AUB_001
Owned by0x44dC2…b7c2C
Project Description
Cellular senescence and mitochondrial dysfunction are interconnected hallmarks of aging that create a metabolically hostile environment characterized by NAD⁺ depletion and oxidative stress. The reduced NAD⁺/NADH ratio in senescent cells results from decreased respiratory capacity and CD38-mediated NAD⁺ consumption, while accumulated dysfunctional mitochondria produce excessive reactive oxygen species (ROS). Despite the therapeutic potential of NAD⁺ precursors and mitochondrial-targeted antioxidants individually, their combined efficacy remains unexplored. We will test the claim that MitoQ + NMN, given either simultaneously (co-treatment) or sequentially (MitoQ→washout→NMN), outperforms monotherapy in restoring cellular homeostasis; the null hypothesis is no improvement versus NMN alone. We will directly compare sequential dosing to co-treatment using a predeclared 0, 24, 48, and 72 hour washout grid with intracellular MitoQ quantified by targeted LC-MS/MS to confirm clearance. Using human dermal fibroblasts, we will induce senescence via H₂O₂ treatment, then randomize to vehicle, MitoQ 500 nM, NMN 1 mM, MitoQ+NMN co-treatment, and sequential MitoQ→NMN at each washout interval (0/24/48/72 h), with a TPP⁺ carrier control included. Primary outcomes include NAD⁺/NADH ratio quantification by LC-MS/MS, mitochondrial function via Seahorse XF analysis, and senescence markers (SA-β-gal, p16^INK4a). In an exploratory endothelial module, primary human endothelial cells are exposed to a low-dose mitochondrial uncoupler in combination with NMN (2×2 design) to quantify synergistic effects on mitochondrial quality control (PINK1/Parkin flux) and nitric oxide bioavailability. This addition mechanistically links mitochondrial quality control to vascular function, aligning the intervention with systemic vascular aging.TBD
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TBD
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