Fight Aging!

Not all tissues are equal in their energy needs. The brain and more consistently active muscles, such as the heart, are at the top of the list. Energy for cell and tissue processes is provided by the chemical energy store molecule adenosine triphosphate (ATP), which is produced by mitochondria. Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria now evolved to become fully integrated cell components. Mitochondria still replicate much like bacteria, each containing a small remnant circular genome. When damaged or dysfunctional, mitochondria are cleared by the complex process of mitophagy, a mitochondrially targeted form of autophagy that recognizes impaired mitochondria and ensures that they are transported to a lysosome for disassembly.

Unfortunately, mitochondria become dysfunctional with age in ways that can (a) promote inflammation, such as via escape of mitochondrial DNA into the cytoplasm where it can trigger defenses that evolved to identify bacterial DNA, and (b) reduce ATP production. Epigenetic changes affect the dynamics of mitochondrial fusion and fission in ways that impair mitophapy. Similarly, epigenetic change leads to a decline in autophagy in general with age. Worn and damaged mitochondria accumulate as a result. Further, mitochondrial DNA is less well protected and repaired than is the case for nuclear DNA. Damage to mitochondrial DNA can disrupt ATP production and in extreme cases produce broken mitochondria that can outcompete their undamaged peers, replicating to overtake a cell. All of this arguably produces the worst outcomes in tissues like the heart and brain, where the demand for ATP is the highest.

Cardiovascular aging: the mitochondrial influence

The beating heart is a highly energy-consuming organ and the cellular energy needed to sustain contraction is primarily generated by mitochondrial oxidative phosphorylation (OXPHOS). Mitochondria are also involved in supporting various metabolic processes, as well as activation of the innate immune response and cell death pathways. Thus, the heart is highly susceptible to the effects of mitochondrial dysfunction. Mitochondria have been directly implicated as underlying drivers of cardiac aging. Studies have reported that the age-related decline in cardiac function is partly attributed to dysregulation of mitochondrial function and a decline in mitochondrial quality control. The aged heart accumulates dysfunctional mitochondria that are deficient in ATP generation and become major sources of reactive oxygen species (ROS) and oxidative stress. Interestingly, various interventions or treatments that directly or indirectly target mitochondria to reduce ROS generation, promote oxidative metabolism or enhance quality control have all been demonstrated to delay cardiac aging and alleviate disease development.

Currently, effective treatments to prevent age-related cardiovascular dysfunction are lacking, but there is a strong interest in developing therapeutics that are aimed at preserving or improving mitochondrial health in cells. Many interventions that protect against cardiac aging, including caloric restriction, exercise, and nicotinamide riboside, spermidine or rapamycin treatments, are mediated at least in part through the preservation of mitochondria. Pre-clinical studies clearly suggest that directly targeting mitochondrial ROS production or enhancing repair and turnover may have promising therapeutic benefits in the aging heart. For example, administration of the mitochondria-targeted antioxidant MitoTEMPO to aged mice reduces oxidative stress and improves systolic and diastolic function, while MitoQ administration ameliorates vascular endothelial dysfunction in aged mice. Treatment of aged mice with the mitochondrially-targeted tetrapeptide SS-31 (elamipretide) for 8 weeks leads to reduced oxidative stress in hearts with improvements in cardiac function and reversal of cardiac hypertrophy.

There is also great interest in developing small molecules that can directly activate mitophagy in cells. VL-004 is a small molecule that increases mitophagy and longevity in C.elegans via dct-1, the worm homolog of mammalian mitophagy receptors Bnip3 and BNIP3L/NIX. VL-004 failed to extend lifespan in dct-1 mutant worms, confirming that the effect on lifespan extension is dependent on mitophagy. Although these studies targeting mitophagy are promising, whether the beneficial effects are preserved in larger organisms remains to be investigated.

Due to the longer lifespan in the population, treatments that prevent late-life morbidities and increase healthspan are urgently needed. Dysfunctional mitochondrial are clearly major contributors to cardiac aging. Although rejuvenating mitochondria to reverse or prevent aging by directly targeting mitochondrial ROS or activating mitophagy seems to have anti-aging benefits, these interventions are not without risks. ROS also function as signaling molecules in cells and complete suppression of mitochondrial ROS has adverse effects on heart function. Similarly, too much activation of mitophagy can lead to excessive clearance of mitochondria. If the clearance exceeds the cells' capacity to generate new mitochondria, it can lead to a catastrophic energy deficiency. Thus, the therapeutic window of these interventions needs to be clearly defined.