Mitophagy in Antiaging Therapies

Intro

Today's article will be a quick review of a biological cleanup process called mitophagy and why it is important for healthy aging. Mitophagy might be the reason why some antiaging therapies work in model organisms.

But first a review on mitochondria...

Mitochondria are an organelle within cells that produce ATP, the energy currency of the cell. Their structure is controlled by dynamic processes based on the internal conditions of the cell. Mitochondria switch back and forth between fusion (fusing together into tubular structures) and fission (splitting apart)[1]. 

Transmission Electron Microscope Image of Mitochondria Public Domain. Author: Louisa Howard

Mitochondrial dysfunction is a hallmark of aging. As we age, the numbers of malfunctioned or broken mitochondria increase. With advancing age, mitochondria populations also tend to participate in fusion more than fission. This results in larger structures that are harder to break down with mitophagy.

 Mitophagy is a special subclass of autophagy, a process of swallowing up and breaking down damaged organelles and proteins, that specifically targets mitochondria. As we age, this process decreases. This results in an accumulation of dysfunctional mitochondria which causes problems in cell and tissue function[1].

Mitophagy and Anti-Aging

A lot of popular life-extending regimens (in lab animals), might work partially because they enhance mitophagy. Both exercise and calorie restriction (reduction of calories by 40% of normal intake without malnutrition) are known to be beneficial to healthy aging and to promote longer lifespans. (For people, the benefit of calorie restriction is still being explored. Exercise is universally recommended, however.) Both of these processes activate the AMPK-Ulk1 complex, a pathway that enhances mitophagy downstream. 

There are also a few drugs that seem to work partially due to their mitophagy enhancing abilities. For example, Urolitin A, which increases fitness in aging C .elegans and muscle function in mice, works by increasing autophagy in general. You might have also heard about different drug approaches to increase levels of NAD+ in the body. It turns out that that also enhances mitophagy.

C. elegans Public Domain. Author: S.Kbradnam

 Probably one of the most famous aging drugs of all, rapamycin, also promotes mitophagy. Rapamycin has increased the lifespan in a slew of organisms including yeast, worms, flies, and mice. It works by inhibiting mTOR, which normally would inhibit autophagy. So by enhancing autophagy altogether rapamycin also increases levels of mitophagy[2].

Conclusion

• Mitophagy is a process that breaks down damaged mitochondria.
• As we age, mitochondria tend to fuse together forming long structures. This makes it harder to break down mitochondria with mitophagy.
• Both calorie restriction and exercise can induce mitophagy in model organisms
• An assortment of antiaging drugs also promote autophagy and mitophagy.

1. The Importance of Mitophagy in Aging. Fight Aging! https://www.fightaging.org/archives/2020/04/the-importance-of-mitophagy-in-aging/ (2020).

2. Chen, G., Kroemer, G. & Kepp, O. Mitophagy: An Emerging Role in Aging and Age-Associated Diseases. Front. Cell Dev. Biol. 8, (2020).