580 A. D ́avalos and M. A. Lasunci ́on
and acyl CoA:cholesterol acyltransferase are the main mechanisms postulated for
the reduced Apo B secretion (Allister et al. 2005; Borradaile et al. 2003; Casaschi
et al. 2002; Wilcox et al. 2001). In animal models, it has also been shown that
grape procyanidins increase cholesterol 7 -hydroxylase (CYP7A1), an observation
which suggests increased cholesterol elimination via bile acids (Del Bas et al. 2005).
CYP7A1 is a liver-specificenzyme that catalyzes the 7 -hydroxylation of choles-
terol, the rate limiting step in the pathway responsible for the conversion of choles-
terol into bile acids. Other sources of polyphenols have also been shown to increase
bile acids, cholesterol, or steroid excretion (Sembries et al. 2006; Yang and Koo
2000). A possible mechanism explaining this effect is through the orphan nuclear
receptor small heterodimer partner (Del Bas et al. 2005).
Evidence from in vitro and in vivo animal models suggests that the increased
LDL receptor expression and the decrease in cholesterol biosynthesis are the main
factors contributing to the polyphenol-induced reduction of plasma LDL-cholesterol
levels (Bursill et al. 2007; Kim et al. 2004; Pal et al. 2003;). It is thought that the
increased expression of LDL receptors is regulated by the SREBP pathway. Inhi-
bition of the ubiquitin/proteasome-mediated degradation of the active SREBP-2,
resulting in up-regulation of LDL receptor expression (Kuhn et al. 2004), enhanced
SREBP processing via the SREBP cleavage activating protein (Mullen et al. 2004),
and increases in the conversion of SREBP-1 to its active form (Bursill and Roach
2006), has been proposed as a possible mechanism. We have observed that polyphe-
nols from grape juice reduce the availability of free cholesterol from endocytosed
LDL in the endoplasmic reticulum for regulatory purposes (D ́avalos et al. 2006).
Thus, SREBP processing is increased and SRE-regulated target genes are induced.
As a result, surface LDL receptor expression is increased and this increases the
clearance of plasma cholesterol, thus decreasing plasma cholesterol levels. Our find-
ings indicate that grape polyphenols disrupt or delay LDL trafficking through the
endocytic pathway (D ́avalos et al. 2006). Several polyphenols have been shown to
be transported by LDL particles (Lamuela-Raventos et al. 1999; Natella et al. 2007).
Whether increased concentrations of polyphenols within the LDL particles or effects
on proteins responsible for cholesterol trafficking disrupt LDL trafficking has not yet
been established.
9E.5 Life Span
Caloric restriction, defined as a reduction in calorie intake below usual ad libitum
intake without malnutrition, has been widely demonstrated to extend life span in
different species from yeast to mammals and delays several age-associated bio-
chemical, physiological, and behavioral changes, thus indicating a broad relation-
ship between energy intake and aging (Fontana and Klein 2007; Masoro 2000;
Sohal and Weindruch 1996). Sirtuins are a family of NAD+-dependent deacety-
lases conserved fromEscherichia colito humans and are known to mediate gene