ATF4

But important differences emerged farther downstream.

The transcription factors ATF4 and CHOP normally increased with age and following muscle stimulation in wild-type animals.

In aged mice lacking ATF5, these increases were blunted.

This suggests that although some initial components of the stress response can still be activated without ATF5, the normal downstream response to contractile stress becomes disrupted with age.

Yet the preserved muscle was more fatigable and contained a larger mitochondrial pool with signs of impaired quality.

The absence of ATF5 was also associated with altered mitochondrial protein balance.

increased oxidative stress in specific mitochondrial populations, reduced LONP, and an impaired ATF4 and CHOP response to contractile stress.

The researchers therefore concluded that ATF5 helps maintain mitochondrial quality control and muscle endurance, but apparently at the expense of muscle mass.

It turns out, though, that mitochondrial researchers have been looking at these two compounds for a number of years, and they're very complementary, but they really don't do the same thing.

But the ATF4 is the convergence point, meaning if we have any kind of cellular threat, we're going to turn on that integrated stress response first.

We'll see elevations of these stress markers of the GDF15 and the FGF21.

And that says that we're sending the signal to the mitochondria to enter CDR2 or CDR.

We also know that it's elevated in kidney disease and other processes too.

So you need to be careful about looking at GDF-15 alone.

In addition to that, FGF21 also goes up when ATF4 is triggered, but FGF21 has broader effects in the body.

And in fact, it might be limited to what's called beta-clotho.