Sestrins Link Tumor Suppressors with the AMPK -TOR Signaling Network

Abstract

The strength of the mechanisms involved in the control of health and lifespan determines the rate of aging in any organism. Aging is fueled by the accumulation of damage in a multitude of tissues, causing many age-related diseases including cardio-vascular diseases, neuro-degenerating diseases, metabolic syndrome and cancer[1]. We know that a healthy life-style, good habits, exercise and positive attitude are all factors that support a healthy, long life while the consumption of unhealthy, low nutritional and high caloric diet, bad ecology, bad habits and constitutive stress are known to shorten life and lead to the accumulation of a number of pathologies. However, exposure to low level stresses, for example induced by exercise, increases our resistance to detrimental stress insults, this process is referred to as hermesis[2]. With respect to what is beneficial and what is detrimental for health, we still do not fully understand the underlying processes that support our health and long life nor what allows us to become more resistant to a constantly changing, and sometimes unfriendly, environment.

The causative link between aging and age-related diseases emphasizes how understanding the mechanisms that control aging could aid in the development of approaches for the prevention and treatment of many human diseases. The involvement of similar signaling pathways in the control of aging and defense against different diseases supports this concept. Two protein kinases, Target of Rapamycine (TOR) and AMP-activated protein kinase (AMPK), are central regulators of aging that are often found to be malfunctioned in many human diseases and, according to different animal models, play a role in cancer, diabetes, neurodegeneration and other syndromes[3, 4]. Strikingly, AMPK directly regulates the TOR activity, indicating that these proteins have overlapping functions and are involved in the same pathways[3]. The proteins involved in the AMPK activation and the TOR suppression are potential regulators of longevity and aging. Among the modulators of AMPK and TOR, tumor suppressors p53 and members of the Forkhead Box O (FoxO) family play a central role in defense from stress, determination of lifespan and protection from age-related pathologies via activation of the stress-responsive Sestrin genes.