Comparison of endothelial function, O₂⁻· and H₂O₂ production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice

Abstract

vari. Comparison of endothelial function, O 2Ϫ ⅐ and H2O2 production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice. Am J Physiol Heart Circ Physiol 291: H2698 -H2704, 2006; doi:10.1152/ajpheart.00534.2006.-Vascular aging is characterized by decreased nitric oxide (NO) bioavailability, oxidative stress, and enhanced apoptotic cell death. We hypothesized that interspecies comparative assesment of vascular function among rodents with disparate longevity may offer insight into the mechanisms determining successful vascular aging. We focused on four rodents that show approximately an order of magnitude range in maximum longevity (ML). The naked mole rat (NMR; Heterocephalus glaber) is the longest-living rodent known (ML Ͼ 28 yr), Damara mole rats (DMRs, Cryptomys damarensis; ML ϳ 16 yr) and guinea pigs (GPs, Cavia porcellus; ML ϳ 6 yr) have intermediate longevity, whereas laboratory mice are short living (ML ϳ 3.5 yr). We compared interspecies differences in endothelial function, O 2 Ϫ ⅐ and H2O2 production, and resistance to apoptotic stimuli in blood vessels. Sensitivity to acetylcholine-induced, NO-mediated relaxation was smaller in carotid arteries from NMRs, GPs, and DMRs than in mouse vessels. Measurements of production of O 2 Ϫ ⅐ (lucigenin chemiluminescence and ethidium bromide fluorescence) and H2O2 (dichlorofluorescein fluorescence) showed that free radical production in vascular endothelial and smooth muscle cells is comparable in vessels of the three longer-living species and in arteries of shorter-living mice. In mouse arteries, H2O2 (from 10 Ϫ6 to 10 Ϫ3 mol/l) and heat exposure (42°C for 15-45 min) enhanced apoptotic cell death, as indicated by an increased DNA fragmentation rate and increased caspase 3/7 activity. In NMR vessels, only the highest doses of H2O2 enhanced apoptotic cell death, whereas heat exposure did not increase DNA fragmentation rate. Interspecies comparison showed there is a negative correlation between H2O2-induced apoptotic cell death and ML. Thus endothelial vasodilator function and vascular production of reactive oxygen species do not correlate with maximal lifespan, whereas increased lifespan potential is associated with an increased vascular resistance to proapoptotic stimuli. senescence; comparative biology; vascular disease; atherosclerosis; IN THE UNITED STATES, the number of persons aged Ն65 years is expected to increase from ϳ35 million in 2000 to an estimated 71 million in 2030 (according to the Center for Disease Control). Epidemiological studies suggest that aging of the vascular system is directly responsible for Ͼ50% of mortality and morbidity in these age groups. Despite the growing incidence of aging-induced coronary artery disease, stroke, and diabetic vasculopathy, the factors determining successful vascular aging are still poorly understood.Vascular aging is characterized by proatherogenic functional and phenotypic alterations, including impaired endothelial nitric oxide (NO) mediation, increased product...

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species

“…Our results are not consistent with a causal role for intracellular antioxidant enzymes in longevity, similar to recent reports from studies utilising genetic modifications of mice (Pérez et al, Biochim Biophys Acta 1790:1005Introduction Since the publication of Harman's free radical theory of ageing (Harman 1956), the contribution of reactive oxygen species (ROS) and oxidative damage to cellular macromolecules to animal ageing and longevity has attracted significant interest amongst biologists. Data have accumulated indicating that longevity is positively correlated with resistance to oxidative stress (Kapahi et al 1999;Salmon et al 2005;Labinskyy et al 2006;Harper et al 2007), which is consistent with Harman's original theory. Identification of the molecular mechanisms conferring the enhanced stress resistance associated with longevity remains a major goal.…”

“…Despite this cellular protective capability, these experimental manipulations have generally failed to extend life span, at least in mice ). In interspecific and intraspecific experimental models of longevity, enhanced cellular resistance to oxidative stress is a very common observation (Kapahi et al 1999;Salmon et al 2005;Labinskyy et al 2006;Harper et al 2007). Whilst it seems intuitive that this oxidative stress resistance might be achieved by increased expression of antioxidant enzymes in long-lived species, experimental evidence generally indicates that this does not occur (e.g.…”

“…Whereas genetic manipulations query whether altering expression of a gene or several genes can alter life span, the comparative approach attempts to determine what molecular characteristics have been selected for during the evolution of longevity. A number of comparative studies have investigated whether mitochondrial ROS production (Labinskyy et al 2006;Lambert et al 2007), cellular resistance to exogenous ROS (Kapahi et al 1999;Salmon et al 2008) or the effectiveness of antioxidant defences correlate with animal species' life spans (Tolmasoff et al 1980;Cutler 1991;Sohal et al 1990;Brown and Stuart 2007). These studies have revealed potentially interesting and important insights into how long-lived species might minimise ROS production or maximise resistance to oxidative stress.…”

Taking a “good” look at free radicals in the aging process

“…Indeed, these animals exhibit higher levels of ROS generation [55] and ROSdependent macromolecular modifications than similar-sized but shorter-lived mice [56]. These observations are not only hard to reconcile with the MFRTA, they also suggest that ROS play a beneficial role in this species [24].…”

Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat

“…Data from long-lived species (such as birds, bats, and MRs), and transgenic mice with altered expression of antioxidants, commonly suggest that oxidative damage is not directly correlated with MLS (15,16). The MR is one of the notable exceptions to the oxidative stress theory of aging (7,14,17,18). It has similar levels of reactive oxygen species (17,18) and antioxidant defenses (19) when compared with shorter-living rodents; however, even at a young age it exhibits higher levels of lipid peroxidation, protein carbonylation, and DNA oxidative damage than do mice (14).…”