by Buck Institute

Cellular Housekeeping: How autophagy models in mice could lead to treatment in humans

By Lukas Fluitt, Geoffrey Meyerhof, & George W. Brownridge III, Dominican Master students in the Kapahi lab

In this modern era of medicine and research increased emphasis is being placed on how we age and how we develop age-related diseases. In this vein, the Levine lab at UT Southwestern has conducted studies on the process of autophagy. Autophagy is the highly regulated natural process through which cells degrade and recycle dysfunctional cellular components, critical in protection against disease and starvation. We know that our ability to perform autophagy declines as we age, and that reducing the ability of animals to perform autophagy significantly reduces their lifespan. Beyond that, however, the effect of autophagy on longevity is not well understood.

In the most common form of autophagy, the components marked for recycling are engulfed to form a structure called an autophagosome. Then the components are transferred to a very acidic lysosome and are eventually degraded through specialized enzymes. Researchers can exploit these processes to change how much autophagy an organism can perform.

In order to study autophagy, researchers have created a mouse model that has increased levels of autophagy. This is performed by mutating a component of what is called the beclin 1 -BCL2 regulatory complex. When BCL2 binds beclin 1, autophagy is turned off. The engineered mutation in beclin 1 prevents BCL2 from binding, and allows beclin 1 to continue to promote the formation of the autophagosome, which results in continuously higher levels of autophagy in the mice.

The results of this study demonstrate that the mice with increased levels of autophagy have a significantly increased lifespan. Studies showed that not only do these beclin 1 mutant mice live longer, but also healthier, having better kidney and heart function as well as less spontaneous tumor formation. Additionally, their premature lethality and infertility is rescued. These results suggest that promoting autophagy in this manner can promote mammalian healthspan and lifespan and should be further studied.

The researchers then wondered if known anti-aging compounds could be producing their effects through a pathway similar to their genetic mouse model. Klotho, a membrane protein, was one such compound they examined. It has previously been shown that animals genetically engineered to be deficient in klotho have reduced lifespan and that administering klotho could extend lifespan. Additionally, it was observed that administering klotho promoted more autophagy. The Levine lab took klotho-deficient mice and observed a noticeable increase in beclin 1 - BCL2 binding, leading to less autophagy. By taking these klotho deficient mice and mutating beclin 1 they were able to rescue the effects of klotho deficiency and return autophagy to normal. Furthermore, by administering klotho to human HeLa cells they were able to reduce beclin 1- BCL2 binding showing that this effect is not isolated to mice, but applicable to humans as well.   

Cell autophagy is a crucial component to keep cells healthy and active throughout our lives.  Any build-up of toxins or compromised cellular machinery has the potential to cause health issues, even lethal ones. Future drug discovery research into beclin 1 - BCL2 complex inhibitors seems to be a highly promising avenue of inquiry. In the meantime, there are steps you can take today towards better health.Proper exercise and diet are believed to promote an increase in cell autophagy.

Science is showing that while chronological aging is inevitable, biological aging is malleable. There's a part of it that you can fight, and we are getting closer and closer to winning that fight.

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