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Mitochondrial health is linked to longer life in female rats with high exercise capacity

Mitochondria generate the chemical energy needed to power cells’ biological processes. A longer lifespan is associated with mitochondrial health and high exercise capacity in female rats, according to findings published in Aging and Mechanisms of Disease.

cross-section of a 3-D computer graphic of cell mitochondria using coils and spheres to represent the different internal anatomy.

A previous study showed that rats selectively bred for high running capacity had up to a 31% increase in lifespan, along with a better-preserved lean muscle mass and relative resistance to obesity, higher insulin sensitivity, lower blood pressure, and improved lipid profile. Building on those results, a research team including scientists at NIA, explored the role of mitochondrial health in aging. Using female rats with high and low treadmill running capacities, they compared metabolic performance and other cellular processes. They found that the mitochondria in the hearts of high-capacity runners had more efficient respiration, including burning more fats over glucose as fuel, and were more resistant to oxidative stress than mitochondria in low-capacity runners. Overall, these results suggest that healthy mitochondria may help protect the aging heart in female rats with high exercise capacity.

Mitochondria are organelles in all cells that use oxygen to convert the fuel from food into chemical energy that a cell can use, in a process called oxidative phosphorylation, or more generally, cellular respiration. In addition to providing a reliable energy supply, mitochondria also help control the amount of free radicals, a form of oxygen that can cause cellular damage. The heart, which uses more oxygen by weight than other organs, is particularly vulnerable to oxidative damage. Typically, the protection provided by the mitochondria and other processes declines with age.

Using two rat strains with different running endurance capacities, referred to as high-capacity runners (HCR) and low-capacity runners (LCR), the researchers explored the relationship of mitochondrial health on cardiorespiratory function and aging. In aging HCR, heart and liver metabolic function, along with physical activity, were better preserved in contrast to aging LCR, where these functions were more compromised.

In parallel experiments, the researchers evaluated mitochondrial function in heart cells isolated from the rat strains at different ages. First, they measured mitochondrial respiration using two types of fuel: glucose and fat. With glucose alone, respiration was essentially the same in both rat strains. In contrast, in the presence of fats, either alone or combined with glucose, HCR cells had significantly higher respiration than LCR cells. Furthermore, this pattern was reflected in the whole animals. Following an extensive metabolic analysis of the whole animals, fat metabolism emerged as the main metabolic pathway used by the HCR heart, regardless of age.

Next, they explored whether HCR’s higher respiration rate was associated with mitochondrial health. Using live-cell imaging, they assessed the efficiency of autophagy, a process in which old or damaged organelles, including mitochondria, are cleared from a cell. At all ages, autophagy was significantly higher in HCR heart cells in comparison to LCR, suggesting robust maintenance of a healthy mitochondrial network in HCR heart cells. Similarly, the HCR heart cells were significantly more resistant to oxidative stress than LCR cells, another positive measure of mitochondrial fitness.

This study provides evidence that healthy mitochondrial function is linked to a fundamental resilience of the heart to oxidative stress in female rats with high exercise capacity. While these findings need to be evaluated in male rats and in humans, they may also inform new research on diet and exercise strategies to support healthy aging and longevity.

This research was supported by the NIA Intramural Research Program and NIH grant P40OD021331.

Reference: Aon MA, et al. Mitochondrial health is enhanced in rats with higher vs. lower intrinsic exercise capacity and extended lifespan. NPJ Aging Mech Dis. 2021;7(1):1. doi: 10.1038/s41514-020-00054-3.