Lifelong SIRT‐1 Overexpression Attenuates Aortic Stiffening with Advancing Age

Abstract

Advanced age is accompanied by aortic stiffening that is associated with decreased vascular expression of the cellular deacetylase, sirtuin‐1 (SIRT‐1). Interventions, such as caloric restriction, that increase SIRT‐1 expression also lower age‐related aortic stiffness. Thus, we sought to determine if lifelong whole body SIRT‐1 overexpression attenuates age‐related aortic stiffening. Aortic stiffness, as determined by aortic pulse wave velocity (PWV), was assessed in SIRT‐1 transgenic overexpressing (SIRTTG) and littermate wild type (WT) control mice at 3‐mo intervals from 3–24 mo of age. To determine the role of aortic structural changes on age‐related aortic stiffening, histological assessment of aortic wall characteristics was performed in young (~5 mo), middle‐age (~12 mo), and old (~24 mo) mice. Aortic SIRT‐1 mRNA gene expression, measured by RT‐PCR, was ~3‐fold higher in young SIRTTG vs. WT mice (P<0.05). Advanced age resulted in a ~6 fold decrease in SIRT‐1 mRNA expression in both old SIRTTG and WT mice (P<0.05), still, SIRT‐1 expression remained >3‐fold higher in old SIRTTG vs. WT mice (P<0.05). Although there was a similar increase in aortic lumen diameter with advancing age in both WT and SIRTTG mice, an age‐related increase in media‐to‐lumen ratio was only present in WT mice (Table 1, P<0.05). Across the age range (3–24 mo), aortic PWV was 8–17% lower in SIRTTG vs. WT mice (P<0.05). Moreover, the slope of age‐related aortic stiffening was 45% lower in SIRTTG vs. WT mice (2.1±0.2 vs. 3.8±0.3 cm/sec/mo, respectively; Figure 1). Aortic elastin content decreased with advancing age in WT mice (Table 1, P<05 old vs. young WT), whereas elastin content was maintained across the lifespan in SIRTTG mice (Table 1, P>0.05). There was an age‐related increase in aortic collagen content, advanced glycation end products (AGEs), and calcification in WT mice (Table 1, P<0.05 old vs. young WT). However, age‐related increases in aortic collagen content, AGEs, or calcification did not occur in SIRTTG mice (Table 1, P>0.05). These findings indicate that lifelong SIRT‐1 overexpression attenuates aortic stiffening with advancing age. These functional data are complemented by histological assessment of aortic wall characteristics, demonstrating that the deleterious changes to the aorta that normally occur with advancing age, such as medial wall hypertrophy, reduced elastin, accumulation of collagen, AGEs, and aortic calcification are all prevented in SIRTTG mice. Thus, the use of SIRT‐1 activators to prevent or reverse the age‐related aortic stiffness may be a viable approach compared to other lifestyle interventions, such as caloric restriction.Support or Funding InformationThis study was funded in part by grants from the National Institutes of Health (R01 AG060395, R01 AG050238, R01 AG048366, K02 AG045339, K99 AT010017) and US Department of Veterans Affairs (I01 BX002151).Scatter plot of aortic stiffening, as determined by pulse wave velocity (PWV), with advancing age in wild type (WT) and sirtuin‐1 transgenic overexpressing (SIRTTG) mice. Separate regression lines are given for WT and SIRTTG mice (dotted lines define 95% confidence intervals).Figure 1 Characteristics of animals used for aortic histology. Table 1 ‐ Animal Characteristics WT SIRTTG Young Middle‐Age Old Young Middle‐Age Old Male:female, n 7:7 7:8 6:4 3:2 7:4 4:6 Age, mo 5.6±0.2 12.2±0.1 † 23.8±0.2 † ‡ 6.0±0.4 12.4±0.0 † 23.9±0.2 † ‡ Body mass, g 26.8±0.9 32.8±1.6 † 30.8±1.5 † ‡ 28.0±1.8 33.4±1.9 † 28.6±0.8 ‡ Lumen Diameter, μm 611±20 634±21 707±31 † ‡ 649±±8 644±18 737±26 † ‡ Medial CSA, mm2 0.81±0.09 0.92±0.08 1.32±0.14 † ‡ 0.90±0.09 0.92±0.12 1.01 ±0.07 * Media‐to‐Lumen Ratio, U 0.27±0.02 0.29±0.03 0.33±0.01 † 0.27±0.03 0.28±0.02 0.24±0.01 * Elastin, AU 1.00±0.06 1.02 ±0.04 0.85±0.05 † ‡ 1.04±0.06 1.06±0.03 1.04±0.04 * Collagen, AU 1.00±0.21 1.60±0.38 2.27±0.50 † 0.78±0.28 1.21±0.35 1.24±0.32 * AGEs, AU 1.00±0.09 1.17±0.16 1.62±0.29 † 1.00±0.21 1.17±0.16 1.21±0.18 Calcified Area, AU 1.00±0.27 1.56±0.15 † 1.47±0.20 † 0.79±0.16 0.47±0.11 * 0.67±0.19 * *P<0.05 vs. WT. †P<0.05 vs. Young. ‡P<0.05 vs. Middle‐Age. Data are mean±SEM. AGEs, advanced glycation endproducts; CSA, cross‐sectional area; SIRTTG, sirtuin‐1 transgenic overexpressing; WT, wild type.