Investigating the Mechanisms by which Klotho Increases Autophagy

Expression of the klotho gene declines with age, while approaches that increase levels of the klotho protein have been demonstrated to slow aging in mice. Some fraction of this outcome stems from increased activity of the cellular housekeeping processes of autophagy, responsible for recycling metabolic waste and damaged molecular machinery and cellular components. Many of the methods of modestly slowing aging in laboratory species are characterized by upregulated autophagy, and some, such as calorie restriction, require functional autophagy in order to slow aging.

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. Researchers 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.


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