https://www.sciencedirect.com/science/article/pii/S156816372600111X
I am unsure as to whether I have done this paper before (ie yesterday). However, I think failure to differentiate is one of the factors at the core of CVD. I agree that lipids matter in a complex manner, but they are not the only issue.
chatGPT:
Summary
This is a 2026 review article on how ageing alters endothelial cells through a linked triad of senescence, mitochondrial dysfunction and metabolic reprogramming. Its central argument is that vascular ageing is not just a passive consequence of damage accumulation, but is actively driven by endothelial metabolic deterioration: reduced nitric oxide availability, higher mitochondrial ROS, impaired vasodilation, pro-inflammatory signalling, pro-thrombotic changes and defective vascular repair.
The paper starts by describing the endothelium as a regulatory interface controlling vascular tone, thrombosis, permeability, immune-cell trafficking and angiogenesis. In healthy vessels, endothelial cells balance vasodilators such as NO, prostacyclin and EDHF against vasoconstrictors such as endothelin-1 and angiotensin II. In ageing, this balance shifts toward vasoconstriction, inflammation and thrombosis.
A major theme is that senescent endothelial cells are not inert. They adopt a SASP-like phenotype, producing inflammatory mediators, procoagulant factors, ROS and extracellular nucleotides such as ATP and ADP. The paper gives particular attention to purinergic signalling: extracellular ATP can amplify endothelial activation and leukocyte adhesion, while conversion of ATP/ADP to adenosine through CD39/CD73 may counteract inflammation; this protective adenosine signal can then be curtailed by endothelial ecto-adenosine deaminase.
The review emphasises that endothelial cells are mostly glycolytic despite oxygen availability and relatively low mitochondrial volume. It notes that about 80% of endothelial ATP derives from aerobic glycolysis, but mitochondria remain important for calcium signalling, NO production, redox control, apoptosis and metabolic flexibility. Endothelial cells can use glucose, fatty acids and glutamine, with glutamine supporting ATP production, protein synthesis and glutathione-based antioxidant defence.
On mitochondrial dysfunction, the paper covers reduced electron transport function, altered mitochondrial morphology, increased ROS, mtDNA damage, calcium dysregulation, impaired mitophagy and altered mitochondrial quality control. It includes original or illustrative data showing that coronary microvascular endothelial cells from failing human hearts had disturbed mitochondrial morphology, including membrane ballooning and degradation, especially at later passage.
The paper also discusses disease contexts: diabetes, atherosclerosis, cancer, early vascular ageing and arterial stiffness. Diabetes is presented as an accelerated model of endothelial ageing because hyperglycaemia drives ROS, DNA damage, AGE formation and mitochondrial stress. Early vascular ageing is linked to endothelial senescence, SASP-driven smooth muscle and matrix remodelling, reduced NO and increased mitochondrial ROS.
Therapeutically, the review surveys mitochondrial and metabolic interventions including MitoQ/mitochondrial CoQ10, MnSOD mimetics, SkQ1, mitochondrial H₂S donors, SS-31/elamipretide, SUL compounds, metformin, telmisartan/azilsartan and SGLT2 inhibitors. The authors frame mitochondrial metabolism and quality control as a promising but still underexploited target for age-related vascular dysfunction.
What is novel or distinctive
The main novelty is integrative rather than experimental. The paper brings together endothelial senescence, mitochondrial bioenergetics, metabolic substrate use, purinergic signalling, glycocalyx integrity, mitophagy, mitochondrial-derived vesicles and vascular stiffness into one ageing-centred framework.
The strongest distinctive elements are:
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Senescence as both consequence and amplifier
The paper does not treat endothelial senescence simply as an endpoint of ageing. It presents senescent endothelial cells as active propagators of vascular dysfunction through SASP, ROS, extracellular ATP/ADP, leukocyte recruitment and pro-thrombotic signalling. -
Metabolic flexibility rather than a simple glycolysis story
Although endothelial cells are mostly glycolytic, the review stresses that mitochondria still matter because they regulate redox tone, calcium-linked NO production, cell survival and adaptation to stress. It also highlights fatty acid oxidation and glutamine metabolism, including increased glutamine utilisation in senescent endothelial cells. -
Quality-control emphasis: mitophagy and MDVs
The review usefully distinguishes general autophagy from more targeted mitochondrial quality control. It argues that modulating mitophagy may be preferable to broad mTOR inhibition, noting that rapamycin can activate autophagy but may impair endothelial repair or be toxic in this context. It also highlights mitochondrial-derived vesicles as a mitophagy-independent quality-control pathway. -
Useful recognition of conflicting metabolic data
The authors acknowledge that studies disagree: some senescent endothelial models show higher ATP and a shift toward fatty acid oxidation, whereas others show reduced ATP with higher glucose consumption and lactate production. They correctly caution that culture conditions and substrate composition may explain part of this inconsistency. -
A broad therapeutic map
The review’s intervention table is useful because it groups direct mitochondrial antioxidants, mitochondrial membrane/ATP efficiency agents, metabolic drugs and nutrient-sensing modulators. It links these to endpoints such as ROS, NO signalling, vasodilation, arterial stiffness and endothelial senescence.
Critique
The review is strong as a conceptual synthesis, but weaker as a causal map. It often presents mitochondrial dysfunction as a central driver, but many of the cited relationships are bidirectional: inflammation damages mitochondria; mitochondrial ROS increases inflammation; senescence alters metabolism; altered metabolism reinforces senescence. The paper would benefit from a clearer hierarchy distinguishing initiating causes, amplifying loops and downstream markers.
A second issue is that the review sometimes moves between cell culture, mouse vessels, human vascular ageing and disease states without fully separating them. The authors do acknowledge that cultured endothelial cells may behave differently from quiescent endothelial cells in vivo, but the broader argument still leans heavily on HUVEC and in vitro senescence models. That matters because endothelial cells differ substantially by vascular bed, flow pattern, oxygen exposure, immune environment and disease context.
The discussion of interventions is informative but somewhat optimistic. Many candidate therapies improve mitochondrial or endothelial markers in cells or mice, but translation to human vascular ageing remains uncertain. The review notes some human data for mitochondrial CoQ10/MitoQ-type approaches, but much of the therapeutic landscape remains preclinical or mechanistically plausible rather than clinically established.
The mitophagy section is good, but it risks oversimplifying mTOR and rapamycin. Saying broad mTOR inhibition is problematic in endothelial repair is reasonable, but rapamycin biology is dose-, timing-, tissue- and context-dependent. A more careful distinction between acute, chronic, intermittent, endothelial-specific and systemic mTOR modulation would improve the argument.
There is also a familiar ROS problem. The review correctly discusses mitochondrial ROS as damaging, but ROS are also signalling molecules. The distinction between pathological ROS excess and physiological redox signalling could be sharper, especially because indiscriminate antioxidant strategies have often translated poorly.
Overall, the paper is a useful, up-to-date review. Its best contribution is framing endothelial ageing as a metabolic-mitochondrial-senescent feedback system rather than a simple decline in NO or accumulation of senescent cells. Its main limitation is that it synthesises a wide literature without always resolving which mechanisms are primary, which are compensatory, and which are merely associated with ageing or disease.