The complex morphological, anatomical, physiological, and chemical mechanisms within the aging brain have been the hot topic of research for centuries. The aging process alters the brain structure that affects functions and cognitions, but the worsening of such processes contributes to the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease. Beyond these observable, mild morphological shifts, significant functional modifications in neurotransmission and neuronal activity critically influence the aging brain. Understanding these changes is important for maintaining cognitive health, especially given the increasing prevalence of age-related conditions that affect cognition. This review aims to explore the age-induced changes in brain plasticity and molecular processes, differentiating normal aging from the pathogenesis of Alzheimer's disease, thereby providing insights into predicting the risk of dementia, particularly Alzheimer's disease.

Postoperative cognitive dysfunction (POCD) is a significant postoperative complication, particularly in the elderly, linked to inflammation-mediated neural dysfunction. Insulin resistance and disruptions in transforming growth factor beta (TGF-β) signalling are associated with cognitive decline in aging, yet their roles in POCD are not fully understood. Here, we demonstrated that both insulin and TGF-β pathways were disrupted in POCD mouse models, with recombinant insulin and TGF-β treatments improving cognitive outcomes. These treatments reversed neuroinflammation in vitro, while CREB knockdown abrogated the protective effects, both in vivo and in vitro. Mechanistically, CREB was found to mediate the protective effects of insulin and TGF-β in POCD by directly regulating the expression of the cognitive-related protein NR2B. Altogether, our study identifies a key molecular target involved in the critical signalling pathways associated with POCD, offering promising therapeutic strategies for prevention and treatment.

The widespread use of single-cell RNA sequencing has generated numerous purportedly distinct and novel subsets of microglia. Here, we challenge this fragmented paradigm by proposing that microglia exist along a continuum rather than as discrete entities. We identify a methodological over-reliance on computational clustering algorithms as the fundamental issue, with arbitrary cluster numbers being interpreted as biological reality. Evidence suggests that the observed transcriptional diversity stems from a combination of microglial plasticity and technical noise, resulting in terminology describing largely overlapping cellular states. We introduce a continuous model of microglial states, where cell positioning along the continuum is determined by biological aging and cell-specific molecular contexts. The model accommodates the dynamic nature of microglia. We advocate for a parsimonious approach toward classification and terminology that acknowledges the continuous spectrum of microglial states, toward a robust framework for understanding these essential immune cells of the CNS.

An in-depth understanding of the molecular processes composing aging is crucial to develop therapeutic approaches that decrease aging as a key risk factor for cognitive decline. Herein, we present a spatio-temporal brain atlas (15 different regions) of microRNA expression across the mouse lifespan (7 time points) and two aging interventions. MicroRNAs are promising therapeutic targets, as they silence genes by complementary base-pair binding of messenger RNAs and mediate aging speed. We first established sex- and brain-region-specific microRNA expression patterns in young adult samples. Then we focused on sex-dependent and independent brain-region-specific microRNA expression changes during aging. We identified three sex-independent brain aging microRNAs (miR-146a-5p, miR-155-5p, and miR-5100). For miR-155-5p, we showed that these expression changes are driven by aging microglia and target mTOR signaling pathway components and other cellular communication pathways. In this work, we identify strong sex-brain-region-specific aging microRNAs and microglial miR-155-5p as a promising therapeutic target.

Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid plaques and neuroinflammation, which collectively result in cognitive decline. Peripheral inflammation, particularly intestinal inflammation, has been implicated in exacerbating AD pathology via the gut-brain axis. This study investigated the effects of dextran sulfate sodium (DSS)-induced colitis on amyloid-beta (Aβ) pathology, synaptic integrity, and cognitive function in 5xFAD mice, and explored the roles of neutrophil elastase (NE) and Cathepsin B in these processes. DSS-induced colitis significantly worsened Aβ pathology, evidenced by increased Aβ plaque deposition and elevated soluble Aβ1-42 levels in the brain of 5xFAD mice. The inflammatory state triggered extensive neutrophil infiltration and elevated NE levels in the hippocampus, which were closely associated with Cathepsin B activation. This enzymatic cascade is associated with synaptic damage and cognitive deficits. Treatment with the NE inhibitor Sivelestat effectively suppressed NE-mediated Cathepsin B activation, reduced Aβ pathology, restored dendritic spine density, and improved cognitive performance. Additionally, the Cathepsin B inhibitor CA-074 methyl ester (CA-074Me) mitigated the adverse effects of DSS-induced colitis, further emphasizing the role of Cathepsin B in mediating inflammation-driven AD pathology. These findings reveal that the NE-Cathepsin B axis links peripheral inflammation to exacerbated Aβ pathology, synaptic damage, and cognitive impairment, underscoring the potential of targeting NE and Cathepsin B as therapeutic strategies for inflammation-driven AD progression.

Blood vessels are critical to deliver oxygen and nutrients to tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier (BBB), which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and protects the neural tissue from toxins and pathogens, and alterations of this barrier are important components of the pathogenesis and progression of various neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the brain endothelial cells (ECs) that form the walls of the blood vessels. These properties are regulated by interactions between different vascular, perivascular, immune, and neural cells. Understanding how these cell populations interact to regulate barrier properties is essential for understanding how the brain functions in both health and disease contexts.

Aging is associated with a gradual decline in cellular function, largely driven by oxidative stress, which leads to cellular senescence. These processes contribute to tissue degeneration and age-related dysfunction. Human dermal fibroblasts (HDFs), critical for maintaining skin structure, are highly vulnerable to oxidative damage, making them key contributors to skin aging. Umbilical cord blood plasma (UCBP), rich in growth factors and regenerative molecules, has shown potential in preventing cellular senescence and addressing key mechanisms of tissue aging. Based on findings from heterochronic parabiosis experiments that demonstrated the rejuvenating effect of young blood, we investigated the effects of UCBP on hydrogen peroxide (H2O2) induced oxidative stress in HDFs and compared its efficacy with adult blood plasma (ABP). Our results indicate that although both UCBP and ABP reduce reactive oxygen species (ROS), UCBP is more effective in suppressing cellular senescence and maintaining fibroblast proliferation. These findings suggest that UCBP's protective effects extend beyond ROS reduction, potentially by modulating the senescence-associated secretory phenotype and the enhancement of tissue repair mechanisms.

Aging-related cognitive decline is closely linked to the reduced function of neural progenitor/stem cells (NPSCs), which can be influenced by the neural microenvironment, particularly astrocytes. The aim of this study was to explore how astrocytes affect NPSCs and cognitive function during aging.

H2O2-treated astrocytes were used to mimic the aging phenotype of astrocytes. Proteomic analysis identified altered protein expression, revealing high levels of colony-stimulating factor-1 (CSF-1) in the supernatant of H2O2-treated astrocytes. Primary NPSCs were isolated and cultured in vitro, then stimulated with varying concentrations of recombinant CSF-1 protein to assess its effects on NPSC proliferation, differentiation, and apoptosis. Transcriptome sequencing identified miR-484 related to CSF-1 in H2O2-treated astrocytes, and a dual-luciferase assay verified the interaction between miR-484 and CSF-1. The impact of miR-484 overexpression on NPSC function and cognitive restoration was evaluated both in vitro and in vivo (in 20-month-old rats).

High concentration of CSF-1 inhibited the NPSC proliferation and differentiation into neurons while inducing apoptosis. Overexpression of miR-484 downregulated CSF-1 expression by binding to its 3' untranslated region, thereby promoting the NPSC proliferation and differentiation into neurons. In 20-month-old rats, miR-484 overexpression improved spatial learning and memory in the Morris water maze, increased NPSC proliferation, and reduced apoptosis.

Our findings reveal that miR-484 regulates CSF-1 to influence NPSC proliferation, differentiation into neurons, and apoptosis, consequently improving cognitive function in 20-month-old rats. This study provides a foundation for developing therapeutic strategies targeting age-related hippocampal cognitive impairments.

Dementia, characterized by loss of cognitive abilities in the elderly, poses a significant global health challenge. This study explores the role of astrocytes, one of most representative glial cells in the brain, in mitigating cognitive decline. Specifically, we investigated the impact of Hevin (also known as SPARC-like1/SPARCL-1), a secreted glycoprotein, on cognitive decline in both normal and pathological brain aging. By using adeno-associated viruses, we overexpressed Hevin in hippocampal astrocytes of middle-aged APP/PSEN mice, an established Alzheimer's disease (AD) model. Results demonstrated that Hevin overexpression attenuates cognitive decline, as evidenced by cognitive tests, increased pre- and postsynaptic markers colocalization, and altered expression of synaptic mediators, as revealed by proteomic profiling. Importantly, Hevin overexpression did not influence the deposition of Aβ plaques in the hippocampus, a hallmark of AD pathology. Furthermore, the study extended its findings to middle-aged wild-type animals, revealing improved cognitive performance following astrocytic Hevin overexpression. In conclusion, our results propose astrocytic Hevin as a potential therapeutic target for age-associated cognitive decline.

Bone has long been acknowledged as a fundamental structural entity that provides support and protection to the body's organs. However, emerging research indicates that bone plays a crucial role in the regulation of systemic metabolism. This is achieved through the secretion of a variety of hormones, cytokines, metal ions, extracellular vesicles, and other proteins/peptides, collectively referred to as bone-derived factors (BDFs). BDFs act as a medium through which bones can exert targeted regulatory functions upon various organs, thereby underscoring the profound and concrete implications of bone in human physiology. Nevertheless, there remains a pressing need for further investigations to elucidate the underlying mechanisms that inform the effects of bone on other body systems. This review aims to summarize the current findings related to the roles of these significant modulators across different organs and metabolic contexts by regulating critical genes and signaling pathways in vivo. It also addresses their involvement in the pathogenesis of various diseases affecting the musculoskeletal system, circulatory system, glucose and lipid metabolism, central nervous system, urinary system, and reproductive system. The insights gained from this review may contribute to the development of innovative therapeutic strategies through a focused approach to bone secretomes. Continued research into BDFs is expected to enhance our understanding of bone as a multifunctional organ with diverse regulatory roles in human health.

This pilot study introduces the concept of a "redox clock," an NRF2-based epigenetic clock that reflects age-related changes in oxidative stress regulation. We examined CpG methylation of the NRF2 promoter across two independent populations: 101 healthy participants (56 males, 45 females) from Gyeongsang National University Hospital (GNUH) and 150 healthy participants (111 males, 39 females) from the National Cancer Center (NCC). Methylation-sensitive HpaII restriction enzyme assays targeted three promoter regions (A, B, and C), while Illumina MethylationEPIC microarray analysis identified two specific CpG sites (cg03988329 and cg15484591) that correlated significantly with age (p < 0.01). Males, in particular, showed heightened CpG methylation in regions A and C with advancing age, alongside higher Ct values for NRF2 and HO-1 transcripts, indicating reduced gene expression. Using these methylation patterns, we developed the "redox clock" to model accelerated aging (AA). Notably, this redox clock discriminated prediagnostic lung cancer cases from healthy controls by revealing significantly greater AA in the cancer cohort, whereas established epigenetic clocks (Horvath, Hannum, and PhenoAge) did not detect this difference. These findings support CpG methylation of the NRF2 promoter, as captured by the redox clock, as a promising biomarker for biological aging and potential risk assessment for age-related diseases such as lung cancer.

Ageing is the most prominent risk factor for Alzheimer's disease (AD). However, the cellular mechanisms linking neuronal proteostasis decline to the characteristic aberrant protein deposits in the brains of patients with AD remain elusive. Here we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains ageing hallmarks and exhibits AD-linked vulnerabilities. Remarkably, AD tNeurons accumulate proteotoxic deposits, including phospho-tau and amyloid β, resembling those in APP mouse brains and the brains of patients with AD. Quantitative tNeuron proteomics identify ageing- and AD-linked deficits in proteostasis and organelle homeostasis, most notably in endosome-lysosomal components. Lysosomal deficits in aged tNeurons, including constitutive lysosomal damage and ESCRT-mediated lysosomal repair defects, are exacerbated in AD tNeurons and linked to inflammatory cytokine secretion and cell death. Providing support for the centrality of lysosomal deficits in AD, compounds ameliorating lysosomal function reduce amyloid β deposits and cytokine secretion. Thus, the tNeuron model system reveals impaired lysosomal homeostasis as an early event of ageing and AD.

Skeletal muscle regulates central nervous system (CNS) function and health, activating the muscle-to-brain axis through the secretion of skeletal muscle-originating factors ("myokines") with neuroprotective properties. However, the precise mechanisms underlying these benefits in the context of Alzheimer's disease (AD) remain poorly understood. To investigate muscle-to-brain axis signaling in response to amyloid β (Aβ)-induced toxicity, we generated 5xFAD transgenic female mice with enhanced skeletal muscle function (5xFAD;cTFEB;HSACre) at prodromal (4-months old) and late (8-months old) symptomatic stages. Skeletal muscle TFEB overexpression reduced Aβ plaque accumulation in the cortex and hippocampus at both ages and rescued behavioral neurocognitive deficits in 8-month-old 5xFAD mice. These changes were associated with transcriptional and protein remodeling of neurotrophic signaling and synaptic integrity, partially due to the CNS-targeting myokine prosaposin (PSAP). Our findings implicate the muscle-to-brain axis as a novel neuroprotective pathway against amyloid pathogenesis in AD.

Recent discoveries have shown that systemic manipulations, such as parabiosis, blood exchange, and young plasma transfer, can counteract many hallmarks of aging. This rejuvenation effect has been attributed to circulatory factors produced by cells from both hematopoietic and non-hematopoietic lineages. However, the specific involvement of bone marrow (BM) or hematopoietic cells in producing such factors and their effects on aging is still unclear. We developed a model of aged mice with transplanted young or old BM cells and assessed the impact on the aging process, specifically on energy metabolism and bone remodeling parameters. The donor BM cell engraftment in the aged mice was confirmed by flow cytometry using a transplanted cell-specific marker (green fluorescent protein). Energy metabolism was assessed using Oxymax indirect calorimetry system after 3 months of transplantation. Tibiae and L3-L4 vertebrae were analyzed using micro-CT, a three-point bending test and bone histomorphometry. Moreover, bone marrow proteome was assessed using proteomics, and blood serum/plasma was collected and analyzed using the Luminex assay. Our results showed that while the effect on energy metabolism was insignificant, rejuvenating the BM through young bone marrow transplantation reversed age-associated low bone mass traits in old mice. Specifically, young bone marrow transplantation improved bone trabecular microarchitecture both in tibiae and vertebrae of old mice and increased the number of osteoblasts and osteoclasts compared to old bone marrow transplantation. In conclusion, young bone marrow cells may represent a future therapeutic strategy for age-related diseases such as osteoporosis. The findings of this study provide important insights into our understanding of aging.

Cognitive impairment in schizophrenia occurs in the early stages of the disease and is closely associated with prognosis. Alleviation of cognitive impairment in schizophrenia faces major challenges owing to the lack of preventive and therapeutic drugs that are novel and effective. Urolithin A (UA) is a gut microbial metabolite of ellagic acid that has demonstrated neuroprotective effects in multiple neurological disease models. Nonetheless, the neuromodulatory role of UA in schizophrenia is yet to be elucidated. Wistar rat pups were separated from their mothers for 24 h on postnatal days (PNDs) 9-10 to establish an early-life stress model. The pups were pretreated with UA at different administration times (2, 4, and 6 weeks) and doses (50, 100, and 150 mg/kg) from adolescence (PND29). Behavioral tests were performed after the end of the administration. Subsequently, hippocampal samples were collected for histopathological and molecular evaluations. Male offspring rats subjected to maternal separation exhibited increased sensitivity to prepulse inhibition and cognitive impairment, accompanied by severe neuroinflammation and impaired neurogenesis. However, UA attenuated maternal separation-induced prepulse inhibition deficits and cognitive impairments and restored hippocampal neurogenesis in a dose-dependent manner. Furthermore, UA pretreatment preserved dendritic spine density, synapses, and presynaptic vesicles. In addition, it exerted anti-inflammatory effects by inhibiting microglial activation and expression of the proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-1β. Potential mechanisms included upregulation of brain-derived neurotrophic factor protein expression and activation of the extracellular signal-regulated kinase signaling pathway. This study is the first preclinical evaluation of the effects of UA on cognitive impairment in schizophrenia. The findings suggest that changes in cognitive function linked to schizophrenia are driven by the interaction among neuroinflammation, neurogenesis, and synaptic plasticity and that UA has the potential to reverse these processes. These observations provide evidence for future clinical trials of UA as a dietary supplement for preventing schizophrenia.

An in-depth understanding of the molecular processes composing aging is crucial to develop therapeutic approaches that decrease aging as a key risk factor for cognitive decline. Herein, we present a spatio-temporal brain atlas (15 different regions) of microRNA (miRNA) expression across the mouse lifespan (7 time points) and two aging interventions composed of 1009 samples. MiRNAs are promising therapeutic targets, as they silence genes by complementary base-pair binding of messenger RNAs and are known to mediate aging speed. We first established sex- and brain-region-specific miRNA expression patterns in young adult samples. Then we focused on sex-dependent and independent brain-region-specific miRNA expression changes during aging. The corpus callosum in males and the choroid plexus in females exhibited strong sex-specific age-related signatures. In this work, we identified three sex-independent brain aging miRNAs (miR-146a-5p, miR-155-5p and miR-5100). We showed for miR-155-5p that these expression changes are driven by aging microglia. MiR-155-5p targets mTOR signaling pathway components and other cellular communication pathways and is hence a promising therapeutic target.

In the context of global ageing, the prevalence of neurodegenerative diseases and dementia, such as Alzheimer's disease (AD), is increasing. However, the current symptomatic and disease-modifying therapies have achieved limited benefits for neurodegenerative diseases in clinical settings. Halting the progress of neurodegeneration and cognitive decline or even improving impaired cognition and function are the clinically meaningful goals of treatments for neurodegenerative diseases. Ageing is the primary risk factor for neurodegenerative diseases and their associated comorbidities, such as vascular pathologies, in elderly individuals. Thus, we aim to elucidate the role of ageing in neurodegenerative diseases from the perspective of a complex system, in which the brain is the core and peripheral organs and tissues form a holistic network to support brain functions. During ageing, the progressive deterioration of the structure and function of the entire body hampers its active and adaptive responses to various stimuli, thereby rendering individuals more vulnerable to neurodegenerative diseases. Consequently, we propose that the prevention and treatment of neurodegenerative diseases should be grounded in holistic antiageing and rejuvenation means complemented by interventions targeting disease-specific pathogenic events. This integrated approach is a promising strategy to effectively prevent, pause or slow down the progression of neurodegenerative diseases.

The aging process results in structural, functional, and immunological changes in the brain, which contribute to cognitive decline and increase vulnerability to neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke-related complications. Aging leads to cognitive changes and also affect executive functions. Additionally, it causes neurogenic and neurochemical alterations, such as a decline in dopamine and acetylcholine levels, which also impact cognitive performance. The chronic inflammation caused by aging contributes to the impairment of the blood-brain barrier (BBB), contributing to the infiltration of immune cells and exacerbating neuronal damage. Therefore, rejuvenating therapies such as heterochronic parabiosis, cerebrospinal fluid (CSF) administration, plasma, platelet-rich plasma (PRP), and stem cell therapy have shown potential to reverse these changes, offering new perspectives in the treatment of age-related neurological diseases. This review focuses on highlighting the effects of rejuvenating interventions on neuroinflammation and the BBB.

Blood-borne factors are essential to maintain neuronal synaptic plasticity and cognitive resilience throughout life. One such factor is osteocalcin (OCN), a hormone produced by osteoblasts that influences multiple physiological processes, including hippocampal neuronal homeostasis. However, the mechanism through which this blood-borne factor communicates with neurons remains unclear. Here we show the importance of a core primary cilium (PC) protein-autophagy axis in mediating the effects of OCN. We found that the OCN receptor GPR158 is present at the PC of hippocampal neurons and mediates the regulation of autophagy machinery by OCN. During aging, autophagy and PC core proteins are reduced in neurons, and restoring their levels is sufficient to improve cognitive impairments in aged mice. Mechanistically, the induction of this axis by OCN is dependent on the PC-dependent cAMP response element-binding protein signaling pathway. Altogether, this study demonstrates that the PC-autophagy axis is a gateway to mediate communication between blood-borne factors and neurons, and it advances understanding of the mechanisms involved in age-related cognitive decline.

Ageing is one of the most important risk factors for chronic health conditions, including neurodegenerative diseases. Inflammation is a feature of ageing, as well as a key pathophysiological mechanism for degenerative diseases. Microglia play multiple roles in the central nervous system; their states entail a complex assemblage of responses reflecting the multiplicity of functions they fulfil both under homeostatic basal conditions and in response to stimuli. Whereas glial cells can promote neuronal homeostasis and limit neurodegeneration, age-related inflammation (i.e. inflammaging) leads to the functional impairment of microglia and astrocytes, exacerbating their response to stimuli. Thus, microglia are key mediators for age-dependent changes of the nervous system, participating in the generation of a less supportive or even hostile environment for neurons. Whereas multiple changes of ageing microglia have been described, here we will focus on the neuron-microglia regulatory crosstalk through fractalkine (CX3CL1) and CD200, and the regulatory cytokine Transforming Growth Factor β1 (TGFβ1), which is involved in immunomodulation and neuroprotection. Ageing results in a dysregulated activation of microglia, affecting neuronal survival, and function. The apparent unresponsiveness of aged microglia to regulatory signals could reflect a restriction in the mechanisms underlying their homeostatic and reactive states. The spectrum of functions, required to respond to life-long needs for brain maintenance and in response to disease, would progressively narrow, preventing microglia from maintaining their protective functions. This article is part of the Special Issue on "Microglia".

Major depressive disorder (MDD) is considered a psychiatric disorder and have a relationship with stressful events. Although the common therapeutic approaches against MDD are diverse, a large number of patients do not present an adequate response to antidepressant treatments. On the other hand, effective non-pharmacological treatments for MDD and their tolerability are addressed. Several affective treatments for MDD are used but non-pharmacological strategies for decreasing the common depression-related drugs side effects have been focused recently. However, the potential of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs), microRNAs (miRNAs) as cell-based therapeutic paradigms, besides other non-pharmacological strategies including mitochondrial transfer, plasma, transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and exercise therapy needs to further study. This review explores the therapeutic potential of cell-based therapeutic non-pharmacological paradigms for MDD treatment. In addition, plasma therapy, mitotherapy, and exercise therapy in several in vitro and in vivo conditions in experimental disease models along with tDCS and TMS will be discussed as novel non-pharmacological promising therapeutic approaches.

Preclinical evidence suggests that young plasma has beneficial effects on multiple organ systems in aged mice. Whether young plasma exerts beneficial effects in an aging human population remains highly controversial. Despite lacking data, young donor plasma infusions have been promoted for age-related conditions. Given the preclinical evidence that young plasma exerts beneficial effects by attenuating inflammation, this study examined whether administering a young plasma protein fraction to an elderly population would exert anti-inflammatory and immune modulating effects in humans, using surgery as a tissue injury model.

This double-blind, placebo-controlled study enrolled and randomized 38 patients undergoing major joint replacement surgery. Patients received four separate infusions of a plasma protein fraction derived from young donors, or placebo one day before surgery, before and after surgery on the day of surgery, and one day after surgery. Blood specimens for proteomic and immunological analyses were collected before each infusion. Based on the high-content assessment of circulating plasma proteins with single-cell analyses of peripheral immune cells, proteomic signatures and cell-type-specific signaling responses that separated the treatment groups were derived with regression models.

Elastic net regression models revealed that administration a young plasma protein fraction significantly altered the proteomic (AUC = 0.796, p = 0.002) and the cellular immune response (AUC 0.904, p < 0.001) to surgical trauma resulting in signaling pathway- and cell type-specific anti-inflammatory immune modulation. Affected proteomic pathways regulating inflammation included JAK-STAT, NF-kappa B, and MAPK (p < 0.001). These findings were confirmed at the cellular level as the MAPK and JAK/STAT signaling responses were diminished and IkB, the negative regulator of NFkB, was elevated in adaptive immune cells.

Reported findings provide a first proof of principle in humans that a young plasma protein fraction actively regulates inflammatory and immune responses in an elderly population. They provide a solid rationale for elucidating active principles in young plasma that may be of therapeutic benefits for a range of age-related pathologies.

ClinicalTrials.gov, NCT03981419.

Aging is associated with a disruptive decline in gastrointestinal health leading to decreased duodenal cell proliferation ultimately affecting the digestive and absorptive capacity of intestines in all species. This study investigates the novel application of blood plasma therapy to enhance duodenal cell proliferation associated with aging. In the presented study, the effects of middle aged plasma therapy on the aged rat duodenum were investigated. For this purpose, using a randomized controlled design, Female Wistar rats (aged 12-15 months) (n:7) were treated with heterologus pooled plasma (0.5 mL per day for 30 days, infused intravenously into the tail vein) collected from middle aged (6 months old, n:28) rats during all stages of the estrous cycle. The groups were divided into three as the Experimental group (aged 12-15 months) receiving middle aged plasma, the control group (aged 12-15 months) not receiving treatment, and the middle aged rat (6 months) as the positive control group. At the end of the experiment, each group's duodenum were collected, fixed, and analyzed using histological techniques for morphometric parameters. Additionally cell proliferation density and proliferation index were determined by proliferating cell nuclear antigen (PCNA). The finding of the study suggests that plasma therapy significantly improves cell proliferation, villus height (µm), crypt depth (µm), total mucosal thickness (µm), the ratio of villus height to crypt depth (µm), and surface absorption area (mm2) in the experimental group compared to control. Likewise, we determined that middle aged plasma application supports cell proliferation. However, further research is warranted to explore the underlying mechanisms and potential clinical applications of this innovative approach.

Brain energy metabolism disorders, including glucose utilization disorders and abnormal insulin sensitivity, are linked to the pathogenesis of postoperative delirium. Intranasal insulin has shown significant benefits in improving glucose metabolism, insulin sensitivity and cognitive function. However, its impact on postoperative delirium and insulin sensitivity biomarkers remains unknown.

This randomized, double-blind, placebo-controlled trial was to evaluate whether intranasal insulin reduces the incidence and severity of postoperative delirium (POD) in older patients undergoing joint replacement, and its effect on insulin sensitivity-related biomarkers.

212 older patients (≥65 years) were randomly assigned to receive either 40 IU of intranasal insulin (n=106) or a placebo (n=106) for 8 days. The primary objective was to determine the incidence and severity of POD within 5 days after surgery, estimated using the Confusion Assessment Method (CAM) and the Delirium Rating Scale (DRS)-98. The secondary objective was insulin sensitivity, which was assessed using the homeostasis model Assessment of Insulin Resistance (HOMA-IR) and biomarkers, including total osteocalcin (tOC), uncarboxylated osteocalcin (ucOC), and brain-derived neurotrophic factor (BDNF).

Compared to placebo, intranasal insulin significantly reduced the incidence of delirium within 5 days after surgery (8 [8.33%] vs 23 [23.23%], P = 0.004, odds ratio [OR] = 3.33 [95% CI 1.41-7.88]) and the severity of delirium (P<0.001). Intranasal insulin elevated the levels of tOC, ucOC, and BDNF in the CSF on D0 (all P<0.001) and tOC levels in the plasma on D0, D1 and D3 (all P<0.001). It elevated ucOC levels in the plasma of the insulin group on D0 but not on D1 and D3 (all P<0.001). Intranasal insulin administration reduced the HOMA-IR on D3 (P=0.002).

Intranasal insulin notably reduced the incidence and severity of POD in older patients undergoing joint replacement, which may be related to the elevation in osteocalcin and BDNF levels.

Chinese Clinical Trial Registry (ChiCTR2300068073).

The enhancement of complex physiological functions such as cognition and exercise performance in healthy individuals represents a challenging goal. Adaptive transcription programs that are naturally activated in animals to mediate cellular plasticity in response to stimulation can be leveraged to enhance physiological function above wild-type levels in young organisms and counteract complex functional decline in aging. In processes such as learning and memory and exercise-dependent muscle remodeling, a relatively small number of molecules such as certain stimulus-responsive transcription factors and immediate early genes coordinate widespread changes in cellular physiology. Adaptive transcription can be targeted by various methods including pharmaceutical compounds and gene transfer technologies. Important problems for leveraging adaptive transcription programs for physiological enhancement include a better understanding of their dynamical organization, more precise methods to influence the underlying molecular components, and the integration of adaptive transcription into multi-scale physiological enhancement concepts.

Recent work has bolstered the possibility that peripheral changes may be relevant to Alzheimer's disease pathogenesis in the brain. While age-associated blood-borne proteins have been targeted to restore function to the aged brain, it remains unclear whether other dysfunctional systemic states can be exploited for similar benefits. Here, we investigate whether APOE allelic variation or presence of brain amyloid are associated with plasma proteomic changes and the molecular processes associated with these changes.

Using the SOMAscan assay, we measured 1305 plasma proteins from 53 homozygous, APOE3 and APOE4 subjects without dementia. We investigated the relationship of either the APOE-ε4 allele or amyloid positivity with plasma proteome changes by linear mixed effects modeling and ontology-based pathway and module-trait correlation analyses.

APOE4 is associated with plasma protein differences linked to atherosclerosis, tyrosine kinase activity, cholesterol transport, extracellular matrix, and synaptogenesis pathways. Independent of APOE4, we found that subjects likely harboring brain amyloid exhibit plasma proteome signatures associated with AD-linked pathways, including neurovascular dysfunction.

Our results indicate that APOE4 status or presence of brain amyloid are associated with plasma proteomic shifts prior to the onset of symptoms, suggesting that systemic pathways in certain risk contexts may be plausible targets for disease modification.

Aging-related cognitive decline is emerging as a health concern during the aging process of the global population. Hahn and colleagues found that glial aging was particularly accelerated in white matter compared to cortical regions. Specialized neuronal populations showed region-specific changes in gene expression. Acute dietary restriction triggers a reprogramming of genes associated with the circadian clock in glial cells, whereas injections of young mouse plasma selectively reverse age-related expression patterns. The discovery of region-specific aging could enhance our understanding of the aging process and offer new possibilities for innovative treatment strategies and interventions for cognitive impairments related to aging.

The peripheral immune system communicates with the brain through complex anatomical routes involving the skull, the brain borders, circumventricular organs and peripheral nerves. These immune-brain communication pathways were classically considered to be dormant under physiological conditions and active only in cases of infection or damage. Yet, peripheral immune cells and signals are key in brain development, function and maintenance. In this Perspective, we propose an alternative framework for understanding the mechanisms of immune-brain communication. During brain development and in homeostasis, these anatomical structures allow selected elements of the peripheral immune system to affect the brain directly or indirectly, within physiological limits. By contrast, in ageing and pathological settings, detrimental peripheral immune signals hijack the existing communication routes or alter their structure. We discuss why a diversity of communication channels is needed and how they work in relation to one another to maintain homeostasis of the brain.

The α-synuclein protein is an established molecule in Lewy body pathology, especially Parkinson's disease (PD). While the pathological role of α-synuclein (α-syn) in PD has been well described, novel evidence may suggest that α-syn interacts with inflammasomes in response to aging. As age is an inevitable physiological state and is also considered the greatest risk factor for PD, this calls for investigation into how α-syn, aging, and PD could be linked. There is a growing amount of data regarding α-syn normal function in the body that includes involvement in cellular transport such as protein complexes assembly, vesicular trafficking, neurotransmitter release, as well as immune cell maturation. Regarding abnormal α-syn, a number of autosomal dominant mutations have been identified as causes of familial PD, however, symptomatology may not become apparent until later in life due to compensatory mechanisms in the dopaminergic response. This potentially links age-related physiological changes not only as a risk factor for PD, but for the concept of "inflammaging ". This is defined as chronic inflammation that accompanies aging observed in many neurodegenerative pathologies, that include α-syn's ability to form oligomers and toxic fibrils seen in PD. This oligomeric α-syn stimulates pro-inflammatory signals, which may worsen PD symptoms and propagate chronic inflammation. Thus, this review will explore a potential link between α-syn's role in the immune system, inflammaging, and PD.

Alzheimer's disease (AD) and osteoporosis (OP) pose distinct but interconnected health challenges, both significantly impacting the aging population. AD, a neurodegenerative disorder characterized by memory impairment and cognitive decline, is primarily associated with the accumulation of abnormally folded amyloid beta (Aβ) peptides and neurofibrillary tangles in the brain. OP, a skeletal disorder marked by low bone mineral density, involves dysregulation of bone remodeling and is associated with an increased risk of fractures. Recent studies have revealed an intriguing link between AD and OP, highlighting shared pathological features indicative of common regulatory pathophysiological pathways. In this article, we elucidate the signaling mechanisms that regulate the pathology of AD and OP and offer insights into the intricate network of factors contributing to these conditions. We also examine the role of bone-derived factors in the progression of AD, underscoring the plausibility of bidirectional communication between the brain and the skeletal system. The presence of amyloid plaques in the brain of individuals with AD is akin to the accumulation of brain Aβ in vascular dementia, pointing towards the need for further investigation of shared molecular mechanisms. Moreover, we discuss the role of bone-derived microRNAs that may regulate the pathological progression of AD, providing a novel perspective on the role of skeletal factors in neurodegenerative diseases. The insights presented here should help researchers engaged in exploring innovative therapeutic approaches targeting both neurodegenerative and skeletal disorders in aging populations.

Aging is the most prominent risk factor for Alzheimer's disease (AD). However, the cellular mechanisms linking neuronal proteostasis decline to the characteristic aberrant protein deposits in AD brains remain elusive. Here, we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains aging hallmarks and exhibits AD-linked vulnerabilities. Remarkably, AD tNeurons accumulate proteotoxic deposits, including phospho-Tau and Aβ, resembling those in AD patient and APP mouse brains. Quantitative tNeuron proteomics identify aging and AD-linked deficits in proteostasis and organelle homeostasis, most notably in endosome-lysosomal components. Lysosomal deficits in aged tNeurons, including constitutive lysosomal damage and ESCRT-mediated lysosomal repair defects, are exacerbated in AD tNeurons and linked to inflammatory cytokine secretion and cell death. Supporting lysosomal deficits' centrality in AD, compounds ameliorating lysosomal function reduce Aβ deposits and cytokine secretion. Thus, the tNeuron model system reveals impaired lysosomal homeostasis as an early event of aging and AD.

The contemporary understanding that the immune response significantly supports higher brain functions has emphasized the notion that the brain's condition is linked in a complex manner to the state of the immune system. It is therefore not surprising that immunity is a key factor in shaping brain aging. In this perspective article, we propose amending the Latin phrase "mens sana in corpore sano" ("a healthy mind in a healthy body") to "a healthy mind in a healthy immune system." Briefly, we discuss the emerging understanding of the pivotal role of the immune system in supporting lifelong brain maintenance, how the aging of the immune system impacts the brain, and how the potential rejuvenation of the immune system could, in turn, help revitalize brain function, with the ultimate ambitious goal of developing an anti-aging immune therapy.

Brain aging leads to a decline in cognitive function and a concomitant increase in the susceptibility to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. A key question is how changes within individual cells of the brain give rise to age-related dysfunction. Developments in single-cell "omics" technologies, such as single-cell transcriptomics, have facilitated high-dimensional profiling of individual cells. These technologies have led to new and comprehensive characterizations of brain aging at single-cell resolution. Here, we review insights gleaned from single-cell omics studies of brain aging, starting with a cell-type-centric overview of age-associated changes and followed by a discussion of cell-cell interactions during aging. We highlight how single-cell omics studies provide an unbiased view of different rejuvenation interventions and comment on the promise of combinatorial rejuvenation approaches for the brain. Finally, we propose new directions, including models of brain aging and neural stem cells as a focal point for rejuvenation.

Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process. Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit "younger" molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150low HSCs from old mice but not their CD150high counterparts can effectively differentiate into downstream lineage cells. Notably, transplantation of old CD150low HSCs attenuates aging phenotypes and prolongs lifespan of elderly mice compared to those transplanted with unselected or CD150high HSCs. Importantly, reducing the dysfunctional CD150high HSCs can alleviate aging phenotypes in old recipient mice. Thus, our study demonstrates the presence of "younger" HSCs in old mice, and that aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.

Sensorineural hearing loss (SNHL) is a prevalent clinical condition primarily attributed to dysfunction within various components of the auditory pathway, spanning from the inner ear to the auditory cortex. Recent research has illuminated immune and inflammation-mediated disorders of the inner ear as critical contributors to SNHL. Disruptions in the equilibrium of inflammatory mediators, chemokines, the complement system, and inflammatory vesicles within the cochlea provoke aberrations in immune cell activity, fostering a chronic pro-inflammatory milieu that detrimentally affects the structural and functional integrity of the inner ear, culminating in hearing impairment. Specific genetic mutations, especially those affecting auditory structures, play an important role in SNHL. These mutations regulate inflammatory mediators and cellular responses, thereby altering the inflammatory dynamics within the cochlea. This review delves into the pathogenesis of sensorineural hearing loss, emphasizing the impact of genetic alterations, immune responses within the inner ear, and inflammatory mediators on auditory function. It highlights the significance of Transmembrane Serine Protease 3 (TMPRSS3) and connexin gene mutations as pivotal genetic elements in SNHL, underscoring the central role of inflammatory responses in cochlear damage. Furthermore, the paper discusses the promise of gene therapy and targeted molecular interventions, underscoring the necessity for continued exploration into the specific actions of various inflammatory agents to refine personalized therapeutic strategies.

Blood plasma therapy, a new treatment method to eliminate the damage and deterioration caused by aging in many organ systems, has attracted increasing attention. The digestive tract, which cooperates with many different systems, has strong effects on our health. In the present study, the effects of plasma therapy on the ileum of elderly rats were investigated. Wistar rats (n = 7; 12-15 months old) were given pooled plasma collected from middle-age rats (6 months, n =28) (for 30 days, 0.3 ml daily, intravenously into the tail vein). At the end of the experiment, villus height, crypt depth, total mucosal thickness and surface absorption area were evaluated. In addition, the effects of IgA, which plays a role in the digestive system's defense against microorganisms, were examined. Both the cell proliferation intensity and proliferation index were evaluated in crypt cells. An increase was determined in all morphological parameters in the experimental group. Similarly, plasma application decreased IgA expression and numbers in the experimental groups. Contrarily, cell proliferation parameters showed a significant increase in the experimental groups' crypt cells. Therefore, we found that the treatment supports the digestive system in terms of both nutrient utilization and absorption-related parameters and has a protective effect on intestinal immune system parameters.

Drug delivery to the brain is challenging due to the restrict permeability of the blood brain barrier (BBB). Recent studies indicate that BBB permeability increases over time during physiological aging likely due to factors (including extracellular vesicles (EVs)) that exist in the bloodstream. Therefore, inspiration can be taken from aging to develop new strategies for the transient opening of the BBB for drug delivery to the brain.

Here, we evaluated the impact of small EVs (sEVs) enriched with microRNAs (miRNAs) overexpressed during aging, with the capacity to interfere transiently with the BBB. Initially, we investigated whether the miRNAs were overexpressed in sEVs collected from plasma of aged individuals. Next, we evaluated the opening properties of the miRNA-enriched sEVs in a static or dynamic (under flow) human in vitro BBB model. Our results showed that miR-383-3p-enriched sEVs significantly increased BBB permeability in a reversible manner by decreasing the expression of claudin 5, an important tight junction protein of brain endothelial cells (BECs) of the BBB, mediated in part by the knockdown of activating transcription factor 4 (ATF4).

Our findings suggest that engineered sEVs have potential as a strategy for the temporary BBB opening, making it easier for drugs to reach the brain when injected into the bloodstream.

Cognitive impairment is common in extracerebral diseases such as chronic kidney disease (CKD). Kidney transplantation reverses cognitive impairment, indicating that cognitive impairment driven by CKD is therapeutically amendable. However, we lack mechanistic insights allowing development of targeted therapies. Using a combination of mouse models (including mice with neuron-specific IL-1R1 deficiency), single cell analyses (single-nuclei RNA-sequencing and single-cell thallium autometallography), human samples and in vitro experiments we demonstrate that microglia activation impairs neuronal potassium homeostasis and cognition in CKD. CKD disrupts the barrier of brain endothelial cells in vitro and the blood-brain barrier in vivo, establishing that the uremic state modifies vascular permeability in the brain. Exposure to uremic conditions impairs calcium homeostasis in microglia, enhances microglial potassium efflux via the calcium-dependent channel KCa3.1, and induces p38-MAPK associated IL-1β maturation in microglia. Restoring potassium homeostasis in microglia using a KCa3.1-specific inhibitor (TRAM34) improves CKD-triggered cognitive impairment. Likewise, inhibition of the IL-1β receptor 1 (IL-1R1) using anakinra or genetically abolishing neuronal IL-1R1 expression in neurons prevent CKD-mediated reduced neuronal potassium turnover and CKD-induced impaired cognition. Accordingly, in CKD mice, impaired cognition can be ameliorated by either preventing microglia activation or inhibiting IL-1R-signaling in neurons. Thus, our data suggest that potassium efflux from microglia triggers their activation, which promotes microglia IL-1β release and IL-1R1-mediated neuronal dysfunction in CKD. Hence, our study provides new mechanistic insight into cognitive impairment in association with CKD and identifies possible new therapeutic approaches.