Research Highlight

Sestrin Protects Fruit Flies From Age-Related Pathologies; NCMIR Image Featured on Cover of Science

mitochondria

Caption: Scanning electron micrograph of the fruit fly Drosophila melanogaster (magnification 80 ×, eyes pseudo-colored). Sestrin, an evolutionarily conserved protein, helps protect fruit flies from age-related pathologies, including fat accumulation, muscle degeneration, and heart failure. Image: T. Deerinck and M. Ellisman/National Center for Microscopy and Imaging Research, University of California, San Diego (from the cover of Science, 05 March 2010).

March 2010 – NCMIR scientists were members of a team of researchers that studied the intricate link of TOR with sestrins, a family of highly conserved proteins whose expression is induced by stress. As the team reported in the March 5th issue of the journal Science, they found that sestrin proteins prevent excessive TOR activation and delay the onset of age-related pathologies through a negative-feedback mechanism.

The target of rapamycin (TOR) kinase plays a key role in controlling metabolic activity including cell growth, proliferation, and immune function. Interestingly, persistent activation of TOR causes an accumulation of damaging reactive oxygen species (ROS), which promote the development of age-related disorders, including cancer, metabolic disease, and age-associated heart and mitochondrial dysfunction. Significantly, the inhibition of TOR by the drug rapamycin increases life span and reduces age-related pathologies.

There are three sestrins in mammals, but only one (dSesn) in the fly Drosophila melanogaster, and thus the fly was used as an optimal model system for studying the physiological functions of sestrins.

Electron microscopy performed on fly heart and skeletal muscle by NCMIR researchers demonstrated that loss of dSesn induced several phenotypes associated with Drosophila dTOR hyperactivation and aging, including lipid accumulation, mitochondrial dysfunction and structural degeneration of cardiac and skeletal myofibrils.

Other work showed the presence of cardiac arrhythmias in dSesn-deficient flies. Strikingly, feeding dSesn-deficient flies with antioxidants, such as vitamin E, or metformin, a pharmacological activator of adenosine monophosphate–activated protein kinase (AMPK), an indirect TOR inhibitor, or a direct TOR inhibitor, rapamycin, prevented the age-related phenotypes, as shown by electron microscopy. Moreover, the TOR pathway has now emerged as a prime candidate for explaining how caloric restriction ameliorates aging and delays the onset of age-related pathologies in many organisms through a dSesn mediated feedback mechanism that keeps dTOR activity in check, thereby maintaining the integrity of mitochondria, a major ROS source. Not surprisingly, some of these pathologies may be due to diminished autophagic removal of damaged mitochondria.

Full text: http://www.sciencemag.org/cgi/content/full/327/5970/1223

Related Publication

Lee, J.H., Budanov, A.V., Park, E.J., Birse, R., Kim, T.E., Perkins, G.A., Ellisman, M.H., Bodmer, R., Bier, E., Karin, M. (2010) Sestrin is a feedback inhibitor of TOR that prevents age-related pathologies. Science, 327: 1223-1228.

Links:

www.sciencemag.org/cgi/content/full/327/5970/1210

http://www.sciencemag.org/cgi/content/full/327/5970/1223

http://ucsdnews.ucsd.edu/newsrel/health/03-04FruitFly.asp