Anti-aging properties of the aminosterols of the dogfish shark

Abstract

The development of anti-aging drugs is challenged by both the apparent complexity of the physiological mechanisms involved in aging and the likelihood that many of these mechanisms remain unknown. As a consequence, the development of anti-aging compounds based on the rational targeting of specific pathways has fallen short of the goal. To date, the most impressive compound is rapamycin, a natural bacterial product initially identified as an antifungal, and only subsequently discovered to have anti-aging properties. In this review, we focus on two aminosterols from the dogfish shark, Squalus acanthias, that we discovered initially as broad-spectrum anti-microbial agents. This review is the first to gather together published studies conducted both in vitro and in numerous vertebrate species to demonstrate that these compounds target aging pathways at the cellular level and provide benefits in multiple aging-associated conditions in relevant animal models and in humans. The dogfish aminosterols should be recognized as potential anti-aging drugs.

Fig. 1. Chemical structure of trodusquemine and squalamine.

The structures are presented as the zwitterions that exist at physiological pH.

Fig. 2. Trodusquemine effects on a model membrane.

The system illustrated is described in ref. , from which the Figure has been modified. A Trodusquemine is attracted electrostatically to the negatively charged GM1 ganglioside and subsequently buries itself in the membrane, as illustrated. The overall negative surface charge of the membrane is reduced due to ion-pairing. As a consequence, amphipathic cationic proteins bound to the membrane are displaced. B The spatial organization of lipids within the membrane is changed. Phospholipids with negatively charged headgroups cluster around the trodusquemine molecules, and cholesterol-rich domains segregate. The tensile strength of the membrane is increased. By this biophysical mechanism trodusquemine appears to defend a biological membrane from the toxic action of misfolded proteins.

Fig. 3. Effects of trodusquemine at a cellular level.

Left panel: Intracellular misfolded proteins are shown to bind to cellular membranes, resulting in organelle dysfunction and ER stress. Intracellular membranes rich in anionic phospholipids preferentially attract misfolded proteins. PTP1B activity is increased, impairing insulin signaling. Right panel: Trodusquemine, an amphipathic cationic zwitterion, integrates into cell membranes and displaces membrane-bound misfolded proteins electrostatically, restoring normal organelle functions. Inhibition of PTP1B restores normal insulin signaling.