ABSTRACT
Considering the eff ects of dysregulated AMs during aging on various ageassociated diseases, to seek possible interventions in age-related AM changes by various means is important, and should be of great interest to researchers. In this section, we present a few known experimental paradigms by which the activation of AMs was eff ectively modulated. Calorie restriction (CR) is the most powerful nutritional intervention of the aging process, and researchers have now accepted CR as the only established antiaging experimental paradigm. Although the molecular mechanism of eff ects of CR is still not clearly known, its anti-aging eff ects are thought to be due mainly to its powerful resistance against oxidative stress and ability to maintain a proper cellular redox status. It has been clearly demonstrated that CR suppresses age-related diseases, modulates redox-sensitive transcription factors and infl ammation, and restores various membrane-associated functions in experimental animals (Chung et al. 2006, Yu and Chung 2006). Accumulating evidence indicates that anti-oxidative CR signifi cantly attenuates NF-κB, TNF-α, interleukins (IL-1β, IL-2, and IL-6), chemokines (IL-8 and RANTES) and AMs (Chung et al. 2009). Th e increased levels of aortic AMs, VCAM-1 and P-selectin, as well as sAMs, E-selectin, P-selectin, VCAM-1 and ICAM-1 during aging in non-restricted old rats were eff ectively blunted by CR, and leukocyte infi ltration in the old rats was also reduced by CR (Son et al. 2005). CR even initiated in late adulthood confers benefi cial eff ects, such as the attenuation of oxidative stress, enhanced expression of HSP-70, neural plasticity markers NCAM, and PSA-NCAM, and reduced levels of GFAP (Kaur et al. 2008). Antioxidants and anti-infl ammatory treatments are also eff ective in controlling the level of AMs in the elderly. Polyphenols or vitamin E may assist in preventing cardiovascular disease, in part by decreasing EC expression of pro-infl ammatory cytokines, AMs, and monocyte adhesions. Ferulate is a well-described natural antioxidant found in plants, and ferulate has exhibited its anti-oxidative action by reducing the NF-κB-induced, pro-infl ammatory VCAM-1 and ICAM-1 in kidney from old Sprague-Dawley rats (Jung et al. 2009). Betaine suppresses pro-infl ammatory signaling during aging including the VCAM-1 and ICAM-1 expression through its anti-oxidative eff ects as betaine is involved in glutathione metabolism. Aberrant AMs with age could also be regulated by anti-infl ammatory treatments. Increased ICAM-1 was decreased by etanercept treatment, which binds and inactivates TNF-a. Anti-TNF-a treatment exerts anti-aging, vasculoprotective eff ects (Csiszar et al. 2007). Aspirin is one of the most commonly used non-steroidal anti-infl ammatory drugs. In a recent study, we investigated the eff ect of short-term, low dose aspirin intake on the modulation of pro-infl ammatory NF-κB activation
in old rats (Jung et al. 2006). Th e data showed that NF-κB activation in the old rats and its associated gene expressions, including VCAM-1 and ICAM-1, were all suppressed by the low dose aspirin supplementation through the inhibition of phosphorylation and degradation of IκBα via the NIK/IKK pathway. Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear hormone receptor superfamily. Several studies have demonstrated that PPARα and PPARγ inhibit the expression of infl ammatory genes, such as cytokines, metalloproteases, and acute phase proteins. Recent data showed that age-related infl ammation and oxidative stress, including the upregulation of VCAM-1 and P-selectin, was ameliorated by PPARγ activator 2,4-thiazolidinedione. Other anti-infl ammatory reagents such as 3-methyl-1,2-cyclopentanedione also showed similar eff ects in regulating age-associated VCAM-1 upregulation. Regarding those AMs that are downregulated by the aging process, new therapeutic strategies are undergoing development. For instance, new evidence showed that the synthetic molecule C3d, which is a peptide mimetic of NCAM, promotes choline acetyltransferase activity in cultured rat embryonic septal neurons. Th ese fi ndings on the possible involvement of AMs may be signifi cant when considering new strategies aimed at stimulating cholinergic function and improving cognition in disorders such as Alzheimer’s disease (Burgess et al. 2009).
