How Aging and Blood Flow Mechanics Drive Metabolic Breakdown in Artery Walls
A comprehensive review reveals how aging and disturbed blood flow reprogram endothelial cell metabolism, fueling atherosclerosis through glycolytic, lipid, and mitochondrial dysregulation.
Summary
This 2025 review from Taiwan's National Health Research Institutes examines how aging and abnormal blood flow patterns synergistically rewire the metabolism of vascular endothelial cells (ECs) lining artery walls. Healthy ECs rely predominantly on glycolysis for ~85% of their ATP, minimizing reactive oxygen species. With aging, compounded by disturbed oscillatory shear stress at arterial branches, ECs undergo metabolic reprogramming—hyperactivated glycolysis, fatty acid imbalance, amino acid dysregulation, and mitochondrial dysfunction. These changes reduce nitric oxide bioavailability, amplify inflammation, increase permeability, and drive endothelial senescence, collectively accelerating atherosclerotic plaque formation. The review also surveys emerging metabolomic profiling methods and therapeutic targets aimed at restoring EC metabolic homeostasis.
Detailed Summary
Atherosclerosis, the leading driver of cardiovascular disease, accounts for roughly 40% of deaths in adults over 65. While genetic and epigenetic contributors to endothelial dysfunction have been well characterized, how cellular metabolism specifically mediates age-related vascular disease has remained underexplored. This comprehensive review synthesizes current evidence on how aging and hemodynamic forces conspire to reprogram endothelial cell (EC) metabolism and accelerate atherosclerosis.
In healthy vasculature, ECs are metabolically quiescent, relying on aerobic glycolysis for approximately 85% of their ATP rather than oxidative phosphorylation (OXPHOS). This strategy limits reactive oxygen species (ROS) production and preserves oxygen for underlying tissues. Laminar shear stress (LS) from steady blood flow reinforces this protective phenotype by maintaining anti-inflammatory signaling, nitric oxide (NO) production via eNOS, and antioxidant defenses. In contrast, disturbed oscillatory shear stress (OS)—prevalent at arterial bifurcations and curvatures—activates pro-atherogenic signaling networks, upregulates PFKFB3-driven glycolysis, and induces inflammation.
Aging profoundly disrupts EC metabolic homeostasis across multiple pathways. Glycolysis becomes dysregulated: PFKFB3 is overexpressed in vulnerable plaques, promoting pathological angiogenesis, EndMT (endothelial-to-mesenchymal transition), and inflammation via NF-κB and HIF-1α. Elevated lactate from hyperactive glycolysis acidifies the extracellular environment, disrupts VE-cadherin-mediated barrier function, and triggers histone lactylation (e.g., H3K18la), epigenetically reinforcing pro-atherogenic gene programs. Conversely, hypo-glycolysis (e.g., miR-143-mediated suppression of HK2 and PKM2) also impairs EC function, underscoring the need for a precise glycolytic balance.
Fatty acid metabolism is similarly perturbed. While ECs normally rely on fatty acid oxidation (FAO) to support nucleotide synthesis and redox balance rather than direct ATP production, aging and OS shift ECs toward aberrant lipid accumulation, impaired FAO, and ceramide-driven apoptosis. Amino acid metabolism—particularly glutamine and arginine pathways—is also disrupted, reducing NO synthesis and depleting antioxidant precursors. Mitochondrial dysfunction, including impaired electron transport chain activity, elevated ROS, reduced NAD+/NADH ratios, and defective mitophagy, further compounds oxidative stress and inflammation in aged ECs.
The review highlights emerging methodologies for profiling EC metabolism in situ, including single-cell metabolomics, stable isotope tracing, and flow-chamber models that replicate physiological shear conditions. Therapeutically, targets such as PFKFB3 inhibitors, NAD+ precursors (NMN, NR), SIRT1/AMPK activators, and mitophagy inducers show promise for restoring EC metabolic homeostasis. The authors argue that a systems-level metabolic perspective is essential for designing interventions that prevent or delay atherosclerosis in aging populations.
Key Findings
- Aged ECs undergo glycolytic dysregulation via PFKFB3 overexpression, driving inflammation, pathological angiogenesis, and EndMT.
- Lactate from hyperactive glycolysis promotes histone lactylation (H3K18la), epigenetically accelerating atherosclerosis progression.
- Disturbed oscillatory shear stress synergizes with aging to reduce NO bioavailability and amplify ROS-driven EC dysfunction.
- Mitochondrial dysfunction with impaired NAD+/NADH balance and defective mitophagy is a central feature of aged, athero-prone ECs.
- Both hyper- and hypo-glycolysis impair EC homeostasis, indicating a narrow metabolic window for vascular health.
Methodology
This is a comprehensive narrative review integrating published experimental studies on EC metabolism, aging, and hemodynamics. Evidence is drawn from in vitro flow-chamber models, mouse atherosclerosis models (e.g., ApoE−/− mice), and human vascular tissue studies. The authors synthesize findings across glycolysis, fatty acid metabolism, amino acid metabolism, and mitochondrial respiration.
Study Limitations
Most underlying studies rely on 2D cell culture systems that do not replicate the 3D vascular microenvironment or organ-specific EC heterogeneity. Additionally, the metabolite profiles in standard culture media differ substantially from in vivo blood composition, limiting direct translational inference. As a review, no new primary data are presented, and causal hierarchies among metabolic pathways remain incompletely established.
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