Deciphering the mechanism of cellular aging: interaction of oxidatively damaged proteins with the cellular membranes

Aging is one of the greatest mysteries in biology and a considerable contemporary societal challenge. Despite extensive research, the etiology of aging remains poorly understood. Most current theories focus on DNA damage as the root cause of aging. However, this view has been challenged by the discovery that oxidative damage to proteins alone is sufficient to recapitulate molecular and cellular hallmarks of aging. In this project, we aim to explore mechanisms through which oxidatively damaged/carbonylated proteins lead to age-associated cellular dysfunction. Our study is based on the knowledge that misfolded, oxidatively damaged proteins may form high molecular weight protein species – oligomers and aggregates. Interestingly, some protein aggregates have been shown to contribute to aging of various tissues. Moreover, toxic protein oligomers compromise the integrity of cellular membranes. Hence, we hypothesize that protein oligomers and/or aggregates ensuing from age-dependent protein oxidation bind cellular membranes, thus leading to membrane permeabilization. To test this hypothesis, we will first characterize oxidatively damaged oligomers and aggregates and assess their association with cellular membranes. Membrane damage will be evaluated in vitro and in vivo, upon exposure of artificial lipid vesicles and living cells to oxidized oligomers. Interdisciplinary approaches will be used, including advanced imaging techniques such as atomic force microscopy, stimulated emission depletion microscopy, Fourier transform infrared microscopy and spectroscopy, mass spectrometry and various biochemical techniques. During the fellowship, the awardee will acquire skills necessary for reaching a leading independent position, basic entrepreneurial experience and will be given an opportunity to promptly commercialize her research. Moreover, the fellowship will lead to the creation of several new sustainable international networks.