A concerted neuron–astrocyte program declines in ageing and schizophrenia

Ling, Emi; Nemesh, James; Goldman, Melissa; Kamitaki, Nolan; Reed, Nora; Handsaker, Robert E.; Genovese, Giulio; Vogelgsang, Jonathan S.; Gerges, Sherif; Kashin, Seva; Ghosh, Sulagna; Esposito, John M.; Morris, Kiely; Meyer, Daniel; Lutservitz, Alyssa; Mullally, Christopher D.; Wysoker, Alec; Spina, Liv; Neumann, Anna; Hogan, Marina; Ichihara, Kiku; Berretta, Sabina; McCarroll, Steven A.

doi:10.1038/s41586-024-07109-5

Cited by 22 publications

(12 citation statements)

References 159 publications

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“…Notably, several studies have indicated a high prevalence of frailty among individuals diagnosed with schizophrenia, including those in younger age groups ( 39 , 40 ). Recent studies also have demonstrated strikingly similar patterns of gene activity in aging and schizophrenic patients, particularly in neurons and astrocytes in the prefrontal cortex ( 41 ). This indicates a potential association between frailty and schizophrenia.…”

Section: Discussionmentioning

confidence: 98%

Bidirectional causal relational between frailty and mental illness: a two-sample Mendelian randomization study

Ma,

Liu,

et al. 2024

Front. Psychiatry

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BackgroundFrailty has been associated with mental illness (MI) observational studies, but the causal relationship between these factors remains uncertain. We aimed to assess the bidirectional causality between frailty and MI by two-sample Mendelian randomization (MR) analyses.MethodsTo investigate the causal relationship among them, summary statistics of frailty index (FI) and six types of MI: anxiety, depression, affective disorder, mania, schizophrenia, and obsessive-compulsive disorder (OCD) were included in this MR study. This MR analysis was performed using inverse variance weighting (IVW), MR-Egger regression, and weighted median. The stability of the results was evaluated using Cochran’s Q test, MR-Egger intercept test, Funnel Plots, and leave-one-out analysis.ResultsGenetic predisposition to FI was significantly associated with increased anxiety (odds ratio [OR] = 1.62, 95% confidence interval [CI] 1.13-2.33, P = 8.18E-03), depression (OR = 1.88, 95% CI 1.30-2.71, P = 8.21E-04), affective disorder (OR = 1.70, 95% CI 1.28-2.27, P = 2.57E-04). However, our study findings do not demonstrate a causal relationship between FI and mania (OR = 1.02, 95% CI 0.99-1.06, P = 2.20E-01), schizophrenia (OR = 1.02, 95% CI 0.07-0.86, P = 9.28E-01). In particular, although the IVW results suggest a potential causal relationship between FI and OCD (OR = 0.64, 95% CI 0.07-0.86, P = 2.85E-02), the directions obtained from the three methods we employed ultimately show inconsistency. Therefore, the result must be interpreted with caution. The results of the reverse MR analysis indicated a statistically significant and causal relationship between anxiety (OR = 1.06, 95% CI 1.01-1.11, P = 2.00E-02), depression (OR = 1.14, 95% CI 1.04-1.26, P = 7.99E-03), affective disorder (OR = 1.15, 95% CI 1.09-1.21, P = 3.39E-07), and schizophrenia (OR = 1.02, 95% CI 1.01-1.04, P = 1.70E-03) with FI. However, our findings do not provide support for a link between mania (OR = 1.46, 95% CI 0.79-2.72, P = 2.27E-01), OCD (OR = 1.01, 95% CI 1.00-1.02, P = 2.11E-01) and an increased risk of FI.ConclusionThe MR results suggest a potential bidirectional causal relationship between FI and anxiety, depression, and affective disorder. Schizophrenia was found to be associated with a higher risk of FI. The evidence was insufficient to support a causal relationship between Fl and other Ml. These findings offer new insights into the development of effective management strategies for frailty and MI.

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Section: Discussionmentioning

confidence: 98%

Bidirectional causal relational between frailty and mental illness: a two-sample Mendelian randomization study

Ma,

Liu,

et al. 2024

Front. Psychiatry

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“…are gut microbes also known for interfering with the dopaminergic signaling, further linking cellular senescence to insufficient DA [31,32]. This is significant since both treated and untreated SCZ patients were found to exhibit body-wide premature cellular/neuronal aging, linking this condition to abnormal intestinal permeability [33,34]. Indeed, SCZ was associated with increased microbial migration into the host systemic circulation [35][36][37].…”

Section: Premature Cellular Senescence In Schizophreniamentioning

confidence: 99%

The Future of Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

Sfera,

Imran,

Sfera

et al. 2024

Preprint

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For the past 70 years, dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling, antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there was limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal, senescence, brain volume loss, attenuation of gamma oscillations on electroencephalogram and oxidation of lipids in plasma and mitochondrial membranes. We surmise that aberrant activation of aryl hydrocarbon receptor by toxins derived from the gut microbes or the environment drives premature cellular, including neuronal, senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: 1. To summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders. 2. To discuss novel strategies for improving long-term outcome in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor.

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“…are gut microbes also known for interfering with dopaminergic signaling, further linking cellular senescence to insufficient DA [ 31 , 32 ]. This is significant since both treated and untreated SCZ patients were found to exhibit body-wide premature cellular/neuronal aging, linking this condition to abnormal intestinal permeability [ 33 , 34 ]. Indeed, SCZ has been associated with increased microbial migration into the host’s systemic circulation [ 35 , 36 , 37 ].…”

Section: Premature Cellular Senescence In Schizophreniamentioning

confidence: 99%

Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

Sfera,

Imran,

Sfera

et al. 2024

IJMS

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For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists.

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A concerted neuron–astrocyte program declines in ageing and schizophrenia

Cited by 22 publications

References 159 publications

Bidirectional causal relational between frailty and mental illness: a two-sample Mendelian randomization study

Bidirectional causal relational between frailty and mental illness: a two-sample Mendelian randomization study

The Future of Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

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