Synergistic Downregulation of Insulin Signaling and Mitochondrial Protein Function Dramatically Extends Lifespan and Alters Physiology in C. elegans

¹Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114

²Biochemistry Discipline, Natural Science Collegium, Eckerd College, 4200 54th Avenue South, St. Petersburg, FL 33711

³Planitary Science Discipline, Harvard College, Cambridge, MA 02138

⁴Broad Institute of Harvard and MIT, Cambridge, MA 02142

⁵Program in Biological and Biomedical Sciences, Division of Medical Science, Harvard Medical School, Boston, MA 02115

⁶Department of Medicine, Harvard Medical School, Boston, MA 02115

*Equal Contribution

Abstract:

Caenorhabditis elegans lives a median of 18 days, but perturbations in metabolic and mitochondrial pathways have been found to dramatically extend lifespan. Loss-of-function mutations in daf-2, an insulin/IGF-1 receptor orthologue, have been shown to extend lifespan up to 2-fold, while disruption of ant-1.1, an adenine nucleotide translocator also involved in complex V of the electron transport chain, yields a modest lifespan extension. When combined, daf-2 and ant-1.1 downregulation produces a synergistic effect, extending lifespan 4-fold to a median of 70 days. This striking increase in lifespan was suspected to also have a concomitant increase in healthspan, as hinted at by a “squaring” of the lifespan curve. To determine whether there was, in fact, a healthspan increase, we leveraged several physiological assays, including stress resistance (oxidative stress, heat shock, cold shock), feeding behavior, and fat mass via Nile Red staining across multiple time points in adulthood. Our findings indicate that lifespan extension in these animals is accompanied by altered stress resilience and metabolic regulation, pointing toward preserved or enhanced healthspan rather than just prolonged morbidity. As C. elegans shares significant genetic overlap with humans, these results provide insight into the mechanisms that may link longevity and healthspan, informing future studies of aging and age-related disease.

For more information:  Scdipaola@eckerd.edu