The Physiology of Sestrin Proteins: Guardians of Metabolic Homeostasis

Sestrins are a family of highly conserved stress-inducible proteins that serve as central integrators of the cell's metabolic state. They act as "metabolic brakes," ensuring that the cell does not grow or divide when resources are scarce or when damage is present.

Functions of Sestrins

1. mTORC1 Inhibition: Sestrins (particularly Sestrin2) act as leucine sensors. When leucine is low, Sestrins bind and inhibit GATOR2, which in turn inhibits mTORC1, the master regulator of protein synthesis.
2. Antioxidant Activity: Sestrins help regenerate peroxiredoxins, enzymes that neutralize hydrogen peroxide, thereby protecting the cell from oxidative damage.
3. AMPK Activation: Sestrins can promote the phosphorylation of AMPK, facilitating a shift from anabolic to catabolic metabolism (e.g., fat burning).

Sestrins and Exercise

Interestingly, Sestrins are upregulated during physical exercise. They appear to mediate many of the benefits of a workout, including improved insulin sensitivity and increased mitochondrial biogenesis. In animal models, mice lacking Sestrins do not show the same endurance improvements after training as wild-type mice.

Longevity and Disease

Because they inhibit mTOR and reduce oxidative stress—two major drivers of aging—Sestrins are considered potent "longevity proteins." Strategies to pharmacologically upregulate Sestrins are currently being explored to treat age-related muscle wasting (sarcopenia) and type 2 diabetes.