Genetics of aging
The first mutation found to increase longevity in an animal was the age-1 gene in Caenorhabditis elegans. Michael Klass discovered that lifespan of C. elegans could be altered by mutations, but Klass believed that the effect was due to reduced food consumption (calorie restriction). Thomas Johnson later showed that life extension of up to 65% was due to the mutation itself rather than due to calorie restriction, and he named the gene age-1 in the expectation that other genes that control aging would be found. The age-1 gene encodes the catalytic subunit of class-I phosphatidylinositol 3-kinase (PI3K).
A decade after Johnson's discovery daf-2, one of the two genes that are essential for dauer larva formation, was shown by Cynthia Kenyon to double C. elegans lifespan. Kenyon showed that the daf-2 mutants, which would form dauers above 25 °C (298 K; 77 °F) would bypass the dauer state below 20 °C (293 K; 68 °F) with a doubling of lifespan. Prior to Kenyon's study it was commonly believed that lifespan could only be increased at the cost of a loss of reproductive capacity, but Kenyon's nematodes maintained youthful reproductive capacity as well as extended youth in general. Subsequent genetic modification (PI3K-null mutation) to C. elegans was shown to extend maximum life span tenfold.
According to the GenAge database of aging-related genes, there are over 1800 genes altering lifespan in model organisms: 838 in the soil roundworm (Caenorhabditis elegans), 883 in the bakers' yeast (Saccharomyces cerevisiae), 170 in the fruit fly (Drosophila melanogaster) and 126 in the mouse (Mus musculus).
Genetic modifications in other species have not achieved as great a lifespan extension as have been seen for C. elegans. Drosophila melanogaster lifespan has been doubled. Genetic mutations in mice can increase maximum lifespan to 1.5 times normal, and up to 1.7 times normal when combined with calorie restriction.
- Klass MR (1983). "A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results". MECHANISMS OF AGEING AND DEVELOPMENT. 22 (3-4): 279–286. doi:10.1016/0047-6374(83)90082-9. PMID 6632998.
- Friedman DB, Johnson TE (1988). "A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility" (PDF). Genetics (journal). 118 (1): 75–86. PMC . PMID 8608934.
- Gottlieb S, Ruvkun G (1994). "daf-2, daf-16 and daf-23: genetically interacting genes controlling Dauer formation in Caenorhabditis elegans". Genetics (journal). 137 (1): 107–120. PMC . PMID 8056303.
- Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993). "A C. elegans mutant that lives twice as long as wild type". Nature. 366 (6454): 461–464. doi:10.1038/366461a0. PMID 8247153.
- Ayyadevara S, Alla R, Thaden JJ, Shmookler Reis RJ (2008). "Remarkable longevity and stress resistance of nematode PI3K-null mutants". Aging Cell. 7 (1): 13–22. doi:10.1111/j.1474-9726.2007.00348.x. PMID 17996009.
- Shmookler Reis RJ, Bharill P, Tazearslan C, Ayyadevara S (2009). "Extreme-longevity mutations orchestrate silencing of multiple signaling pathways". Biochimica et Biophysica Acta. 1790 (10): 1075–1083. doi:10.1016/j.bbagen.2009.05.011. PMC . PMID 19465083.
- "GenAge database". Retrieved 2016-02-11.
- Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (1988). "A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function". Science. 292 (5514): 107–110. doi:10.1126/science.1057987. PMID 11292875.
- Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS (2001). "Extending the lifespan of long-lived mice". Nature. 414 (6862): 412. doi:10.1038/35106646. PMID 11719795.