And the beat goes on: maintained cardiovascular function during aging in the longest-lived rodent, the naked mole-rat

Abstract

The naked mole-rat (NMR) is the longest-lived rodent known, with a maximum lifespan potential (MLSP) of >31 years. Despite such extreme longevity, these animals display attenuation of many age-associated diseases and functional changes until the last quartile of their MLSP. We questioned if such abilities would extend to cardiovascular function and structure in this species. To test this, we assessed cardiac functional reserve, ventricular morphology, and arterial stiffening in NMRs ranging from 2 to 24 years of age. Dobutamine echocardiography (3 μg/g ip) revealed no age-associated changes in left ventricular (LV) function either at baseline or with exercise-like stress. Baseline and dobutamine-induced LV pressure parameters also did not change. Thus the NMR, unlike other mammals, maintains cardiac reserve with age. NMRs showed no cardiac hypertrophy, evidenced by no increase in cardiomyocyte cross-sectional area or LV dimensions with age. Age-associated arterial stiffening does not occur since there are no changes in aortic blood pressures or pulse-wave velocity. Only LV interstitial collagen deposition increased 2.5-fold from young to old NMRs (P < 0.01). However, its effect on LV diastolic function is likely minor since NMRs experience attenuated age-related increases in diastolic dysfunction in comparison with other species. Overall, these findings conform to the negligible senescence phenotype, as NMRs largely stave off cardiovascular changes for at least 75% of their MLSP. This suggests that using a comparative strategy to find factors that change with age in other mammals but not NMRs could provide novel targets to slow or prevent cardiovascular aging in humans.

Keywords: arterial stiffness; cardiac reserve; cardiovascular aging; naked mole-rat; negligible senescence.

Fig. 1.

Representative m-mode echocardiography shows that left ventricular contractility does not change with age at baseline under nonstressed conditions or after dobutamine-induced cardiac stress in naked mole-rats. Each image represents a half-second of cardiac function.

Fig. 2.

Naked mole-rat cardiac reserve is maintained during aging, indicated by the lack of an age effect on the percent changes in response to dobutamine stress in the cardiac function variables measured by echocardiography. A: heart rate (HR). B: fractional shortening (FS). C: ejection fraction (EF). D: cardiac output (CO). E: stroke volume (SV). F: linear regression equations are presented where x is the age of the animal (in years) and y is the percent change in response to dobutamine stress of the cardiac function variable. None of the linear regression analyses were significant as shown by correlation coefficients. Dotted lines denote the 95% confidence intervals of the regressions. Sample size is n = 45.

Fig. 3.

Cardiomyocyte cross-sectional area does not change with age in naked mole-rats. Representative images are at ×40 of hematoxylin and eosin-stained left ventricle midwall sections with highlighted cells that are considered suitable for quantification. All values are means ± SE. Sample sizes are n = 8 (4/sex) per cohort.

Fig. 4.

Naked mole-rats exhibit increased ventricular fibrosis with age. Representative images are at ×20 of picrosirius red-stained left ventricle midwall sections with arrows pointing to collagen fibers. All values are means ± SE. Sample sizes are n = 8 (4/sex) per cohort.

Fig. 5.

No age-related increase in naked mole-rat arterial stiffness as measured by pulse-wave velocity (PWV). The dotted line denotes the 95% confidence interval of the regression. Sample size is n = 36.