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Background: Aging is associated with multiple neurodegenerative conditions that severely limit quality of life and can shorten lifespan. Studies in rodents indicate that in addition to extending lifespan, the ketogenic diet (KD) improves cognitive function in aged animals, yet long term adherence to KD in Humans is poor. Objectives: To broadly investigate what mechanisms might be activated in the brain in response to ketogenic diet. Methods: We conducted transcriptome wide analysis on whole brain samples from 13-month-old mice, 13-month-old mice fed a ketogenic diet for 1 month, 26-month-old mice, and 26-month-old mice fed a ketogenic diet for 14 months. Results: As expected, analysis of differently expressed genes between the old (26 month) vs younger mice (13 month) showed clear activation of inflammation and complement system pathways with aging. Analysis between the 26-month-old animals fed ketogenic diet for 14 months with 26-month-old animals fed control diet indicate that long-term KD resulted in activation of LRP, TCF7L2 (WNT pathway), and IGF1 signaling. There was also a significant increase in the expression of SOX2-dependent oligodendrocyte/myelination markers, though TCF7L2 and SOX2 dependent gene sets were largely overlapping. Remarkably, the effect of 1 month of ketogenic diet was minimal and there was no congruence between gene expression effects of short-term KD vs long-term KD. Conclusions: This work informs target identification efforts for aging and neurodegenerative disorder therapeutics discovery while also establishing differential effects of short-term vs long-term KD on gene expression in the brain.

Humans are frequently exposed to Quaternary Ammonium Compounds (QACs). QACs are ubiquitously used in medical settings, restaurants, and homes as cleaners and disinfectants. Despite their prevalence, nothing is known about the health effects associated with chronic low-level exposure. Chronic QAC toxicity, only recently identified in mice, resulted in developmental, reproductive, and immune dysfunction. Cell based studies indicate increased inflammation, decreased mitochondrial function, and disruption of cholesterol synthesis. If these findings translate to human toxicity, multiple physiological processes could be affected. This study tested whether QAC concentrations could be detected in the blood of 43 human volunteers, and whether QAC concentrations influenced markers of inflammation, mitochondrial function, and cholesterol synthesis. QAC concentrations were detected in 80 % of study participants. Blood QACs were associated with increase in inflammatory cytokines, decreased mitochondrial function, and disruption of cholesterol homeostasis in a dose dependent manner. This is the first study to measure QACs in human blood, and also the first to demonstrate statistically significant relationships between blood QAC and meaningful health related biomarkers. Additionally, the results are timely in light of the increased QAC disinfectant exposure occurring due to the SARS-CoV-2 pandemic. Main Findings: This study found that 80 % of study participants contained QACs in their blood; and that markers of inflammation, mitochondrial function, and sterol homeostasis varied with blood QAC concentration.

Maternal inheritance of a pathogenic point mutation within complex I of the mitochondrial genome causes Leber's hereditary optic neuropathy (LHON), resulting in the neurodegeneration and demyelination of the optic nerve. The integrated stress response (ISR), a signaling pathway that responds to various stresses by activating a common set of genes, has been linked to both mitochondrial defects and demyelinating diseases. Therefore, we wanted to determine whether mitochondrial dysfunction induced by complex I inhibition with rotenone can activate the ISR, specifically by the ER kinase PERK, in oligodendroglial cells. Our complex I-deficient oligodendroglial model reproduced similar biochemical defects as in LHON by decreasing ATP synthesis and ATP levels. The same doses of rotenone that reduced ATP production also induced dose-dependent increases in PERK and eIF2α phosphorylation as well as activated the ISR stress genes, ATF4 and CHOP. In addition, complex I inhibition at these same concentrations induced a PERK-dependent activation of the cell death kinase, JNK, and inhibited oligodendroglial proliferation. Taken together, our results demonstrate that activation of the ISR may be one example of mitochondrial retrograde signaling in response to complex I deficiency and we suggest that this response mechanism may be relevant to the pathophysiology of LHON.