Vascular aging in the longest-living rodent, the naked mole rat

Abstract

The naked mole rat (NMR; Heterocephalus glaber) is the longest-living rodent known [maximum lifespan potential (MLSP): >28 yr] and is a unique model of successful aging showing attenuated declines in most physiological function. This study addresses age-related changes in endothelial function and production of reactive oxygen species in NMR arteries and vessels of shorter-living Fischer 344 rats (MLSP: approximately 3 yr). Rats exhibit a significant age-dependent decline in acetylcholine-induced responses in carotid arteries over a 2-yr age range. In contrast, over a 10-yr age range nitric oxide (NO)-mediated relaxation responses to acetylcholine and to the NO donor S-nitrosopencillamine (SNAP) were unaltered in NMRs. Cellular superoxide anion (O(2)(*-)) and H(2)O(2) production significantly increased with age in rat arteries, whereas they did not change substantially with age in NMR vessels. Indicators of apoptotic cell death (DNA fragmentation rate, caspase 3/7 activity) were significantly enhanced ( approximately 250-300%) in arteries of 2-yr-old rats. In contrast, vessels from 12-yr-old NMRs exhibited only a approximately 50% increase in apoptotic cell death. In the hearts of NMRs (2 to 26 yr old), expression of endothelial NO synthase, antioxidant enzymes (Cu,Zn-SOD, Mn-SOD, catalase, and glutathione peroxidase), the NAD(P)H oxidase subunit gp91(phox), and mitochondrial proteins (COX-IV, ATP synthase, and porin, an indicator of mitochondrial mass) did not change significantly with age. Thus long-living NMRs can maintain a youthful vascular function and cellular oxidant-antioxidant phenotype relatively longer and are better protected against aging-induced oxidative stress than shorter-living rats.

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

“…This is in accordance with previous results reported by us and others Csiszar et al 2007a;Blackwell et al 2004;Modrick et al 2009;Hatake et al 1990). 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 with conduit arteries Csiszar et al 2007a), we find that in cerebral arteries, the impairments in EDD with age are a result of reduced NO bioavailability. Furthermore, we demonstrate that greater NO bioavailability is the mechanism for the partial prevention of age-related decline in MCA EDD with life-long CR.…”

“…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.…”

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis

“…The oxidative fluorescent dye dihydroethidium (DHE) was used to assess vascular O 2 − production in segments of the aortas as we have previously reported (Csiszar et al 2007;Pearson et al 2008;Ungvari et al 2003Ungvari et al , 2010. In brief, freshly isolated aorta segments were incubated with DHE (3 × 10 −6 mol/L; for 30 min, at 37°C, in the dark).…”

“…Fluorescent images of the aorta sections were captured using a Leica SP2 confocal laser scanning microscope (Leica Microsystems GmbH, Wetzlar, Germany). Average nuclear DHE fluorescence intensities were assessed using the Metamorph software (Molecular Devices LLC, Sunnyvale, CA) and values for each animal in each group were averaged as reported (Csiszar et al 2007;Pearson et al 2008;Ungvari et al 2003Ungvari et al , 2010. Unstained aortas were used for background correction.…”