Mitochondrial health is enhanced in rats with higher vs. lower intrinsic exercise capacity and extended lifespan

Miguel A Aon,José M Villalba,Rafael De Cabo,Sarah J Mitchell,Lauren G Koch,Irene Alfaras,Jessie E C Axsom,Andrew D Lachance,Bruce D Ziman,Edward G Lakatta,José A González-Reyes,Magdalena Juhaszova,Miguel Calvo-Rubio,Steven L Britton,Kelsey N Murt,Steven J Sollott,Sonia Cortassa

doi:10.1038/s41514-020-00054-3

Abstract

The intrinsic aerobic capacity of an organism is thought to play a role in aging and longevity. Maximal respiratory rate capacity, a metabolic performance measure, is one of the best predictors of cardiovascular- and all-cause mortality. Rats selectively bred for high-(HCR) vs. low-(LCR) intrinsic running-endurance capacity have up to 31% longer lifespan. We found that positive changes in indices of mitochondrial health in cardiomyocytes (respiratory reserve, maximal respiratory capacity, resistance to mitochondrial permeability transition, autophagy/mitophagy, and higher lipids-over-glucose utilization) are uniformly associated with the extended longevity in HCR vs. LCR female rats. Cross-sectional heart metabolomics revealed pathways from lipid metabolism in the heart, which were significantly enriched by a select group of strain-dependent metabolites, consistent with enhanced lipids utilization by HCR cardiomyocytes. Heart–liver–serum metabolomics further revealed shunting of lipidic substrates between the liver and heart via serum during aging. Thus, mitochondrial health in cardiomyocytes is associated with extended longevity in rats with higher intrinsic exercise capacity and, probably, these findings can be translated to other populations as predictors of outcomes of health and survival.

Highlights

The intrinsic aerobic exercise capacity of an organism can play a role in determining healthspan and lifespan, as suggested by the predictive power of low exercise capacity on premature morbidity and mortality for healthy adults, as well as those with cardiovascular disease[1]
Mitochondrial respiration scales as a function of body size both at rest and maximal metabolic performance, and the aerobic capacity of locomotor muscle scales with maximal metabolic rate (MMR), which, in turn, scales with the surface area of inner mitochondrial membranes, where oxidative phosphorylation (OxPhos) takes place, underscoring the fundamental role of mitochondrial molecular mechanisms in determining aerobic capacity[5]
HCR cardiomyocytes exhibit significantly we investigated whether a higher respiratory reserve (Rres) was associated with higher Rres than LCR in the presence of Palm or Gluc + Palm, mitochondrial fitness and turnover linked to autophagy/mitoacross the ages, except in Palm at 24 months where a phagy

Summary

Introduction

The intrinsic aerobic exercise capacity of an organism can play a role in determining healthspan and lifespan, as suggested by the predictive power of low exercise capacity on premature morbidity and mortality for healthy adults, as well as those with cardiovascular disease[1]. Mitochondrial respiration scales as a function of body size both at rest and maximal metabolic performance, and the aerobic capacity of locomotor muscle scales with MMR, which, in turn, scales with the surface area of inner mitochondrial membranes, where oxidative phosphorylation (OxPhos) takes place, underscoring the fundamental role of mitochondrial molecular mechanisms in determining aerobic capacity[5]. A healthy mitochondrial network function might be of critical importance for limiting cellular damage accumulation, slowing the rate of senescence, and leading to improvements in healthspan and lifespan The susceptibility to mitochondrial permeability transition pore (mPTP) opening, a proxy of mitochondrial fitness, is a key player in the integration of mitochondrial energy metabolism to cell life and death decisions[7,8,9]

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Results

Conclusion