Normal aging induces PD-1-enriched exhausted microglia and A1-like reactive astrocytes in the hypothalamus.

Hypothalamic aging is considered to be critical for systemic aging, and the accumulation of "exhausted glial cells" in the hypothalamus may contribute to brain dysfunction. In this study, we used normal aging mice and investigated aging-specific transcriptional identities of microglia and astrocytes in the hypothalamus. We confirmed that normal aging promoted anxiety, induced impairment of motor coordination and reduced physical strength of muscle in mice. To investigate the senescence of hypothalamic glial cells, we isolated CD11b-positive microglia and ACSA-2-positive astrocytes from the hypothalamus of aged mice using magnetic-activated cell sorting (MACS). The mRNA level of p16INK4A was dramatically increased in the hypothalamic microglia of aged mice compared to young mice. Furthermore, the expression of programmed cell death 1 (PD-1) as well as A1-like astrocyte mediators in the hypothalamic microglia was dramatically induced by aging, indicating that normal aging may produce PD-1-enriched "exhausted microglia" in the hypothalamus. Furthermore, neuroinflammatory A1-like reactive astrocytes with a p16INK4A-positive senescent state were predominantly detected in the hypothalamus of aged mice. Exhausted microglia were also detected in the prefrontal cortex of aged mice, whereas astrocytic neuroinflammation was milder than that observed in the hypothalamus, even with p16INK4A-positive senescence. These results suggest that the production of PD-1-enriched exhausted and senescent microglia and neuroinflammatory A1-like reactive astrocytes in the hypothalamus may partly contribute to aging-related emotional and physical dyscoordination.

Association between bone mineral density, muscle volume, walking ability, and geriatric nutritional risk index in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Hemodialysis patients are at risk for bone loss and sarcopenia, characterized by reduced muscle mass and limited mobility/function. Osteoporosis and sarcopenia both increase the risk of hospitalization and death in affected individuals. Malnutrition also occurs as a complication of hemodialysis and has been identified as a risk factor for osteoporosis and sarcopenia. In this study, we examined the relationship between osteoporosis, muscle volume, walking ability, and malnutrition in hemodialysis patients. METHODS AND STUDY DESIGN: Forty-five hemodialysis patients were evaluated. Bone mineral density (BMD) and muscle volume were measured by dual-energy X-ray absorptiometry. Muscle volume and strength were evaluated using lean mass index (LMI), handgrip strength, and walking ability. The time required for a patient to walk 10 meters was measured to evaluate walking ability. The geriatric nutritional risk index (GNRI) was used to assess malnutrition. RESULTS: Multiple linear regression analysis showed that older age, female sex, lower LMI, and higher total type I procollagen N-terminal propeptide were correlated with lower BMD of lumbar spine. Higher age and lower LMI were correlated with lower BMD of the femoral neck. Female sex and lower GNRI were correlated with lower LMI. Longer duration of hemodialysis was correlated with lower walking ability. CONCLUSIONS: Our findings suggest that muscle preservation is required to maintain both lumbar spine and femoral neck BMD. Similarly, nutritional management is necessary to maintain BMD via preservation of muscle volume. Complementary nutritional therapies are needed to improve osteoporosis and sarcopenia in high-risk hemodialysis patients.

Association between Bone Mineral Density of Femoral Neck and Geriatric Nutritional Risk Index in Rheumatoid Arthritis Patients Treated with Biological Disease-Modifying Anti-Rheumatic Drugs.

Treatment of rheumatoid arthritis (RA) with biological disease-modifying anti-rheumatic drugs (bDMARDs) induces rapid remission. However, osteoporosis and its management remains a problem. The Geriatric Nutritional Risk Index (GNRI) evaluates the risk of malnutrition-related complications in elderly patients and has been shown to be a significant predictor of many diseases. We evaluated the correlation between GNRI and RA activity. In addition, risk factors for femoral neck bone loss were evaluated in RA patients treated with bDMARDs. We retrospectively examined the medical records of 146 patients with RA, collecting and recording the patients' demographic and clinical characteristics. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Inverse correlations were observed between GNRI and disease duration, disease activity score-28 joint count serum C-reactive protein (CRP), simple disease activity index, modified health assessment questionnaire score and CRP. GNRI showed correlation with femoral neck BMD and femoral neck BMD ≤ 70% of young adult men (YAM). Multiple regression analysis showed that female sex, increased age and lower GNRI were risk factors for lower BMD of the femoral neck. Multivariate binomial logistic regression analysis showed that female sex (odd ratio: 3.67) and lower GNRI (odd ratio: 0.87) were risk factors for BMD ≤ 70% of YAM. Because the GNRI is a simple method, it might be a simple predictor for RA activity and BMD status in RA patients. Complementary nutritional therapies might improve RA activity and osteoporosis in RA patients who have undergone treatment with bDMARDs.

Risk factors for bone loss in patients with rheumatoid arthritis treated with biologic disease-modifying anti-rheumatic drugs.

OBJECTIVE: Osteoporosis is a complication of rheumatoid arthritis. We examined the risk factors for bone loss in rheumatoid arthritis patients receiving biological disease-modifying anti-rheumatic drugs. Lumbar spine and femoral neck bone mineral density was measured at two time points in 153 patients with rheumatoid arthritis managed with biological disease-modifying anti-rheumatic drugs. We examined patients' variables to identify risk factors for least significant reduction of bone mineral density. RESULTS: Least significant reduction of lumbar spine bone mineral density (≤ - 2.4%) was seen in 13.1% of patients. Least significant reduction of femoral neck bone mineral density (≤ - 1.9%) was seen in 34.0% of patients. Multiple logistic regression analysis showed that a risk factor for least significant reduction of the lumbar spine was high-dose methylprednisolone use. Multiple regression analysis showed that a risk factor for least significant reduction of the femoral neck was short disease duration. Our findings showed that a risk factor for femoral neck bone mineral density reduction was a short disease duration. These findings suggest that rheumatoid arthritis patients receiving treatment with biological disease-modifying anti-rheumatic drugs may benefit from earlier osteoporosis treatments to prevent femoral neck bone loss.