Diabetes mellitus (DM) is well-known to exert complications such as retinopathy, cardiomyopathy and neuropathy. However, in recent years, an elevated osteoarthritis (OA) complaints among diabetics have been observed, portending the risk of diabetic OA. Since formation of advanced glycation end products (AGE) is believed to be the etiology of various diseases under hyperglycemic conditions, we firstly established that streptozotocin-induced DM could potentiate the development of OA in C57BL/6J mouse model, and further explored the intra-articularly administered adipose-derived stem cell (ADSC) therapy focusing on underlying AGE-associated mechanism. Our results demonstrated that hyperglycemic mice exhibited OA-like structural impairments including a proteoglycan loss and articular cartilage fibrillations in knee joint. Highly expressed levels of carboxymethyl lysine (CML), an AGE and their receptors (RAGE), which are hallmarks of hyperglycemic microenvironment were manifested. The elevated oxidative stress in diabetic OA knee-joint was revealed through increased levels of malondialdehyde (MDA). Further, oxidative stress-activated nuclear factor kappa B (NF-κB), the marker of proinflammatory signalling pathway was also accrued; and levels of matrix metalloproteinase-1 and 13 were upregulated. However, ADSC treatment attenuated all OA-like changes by 4 weeks, and dampened levels of CML, RAGE, MDA, NF-κB, MMP-1 and 13. These results suggest that during repair and regeneration, ADSCs inhibited glycation-mediated inflammatory cascade and rejuvenated cartilaginous tissue, thereby promoting knee-joint integrity in diabetic milieu.

Although autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, are frequently associated with premature aging of the thymus, a direct link is missing between autoimmunity and thymic atrophy. Here we monitored the progression of thymic involution in Aire-deficient mice, in which defective negative selection causes spontaneous and progressive development of autoimmunity. In young and middle-aged mice, Aire deficiency appeared to be protective as supported by the reduced β-gal⁺ epithelial cells and the enhanced thymic output. However, once the autoimmune phenotype was fully developed in aged Aire-deficient mice, their thymuses underwent accelerated involution. In comparison to the age-matched wildtype littermates, old Aire-deficient mice showed lower numbers of total thymocytes and recent thymic emigrants but more β-gal⁺ thymic epithelial cells. This phenomenon may partly be attributable to the increased number of activated Th1 cells homing to the thymus. This speculation was further supported by the enhanced thymic aging following repeated challenges with complete Freund’s adjuvant immunization. Taken together, the present study highlights a unique mechanism by which autoimmunity facilitates the senescence of thymic epithelial cells through returning Th1 cells.

The APOE and fibroblast growth factor 1 (FGF1) have both been associated with amyloid β accumulation and neurodegeneration. Investigation the effect of APOE-FGF1 interactions on episodic memory (EM) deficits and hippocampus atrophy (HA) might elucidate the complex clinical-pathological relationship in Alzheimer’s disease (AD). EM performance and hippocampal volume (HV) were characterized in patients with mild AD based on APOE-ε4 carrier status (APOE-ε4 carriers versus non-carriers) and FGF1 single nucleotide polymorphism (FGF1-rs34011-GG versus FGF1-rs34011-A-allele carriers). The clinical-pathological relationships within each genotypic group (ε4+/GG-carrier, ε4+/A-allele-carrier, ε4-/GG-carrier and ε4-/A-allele-carrier) were analyzed. There were no significant differences between the FGF1-rs34011-GG and FGF1-rs34011-A-allele carriers for the level of EM performance or HV (p> 0.05). The bilateral HV was significantly smaller and EM impairment was significantly worse in ε4+/GG-carrier than in ε4-/A-allele-carrier, and an interaction effect of APOE (APOE-ε4 carriers versus non-carriers) with FGF1 (FGF1-rs34011-GG versus FGF1-rs34011-A-allele carriers) predicted EM impairment (F4,92= 3.516, p= 0.018) and structural changes in voxel-based morphometry. Our data shows that concurrent consideration of APOE and FGF1 polymorphisms might be required to understand the clinical-pathological relationship in AD.

No recent study has focused on clinical features of subclinical hypothyroidism (SCH), especially in older patients. TSH measurement has remarkably evolved these last 20 years and thus reconsideration is needed. In our prospective multicenter study (2012-2014) including 807 subjects aged <60 years (<60y) and 531 subjects ≥60 years (≥60y), we have monitored 11 hypothyroidism-related clinical signs (hCS) together with TSH, FT4, FT3 and anti-thyroperoxidase antibodies values. hCS expression has been compared in patients with SCH vs euthyroidism in each age group. The number of hCS above 60y of age were found to be more elevated in the euthyroid population (1.9 vs 1.6, p<0.01) than in the SCH population (2.3 vs 2.6, p=0.41) while increase in hCS is limited to SCH subjects in the <60y group (p<0.01). The percentage of subjects with at least 3 signs increased with SCH in the <60y group (42.6% vs 25.0%, p<0.01) but not ≥60y (34.4% vs 33.9%, p=0.96). In older individuals, only three hCS could be related to both SCH and a decreased T3/T4-ratio (0.26 vs 0.27, p<0.01), suggesting either a reduced activity of TSH, or an adaptive response with aging. While hCS are clearly associated with SCH in patients <60y, they are not so informative in older subjects. TSH measurements carried out on the basis of hCS need to be interpreted with caution in aged patients. A reassessment of the TSH reference range in older patients is clearly needed and should be associated to more appropriate monitoring of thyroid dysfunction

The level of cerebellar activity in stroke patients has been shown to correlate with the extent of functional recovery. We reasoned that the cerebellum may be an important player in post-stroke rehabilitation. Because the neurons in the deep cerebellar nuclei (DCN) represent virtually all of the output from the cerebellum, in this study, using environmental enrichment (EE) to promote rehabilitation, we investigated the influence of the optogenetic neuronal modulation of DCN on EE-induced rehabilitation. We found that neuronal inhibition of the DCN almost completely blocked motor recovery in EE treated mice, but the stroke mice with neuronal activation of the DCN achieved a similar recovery level as those in the EE treated group. No difference was observed in anxiety-like behavior. Moreover, Htr2a in the DCN, the gene encoding 5-HT2A receptor, was shown to be a hub gene in the protein-protein interaction network identified using RNA-seq. This indicated that 5-HT2A receptor-mediated signaling may be responsible for DCN-dependent functional improvement in EE. We further verified this using the 5-HT2A receptor antagonist, MDL100907, to inhibit the function of 5-HT2A receptor in the DCN. This treatment resulted in impaired recovery in EE treated mice, who performed at a level as poor as the stroke-only group. Thus, this work contributes to an understanding of the importance of the DCN activation in EE-induced post-stroke rehabilitation. Attempts to clarify the mechanism of 5-HT2A receptor-mediated signaling in the DCN may also lead to the creation of a pharmacological mimetic of the benefits of EE-induced rehabilitation.

The inflammatory response is an unavoidable process and contributes to the destruction of cerebral tissue during the acute ischemic stroke (AIS) phase and has not been addressed fully to date. Insightful understanding of correlation of inflammatory mediators and stroke outcome may provide new biomarkers or therapeutic approaches for ischemic stroke. Here, we prospectively recruited 180 first-ever AIS patients within 72 hrs after stroke onset. We used the National Institutes of Health Stroke Scale (NIHSS) to quantify stroke severity and modified Rankin scale (mRS) to assess the 3-month outcome for AIS patients. Initially, we screened 35 cytokines, chemokines, and growth factors in sera from 75 AIS patients and control subjects. Cytokines that were of interest were further investigated in the 180 AIS patients and 14 heathy controls. We found that IL-1RA, IL-1β, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, IL-15, EGF, G-CSF, Flt-3L, GM-CSF and Fractalkine levels were significantly decreased in severe stroke patients. In particular, IL-1β, IL-4, IL-5, IL-7, IL-9, IL-10, IL-15, G-CSF and GM-CSF were significantly reduced in AIS patients with poor outcome, compared to those with good prognosis. IL-6 was notably higher in the poor outcome group. Only IL-9 level decreased in the large infarct volume group. After adjusting for confounders, we found that IL-5 was an independent protective factor for prognosis in AIS patients with an adjusted OR of 0.042 (P = 0.007), whereas IL-6 was an independent risk predictor for AIS patients with an adjusted OR of 1.293 (P = 0.003). Our study suggests the levels of serum cytokines are related to stroke severity, short-term prognosis and cerebral infarct volume in AIS patients.

Sleep duration and quality have been associated with poor physical function, but both the temporality of the association and the independence of sleep duration and quality are unclear. We examined the prospective association of sleep duration and quality with physical function impairment and disability in older adults. Data were taken from participants in the Seniors-ENRICA (2012-2015, n= 1,773) and in the ELSA cohort (waves 4 and 6, n=4,885) aged ≥60 years. Sleep duration and quality were self-reported. Physical function impairment and disability was obtained either from self-reports (ENRICA and ELSA) or from performance assessment (ENRICA). Logistic regression models were adjusted for potential confounders. After a follow-up of 2.0-2.8 years, no association was found between changes in sleep duration and physical function impairment or disability. However, in both studies, poor general sleep quality was linked to higher risk of impaired agility [OR: 1.93 (95% CI: 1.30-2.86) in Seniors-ENRICA and 1.65 (1.24-2.18) in ELSA study] and mobility [1.46 (0.98-2.17) in Seniors-ENRICA and 1.59 (1.18-2.15) in ELSA study]. Poor general sleep quality was also associated with decreased physical component summary (PCS) [1.39 (1.05-1.83)], disability in instrumental activities of daily living [1.59 (0.97-2.59)] and in basic activities of daily living [1.73 (1.14-2.64)] in Seniors-ENRICA. In addition, compared to those with no sleep complaints, participants with 2 or more sleep complaints had greater risk of impaired agility, impaired mobility, decreased PCS and impaired lower extremity function in both cohorts. Poor sleep quality was associated with higher risk of physical impairment and disability in older adults from Spain and from England.

The relationship between recurrent intracerebral hemorrhage (ICH) and total burden of cerebral small vessel disease (CSVD) is not completely investigated. We aimed to study whether recurrent intracerebral hemorrhage (ICH) had higher CSVD score than first-ever ICH. Lacunes, white matter hyperintensities (WMH), cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVS), cortical superficial siderosis (cSS) and CSVD score were rated on brain magnetic resonance imaging (MRI) in primary ICH patients. Recurrent ICHs were confirmed by reviewing the medical records and MRI scans. Mixed hematomas were defined as follows: deep + lobar, deep + cerebellar, or deep + lobar + cerebellar. Of the 184 patients with primary ICH enrolled (mean age, 61.0 years; 75.5% men), recurrent ICH was present in 45 (24.5%) patients; 26.1% (48/184) had ≥2 hematomas, 93.8% (45/48) of which exhibited recurrent ICH. Mixed hematomas were identified in 8.7% (16/184) of patients and bilateral hematomas in 17.9% (33/184). All mixed hematomas and bilateral hematomas were from cases of recurrent ICH. Patients with mixed etiology-ICH were more likely to have recurrent ICH than patients with cerebral amyloid angiopathy (CAA) or hypertensive angiopathy (HA)-related ICH (36.8% vs17.8%, p=0.008). Multivariate ordinal regression analysis showed that the presence of recurrent ICH (p=0.001), ≥2 hematomas (p=0.002), mixed hematomas (p<0.00001), and bilateral hematomas (p=0.002) were separately significantly associated with a high CSVD score. Recurrent ICH occurs mostly among patients with mixed etiology-ICH and is associated with a higher CSVD burden than first-ever ICH, which needs to be verified by future larger studies.

Liuwei Dihuang (LWDH), a famous traditional Chinese medicine, is widely used in the clinical treatment of aging-related diseases in China. However, its pharmacological mechanisms are not clear. In the present study, we evaluated the lifespan extension effect of LWDH in C. elegans and mice and revealed its underlying mechanisms. The results showed that LWDH significantly extended the lifespan of C. elegans in a dose-dependent manner. LWDH also conferred protection to nematodes against oxidative stress and reduced their fat storage. Genetics analysis and microarray data showed that the longevity effect of LWDH was attributed to the regulation of the innate immune response, proteolysis, lipid metabolism, and the oxidation-reduction process and was dependent on daf-16. Among the six herbs in the formula, Radix Rehmanniae Preparata and Fructus Macrocarpii contributed most to the longevity effect of this medicine, while the other four components had a synergistic effect on the longevity effect of the prescription. The lack of any single herb reduced the efficacy of the complete formula. LWDH also extended the lifespan and reduced both the weight and oxidant stress status in aged mice. Taken together, these results suggested that LWDH might function in a multi-target manner to extend the lifespan in both C. elegans and aged mice, and the best effect was achieved with the complete formula.

Type 2 diabetes mellitus (T2DM) is more prevalent in aging populations. Older adults with diabetes have higher rates of macro and micro vascular complications. Our study assessed whether age is an independent factor for both large and small nerve dysfunctions in Chinese patients with T2DM. This cross-sectional study involved a total of 950 patients with type 2 diabetes (mean age: 60.01±12.30 years). Diabetic peripheral neuropathy (DPN) was assessed according to clinical symptoms and physical examinations by using neuropathy symptom score (NSS), the neuropathy disability score (NDS), Michigan Neuropathy Screening Instrument (MNSI score), vibration perception threshold (VPT) and SUDOSCAN test. By using independent logistic regression model, we showed that age was an independent risk factor of DPN (odds ratio [OR] = 1.036, 95% confidence interval [CI] 1.018-1.054, P< 0.01). T2DM patients over 71 years had a higher risk of DPN determined by using NSS/NDS (OR= 2.087; 95% CI 1.112-3.918; P <0.05), MNSI (OR=1.922; 95% CI 1.136-3.252; P<0.05), VPT (OR=3.452; 95%CI 1.052-11.332; P<0.05) and SUDOSCAN (OR=1.922; 95%CI 1.136-3.252; P<0.05) as diagnostic criteria respectively. The results of spline analysis showed a non-linearly positive association between age and OR of DPN. Individuals with 40, 50, 60, and 70 years old had LnOR of 1.22 (95%CI: 0.44- 2.00), 1.79(95%CI: 0.67- 2.91), 2.29 (95% CI: 0.98- 3.59), and 2.67(95% CI: 1.38-3.96) in DPN risk compared to T2DM patients with 19 years old, respectively. All of the above results in our study suggested age as an independent risk factor for the development of diabetic neuropathy in T2DM patients is significantly associated with the occurrence of both small and large nerve dysfunction, independent of other risk factors.

Mitochondrial creatine kinase (MtCK) is vital in the process of mitochondrial energy metabolism, and mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson’s disease (PD). Therefore, we speculated that MtCK activity could be altered in the serum of PD patients. However, no studies to date have investigated this specific topic, so we sought to investigate the serum MtCK activities among a cohort of PD patients. 50 patients with PD and 30 age-matched controls were recruited for this study. Serum ubiquitous MtCK (uMtCK) and sarcomeric MtCK (sMtCK) activities were assayed using an immunoinhibition method. Correlations between serum uMtCK/sMtCK activities and clinical features/parameters were explored in the PD group. Our study revealed a significant decrease in the uMtCK activity in the PD group when compared with the control group. No significant difference was found in the serum sMtCK activity between the PD and control groups. There was a significant correlation between serum uMtCK activities and the disease progression rate, duration, and age at onset in PD patients. While no significant relationship was found between the serum uMtCK activities and the Hoehn & Yahr stage or main non-motor symptoms scale. There was a significant decrease in the uMtCK activity in the serum of PD patients, which was associated with the rate of disease progression, duration, and age at onset of disease. Therefore, uMtCK activity in serum offers a useful clue for identification of PD biomarkers.

Diabetes is a systemic disease that can cause brain damage such as synaptic impairments in the hippocampus, which is partly because of neuroinflammation induced by hyperglycemia. Brain-derived neurotrophic factor (BDNF) is essential in modulating neuroplasticity. Its role in anti-inflammation in diabetes is largely unknown. In the present study, we investigated the effects of BDNF overexpression on reducing neuroinflammation and the underlying mechanism in mice with type 1 diabetes induced by streptozotocin (STZ). Animals were stereotactically microinjected in the hippocampus with recombinant adeno-associated virus (AAV) expressing BDNF or EGFP. After virus infection, four groups of mice, the EGFP+STZ, BDNF+STZ, EGFP Control and BDNF Control groups, received STZ or vehicle treatment as indicated. Three weeks later brain tissues were collected. We found that BDNF overexpression in the hippocampus significantly rescued STZ-induced decreases in mRNA and protein expression of two synaptic plasticity markers, spinophilin and synaptophysin. More interestingly, BDNF inhibited hyperglycemia-induced microglial activation and reduced elevated levels of inflammatory factors (TNF-α, IL-6). BDNF blocked the increase in HMGB1 levels and specifically, in levels of one of the HMGB1 receptors, RAGE. Downstream of HMGB1/RAGE, the increase in the protein level of phosphorylated NF-κB was also reversed by BDNF in STZ-treated mice. These results show that BDNF overexpression reduces neuroinflammation in the hippocampus of type 1 diabetic mice and suggest that the HMGB1/RAGE/NF-κB signaling pathway may contribute to alleviation of neuroinflammation by BDNF in diabetic mice.

In recent years, cation-chloride cotransporters (CCCs) have drawn attention in the medical neuroscience research. CCCs include the family of Na⁺-coupled Cl^- importers (NCC, NKCC1, and NKCC2), K⁺-coupled Cl^- exporters (KCCs), and possibly polyamine transporters (CCC9) and CCC interacting protein (CIP1). For decades, CCCs have been the targets of several commonly used diuretic drugs, including hydrochlorothiazide, furosemide, and bumetanide. Genetic mutations of NCC and NKCC2 cause congenital renal tubular disorders and lead to renal salt-losing hypotension, secondary hyperreninemia, and hypokalemic metabolic alkalosis. New studies reveal that CCCs along with their regulatory WNK (Kinase with no lysine (K)), and SPAK (Ste20-related proline-alanine-rich kinase)/OSR1(oxidative stress-responsive kinase-1) are essential for regulating cell volume and maintaining ionic homeostasis in the nervous system, especially roles of the WNK-SPAK-NKCC1 signaling pathway in ischemic brain injury and hypersecretion of cerebrospinal fluid in post-hemorrhagic hydrocephalus. In addition, disruption of Cl^- exporter KCC2 has an effect on synaptic inhibition, which may be involved in developing pain, epilepsy, and possibly some neuropsychiatric disorders. Interference with KCC3 leads to peripheral nervous system neuropathy as well as axon and nerve fiber swelling and psychosis. The WNK-SPAK/OSR1-CCCs complex emerges as therapeutic targets for multiple neurological diseases. This review will highlight these new findings.

Oxidative stress is defined as an imbalance between production of free radicals and reactive metabolites or [reactive oxygen species (ROS)] and their elimination by through protective mechanisms, including (antioxidants). This Such imbalance leads to damage of cells and important biomolecules and cells, with hence posing a potential adverse impact on the whole organism. At the center of the day-to-day biological response to oxidative stress is the Kelch-like ECH-associated protein 1 (Keap1) - nuclear factor erythroid 2-related factor 2 (Nrf2)- antioxidant response elements (ARE) pathway, which regulates the transcription of many several antioxidant genes that preserve cellular homeostasis and detoxification genes that process and eliminate carcinogens and toxins before they can cause damage. The redox-sensitive signaling system Keap1/Nrf2/ARE plays a key role in the maintenance of cellular homeostasis under stress, inflammatory, carcinogenic, and pro-apoptotic conditions, which allows us to consider it as a pharmacological target. Herein, we review and discuss the recent advancements in the regulation of the Keap1/Nrf2/ARE system, and its role under physiological and pathophysiological conditions, e.g. such as in exercise, diabetes, cardiovascular diseases, cancer, neurodegenerative disorders, stroke, liver and kidney system, etc. and such.

The innate immune system is an ancient and primary component system that rapidly reacts to defend the body against external pathogens. C1 is the initial responder of classical pathway of the innate immune system. C1 is comprised of C1q, C1r, and C1s. Among them, C1q is known to interact with diverse ligands, which can perform various functions in physiological and pathophysiological conditions. Because C1q participates in the clearance of pathogens, its interaction with novel receptors is expected to facilitate apoptosis induction, which could prevent the onset or progression of neurodegenerative diseases and could delay the aging process. Because senescence-associated secreting phenotype determinants are generally inflammatory cytokines or immune factors to activate immune cells. In the central nervous system, C1q has diverse neuroprotective roles against pathogens and inflammation. Most of neurodegenerative diseases show region specific pathology feature in the brain. It has been suggested the evidences that the active site and amount of C1q may be disease specific. This review considers currently the emerging and under-recognized roles of C1q in neurodegeneration and highlights the need for further research to clarify these roles. Future studies on the roles of C1q in regulating disease progression should consider these aspects, including the age-dependent onset time of each neurodegenerative disease progression.

Astrocytes, the largest and most numerous glial cells in the central nervous system (CNS), play a variety of important roles in regulating homeostasis, increasing synaptic plasticity and providing neuroprotection, thus helping to maintain normal brain function. At the same time, astrocytes can participate in the inflammatory response and play a key role in the progression of neurodegenerative diseases. Reactive astrocytes are strongly induced by numerous pathological conditions in the CNS. Astrocyte reactivity is initially characterized by hypertrophy of soma and processes, triggered by different molecules. Recent studies have demonstrated that neuroinflammation and ischemia can elicit two different types of reactive astrocytes, termed A1s and A2s. However, in the case of astrocyte reactivity in different neurodegenerative diseases, the recently published research issues remain a high level of conflict and controversy. So far, we still know very little about whether and how the function or reactivity of astrocytes changes in the progression of different neurodegenerative diseases. In this review, we aimed to briefly discuss recent studies highlighting the complex contribution of astrocytes in the process of various neurodegenerative diseases, which may provide us with new prospects for the development of an excellent therapeutic target for neurodegenerative diseases.

Aging is the progressive decline of physiological functions necessary for survival and reproduction. In gaining a better understanding of the inevitable aging process, the hope is to preserve, promote, or delay healthy aging through the treatment of common age-associated diseases. Although there are theories that try to explain the aging process, none of them seem to fully satisfy. Microcirculation describes blood flow through the capillaries in the circulatory system. The main functions of the microcirculation are the delivery of oxgen and nutrients and the removal of CO₂, metabolic debris, and toxins. The microcirculatory impairment or dysfunction over time will result in the accumulation of toxic products and CO₂ and loss of nutrition supplementation and O₂ in corresponding tissue systems or internal organs, which eventually affect normal tissue and organ functions, leading to aging. Therefore, I propose a microcirculatory theory of aging: aging is the process of continuous impairment of microcirculation in the body.