Future: Aging – Facing the Challenge

Professor of Genetics, Department of Molecular Biology, Massachusetts General Hospital, Harvard University.

Gary Ruvkun made a major contribution to the future of human health with the discovery of conserved hormonal signaling pathways with universal influence on animal aging. He is a key figure in defining the genetic basis for human health during aging with his discovery of a core set of hormonal signals and signaling pathways that regulate aging and lifespan in animal models – likely to act in humans as well.

In a series of reports starting in the early 1990s, Ruvkun defined an insulin signaling pathway that regulates aging in C. elegans worms. He demonstrated that the essential elements of this pathway are conserved in mice and humans. He discovered that like mammals, C. elegans uses an insulin-like signaling pathway to control its metabolism and longevity, suggesting that insulin-like regulation of longevity and metabolism is ancient and universal.

The Ruvkun lab discovered the molecular identity of the many genes in the pathway, including the daf-2 insulin receptor, the many insulins that act upstream of the daf-2 receptor, the signal transduction components downstream of the insulin receptor such as age-1, daf-18, pdk-1, akt-1, and akt-2, and the downstream transcription factors daf-16 and daf-3, to reveal the signaling pathway from hormone to membrane receptor to the gene expression changes in the nucleus that regulate metabolism and longevity.

Their finding that the DAF-16/FoxO transcription factor is coupled to insulin signaling via conserved interactions with the kinases AKT and PDK also points to these transcriptional cascades as key in metabolic responses to insulin. This discovery has been important for understanding the defects in diabetes as well as for aging research, since the mammalian orthologs of daf-16, the FoxO transcription factors, are regulated by insulin and are emerging now as key outputs of insulin signaling.

Recent insulin signaling mutant analyses in mice and in humans have validated the generality of these discoveries in other animals. Not surprisingly, an insulin-like pathway is now a major theme in animal aging regulation, with many reports of insulin-like regulation of lifespan in Drosophila, mice and even humans beginning to emerge.

This work had an enormous impact on aging research relevant to longevity and later-life health. These findings catalyzed developments across biogerontology by defining hormone interventions with direct relevance to clinical practice and drug development.

Ruvkun is now using RNAi screens and comparative genomics to reveal the downstream genes regulated by insulin signaling. He discovered a connection between longevity and small RNA pathways, with the production of specific small RNA factors induced in long-lived mutant animals.

Among Gary Ruvkun’s awards are: Benjamin Franklin Medal, Franklin Institute; Albert Lasker Award for Basic Medical Research; member of the American Academy of Arts and Sciences; and member of the National Academy of Sciences.