Mitophagy‑Enhanced Endothelial Mitochondrial Quality Control Breaks the NO‑ADMA‑Stiffness Cycle to Slow Tau Pathogenesis

Hypothesis: Enhancing endothelial mitochondrial quality control through pharmacologic mitophagy induction will restore nitric oxide (NO) bioavailability, reduce asymmetric dimethylarginine (ADMA) levels, and thereby decrease arterial stiffness, which in turn attenuates downstream tau‑related neurodegeneration in cognitively normal older adults.

Rationale: Endothelial senescence and oxidative stress drive eNOS uncoupling and ADMA accumulation, creating a feed‑forward loop that lowers NO, increases peroxynitrite, and promotes vascular stiffening via SASP‑mediated smooth‑muscle remodeling【https://www.explorationpub.com/Journals/ec/Article/101279】. Mitochondrial ROS from NADPH oxidases and uncoupled eNOS are major contributors to this redox burden【https://www.explorationpub.com/Journals/ec/Article/101279】. Recent work shows that mitophagy defects exacerbate mitochondrial ROS production in aging endothelium, while pharmacologic activators of mitophagy (e.g., urolithin A) improve endothelial function in preclinical models【https://pmc.ncbi.nlm.nih.gov/articles/PMC11198378/】. We propose that mitophagy‑mediated clearance of damaged mitochondria lowers superoxide generation, allowing eNOS to remain coupled, decreasing ADMA synthesis (since ADMA formation is up‑regulated by oxidative activation of protein arginine methyltransferases) and increasing NO bioavailability. Reduced ADMA and increased NO will improve vasodilatory tone, lower carotid‑femoral pulse wave velocity (cfPWV), and diminish mechanical stress that drives endothelial senescence. Consequently, arterial stiffening—shown to correlate more strongly with biological age than chronological age【https://academic.oup.com/ajh/article/38/9/706/8117235】—will be attenuated, breaking the SASP‑driven cycle that stimulates vascular smooth‑muscle phenotype switching and extracellular‑matrix deposition【https://www.explorationpub.com/Journals/ec/Article/101279】. Improved arterial compliance will enhance cerebral perfusion and reduce pulsatile stress on the blood‑brain barrier, limiting the influx of inflammatory mediators that promote astrocytic activation and tau phosphorylation【https://pubmed.ncbi.nlm.nih.gov/41763008/】【https://www.marcusinstituteforaging.org/news/stiff-arteries-may-amplify-early-memory-decline-older-adults】.

Testable prediction: A 6‑month, double‑blind, randomized controlled trial assigning older adults (60‑80 yr) with elevated baseline cfPWV (>10 m/s) to receive either a mitophagy inducer (urolithin A 500 mg daily) or placebo will show: (1) a ≥10 % increase in plasma nitrate/nitrite (NOx) and a ≥15 % reduction in ADMA; (2) a ≥0.5 m/s decrease in cfPWV; and (3) a concomitant reduction in plasma p‑tau181 and neurofilament light (NfL) levels compared with placebo. Mediation analysis will test whether changes in cfPWV mediate the effect of the intervention on p‑tau181/NfL. Failure to observe these changes would falsify the hypothesis that endothelial mitochondrial quality control links NO‑ADMA dynamics to arterial stiffness and downstream tau pathology.