the dysfunction of the BBB. Our results suggest that the transition from young to aged BBB is mediated, at least in part by BEC senescence., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The natural aging process is accompanied by changes in exosomes, gut microbiota, and metabolites. This study aimed to reveal the anti-aging effect and mechanisms of fecal microbiota transplantation (FMT) from young donors on the natural aging process in mice by analyzing exosomes, gut microbiota, and metabolomics. Aging-relevant telomeric length, oxidative stress indexes in brain tissue, and serum cytokine levels were measured. Flow analysis of T-regulatory (Treg), CD4 + , and CD8 + cells was performed, and the expression levels of aging-related proteins were quantified. High-throughput sequencing technology was used to identify differentially expressed serum exosomal miRNAs. Fecal microbiota was tested by 16 S rDNA sequencing. Changes in fecal metabolites were analyzed by UPLC-Q-TOF/MS. The results indicated that the expression of mmu-miR-7010-5p, mmu-miR-376b-5p, mmu-miR-135a-5p, and mmu-miR-3100-5p by serum exosomes was down-regulated and the abundance of opportunistic bacteria (Turicibacter, Allobaculum, Morganella.) was decreased, whereas the levels of protective bacteria (Akkermansia, Muribaculaceae, Helicobacter.) were increased after FMT. Metabolic analysis identified 25 potential biomarkers. Correlation analysis between the gut microbiota and metabolites suggested that the relative abundance of protective bacteria was positively correlated with the levels of spermidine and S-adenosylmethionine. The study indicated that FMT corrected brain injury due to aging via lipid metabolism, the metabolism of cofactors and vitamins, and amino acid metabolism., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest or competing interest exists., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A central hallmark of neurodegenerative diseases is the irreversible accumulation of misfolded proteins in the brain by aberrant phosphorylation. Understanding the mechanisms underlying protein phosphorylation and its role in pathological protein aggregation within the context of aging is crucial for developing therapeutic strategies aimed at preventing or reversing such diseases. Here, we applied multi-protease digestion and quantitative mass spectrometry to compare and characterize dysregulated proteins and phosphosites in the mouse brain proteome using three different age groups: young-adult (3-4 months), middle-age (10 months), and old mice (19-21 months). Proteins associated with senescence, neurodegeneration, inflammation, cell cycle regulation, the p53 hallmark pathway, and cytokine signaling showed significant age-dependent changes in abundances and level of phosphorylation. Several proteins implicated in Alzheimer's disease (AD) and Parkinson's disease (PD) including tau (Mapt), Nefh, and Dpysl2 (also known as Crmp2) were hyperphosphorylated in old mice brain suggesting their susceptibility to the diseases. Cdk5 and Gsk3b, which are known to phosphorylate Dpysl2 at multiple specific sites, had also increased phosphorylation levels in old mice suggesting a potential crosstalk between them to contribute to AD. Hapln2, which promotes α-synuclein aggregation in patients with PD, was one of the proteins with highest abundance in old mice. CD9, which regulates senescence through the PI3K-AKT-mTOR-p53 signaling was upregulated in old mice and its regulation was correlated with the activation of phosphorylated AKT1. Overall, the findings identify a significant association between aging and the dysregulation of proteins involved in various pathways linked to neurodegenerative diseases with potential therapeutic implications., Competing Interests: Conflict of interest The authors declare no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Calorie restriction (CR) is a robust intervention that can slow biological aging and extend lifespan. In the brain, terminally differentiated neurons and glia accumulate oxidative damage with age, reducing their optimal function. We investigated if CR could reduce oxidative DNA damage to white matter oligodendrocytes and microglia. This study utilized post-mortem brain tissue from rhesus monkeys that died after decades on a 30 % reduced calorie diet. We found that CR subjects had significantly fewer cells with oxidative damage within the corpus callosum and the cingulum bundle. Oligodendrocytes specifically showed the greatest response to CR with a robust reduction in DNA damage. Additionally, we observed alterations in microglia morphology with CR subjects having a higher proportion of ramified, homeostatic microglia and fewer pro-inflammatory, hypertrophic microglia relative to controls. Furthermore, we determined that the observed attenuation in damaged DNA occurs primarily within mitochondria. Overall, these data suggest that long-term CR can reduce oxidative DNA damage and offer a neuroprotective effect in a cell-type-specific manner in the aging monkey brain., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aging is one of the main risk factors for neurodegenerative disorders, which represent a global burden on healthcare systems. Therefore, identifying new strategies to slow the progression of brain aging is a compelling challenge. In this article, we first assessed the potential anti-aging effects of the Citrus flavanone naringenin (NAR), an activator of the enzyme sirtuin-1 (SIRT1), in a 3R-compliant and short-lived aging model (i.e., the nematode C. elegans). Then, we investigated the preventive effects of a 6-month treatment with NAR (100 mg/kg, orally) against brain aging and studied its mechanism of action in middle-aged mice. We demonstrated that NAR (100 μM) extends lifespan and improves healthspan in C. elegans. In the brain of middle-aged mice, NAR promotes the activity of metabolic enzymes (citrate synthase, cytochrome C oxidase) and increases the expression of the SIRT1 enzyme. Consistently, NAR up-regulates the expression of downstream antioxidant (Foxo3, Nrf2, Ho-1), anti-senescence (p16), and anti-inflammatory (Il-6, Il-18) markers. Our findings support NAR supplementation to slow the signs of brain aging., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aging is a multifactorial process occurring in a pathophysiological continuum which leads to organ and system functional loss. While aging is not a disease, its pathophysiological continuum predisposes to illness and multimorbidity clusters which share common biomolecular mechanisms-the pillars of aging. Brain aging and neurodegeneration share many hallmarks with other age-related diseases. The central nervous system is often the weakest link susceptible to the aging process and its deterioration, resulting in cognitive impairment and other symptoms; the aging process is associated with proteostasis collapse, stem cell exhaustion, repair mechanisms, altered brain nutrient sensing, endothelial changes, inflammation, oxidative distress, and energy unbalance, as well as other disturbances. These mechanisms are highly interwoven, and considerable research is aimed at their disentanglement and detection of their clinically relevant impact, particularly in order to identify pharmacological and non-pharmacological preventive and therapeutic strategies., (© 2024 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

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).)