Looked for a recent follow-on study of the 2021 Precondition your defenses with broccoli sprouts, specifically:
“NFE2L2/NRF2 is a target gene of TFEB (transcription factor EB), a master regulator of autophagic and lysosomal functions, which we show here to be potently activated by sulforaphane.”
Some interesting papers cited it, but no studies continued its sulforaphane/TFEB line of inquiry. A 2022 review made a good point when citing this study for TFEB, but didn’t tie it in with sulforaphane:
“TFEB is translocated into the nucleus with a moderate increase of ROS through a Ca2+-dependent, but mTOR (mechanistic target of rapamycin kinase)-independent mechanism. Essential genes involved in lysosome biogenesis and autophagosome are activated, which are crucial for removal of damaged mitochondria.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9730074/ “Phytochemicals and modulation of exercise-induced oxidative stress: a novel overview of antioxidants”
A search of TFEB brought up a 2023 nematode study:
“We searched for effectors acting downstream of the transcription factor EB (TFEB), known as HLH-30 in C. elegans, because TFEB/HLH-30 is necessary across anti-aging interventions. Its overexpression is sufficient to extend C. elegans lifespan, and reduce biomarkers of aging in mammals including humans.
While investigating the potential role of autophagy in hlh-30 dependent longevity of the mxl-3 C. elegans mutant, we found that the current model has exceptions. Contrary to expectation, we found that autophagy is not activated in the mxl-3 mutant, and that neither autophagy nor lysosomal activity are required for the longevity phenotype observed in these mutant animals. mxl-3 longevity is hlh-30-dependent but autophagy-independent.
Instead, we found the gene encoding Alcohol DeHydrogenase ADH-1 induced in mxl-3 and other hlh-30-dependent anti-aging interventions. adh-1 is induced in an hlh-30-dependent manner in longevity models caloric restriction (eat-2), insulin insensitivity (daf-2), and mTOR inhibition (let-363 RNAi).
We present an alcohol-dehydrogenase-mediated anti-aging response (AMAR) that is essential for C. elegans longevity driven by HLH-30 overexpression, caloric restriction, mTOR inhibition, and insulin-signaling deficiency. Overexpression of ADH-1 is sufficient to activate AMAR, which extends healthspan and lifespan by reducing levels of glycerol, an age-associated and aging-promoting alcohol.”
https://www.cell.com/current-biology/fulltext/S0960-9822(23)00128-8 “Increased alcohol dehydrogenase 1 activity promotes longevity” (not freely available) Thanks to Dr. Eyleen O’Rourke for providing a copy.
A 2022 human study found that chronic ADH1 activation occurs in liver disease:
“Activity of total ADH, ADH isoenzymes and aldehyde dehydrogenase (ALDH) was evaluated in the blood serum of patients with primary biliary cholangitis (PBC), a chronic autoimmune disease of the liver. An increase in class I ADH and total ADH activity indicates that the isoenzyme class I ADH is released by compromised liver cells and can be useful diagnostic markers of PBC.”
https://link.springer.com/article/10.1007/s00005-022-00667-4 “An Assessment of the Serum Activity of ADH and ALDH in Patients with Primary Biliary Cholangitis”
Chronically activating any of the body’s systems points to a problem. There’s has to be a balance.
A 2022 rodent study investigated ADH1 activation and MEK1/2 inhibitors for beneficial effects:
“Alcohol is mainly catabolized by class I alcohol dehydrogenase (ADH1) in liver. ADH deficiency can aggravate ethanol-induced tissue injury.
Extracellular signal-regulated kinases 1/2 (ERK1/2) is involved in alcohol metabolism. However, the relationship between ERK1/2 and ADH1 remains unclear.
Mitogen-activated protein kinases 1/2 (MEK1/2) is required to phosphorylate and activate ERK1/2. Protein expression of phosphorylated ERK1/2 in liver is inversely associated with ethanol-induced liver injury and hepatocytes apoptosis, suggesting inhibition of ERK1/2 may protect hepatocytes from ethanol-induced cytotoxicity. We hypothesize that inhibition of ERK1/2 by MEK1/2 inhibitors may protect hepatocytes from ethanol cytotoxicity by activating ADH1 expression.
Results showed MEK1/2 inhibitors significantly increased ADH1 protein expression by inducing its transcription activity. Our findings revealed inhibition of ERK1/2 can significantly increase ADH1 expression, indicating MEK1/2 inhibitors may possess potential application in alcohol-related diseases.”
https://link.springer.com/article/10.1007/s11033-022-07361-w “MEK1/2 inhibitors induce class I alcohol dehydrogenase (ADH1) expression by regulating farnesoid X receptor in hepatic cell lines and C57BL/6J mouse” (not freely available)
Chronically inhibiting any of the body’s systems also points to a problem.
A 2022 rodent study investigated TFEB activation and MEK1/2 inhibitors for beneficial effects:
“Inhibiting MEK/ERK signaling using a clinically available MEK1/2 inhibitor induces protection of neurons through autophagic lysosomal activation mediated by transcription factor EB (TFEB) in a model of AD.”
https://www.nature.com/articles/s41380-022-01713-5 “MEK1/2 inhibition rescues neurodegeneration by TFEB-mediated activation of autophagic lysosomal function in a model of Alzheimer’s Disease”
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