The Roles of White Adipose Tissue and Liver NADPH in Dietary Restriction-Induced Longevity

Antioxidants, Journal Year: 2024, Volume and Issue: 13(7), P. 820 - 820

Published: July 8, 2024

Dietary restriction (DR) protocols frequently employ intermittent fasting. Following a period of fasting, meal consumption increases lipogenic gene expression, including that NADPH-generating enzymes fuel lipogenesis in white adipose tissue (WAT) through the induction transcriptional regulators SREBP-1c and CHREBP. knockout mice, unlike controls, did not show an extended lifespan on DR diet. WAT cytoplasmic NADPH is generated by both malic enzyme 1 (ME1) pentose phosphate pathway (PPP), while liver primarily synthesized folate cycle provided one-carbon units serine catabolism. During daily fasting diet, fatty acids are released from transported to peripheral tissues, where they used for beta-oxidation phospholipid lipid droplet synthesis, monounsaturated (MUFAs) may activate Nrf1 inhibit ferroptosis promote longevity. Decreased PPP stimulated browning protected high-fat high levels macrophages linked obesity. But oscillations [NADPH]/[NADP+] feeding cycles play important role maintaining metabolic plasticity drive Studies measuring malate/pyruvate as proxy [NADPH]/[NADP+], well studies using fluorescent biosensors expressed animal models monitor changes needed during ad libitum diets determine associated with

Language: Английский

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S-adenosylmethionine synthases specify distinct H3K4me3 populations and gene expression patterns during heat stress

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Feb. 9, 2023

Methylation is a widely occurring modification that requires the methyl donor S-adenosylmethionine (SAM) and acts in regulation of gene expression other processes. SAM synthesized from methionine, which imported or generated through 1-carbon cycle (1 CC). Alterations 1 CC function have clear effects on lifespan stress responses, but wide distribution this has made identification specific mechanistic links difficult. Exploiting dynamic stress-induced transcription model, we find two synthases Caenorhabditis elegans , SAMS-1 SAMS-4 contribute differently to H3K4me3, survival. We sams-4 enhances H3K4me3 heat shocked animals lacking sams-1 however, cannot compensate for required survive stress. This suggests regulatory functions depend its enzymatic source provisioning may be an important step linking phenotypes aging

Language: Английский

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Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 22, 2023

Abstract Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of mitochondrial Krebs cycle immunity remains largely unknown, particular at organism level. Here we show aconitase, ACO-2, a enzyme catalyzes conversion citrate to isocitrate, inhibits against pathogenic bacteria C. elegans . We find genetic inhibition aco-2 decreases level oxaloacetate. This increases unfolded protein response, subsequently upregulating transcription factor ATFS-1, which contributes enhanced bacteria. mammalian ACO2 by modulating response and oxaloacetate levels cultured cells. Because aconitase is highly conserved across phyla, therapeutic strategy targeting may eventually help properly control humans.

Language: Английский

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Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4

Cell Reports, Journal Year: 2022, Volume and Issue: 42(1), P. 111928 - 111928

Published: Dec. 30, 2022

The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation geroprotective pharmaceuticals. Here we find anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan health span in C. elegans, independent electron transport chain impairment or ROS accumulation. Rather, treatment modifies pyrimidine metabolism transcripts related proteostasis. Testing regulators mitochondrial stress proteostasis shows that extension dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by stress, specifically communication between cytosolic translation. Translation reduced zidovudine-treated worms, also ATF-4. Finally, show ATF-4-dependent didanosine, another NRTI. Altogether, our work elucidates effects NRTIs such as vivo, via reduction translation

Language: Английский

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Combinatorial interventions in aging

Nature Aging, Journal Year: 2023, Volume and Issue: 3(10), P. 1187 - 1200

Published: Oct. 2, 2023

Language: Английский

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