Naked mole-rats maintain cardiac function and body composition well into their fourth decade of life

Abstract

The prevalence of cardiovascular disease increases exponentially with age, highlighting the contribution of aging mechanisms to cardiac diseases. Although model organisms which share human disease pathologies can elucidate mechanisms driving disease, they do not provide us with innate examples how cardiac aging might be slowed or attenuated. The identification of animal models that preserve cardiac function throughout most of life offers an alternative approach to study mechanisms which might slow cardiac aging. One such species may be the naked mole-rat (NMR), a mouse-sized (40 g) rodent with extraordinary longevity (> 37 years), and constant mortality hazard over its four decades of life. We used a cross-sectional study design to measure a range of physiological parameters in NMRs between 2 and 34 years of age and compared these findings with those of mice aged between 3 months and 2.5 years. We observed a rapid decline in body fat content and bone mineral density in old mice, but no changes in NMRs. Similarly, rhythm disorders (premature atrial and ventricular complexes) occurred in aged mice but not in NMRs. Magnetic resonance and ultrasound imaging showed age-dependent increases in cardiac hypertrophy and diastolic dysfunction in mice which were absent in NMRs. Finally, cardiac stress tests showed an age-dependent decline in normalized cardiac output in mice, which was absent in NMRs. Unlike mice, that manifest several aspects of human cardiac aging, NMRs maintain cardiac function and reserve capacity throughout their long lives and may offer insights on how to delay or prevent cardiac aging.

Keywords: Aging; Arrhythmia; Cardiac function; Echocardiography; Electrocardiogram; Magnetic resonance imaging; Mouse; Naked mole rat.

Fig. 1

Unlike mice, NMR body composition and bone mineral density show minimal age-related changes. a, b Representative X-ray images of young and old NMRs as well as mice (NMR: 3 and 26.5 years; mouse: 3 months and 2.5 years). Arrows indicate radio frequency identification chips, while green circles illustrate regions of interest used to exclude heads from the analysis. c NMR body weight showed a small quadratic age dependence (n: ♀ = 48 ♂ = 72, Age β = 0.87, Age² β =  − 0.85, P = 0.06). d Mouse body weight showed a strong quadratic age dependence (n: ♀ = 62 ♂ = 70, Age ♀β = 3.10, Age² ♀β =  − 2.39, P < 2.2E − 16, Age ♂β = 2.57, Age² ♂β =  − 1.93, P < 2.2E − 16). e NMR lean body mass (excluding head) did not change with age (n: ♀ = 48 ♂ = 72, Age β = 0.08, P = 0.38). f Mouse lean body mass (excluding head) started to decline at 2 years of age for females and later for males (n: ♀ = 62 ♂ = 73, Age ♀β = 1.07, Age² ♀β =  − 0.27 P < 2.2E − 16, Age ♂β = 2.52, Age² ♂β =  − 1.68, P < 0.001). g NMR body fat fraction declined 12% over 33 years (n: ♀ = 48 ♂ = 72, Age β =  − 0.21, P = 0.02). (h) Mouse body fat fraction declined after peaking around 1.5 years of age in females and males (n: ♀ = 62 ♂ = 70, Age ♀β = 3.61, Age² ♀β =  − 3.70, P < 0.001, Age ♂β = 3.04, Age² ♂β =  − 2.84, P < 0.001), with the average being 41% lower in the oldest cohort when compared to the 18-month-old cohort. i NMR femur bone mineral density (BMD) did not change with age (n: ♀ = 48 ♂ = 72, Age β = 0.01, P = 0.87). j Mouse femur bone mineral density started to decline after 1.5 years of age in females and males (n: ♀ = 62 ♂ = 70, Age ♀β = 1.41, Age² ♀β =  − 1.96, P = 2.1E − 7, Age ♂β = 0.54, Age² ♂β =  − 1.14, P = 3.1E − 8). Scale bars: 10 mm

Fig. 2

Naked mole-rat QRS, PR, and PQ duration do not increase with age. a, b Representative ECG traces (average of 100 heartbeats, lead 1) of young (3 years) and old (32.5 years) male NMRs. c, d Representative ECG traces of young (0.3 years) and old male (2.5 years) mice. e Heart rates (under light anesthesia) of NMRs showed a quadratic age dependence (n: ♀ = 48 ♂ = 72, Age β =  − 1.16, Age² β = 1.02, P = 2.9E − 3). But heart rates were similar for the youngest and oldest cohorts (242 ± 23 and 238 ± 13 bpm, P = 0.43). f Heart rates of mice (under light anesthesia) increased linearly with age (n: ♀ = 62 ♂ = 70, β = 0.46, P = 3.7E − 7). g NMR QRS duration did not change with age (n: ♀ = 48 ♂ = 72, Age β = 0.08, P = 0.37). h Mouse QRS duration increased linearly with age (n: ♀ = 62 ♂ = 70, β = 0.48, P = 4.63E − 9). i NMR PR intervals were quadratically age dependent (n: ♀ = 48 ♂ = 72, Age β = 0.89, Age² β =  − 0.71, P = 0.01). j Mouse PR intervals increased linearly with age with a small sex difference (n: ♀ = 62 ♂ = 70, Age ♀β = 0.53, P = 1.3E − 5, ♂β = 0.59, P = 7.8E − 8). k NMR PQ intervals were quadratically age dependent (n: ♀ = 48 ♂ = 72, Age β = 0.93, Age² β =  − 0.76, P = 0.01). l Mouse PQ intervals increased linearly with age with a small sex difference (n: ♀ = 62 ♂ = 70, Age ♀β = 0.48, P = 8.1E − 5, ♂β = 0.52, P = 4.7E − 6)

Fig. 3

Arrhythmia frequency increases with age in mice. a Arrhythmia frequency increases with age in mice with a slightly faster rate in males (n: ♀ = 62 ♂ = 70, Age ♀β = 0.24, P = 0.05, Age ♂β = 0.32, P = 0.01). b No arrhythmias were detected in naked mole-rats (n: ♀ = 48 ♂ = 72). c–f Representative Lead-I ECG traces from 2.2-year-old male mice showing commonly observed arrhythmias: atrial premature beat (APB) indicated by red arrows, ventricular premature beat (VPB) indicated by green arrows, and junctional premature beat (JPB) indicated by blue arrows. g Percentage of mice with different arrhythmia types across the observed age range (n: ♀ = 62 ♂ = 70)

Fig. 4

NMR cardiac function at rest does not change with age. a, b Representative magnetic resonance 4-chamber long axis images of a young (2 years) and old (32 years) NMR heart as well as young (0.3 years) and old (2.5 years) mouse heart at end-diastole and end-systole. c, d NMR end-diastolic volume and end-systolic volumes (ultrasound) did not change with age (n: ♀ = 48 ♂ = 72, Age β =  − 4.4E − 3, P = 0.96 and Age β =  − 0.03, P = 0.76). e, f Mouse end-diastolic and end-systolic volumes increased linearly with age (n: ♀ = 47 ♂ = 49, Age β = 0.57, P = 1.2E − 9 and Age β = 0.53, P = 2.9E − 8). g, h NMR left ventricular stroke volumes and ejection fraction (ultrasound) did not change with age (n: ♀ = 48 ♂ = 72, Age β = 0.05, P = 0.62 and Age β = 0.11, P = 0.21). (i) NMR cardiac output (ultrasound) normalized to body weight did not change with age (n: ♀ = 48 ♂ = 72, Age β = 0.01, P = 0.93). j NMR left ventricular (LV) anterior wall thickness (ultrasound) at end-diastole showed a small age associated decline (n: ♀ = 48 ♂ = 72, Age β =  − 0.21, P = 0.02). k, l Mouse left ventricular stroke volume increased with age while ejection fraction declined linearly with age (n: ♀ = 47 ♂ = 49, Age ♀β = 0.54, P = 7.7E − 5, Age ♂β = 0.48, P = 4.6E − 4 and Age ♀β =  − 0.44 P = 2.1E − 3, Age ♂β =  − 0.44, P = 1.5E − 3). m Mouse cardiac output normalized to body weight showed a quadratic age dependency (n: ♀ = 47 ♂ = 49, Age β =  − 1.91, Age² β = 1.82, P = 3.3E − 4), but there was no difference between the youngest and oldest cohort (Wilcoxon, P = 0.89). n Mouse left ventricular mid anterior wall thickness at end-diastole increased linearly with age (n: ♀ = 47 ♂ = 49, Age ♀β = 0.62, P = 2.82E − 6, Age ♂β = 0.28, P = 0.05). o Young and old male NMR left ventricular stroke volume (MRI) were not significantly different (n: ♂ = 12 ♂ = 13, Wilcoxon, P = 0.23). p, q NMR left ventricular ejection fraction and normalized cardiac output (MRI) of young and old NMRs were not significantly different (n: ♂ = 12 ♂ = 13, Wilcoxon, P = 0.81 and P = 0.17). r Young and old NMR left ventricular wall thicknesses (MRI) at end-diastole were not significantly different (n: ♂ = 12 ♂ = 13, Wilcoxon, P = 0.78). LV: left ventricular, scale bars 1 mm

Fig. 5

NMRs did not show age associated diastolic dysfunction. a, b Representative Doppler left ventricular flow measurements in a young (2 years) and old (26.5 years) NMR as well as young (0.3 years) and old (2.5 years) mouse heart. c NMR early/atrial (E/A) filling ratios did not change with age (n: ♀ = 22 ♂ = 29, Age β =  − 1.14, P = 0.33). d Mouse E/A ratios declined linearly with age (n: ♀ = 52 ♂ = 61, Age β =  − 0.64, P = 5.9E − 14). e NMR early peak filling velocities did not change with age (n: ♀ = 48 ♂ = 71, Age β = 0.05, P = 0.63). f Mouse early peak filling velocities declined linearly with age (n: ♀ = 52 ♂ = 61, Age β =  − 0.45, P = 4.1E − 7). E: early filling velocity, A: atrial filling velocity, Scale bars 0.1 s

Fig. 6

NMR cardiac function under dobutamine stress did not decline with age. a, b Representative magnetic resonance mid-ventricular short axis images of a young (2 years) and old (32 years) NMR heart as well as a young (0.3 years) and old (2.5 years) mouse heart at end-diastole and end-systole prior to and approximately nine minutes after intraperitoneal infusion of 1.5 mg/kg dobutamine. c) NMR heart rate under dobutamine stress showed a quadratic age association (n: ♀ = 48 ♂ = 72, Age β =  − 1.58, Age² β = 1.45, P = 2.6E − 5). d NMR heart rate changes following dobutamine administration did not change with age (n: ♀ = 48 ♂ = 72, Age β =  − 0.008, P = 0.39). e Mouse heart rate under dobutamine stress declined linearly with age (n: ♀ = 45 ♂ = 47, Age β =  − 0.37, P = 2.0E − 4). f Mouse heart rate changes following dobutamine administration were quadratically age associated (n: ♀ = 45 ♂ = 47, Age ♀β = 1.12 Age² ♀β =  − 1.06, P = 0.33, Age ♂β = 0.80 Age² ♂β =  − 0.90, P = 0.39). g, h NMR stroke volume change (ultrasound) from baseline and ejection fraction under dobutamine stress did not change with age (n: ♀ = 48 ♂ = 72, Age β = 0.12, P = 0.18 and Age β = 0.01, P = 0.88). i NMR ejection fraction change (ultrasound) following dobutamine administration remained constant with increasing age (n: ♀ = 48 ♂ = 72, Age β =  − 0.08, P = 0.38). j NMR normalized cardiac output changes (ultrasound) following dobutamine administration were quadratically age associated (n: ♀ = 48 ♂ = 72, Age β =  − 0.75, Age² β = 0.87, P = 0.03). k Mouse left ventricular stroke volume changes (MRI) following dobutamine administration declined linearly with age (n: ♀ = 45 ♂ = 47, Age β =  − 0.55, P = 1.8E − 8). l, m Mouse left ventricular ejection fraction under dobutamine stress did not change with age while ejection fraction changes following dobutamine administration did increase linearly with age (n: ♀ = 45 ♂ = 47, Age β =  − 0.14, P = 0.18 and Age ♀β = 0.44, P = 2.2E − 3; Age ♂β = 0.47, P = 8.4E − 4). n Mouse normalized cardiac output changes following dobutamine administration declined linearly with age (n: ♀ = 45 ♂ = 47, Age β =  − 0.57, P = 3.0E − 9). o Stroke volume changes (MRI) following dobutamine administration were slightly higher in old male NMRs (n: ♂ = 12 ♂ = 13, Wilcoxon, P = 0.05). p Ejection fraction under dobutamine stress (MRI) was higher in young NMRs (n: ♂ = 12 ♂ = 13, Wilcoxon, P = 0.03). q, r Ejection fraction and cardiac output changes (MRI) following dobutamine administration were not significantly different between young and old male NMRs (n: ♂ = 12 ♂ = 13, Wilcoxon, P = 0.38 and P = 0.09). Δ: change from unstressed baseline values, Db: dobutamine, scale bars 1 mm