REJUVENATION RESEARCH Volume 12, Number 2, 2009 © Mary Ann Liebert, Inc. DOI: 10.1089/rej.2009.0840 Age-Associated Decrease of High-Density Lipoprotein-Mediated Reverse Cholesterol Transport Activity Hicham Berrougui 1,2 and Abdelouahed Khalil 1,2 Abstract High-density lipoproteins (HDL) are considered atheroprotective in contrast to low-density lipoproteins (LDL), which are atherogenic in their oxidized form. A growing body of evidence suggests that HDL exert part of their antiatherogenic effect by counteracting LDL oxidation as well as their proinflammatory effect. However, a num- ber of studies, carried over the past 30 years, have shown that cholesterol efflux plays a major role in the athero- protective effects of HDL and cholesterol homeostasis. These studies have further identified the scavenger re- ceptor type B-I (SR-BI), the adenosine triphosphate (ATP)-binding cassette transporters ATP-binding cassette subfamily A1 (ABCA1), ATP-binding cassette subfamily G1 (ABCG1) and ABCG4, the liver X receptor/retinoid X receptor (LXR/RXR) and peroxisome proliferator-activated receptor (PPAR) transcription factors, the HDL components apolipoprotein A-I (apoA-I), lecithin-cholesterol acyltransferase (LCAT), and phospholipids as ad- ditional mediators of cholesterol transport. Cholesterol efflux occurs via three independent pathways: (1) aque- ous diffusion, (2) nonspecific efflux via SR-BI receptors, and (3) specific efflux via cholesterol-responsive mem- bers of the ABC superfamily. Whereas aqueous diffusion and scavenger receptor class B, type I (SR-BI)-mediated efflux transport free cholesterol to a wide variety of cholesterol acceptors (particles containing phospholipids, HDL, and lipidated apo-lipoproteins; LDL, etc), the ABCA1 pathway mediates the transport of cholesterol in a unidirectional manner, mainly to lipid-poor apoA-I. In contrast, the ABCG1 pathway is responsible for the transport of cholesterol to all the subfamily members of HDL. Although HDL-mediated cholesterol efflux is apoA-I-dependent, recent studies have suggested an involvement of the enzyme paraoxonase 1 (PON1). Cho- lesterol efflux is carried on by a number of factors such as genetic mutations, smoking, stress, and high-fat di- ets. It is attenuated with aging due to changes in the composition and structure of HDL, especially the phos- phatidylcholine/sphingomyelin ratio, the fluidity of the phospholipidic layer, the concentration of apoA-I, and the activity of PON1. This review summarizes the findings that cholesterol homeostasis is disrupted with ag- ing as a consequence of dysfunctional cholesterol efflux and the impairment of physiological functions. 117 Introduction A HALF-CENTURY OF INVESTIGATIONS, including epidemio- logical, interventional, and molecular studies, have re- vealed that there is an inverse relationship between plasma high-density lipoprotein (HDL) levels and cardiovascular disease (CVD). 1 HDL particles consist of an outer amphipatic layer of free cholesterol, phospholipids, apolipoproteins (mainly apolipoprotein A-I [apoA-I], but also apoA-II, apoC, apoE, apoA-IV, apo-J, and apo-M), and a triglyceride- and cholesterol ester-rich hydrophobic core. Enzymes such as paraoxonase 1 (PON1), platelet-activating factor-acetyl- hydrolase (PAF-AH), lecithin-cholesterol acyltransferase (LCAT), and cholesteryl ester transfer protein (CETP) are also components of HDL. 2 The protective effect of HDL has been classically ascribed to HDL-mediated reverse cholesterol transport (RCT). The concept of RCT, which was initially proposed by Glomest, 3 involves the transport by HDL or associated proteins (apoA- I) of excess free cholesterol from peripheral cells to the liver for elimination. RCT has been ascribed a major role in main- taining cholesterol homeostasis in the body. 3–5 Cholesterol efflux is the result of unspecific and passive as well as spe- 1 Research Center on Aging, Sherbrooke University Geriatric Institute, Sherbrooke, Quebec, Canada. 2 Geriatrics Service, Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.