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.
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Introduction
With aging human populations cardiovascular diseases have become the primary cause of death globally and a substantial burden for healthcare systems [1]. Indeed, age is the strongest risk factor for cardiovascular diseases [2]. Furthermore, the prevalence of many comorbidities such as obesity, dyslipidemia, and diabetes also increases substantially with age compounding the severity of cardiovascular pathology and mortality [3]. Mice manifest many aspects of cardiac aging that are commonly observed in humans. For example, cardiac hypertrophy, diastolic dysfunction, increased rates of arrhythmia, and decreased functional reserve capacity become evident at less than half of their observed maximum lifespan [4,5,6,8, 13, 42, 43], suggesting that left ventricular compliance is well maintained in NMRs. Several factors affect E/A ratios limiting its sensitivity. Newer methods such as E′/A′ and E/E′ particularly when combined with atrial area measurements provide a more sensitive and robust assessment of diastolic dysfunction [44].
Large age-associated changes have been reported for human cardiac reserve capacity [45]. We therefore examined age-associated changes in cardiac reserve capacity in mice and NMRs following beta adrenergic stimulation with dobutamine. Dobutamine administration increased heart rates and contractility in both species, but there was a decline in the chronotropic response in older mice compared to young mice. A decreasing ability to increase heart rates following beta adrenergic stimulation in mice has been reported previously [46], and similar effects have been observed in humans [45, 47,48,49]. While beta adrenergic stimulation led to a small increase in stroke volume in young mice, it reduced stroke volumes in older mice leading to a linear decline in normalized cardiac output with advancing age. Our observations in young mice agree with a previous cardiac MRI study [50], but MRI data for older mice is missing in the literature. Similar to our observation in mice a substantial decline in cardiac reserve capacity with advancing age has been observed in humans [45, 47,48,49]. In contrast to mice and humans, dobutamine-induced increases in stroke volume and cardiac output did not change with age in NMRs indicating preserved cardiac reserve capacity with advancing age.
We relied primarily on ultrasound to measure cardiac parameters in NMRs as all our NMRs are identified by RFID chips, implanted at 90 days in the sub scapular region. These chips often migrate and are found within 3–4 cm from the heart leading to significant signal drop-out on gradient-echo-based MRI. Cardiac MRI is the gold standard for functional assessments in rodents and humans since it does not rely on any geometric assumptions offering full three-dimensional coverage and low variability [51, 52]. The higher variability of ultrasound-based measurements lowers the ability to detect small changes and makes comparisons to MRI based measurements difficult. We consequently performed cardiac MRI on a separate cohort of young and old NMRs whose RFID chips were sufficiently distant from the heart. This analysis showed that NMR cardiac function at rest and under stress does not change with age. It also showed that NMR ejection fraction at rest is approximately 60% and dobutamine increases cardiac output by roughly 10% which is closer to what has been observed in mice than a prior study suggested [53]. The less variable and more precise MRI study confirmed our ultrasound-based findings that NMR cardiac function at rest and under stress does not change with age.
Our ability to detect age-associated changes is limited by two factors: First, the cross-sectional design of our study leads to higher biological variability compared to a longitudinal study where individual baselines can be used for analysis. However, with a maximum lifespan > 38 years in NMRs, longitudinal studies would take decades to complete. Second, the coefficient of variation for the different assays used together with the sample size determines the minimum age-associated change which can be detected. For example, the coefficient of variation for bone mineral density measurements was 2.9% with group sizes n > 24 (assuming no sexual dimorphism) limiting the detectable relative change to 2.4% for a two-point comparison. Using the same assumptions with coefficient of variations for MRI-based stroke volume, ejection fraction, and posterior wall thickness measurements of 12.1, 6.1, and 5.9, respectively, we can expect to detect relative changes greater than 10, 5, and 4.9%. There is also a possibility that differences in response to anesthetic gases between young and old animals affect measurements despite standardized temperatures and breathing rates for data acquisition.
Conclusion
This study demonstrates that unlike mice that exhibit pronounced declines in body composition and cardiac function commencing shortly after sexual maturity, NMRs can maintain tissue homeostasis throughout their four-decade long maximum lifespan. Furthermore, NMRs do not show any signs of diastolic dysfunction or cardiac hypertrophy and maintain similar functional cardiac reserve capacity at advanced age to that exhibited when young adults, at the prime of life. Collectively, these data reveal that the naked mole-rat provides a proof-of-concept that age-related declines in body composition and cardiac function are not inevitable. Elucidating these mechanisms may lead to the discovery of therapies to reduce the burden of age-associated cardiovascular pathology, morbidity, and mortality and thereby enhance quality of life in older humans.
Data availability
Raw data is available upon request.
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Custom processing scripts are available upon request.
Change history
19 February 2022
A reference entry Laborde S, et al has been changed to Piantoni C, et al.
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Acknowledgements
We would like to thank the animal care specialists in the Buffenstein laboratory for providing excellent NMR care and assistance with NMR handling.
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This study was funded by Calico Life Sciences LLC.
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E.C., M.S., R.B., and J.R. are employees of Calico Life Sciences LLC.
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Can, E., Smith, M., Boukens, B.J. et al. Naked mole-rats maintain cardiac function and body composition well into their fourth decade of life. GeroScience 44, 731–746 (2022). https://doi.org/10.1007/s11357-022-00522-6
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DOI: https://doi.org/10.1007/s11357-022-00522-6