Award for Research May Lead to Drugs To Lengthen Human Life Span

Dec 20, 2001

Dr. Jochen Buck, an Associate Professor in the Department of Pharmacology at Weill Cornell Medical College, has been selected to receive a Senior Scholar in Aging Award by the Ellison Medical Foundation. The prestigious award, which comes with one-million dollars to help support his research for the next four years, is intended to encourage Dr. Buck's exploration of the role of the enzyme soluble adenylyl cyclase (sAC) in the aging process.

Dr. Buck, who earned his M.D. and Ph.D. from the University of Tübingen in Germany, has been a faculty member at Weill Cornell since 1992. His research into sAC has been done in collaboration with another member of the medical school's Pharmacology Department, Dr. Lonny Levin.

The significance of Dr. Buck's research derives from the well-established fact that restricting caloric intake tends to extend life span in a wide variety of organisms, from yeast to mammals, and that the responses of cells to this intake are mediated by the cAMP signaling pathway. Up to now, this pathway has generally been known by the cAMP signaling cascade defined by transmembrane adenylyl cyclases (tmACs). TmACs are responsive to hormones and regulated by G proteins. What Dr. Buck recently discovered with Dr. Levin is a second, novel cAMP signaling cascade in mammals. This second cascade is defined by an intracellular form of adenylyl cyclase—that is, soluble adenylyl cyclase.

"SAC seems to be ubiquitously expressed, and is targeted to distinct subcellular locations within cells—i.e., nucleus, cytoskeleton, and mitochondria," Dr. Buck says. "SAC is not subject to regulation via G proteins, and its catalytic regions are more similar to cyanobacterial adenylyl cyclase (AC) catalytic domains than to other cyclases in multi-celled organisms."

Dr. Buck has shown that, among mammalian cyclases, sAC is uniquely regulated by bicarbonate ions. "Intracellular carbonic anhydrases are present in all living organisms, and they instantaneously equilibrate cellular carbon dioxide and bicarbonate levels," Dr. Buck says. "Because energy metabolism produces carbon dioxide, the bicarbonate regulation of sAC and cAMP levels may be found to be an intrinsic mechanism for sensing the metabolic state of cells."

All of this leads to the possibility that the second signaling pathway, originating from sAC-generated cAMP, monitors the cell's nutritional state. As a practical effect, a reduction in sAC activity in a laboratory animal might lengthen its life span. If this proves to be true, the basic research by Drs. Buck and Levin could in the future lead to a revolutionary result: novel drugs to lengthen human life span.