Age-Related Impairments in Immune Cell Efferocytosis and Autophagy Hinder Atherosclerosis Regression
Bibliographic record
Abstract
BACKGROUND: Aging is a well-established risk factor for the development and progression of atherosclerosis, but the molecular mechanisms underlying this relationship remain poorly defined, and its role in atherosclerosis regression is unknown. To uncover age-related alterations that may impair atherosclerosis regression, we investigated the response of young and old macrophages to atherogenic lipoproteins in vitro and in vivo. METHODS: Metabolic and proteomic studies were performed in vitro using macrophages differentiated from the bone marrow of young or old mice. To test the role of immune cell aging in atherosclerosis regression, bone marrow from young and old donors was transplanted into irradiated young recipient mice expressing gain-of-function AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9). Following 14 weeks of Western diet feeding, atherosclerosis regression was induced by switching to a standard laboratory diet for 4 weeks. RESULTS: Compared with young macrophages, old macrophages accumulated more lipid droplets upon lipid loading with the pro-atherogenic lipoprotein aggregated LDL (low-density lipoprotein), accompanied by a failure to proportionally induce autophagy and cholesterol efflux. Proteomic analysis of bone marrow–derived macrophages revealed that pathways related to endocytosis, engulfment, and phagocytosis were downregulated in old lipid-loaded macrophages. Functional studies confirmed a reduction in efferocytic capacity in old macrophages. In recipient mice transplanted with old bone marrow, atherosclerosis regression was impaired, as evidenced by inefficient resolution of circulating inflammatory cell levels, reduced activation of plaque autophagy and apoptotic cell clearance, and persistent plaque CD45 + and CD68 + content. CONCLUSIONS: Aging impairs macrophage function through reduced efferocytosis and autophagy activation, limiting atherosclerosis regression. These results highlight the need to better define the mechanisms linking aging to atherosclerosis to develop targeted therapies for the aging population.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".