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The quantity of high-density lipoproteins (HDL) is represented as the serum HDL-C concentration (mg/dL), while the HDL quality manifests as the diverse features of protein and lipid content, extent of oxidation, and extent of glycation. The HDL functionality represents several performance metrics of HDL, such as antioxidant, anti-inflammatory, and cholesterol efflux activities. The quantity and quality of HDL can change during one’s lifetime, depending on infection, disease, and lifestyle, such as dietary habits, exercise, and smoking. The quantity of HDL can change according to age and gender, such as puberty, middle-aged symptoms, climacteric, and the menopause. HDL-C can decrease during disease states, such as acute infection, chronic inflammation, and autoimmune disease, while it can be increased by regular aerobic exercise and healthy food consumption. Generally, high HDL-C at the normal level is associated with good HDL quality and functionality. Nevertheless, high HDL quantity is not always accompanied by good HDL quality or functionality. The HDL quality concerns the morphology of the HDL, such as particle size, shape, and number. The HDL quality also depends on the composition of the HDL, such as apolipoproteins (apoA-I, apoA-II, apoC-III, serum amyloid A, and α-synuclein), cholesterol, and triglyceride. The HDL quality is also associated with the extent of HDL modification, such as glycation and oxidation, resulting in the multimerization of apoA-I, and the aggregation leads to amyloidogenesis. The HDL quality frequently determines the HDL functionality, which depends on the attached antioxidant enzyme activity, such as the paraoxonase and cholesterol efflux activity. Conventional HDL functionality is regression, the removal of cholesterol from atherosclerotic lesions, and the removal of oxidized species in low-density lipoproteins (LDL). Recently, HDL functionality was reported to expand the removal of β-amyloid plaque and inhibit α-synuclein aggregation in the brain to attenuate Alzheimer’s disease and Parkinson’s disease, respectively. More recently, HDL functionality has been associated with the susceptibility and recovery ability of coronavirus disease 2019 (COVID-19) by inhibiting the activity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The appearance of dysfunctional HDL is frequently associated with many acute infectious diseases and chronic aging-related diseases. An HDL can be a suitable biomarker to diagnose many diseases and their progression by monitoring the changes in its quantity and quality in terms of the antioxidant and anti-inflammatory abilities. An HDL can be a protein drug used for the removal of plaque and as a delivery vehicle for non-soluble drugs and genes. A dysfunctional HDL has poor HDL quality, such as a lower apoA-I content, lower antioxidant ability, smaller size, and ambiguous shape. The current review analyzes the recent advances in HDL quantity, quality, and functionality, depending on the health and disease state during one’s lifetime.

The Current Status of Research on High-Density Lipoproteins (HDL): A Paradigm Shift from HDL Quantity to HDL Quality and HDL Functionality