Regulation of Aging in C. elegans
Beatrix Grubeck-Loebenstein

Cynthia Kenyon made her groundbreaking discoveries in the field of biogerontology. When she started research on the biology of aging in the early 1990s, aging research was not yet well respected. There were many theories, but only few hard facts. Aging was mostly thought to be a passive, unregulated process. This view was dramatically changed by the work of Cynthia Kenyon.

Her hypothesis was the following: if proteins regulate life span, mutations of these proteins should change the rate of aging. Her research tool, the small worm C. elegans, presented an ideal tool for her studies. It has a very short life span of approximately 19 days and has a relatively low number of genes which can be mutated and analyzed. Soon she was able to define a gene, the mutation of which doubled the life span of the worm. The name of the gene is Daf-2. It was later cloned by the group of Gary Ruvkun and was found to encode the C.elegans orthology of the mammalian insulin/IGF-1 receptor. It was thus proven that life span was under hormonal control and influenced by nutrition. The next important step was the discovery that decreased function of Daf-2, as observed in mutant animals, led to the up-regulation of another gene, Daf-16, which encodes a FOXO-family transcription factor. This transcription factor obviously plays a central role in regulating life span, as it regulates a large set of further genes, which encode functionally significant and beneficial proteins. These proteins include antioxidants, chaperones and antibacterial effector molecules. This was another step of great importance, as it demonstrated that there was not one aging gene, but that a whole cascade of molecular events was responsible, possibly under metabolic control. And there were many more exciting discoveries.

What is the input of her research, how does it relate to mammals and in particular to human therapies? The last few years have brought us exciting new insights. Cynthia Kenyon’s concepts have been followed up by many labs. It has become clear that disturbances in the insulin/IGF signaling also result in increased life spans of flies and mice and that the details of the regulation seem remarkably conserved. Thus, it seems likely that human aging will be regulated similarly, raising the possibility of life span expansion by therapeutic intervention. In this context it is of particular interest that age-related diseases can be delayed in model organisms rendered long-lived by mutations. Thus, postponing cellular aging may at the same time postpone or even prevent age-related diseases.

Healthy aging is obviously what we hope to achieve for us and our children. Cynthia Kenyon’s work is an important mile stone in this direction.