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Previous studies suggested the role of cellular senescence in late-life depression (LLD). However, it is unclear how this finding relates to common features of LLD, such as medical and cognitive problems. We applied factor analyses to an extensive battery of clinical variables in 426 individuals with LLD. Here we tested the relationship between these factors, age and sex, with an index of cellular senescence based on 22 senescence-associated secretory phenotype proteins. We found four factors: ‘depression and anxiety severity’, ‘cognitive functioning’, ‘cardiovascular and cardiometabolic health’ and ‘blood pressure’. A higher senescence-associated secretory phenotype index was associated with poorer ‘cognitive functioning’ and ‘cardiovascular and cardiometabolic health’ but not with ‘depression and anxiety severity’. These findings highlight the role of cellular senescence in poorer physical and cognitive health in LLD. They are consonant with the viewpoint that co-occurring medical burdens and their associated disabilities are part of a phenotype of accelerated ageing in LLD.

In older adults, major depressive disorder (MDD) is associated with accelerated physiological and cognitive aging, generating interest in uncovering biological pathways that may be targetable by interventions. Growth differentiation factor-15 (GDF-15) plays a significant role in biological aging via multiple biological pathways relevant to age and age-related diseases. Elevated levels of GDF-15 correlate with increasing chronological age, decreased telomerase activity, and increased mortality risk in older adults. We sought to evaluate the circulating levels of GDF-15 in older adults with MDD and its association with depression severity, physical comorbidity burden, age of onset of first depressive episode, and cognitive performance.This study assayed circulating levels of GDF-15 in 393 older adults (mean ± SD age 70 ± 6.6 years, male:female ratio 1:1.54), 308 with MDD and 85 non-depressed comparison individuals.After adjusting for confounding variables, depressed older adults had significantly higher GDF-15 serum levels (640.1 ± 501.5 ng/mL) than comparison individuals (431.90 ± 223.35 ng/mL) (t=3.75, d.f.= 391, p=0.0002). Among depressed individuals, those with high GDF-15 had higher levels of comorbid physical illness, lower executive cognitive functioning, and higher likelihood of having late-onset depression.Our results suggest that depression in late life is associated with GDF-15, a marker of amplified age-related biological changes. GDF-15 is a novel and potentially targetable biological pathway between depression and accelerated aging, including cognitive aging.

Alzheimer's disease (AD) is characterized by progressive, irreversible loss of memory and cognitive function. Drosophila melanogaster and other animal models are used to study several diseases, in order to elucidate unknown mechanisms and develop potential therapies. Molecular studies require biological samples and, for neuropathologies such as AD biopsy of the human brain, are invasive and potentially damaging. The solution is to use animal models, such as D. melanogaster, which is a model organism that can replace mammalian organisms in such studies. In this study, we evaluated the climbing ability and differential gene expression during AD progression due to the amylodoigenic pathway using RNA-seq, and we performed an in silico analysis of a fruit fly AD-like GFP (Green Fluorescent Protein) model with GFP expression in the pan-neural elav driver. A total of 1388 genes were differentially expressed in all analyzed groups. The main pathways related to those Differentially Expressed Genes (DEGs) during aging and AD progression were evaluated using the fly genes and human orthologs, in order to link genomic information to higher-order functional information with gene pathway mapping. We identified pathways present in all analyzed groups, such as metabolic pathways, ribosomal pathways, proteasome pathways and immune system pathways. Some of the genes were validated by qPCR. Knockdown of CG17754 gene by RNAi promoted degeneration in the fly eye, validating these findings in vivo. The identification of similarities in molecular pathways between the transgenic fly AD-like GFP model and mammals related to AD provides new insights into the use of this fly in screening novel anti-AD drugs.

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.

Objective To evaluate the circulating cell-free mitochondrial DNA (ccf-mtDNA) levels, a marker of cellular stress and damage, in older adults with late-life depression (LLD) and frailty. We hypothesize that individuals with both frailty and LLD will have higher ccf-mtDNA levels than individuals with either condition in isolation. Methods Fifty-three older adults (Never Depressed+Robust (reference group, n = 16), LLD+Robust (n = 9), Never Depressed+Prefrail/Frail (n = 5), and LLD+Prefrail/Frail (n = 23)) were included in the study. DNA was extracted from EDTA plasma samples, and ccf-mtDNA was quantified by RT-PCR. Results We found a statistically significant difference in the levels of ccf-mtDNA across groups (F(3,49) = 3.07, p = 0.036), with individuals in the LLD+Prefrail/Frail group showing the highest levels of ccf-mtDNA. Conclusion The coexistence of LLD and frailty is associated with increased markers of cellular damage and stress (i.e., ccf-mtDNA). Our results suggest that these conditions may share cellular stress and mitochondrial dysfunction phenomena as a common biological mechanism, offering potential future opportunities for geroscience-guided interventions for these conditions.

Objectives Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late‐life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults. Methods/design We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM‐V criteria), aged 60–90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve. Results TL was significantly shorter in the LLD compared with control participants (p = .039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale‐21, r = −0.325, p = .004) and medical burden (r = −0.271, p = .038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p = .21). Conclusions We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age‐associated adverse outcomes linked to depression., Our study explores and examines the relationship between telomere length (TL) and Late‐Life Depression (LLD), considering the severity of depressive episodes. We found that TL was significantly shorter in the LLD than control participants and was negatively correlated with the severity of depressive symptoms and medical burden. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age‐associated adverse outcomes linked to depression.

Many older adults with depression do not experience remission with antidepressant treatment, and markers of cellular senescence in late-life depression (LLD) are associated with greater severity of depression, greater executive dysfunction, and higher medical illness burden. Since these clinical characteristics are associated with remission in LLD, molecular and cellular senescence abnormalities could be a possible biological mechanism underlying poor treatment response in this population.To examine whether the senescence-associated secretory phenotype (SASP) index was associated with the likelihood of remission from a depressive episode in older adults.A nonrandomized, open-label clinical trial was conducted between August 2009 and August 2014 in Pittsburgh, Pennsylvania; St Louis, Missouri; and Toronto, Ontario, Canada, with older adults in a current major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnostic criteria. Data from biomarker analyses were reported according to the clinical trial archived plasma samples run in March 2021. Data were analyzed from June to November 2021.Venlafaxine extended release (dose ranging from 37.5 mg to 300 mg daily) for up to 12 weeks.The association between a composite biomarker-based index (SASP index) and treatment remission in older adults with major depression was measured using clinical data and blood samples.There were 416 participants with a mean (SD) age of 60.02 (7.13) years; 64% (265 participants) were self-reported female, and the mean (SD) Montgomery-Asberg Depression Rating Scale score was 26.6 (5.7). Higher SASP index scores were independently associated with higher rates of nonremission, with an increase of 1 unit in the SASP index score increasing the odds of nonremission by 19% (adjusted odds ratio, 1.19; 95% CI, 1.05-1.35; P = .006). In contrast, no individual SASP factors were associated with remission in LLD.Using clinical data and blood samples from a nonrandomized clinical trial, the results of this study suggest that molecular and cellular senescence, as measured with the SASP index, is associated with worse treatment outcomes in LLD. Combining this index score reflecting interrelated biological processes with other molecular, clinical, and neuroimaging markers may be useful in evaluating antidepressant treatment outcomes. These findings inform a path forward for geroscience-guided interventions targeting senescence to improve remission rates in LLD.ClinicalTrials.gov Identifier: NCT00892047.

Background Oxidative stress (OS) has been implicated in the pathophysiology of late-life depression (LLD). Mitochondria are the primary source of oxidative stress and can be significantly damaged with increased OS. Circulating cell-free mtDNA (ccf-mtDNA) is a marker of cellular stress and mitochondria damage triggered by oxidative stress. Methods We evaluated the plasma levels of ccf-mtDNA in between 32 LLD and 21 never-depressed participants. We also investigated the association between ccf-mtDNA and the severity of depressive episodes and cognition performance. Results We found a higher ccf-mtDNA level in LLD cases compared with controls (t = −2.91, p = 0.005). Also, ccf-mtDNA was significantly correlated with the severity of depression (r = 0.42, p = 0.001). There was no significant correlation between ccf-mtDNA and measures of cognitive decline. Limitations The small sample size and cross-sectional design were the main limitations of this study. Conclusion Our results suggest that LLD is associated with elevated mitochondrial damage and cellular stress. If validated, the measurement of ccf-mtDNA in LLD can guide the development of novel treatments focused on cytoprotection and reduction of mitochondrial dysfunction for this condition.

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

DNA oxidative damage is a marker of increased oxidative stress activity. Elevated DNA oxidative damage has been associated with major depressive disorder in young adults, but there is no information about DNA oxidative damage in late-life depression. This study aims to evaluate whether older adults with late-life depression (LLD) has increased DNA oxidative damage compared to healthy older adults.We included 92 participants (57 with LLD [73.2 ± 7.7 years-old] and 35 non-depressed subjects (Controls) [70.5 ± 7.4 years-old]). We analyzed the plasma 8‑hydroxy-2'-deoxyguanosine (8-oxo-dG), a marker of DNA oxidation, using a commercially-available ELISA assay.LLD participants had significantly higher 8-oxo-DG levels compared to controls (P0.001). 8-oxo-dG levels were significantly correlated with depressive symptoms as assessed by the Hamilton Depression Rating Scale (rho=0.34, p0.001). The plasma levels of 8-OHdG were not significantly correlated with other clinical, neurocognitive, and demographic variables.Our current results are limited by the relatively small sample size, cross-sectional design, and the recruitment of participants in tertiary center for assessment and treatment of LLD.Older adults with LLD have increased DNA oxidative damage. Our findings provide additional evidence for elevated oxidative stress activity in LLD and the possible activation of age-related biological pathways and enhanced biological aging changes in LLD.

Introduction Major depressive disorder (MDD) and frailty are common disorders in elderly populations. These conditions are associated with a higher rate of negative health outcomes and comorbidity. In previous studies, the measurement of circulating cell-free mtDNA (ccf-mtDNA) has been used as biomarkers for cellular stress from increased oxidative stress. No study has yet examined if there are synergistic effects of MDD and frailty in older adults through ccf-mtDNA levels. We hypothesized that individuals diagnosed with both frailty and MDD will have higher ccf-mtDNA levels in comparison to individuals with those conditions in isolation. Methods Fifty-three older adults (21 with MDD and 32 controls who were never-depressed) were included in this analysis. Pre-Frail/Frail status was determined by the FRAIL scale. Plasma samples were collected from peripheral blood collections through venipuncture in EDTA tubes. The DNA was extracted from the plasma samples using the QIAmp 96 DNA Blood Kit. The ccf-mtDNA was quantified by RT-PCR. Results There were 5 subjects classified as never-depressed and pre-frail/frail. In addition, 23 subjects were identified as depressed and pre-frail/frail. The ccf-mtDNA was significantly higher in those with MDD compared to the control group (p Conclusions We found a significant interaction between MDD and frailty increasing the ccf-mtDNA. The higher levels of ccf-mtDNA could indicate worsened cellular stress and mitochondrial dysfunction among those with MDD and Frailty. Our data suggest that frailty and MDD have synergistic effects that increase co-morbidity. Future directions could include increasing the sample size to ensure the validity of the findings. Funding Funding was provided by the National Institute of Mental Health (NIMH), USA, and other Canadian funding agencies.

Objective The clinical–epidemiological relationship between major depressive disorder (MDD) and Alzheimer disease (AD) suggests that they may share common neurobiologic abnormalities. Methods The authors conducted a systematic review and identified microRNAs abnormally expressed in both AD and MDD. The pattern of microRNA regulation in each disorder and the genes regulated by each microRNA and the biologic processes and pathways regulated by these genes were identified. Results Seventy-four microRNAs were abnormally expressed in AD and 30 in MDD; 7 were common for both disorders (hsa-let-7f-5p, hsa-miR-664a-3p, hsa-miR-361-5p, hsa-let-7g-5p, hsa-let-7d-5p, hsa-miR-191-5p, hsa-miR-26b-5p). These microRNAs interact with 45 validated genes, and the main biologic pathways and processes regulated by them were proteostasis control, maintenance of genomic integrity, regulation of transcriptional activity, immune-inflammatory control, and neurotrophic support. Conclusion The current results suggest that the maintenance of genomic integrity, proteostasis control, immune-inflammatory regulation, and neurotrophic support are key neurobiologic links between these conditions. A comprehensive hypothetical model for the interaction between MDD, aging, and the development of AD is provided.

Changes in microRNAs (miRNAs) expression have been described in major depressive disorder in young and middle-aged adults. However, no study has evaluated miRNA expression in older adults with major depression (or late-life depression [LLD]). Our primary aim was to evaluate the expression of miRNAs in subjects with LLD. We first evaluated the miRNA expression using next-generation sequencing (NGS) and then we validated the miRNAs found in NGS in an independent sample of LLD patients, using RT-qPCR. Drosophila melanogaster model was used to evaluate the impact of changes in miRNA expression on behavior. NGS analysis showed that hsa-miR-184 (log2foldchange = −4.21, p = 1.2 × 10−03) and hsa-miR-1-3p (log2foldchange = −3.45, p = 1.3 × 10−02) were significantly downregulated in LLD compared to the control group. RT-qPCR validated the downregulation of hsa-miR-184 (p

Epidermal growth factor (EGF) and Fibroblast Growth Factor-2 (FGF-2) are growth factors involved neuronal growth and synaptic plasticity. These markers have been implicated in neuropsychiatric disorders, including major depression. However, no particular studies of EGF and FGF-2 have been conducted in older adults with major depressive disorder (MDD). In this study, we aim to investigate the plasma levels of EGF and FGF-2 in elderly with MDD. We included 89 older adults with MDD and 51 older (healthy control, HC) adults. The cognitive performance was evaluated by the Mattis Dementia Rating Scale (MDRS). The EGF and FGF-2 were measured by using multiplex assay for LUMINEX platform. There were also no significant differences between the patient group in terms of plasma levels of EGF and FGF-2 when compared to the HC group. There were not any significant correlations between plasma levels of EGF or FGF2 and MDRS total or individual scores in patient group and HC. There were significant correlations between plasma levels of EGF and FGF2 in both patient group and HC. Further study on plasma levels of EGF and FGF2 should be implemented in larger samples in elderly with MDD.

A depressão é a desordem psiquiátrica mais comum e causa graves consequências em idosos. Os mecanismos biológicos envolvidos na depressão geriátrica (DG) são complexos e envolvem muitos genes. Os MicroRNAs (miRNAs) são pequenos RNAs não codificadores que regulam pós transcricionalmente a expressão gênica. O desequilíbrio na expressão de miRNAs está relacionado a muitas doenças, incluindo DG. Nosso objetivo foi avaliar os miRNAs plasmáticos associados à DG e possivelmente à gravidade dos sintomas depressivos e ao desempenho cognitivo nesses indivíduos. Um total de 116 amostras de plasma de idosos (63 com DG e 53 controles) foram divididas aleatoriamente para fazer o sequenciamento de nova geração (SNG) e a validação por RT-qPCR. Drosophila melanogaster foi utilizado como modelo translacional para avaliar fenômenos comportamentais associados à superexpressão e ao nocaute do ortólogo de hsa-miR-184. A análise SNG encontrou o hsa-miR-184 (log2foldchange=-4,205 e p-valor=1,195e-03) e o hsamiR-1-3p (log2foldchange=-3,444 e p-valor=1,3251e-02) diferencialmente expressos em indivíduos com DG, mas apenas o hsa-miR-184 (AUC=8378, p valor

Objective: A consistent body of research has confirmed that patients with major depressive disorder (MDD) have increased concentrations of pro-inflammatory cytokines, including IL-6, TNF-α, IL-1β, the soluble IL-2 receptor, and C-reactive protein, compared to controls; however, there is limited information on IL-17A in MDD. Moreover, information about IL-17A in older populations, i.e., patients with late-life depression (LLD), is conspicuously missing from the literature. The purpose of this study was to investigate the role of IL-17A in LLD. Methods: A convenience sample of 129 individuals, 74 with LLD and 55 non-depressed controls, were enrolled in this study. The Mann-Whitney U test was used to compare plasma IL-17A levels between LLD and controls subjects, and Spearman’s rank order correlation was used to investigate correlation of these levels with clinical, neuropsychological, and cognitive assessments. Results: Plasma IL-17A levels were not statistically different between LLD patients and controls (p = 0.94). Among all subjects (LLD + control), plasma IL-17A did not correlate significantly with depressive symptoms (rho = -0.009, p = 0.92) but a significant correlation was observed with cognitive assessments (rho = 0.22, p = 0.01). Conclusion: Our findings do not support an association between plasma IL-17A levels and LLD. Nevertheless, IL-17A may be associated with cognitive impairment in LLD patients. If this finding is confirmed in future longitudinal studies, modulation of the T-helper 17 cell (Th17) immune response may be a treatment target for cognitive impairment in this population.

A soja é uma cultura de grande importância, movimentando aproximadamente 230 bilhões de dólares em todo o mundo, com produção anual estimada de 267,61 milhões de toneladas. Os percevejos sugadores de sementes são considerados uma das pragas de maior importância para a cultura da soja, sendo as espécies Euschistus heros (E.), Piezodorus guildinii (West.) e Nezara viridula (L.) as mais abundantes no Brasil. O ataque por percevejos causa diversos problemas como o atraso da maturação fisiológica, retenção foliar, perdas no rendimento e diminuição da qualidade e potencial germinativo das sementes. Esses insetos são responsáveis ainda pela transmissão de patógenos, e podem causar alterações na composição de óleos, proteínas e ácidos graxos das sementes. A obtenção de cultivares com resistência genética é indispensável, a fim de minimizar a necessidade de utilização de defensivos agrícolas. Dessa forma, este trabalho identificou genes possivelmente associados à resposta de resistência pela comparação da expressão gênica diferencial entre genótipos de soja resistente (IAC-100) e suscetível (CD-215), a partir da metodologia de sequenciamento de RNA (RNA-Seq). As vagens foram submetidas a dois tratamentos por 24 horas: infestação por percevejos Piezodorus guildinii (West.) e não infestação. Foi utilizado o alinhador STAR contra o genoma hardmasked do phytozome e o pacote cufflinks.Com os resultados das análises dos genes diferencialmente expressos e uma posterior filtragem foi possível identificar 128 genes candidatos, dentre estes: genes relacionados com defesa, metabolismo secundário de produção de terpenos e proteínas LRR de sinalização celular. Soybeans are an important crop with a world-wide annual production of 267.61 tons, worth 230 billion dollars. Stink bugs are a major soybean pest. The most abundant species in Brazil are Euschistus heros (E.), Piezodorus guildinii (West.) and Nezara viridula (L.). Stink-bug attack causes several problems, including delayed physiological maturity, leaf retention, yield losses, decreased seed quality, and decreased germination potential. The bugs are responsible for transmitting pathogens, and they can cause changes in the oil, protein, and fatty acids composition in the seed. Producing genetically resistant cultivars is critical in order to minimize the need for agricultural pesticides. Our work aims to identify genes associated with the stink-bug resistance response in soybean by comparing differential gene expression between resistant (IAC-100) and susceptible (CD-215) genotypes by analyzing RNA sequencing (RNA-Seq) data. Data was from soybean pods that were subjected to two treatments for 24 hours: infestation by the stink bug Piezodorus guildinii (West.), and non-infestation. STAR aligner was used against the hard-masked genome sequence from Phytozome, followed by analysis using the Cufflinks package. Analysis of the results of the differentially expressed genes and a subsequent filtering identified 128 candidate defense-associated genes, among them, defense-related such as LRR-RLKs and production of secondary metabolites like terpenes.