Sestrins as Multifunctional Regulators of Cell Viability on the Pathways from Stress to Aging

The interaction of cells with their environment is crucial for maintaining cellular homeostasis, and disruption of these interactions causes cellular stress and cell death. Thus, cell survival depends on the balance between proteins responsible for cell protection and those inducing cell death. Sestrins are evolutionarily conserved stress-inducible proteins that modulate cell survival under stress conditions. While prokaryotic precursors of Sestrins play a key role in protecting against oxidative stress, eukaryotic Sestrins are critically important for regulating mTORC1 and mTORC2 kinases, as well as for controlling the expression of various proteins responsible for protection against stress, mitochondrial functions, and cell death. Sestrins sustain mitochondrial activity and metabolism, activate autophagy, and limit oxidative damage, thereby promoting cell survival. Conversely, in response to DNA damage and cytokine production, Sestrins promote apoptosis by suppressing the expression of anti-apoptotic proteins, which helps prevent carcinogenesis. As modulators of cellular responses to stress, Sestrins may also serve as markers of various diseases associated with stress responses. In some tissues, expression of all Sestrin genes declines with age, which impairs the regulation of metabolism and cell death and weakens protection against age-related diseases. Thus, maintaining Sestrin activity may contribute to the prevention and treatment of various age-related diseases.