A recent research report indicates that sestrin proteins can inhibit age-related pathologies in fruit flies and contribute to their longevity. The genes and biological pathways involved exist also in humans. This blog post reviews what the sestrin genes are, what the sestrin proteins do, the new research describing the channels through which sestrins promote longevity, and how sestrins protect against cancer.
Sestrins are small protein molecules produced by three evolutionary conserved genes in mammals, of which the sesn1 and sesn2 genes are activated by the p53 tumor-suppressor gene(ref)(ref). Normally, when oxidative or other forms of stress activate p53, the target sesn1 and sesn2 genes are activated in turn. These genes in turn activate AMP-dependent protein kinase (AMPK), which serves to inhibit the Target of Rapamycin. E.g. inhibit mTOR signaling(ref). Sestrins also provide a level of antioxidant defense in cells(ref). The 2007 publication p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling provides ample detail for those of you who may wish to dig deeper.
Sestrins and longevity
The actions of sestrins are interesting from the viewpoint of longevity because for some time it has been known that inhibiton of mTOR signaling can lead to longer lifespans. See the earlier blog post “In my May 2009 blog post , I discussed the mTOR signaling pathway in mammals, its role in diseases, the relationship of mTOR to mitochondrial activity and how inhibiting mTOR could conceivably be a strategy for extending longevity. In my Anti-Aging Firewalls treatise I subsequently added ABERRANT mTOR SIGNALLING as one of six additional candidate theories of aging to be considered.” See also the blog entry Viva mTOR! Caveat mTOR!. Note that the m in mTOR stands for mammalian.“
The role of AMPK in regulating cellular energy charge places this enzyme at a central control point in maintaining energy homeostasis. More recent evidence has shown that AMPK activity can also be regulated by physiological stimuli, independent of the energy charge of the cell, including hormones and nutrients(ref).” Exercise can increase AMPK activity as can taking certain polyphenol supplements like resveratrol(ref). Another of the conditions that can activate AMPK is calorie restriction, a condition that slows down aging. On the other hand, over-nutrition activates mTOR, accelerating aging.
The latest result appeared in the March 5 issue of Science: Sestrin as a Feedback Inhibitor of TOR That Prevents Age-Related Pathologies. “We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO). Loss of dSesn resulted in age-associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacological activation of AMPK or inhibition of TOR. Hence, dSesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids.” In other words, if TOR gets ramped up, in the absence of genetic damage it turns on sestrin which ramps TOR down again before TOR activity creates major damage.
According to a Science Daily article about this latest research, “They also showed that Sestrin, whose structure and biochemical function are conserved between flies and humans, is needed for regulation of a signaling pathway that is the central controller of aging and metabolism. – The new study took advantage of the finding that the fruit fly Drosophila, whose AMPK-TOR signaling pathway functions in the same manner as its mammalian equivalent, contains a single Sestrin gene. Using a variety of genetic techniques, first author Jun Hee Lee inactivated the Sestrin gene of Drosophila and found that although Sestrin-deficient flies do not exhibit any developmental abnormalities, they suffer from under-activation of AMPK and over-activation of TOR — confirming that Sestrin is needed for keeping this pathway in check. Most importantly, the biochemical imbalance incurred by loss of Sestrin expression resulted in several age-related pathologies. — “Strikingly, the pathologies caused by the Sestrin deficiency included accumulation of triglycerides, cardiac arrhythmia and muscle degeneration that occurred in rather young flies,” said Karin. “These pathologies are amazingly similar to the major disorders of overweight, heart failure and muscle loss that accompany aging in humans.” — Lee and colleagues at UC San Diego and the Sanford-Burnham Institute in La Jolla, California, went on to demonstrate that feeding flies with drugs that either activate AMPK or inhibit TOR conferred protection against most of these early aging, degenerative symptoms. The researchers also found that over-activation of TOR is likely to accelerate aging of heart and skeletal muscles by disrupting an important “quality control” process called autophagy. Autophagy allows cells to rid themselves of and replace damaged mitochondria, the little power plants that provide all cells, especially muscles, with energy. However, when mitochondria get old, they produce high concentrations of reactive oxygen species (ROS), or free radicals, that can lead to tissue damage.”
I have previously discussed how an effective antiaging intervention might be inhibition of mTOR. The new research goes on to say how this might be accomplished through activation of sestrins.
Sestrins and cancer
In many cancers, oncogenic mutations in RAS genes result in inactivation of p53 genes and resulting failure of activation of sestrin genes which results in increased ROS (reactive oxygen species) levels and further oncogenic mutations. This scenario is depicted in the 2007 paper Repression of Sestrin Family Genes Contributes to Oncogenic Ras-Induced Reactive Oxygen Species Up-regulation and Genetic Instability. “Oncogenic mutations within RAS genes and inactivation of p53 are the most common events in cancer. Earlier, we reported that activated Ras contributes to chromosome instability, especially in p53-deficient cells. — Introduction of oncogenic RAS resulted in repression of transcription from sestrin family genes SESN1 and SESN3, which encode antioxidant modulators of peroxiredoxins. Inhibition of mRNAs from these genes in control cells by RNA interference substantially increased ROS levels and mutagenesis. — Thus, changes in expression of sestrins can represent an important determinant of genetic instability in neoplastic cells showing simultaneous dysfunctions of Ras and p53.”