Sestrin family - the stem controlling healthy ageing.

Sestrins are a family of stress-responsive antioxidant proteins responsible for regulation of cell viability and metabolism. The best known Sestrin targets are mTORC1 and mTORC2 kinases that control different cellular processes including growth, viability, autophagy, and mitochondrial metabolism. Inactivation of the single Sestrin gene in invertebrates has an adverse impact on their healthspan and longevity, whereas each of the three Sestrin genes in mammals and other vertebrate organisms has a different impact on maintenance of a particular tissue, affecting its stress tolerance, function and regenerative capability. As a result, Sestrins attenuate ageing and suppress development of many age-related diseases including myocardial infarction, muscle atrophy, diabetes, and immune dysfunction, but exacerbate development of chronic obstructive pulmonary disease. Moreover, Sestrins play opposite roles in carcinogenesis in different tissues. Stem cells support tissue remodelling that influences ageing, and Sestrins might suppress ageing and age-related pathologies through control of stem cell biology. In this review, we will discuss the potential link between Sestrins, stem cells, and ageing.

p53-inducible SESTRINs might play opposite roles in the regulation of early and late stages of lung carcinogenesis.

SESTRINs (SESN1-3) are proteins encoded by an evolutionarily conserved gene family that plays an important role in the regulation of cell viability and metabolism in response to stress. Many of the effects of SESTRINs are mediated by negative and positive regulation of mechanistic target of rapamycin kinase complexes 1 and 2 (mTORC1 and mTORC2), respectively, that are often deregulated in human cancers where they support cell growth, proliferation, and cell viability. Besides their effects on regulation of mTORC1/2, SESTRINs also control the accumulation of reactive oxygen species, cell death, and mitophagy. SESN1 and SESN2 are transcriptional targets of tumor suppressor protein p53 and may mediate tumor suppressor activities of p53. Therefore, we conducted studies based on a mouse lung cancer model and human lung adenocarcinoma A549 cells to evaluate the potential impact of SESN1 and SESN2 on lung carcinogenesis. While we observed that expression of SESN1 and SESN2 is often decreased in human tumors, inactivation of Sesn2 in mice positively regulates tumor growth through a mechanism associated with activation of AKT, while knockout of Sesn1 has no additional impact on carcinogenesis in Sesn2-deficient mice. However, inactivation of SESN1 and/or SESN2 in A549 cells accelerates cell proliferation and imparts resistance to cell death in response to glucose starvation. We propose that despite their contribution to early tumor growth, SESTRINs might suppress late stages of carcinogenesis through inhibition of cell proliferation or activation of cell death in conditions of nutrient deficiency.