Reductions in arterial SIRT1 expression and activity with aging are linked to vascular endothelial dysfunction. We tested the hypothesis that the specific SIRT1 activator SRT1720 improves endothelial function [endothelium-dependent dilation (EDD)] in old mice. Young (4-9 mo) and old (29-32 mo) male B6D2F1 mice treated with SRT1720 (100 mg/kg body wt) or vehicle for 4 wk were studied with a group of young controls. Compared with the young controls, aortic SIRT1 expression and activity were reduced (P < 0.05) and EDD was impaired (83 ± 2 vs. 96 ± 1%; P < 0.01) in old vehicle-treated animals. SRT1720 normalized SIRT1 expression/activity in old mice and restored EDD (95 ± 1%) by enhancing cyclooxygenase (COX)-2-mediated dilation and protein expression in the absence of changes in nitric oxide bioavailability. Aortic superoxide production and expression of NADPH oxidase 4 (NOX4) were increased in old vehicle mice (P < 0.05), and ex vivo administration of the superoxide scavenger TEMPOL restored EDD in that group. SRT1720 normalized aortic superoxide production in old mice, without altering NOX4 and abolished the improvement in EDD with TEMPOL, while selectively increasing aortic antioxidant enzymes. Aortic nuclear factor-κB (NF-κB) activity and tumor necrosis factor-α (TNF-α) were increased in old vehicle mice (P < 0.05), whereas SRT1720 normalized NF-κB activation and reduced TNF-α in old animals. SIRT1 activation with SRT1720 ameliorates vascular endothelial dysfunction with aging in mice by enhancing COX-2 signaling and reducing oxidative stress and inflammation. Specific activation of SIRT1 is a promising therapeutic strategy for age-related endothelial dysfunction in humans.

We tested the hypothesis that peripheral blood mononuclear cells (PBMC) of older adults demonstrate a proinflammatory/-oxidative gene expression profile that can be improved by regular aerobic exercise. PBMC were isolated from young (n ϭ 25, 18 -33 yr) and middle-aged/older (n ϭ 40, 50 -76 yr) healthy adults. The older adults had greater mRNA expression (real-time RT-PCR) of the proinflammatory/-oxidant transcription factor nuclear factor-B (1.58-fold, P Ͻ 0.05) and receptor for advanced glycation end products (1.12-fold, P Ͻ 0.05), the proinflammatory cytokines tumor necrosis factor-␣ (1.90-fold, P Ͻ 0.05) and monocyte chemoattractant protein-1 (1.47-fold, P Ͻ 0.05), and the oxidant-producing enzymes nicotinamide adenine dinucleotide phosphate-oxidase (0.91-fold, P Ͻ 0.05) and inducible nitric oxide synthase (2.60-fold, P Ͻ 0.05). In 11 subjects (58 -70 yr), maximal oxygen consumption (ϩ11%) and exercise time (ϩ19%) were increased (both P Ͻ 0.001), and expression of the above proinflammatory/-oxidative genes was or tended to be decreased in PBMC after vs. before 2 mo of aerobic exercise (brisk walking ϳ6 days/wk, 50 min/day, 70% of maximal heart rate). Expression of interleukin-6 was not different with age or exercise intervention. Age group-and exercise intervention-related differences in gene expression were independent of other factors. PBMC of healthy older adults demonstrate increased expression of several genes associated with inflammation and oxidative stress, which is largely ameliorated by habitual aerobic exercise. This proinflammatory/-oxidative gene signature may represent a therapeutic target for lifestyle and pharmacological prevention and treatment strategies. aging; oxidative stress; inflammation; cytokines; immune cells AGE IS THE MAJOR RISK FACTOR for cardiovascular diseases (CVD), largely as the result of vascular dysfunction (18). Chronic low-grade inflammation and oxidative stress are believed to play important roles in the development of vascular disorders with age (1, 29, 31). Plasma markers of inflammation and oxidative stress often are elevated in older adults (9,11,13). Proinflammatory changes to the intimal layer of arteries with aging have been reported on autopsy (34). Moreover, we recently found increased expression of the redox-sensitive proinflammatory nuclear transcription factor nuclear factor B (NF-B), the proinflammatory cytokines tumor necrosis factor-␣ (TNF-␣), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1), and the oxidant enzyme nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase in vascular endothelial cells obtained from older compared with young adults (9, 10). The proinflammatory/redox-sensitive proteins receptor for advanced glycation end products (RAGE) and inducible nitric oxide synthase (iNOS) also have been found to increase with age (2, 15).Although evidence is accumulating for inflammation and oxidative stress in plasma and vascular cells/tissues with advancing age in humans, relatively little is known about the possibility of such...

Endothelial dysfunction develops with aging due to reductions in nitric oxide (NO)‐ and/or cyclooxygenase (COX)‐related vasodilation. Treatment with SRT1720 (Sirtris) increases arterial SIRT1 activity and restores endothelium‐dependent dilation (EDD) independent of NO. We hypothesized that COX‐2 vasodilators mediate the improvements in EDD with SRT1720 treatment. Old mice (29–32 mo) were treated with SRT1720 (100 mg/kg BW; OS) or vehicle (OV) for 4 weeks. Maximal ex vivo carotid artery EDD to acetylcholine was reduced with age (Young, 4–9 mo [Y]: 95±1% vs OV: 83±3%, p<0.01) and rescued with SRT1720 (OS: 95±1%, p<0.01). Inhibition of COX‐1 & −2 (indomethacin) reduced max EDD in Y (88±3%, p<0.01) and OS (82±6%, p<0.01), but not in OV (p=0.55), abolishing all group differences (p=0.64). Inhibition of COX‐2 (NS‐398) reduced max EDD in OS (82±6%, p<0.01), but not in Y or OV (p>0.05), and abolished SRT1720 treatment differences (p=0.69). Aortic COX‐2 protein was reduced with age (Y: 0.9±0.2 AU vs OV: 0.5±0.1 AU, p=0.06) and restored with SRT1720 (OS: 1.1±0.2, p<0.05). COX‐1 protein was not different between groups (p=0.23). These results demonstrate that aging is associated with a reduction in COX mediated EDD. SIRT1 activation reverses vascular endothelial dysfunction with aging via COX‐2 specific vasodilators. These results suggest a novel protective effect of SRT1720 treatment on the aged arterial endothelium.