Elevated senescence-associated secretory phenotype index in late-life bipolar disorder.

BACKGROUND: The senescence-associated secretory phenotype (SASP) is a biomarker index based on the profile of 22 blood proteins associated with cellular senescence. The SASP index has not been assessed in older patients with bipolar disorder (BD). We hypothesized that older adults with BD will have elevated cellular senescence burden as measured by the SASP index. METHODS: We measured the 22 SASP proteins to calculate the SASP index in 38 older patients with BD and 34 non-psychiatric comparison individuals (HC). RESULTS: The SASP index scores were significantly higher in BD than HC after controlling for age, sex, psychopathology, and physical health (F(1,8) = 5.37, p = 0.024, η2 = 0.08). SASP index scores were also associated with higher age, more severe depressive symptoms, and physical illness burden (p < 0.05) in the whole sample. LIMITATION: Cross-sectional study and small sample size. CONCLUSION: This is the first report of increased SASP index scores in older adults with BD. Our results suggest that dysregulation of age-related biological processes may contribute to more severe depressive symptoms and worse physical health in older adults with BD.

Plasma proteomic signature of major depressive episode in the elderly.

Depression is a complex and multifactorial disease, affecting about 6.5% of the elderly population in what is referred to as late-life depression (LLD). Despite its public health relevance, there is still limited information about the molecular mechanisms of LLD. We analyzed the blood plasma of 50 older adults, 19 with LLD and 31 controls, through untargeted mass spectrometry, and used systems biology tools to identify biochemical pathways and biological processes dysregulated in the disease. We found 96 differentially expressed proteins between LLD patients and control individuals. Using elastic-net regression, we generated a panel of 75 proteins that comprises a potential model for determining the molecular signature of LLD. We also showed that biological pathways related to vesicle-mediated transport and voltage-dependent calcium channels may be dysregulated in LLD. These data can help to build an understanding of the molecular basis of LLD, offering an integrated view of the biomolecular alterations that occur in this disorder. SIGNIFICANCE: Major depressive disorder in the elderly, called late-life depression (LLD), is a common and disabling disorder, with recent prevalence estimates of 6.5% in the general population. Despite the public health relevance, there is still limited information about the molecular mechanisms of LLD. The findings in this paper shed light on LLD heterogeneous biological mechanisms. We uncovered a potential novel biomolecular signature for LLD and biological pathways related to this condition which can be targets for the development of novel interventions for prevention, early diagnosis, and treatment of LLD.

Metabotropic glutamate receptor 5 knockout rescues obesity phenotype in a mouse model of Huntington's disease.

Obesity represents a global health problem and is characterized by metabolic dysfunctions and a low-grade chronic inflammatory state, which can increase the risk of comorbidities, such as atherosclerosis, diabetes and insulin resistance. Here we tested the hypothesis that the genetic deletion of metabotropic glutamate receptor 5 (mGluR5) may rescue metabolic and inflammatory features present in BACHD mice, a mouse model of Huntington's disease (HD) with an obese phenotype. For that, we crossed BACHD and mGluR5 knockout mice (mGluR5-/-) in order to obtain the following groups: Wild type (WT), mGluR5-/-, BACHD and BACHD/mGluR5-/- (double mutant mice). Our results showed that the double mutant mice present decreased body weight as compared to BACHD mice in all tested ages and reduced visceral adiposity as compared to BACHD at 6 months of age. Additionally, 12-month-old double mutant mice present increased adipose tissue levels of adiponectin, decreased leptin levels, and increased IL-10/TNF ratio as compared to BACHD mice. Taken together, our preliminary data propose that the absence of mGluR5 reduce weight gain and visceral adiposity in BACHD mice, along with a decrease in the inflammatory state in the visceral adipose tissue (VAT), which may indicate that mGluR5 may play a role in adiposity modulation.

Mild cognitive impairment and major depressive disorder are associated with molecular senescence abnormalities in older adults.

INTRODUCTION: The biological mechanisms linking mild cognitive impairment (MCI) and major depressive disorder are not well understood. We investigated whether molecular senescence changes in older adults are associated with a history of major depressive disorder (MDD) or MCI. METHODS: We included 371 participants: 167 with MCI; 62 cognitively normal with a history of MDD; 97 with MDD+MCI; and 45 cognitively unimpaired (CU) without a history of MDD. The candidate Senescence-Associated Secretory Phenotype (SASP) biomarkers were measured in the plasma using a customized LUMINEX assay. RESULTS: The MDD+MCI group had a higher SASP index than the other groups (P < .001). A higher SASP index was significantly associated with worse global cognitive performance, executive dysfunction, slower processing speed, and episodic memory deficits. DISCUSSION: Our study suggests that increased molecular changes are associated with cognitive impairment in older adults with MDD and indicate that accelerated biological aging is an underlying feature of MDD.

Negative Modulation of the Metabotropic Glutamate Receptor Type 5 as a Potential Therapeutic Strategy in Obesity and Binge-Like Eating Behavior.

Obesity is a multifactorial disease, which in turn contributes to the onset of comorbidities, such as diabetes and atherosclerosis. Moreover, there are only few options available for treating obesity, and most current pharmacotherapy causes severe adverse effects, while offering minimal weight loss. Literature shows that metabotropic glutamate receptor 5 (mGluR5) modulates central reward pathways. Herein, we evaluated the effect of VU0409106, a negative allosteric modulator (NAM) of mGluR5 in regulating feeding and obesity parameters. Diet-induced obese C57BL/6 mice were treated for 14 days with VU0409106, and food intake, body weight, inflammatory/hormonal levels, and behavioral tests were performed. Our data suggest reduction of feeding, body weight, and adipose tissue inflammation in mice treated with high-fat diet (HFD) after chronic treatment with VU0409106. Furthermore, a negative modulation of mGluR5 also reduces binge-like eating, the most common type of eating disorder. Altogether, our results pointed out mGluR5 as a potential target for treating obesity, as well as related disorders.