Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: Role of circulating factors and SIRT1

Abstract

Endothelial-dysfunction, oxidative stress and inflammation are associated with vascular aging and promote the development of cardiovascular-disease. Caloric restriction (CR) mitigates conditions associated with aging, but its effects on vascular dysfunction during aging remain poorly defined. To determine whether CR exerts vasoprotective effects in aging, aortas of ad libitum (AL) fed young and aged and CR-aged F344 rats were compared. Aging in AL-rats was associated with impaired acetylcholine-induced relaxation, vascular oxidative stress and increased NF-κB-activity. Lifelong CR significantly improved endothelial function, attenuated vascular ROS production, inhibited NF-κB activity and down-regulated inflammatory genes. To elucidate the role of circulating factors in mediation of the vasoprotective effects of CR, we determined whether sera obtained from CR-animals can confer anti-oxidant and anti-inflammatory effects in cultured coronary-arterial endothelial cells (CAECs), mimicking the effects of CR. In CAECs cultured in the presence of AL-serum TNFα elicited oxidative-stress, NF-κB-activation and inflammatory gene expression. By contrast, treatment of CAECs with CR-serum attenuated TNFα-induced ROS generation and prevented NF-κB-activation and induction of inflammatory genes. siRNA-knockdown of SIRT1 mitigated the antioxidant and anti-inflammatory effects of CR-serum. CR exerts anti-oxidant and anti-inflammatory vascular effects, which are likely mediated by circulating factors, in part, via a SIRT1-dependent pathway.

Beneficial effects of lifelong caloric restriction on endothelial function are greater in conduit arteries compared to cerebral resistance arteries

“…Although we cannot compare absolute differences in the amount of superoxide production between arteries due (Miller et al 2005(Miller et al , 2009. Similar to previous studies, we find that scavenging superoxide improves EDD in conduit and cerebral arteries from old mice (Blackwell et al 2004;Lesniewski et al 2009;Mayhan et al 2008;Modrick et al 2009) and does not affect EDD in conduit arteries from young or old CR mice (Csiszar et al 2009). However, we demonstrate that scavenging superoxide in the MCA from young and old CR mice results in reduced EDD, which is in accordance with previous studies demonstrating reactive oxygen species contribute to the dilation of resistance arteries in skeletal muscle (Sindler et al 2013;Trott et al 2011), cardiac muscle (Miura et al 2003;Feng et al 2010;Kang et al 2011), and cerebral tissue (Drouin et al 2007).…”

“…Lifelong CR completely prevented this age-related decline in EDD in conduit arteries (carotid), but only partially prevents the decline in cerebral resistance arteries (MCA). As previous studies have only focused on the effect of lifelong CR on conduit artery function (Csiszar et al 2009) …”

“…Older humans and rodents exhibit impaired EDD in conduit arteries as well as cerebral arteries Csiszar et al 2007a;Blackwell et al 2004;Modrick et al 2009;Hatake et al 1990;Eskurza et al 2004;Celermajer et al 1994). It has been shown previously that lifelong CR can prevent the age-related decline in EDD in the aorta (Csiszar et al 2009), but the effect of CR on resistance artery EDD has not been studied. With advancing age, endothelial dysfunction primarily results from reduced nitric oxide (NO) bioavailability (Taddei et al 2001).…”

“…Expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a key producer of superoxide in vascular tissue, is increased in conduit and cerebral arteries with advancing age (Miller et al 2005;Durrant et al 2009), and inhibiting NADPH oxidase in conduit arteries from old animals improves EDD Rippe et al 2010). Lifelong CR prevents the increase in oxidative stress with aging in a number of tissues including large arteries (Csiszar et al 2009;Sohal and Weindruch 1996). However, the effect of lifelong CR on oxidative stress in resistance arteries has not been explored.…”

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

“…We have previously demonstrated that arterial SIRT1 activity is reduced with aging and contributes to the age‐related impairment in endothelial function (Donato et al ., 2011; Gano et al ., 2014). We and others also have shown that lifelong CR prevents (Csiszar et al ., 2009; Donato et al ., 2013) and short‐term CR reverses (Rippe et al ., 2010) the age‐associated decline in endothelial function and that these effects are associated with enhanced arterial SIRT1 activity. Consistent with these observations, we recently found that 4 weeks of treatment with the SIRT1 activator SRT1720 restores endothelial function (i.e., EDD) in old mice (Gano et al ., 2014).…”