What biological mechanisms govern adult health and life span? Genetic and environment components contribute to a long healthy life. The longevity manipulations we use in C. elegans are: 1) mutation of the daf-2 gene, which is homologous to insulin/IGF1 signaling pathways, and 2) cultivation at a cool temperature. Both cooler core body temperatures and reduction of the daf-2/insulin/IGF-1 signaling pathway are pro-survival in multiple species including humans. We are defining environment by genotype interactions that alter gene transcription (epigenetics) and then testing the functional contribution to adult health and life span. For this our studies include different genotypes at different non-stress-inducing temperatures. We have found that health can be uncoupled from long life. Environmental changes trigger beneficial and detrimental responses. By associating molecular signatures with phenotypes, we can better predict adult health and life span outcomes in different genotypes and environments.
The figure shows results from a neurological exam we did on individuals each day from when they were healthy middle-aged adults. In wild type, we find locomotion slows with age and a small number become paralyzed when old. When we inhibit our candidate adaptive response, we see nearly all show progressive paralysis and yet the life span is not significantly shorter.
Saiki R, Lunceford AL, Bixler T, Dang P, Lee W, Furukawa S, Larsen PL, Clarke CF. Altered bacterial metabolism, not coenzyme Q content, is responsible for the lifespan extension in Caenorhabditis elegans fed an Escherichia coli diet lacking coenzyme Q. Aging Cell. 2008 Jun;7(3):291-304.
Banfield KL, Gomez TA, Lee W, Clarke S, Larsen PL. Protein-repair and hormone-signaling pathways specify dauer and adult longevity and dauer development in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci. 2008 Aug;63(8):798-808.
Curran SP, Leverich EP, Koehler CM, Larsen PL. Defective mitochondrial protein translocation precludes normal Caenorhabditis elegans development. J Biol Chem. 2004 Dec 24;279(52):54655-62.
Larsen PL. Direct and indirect transcriptional targets of DAF-16. Sci Aging Knowledge Environ. 2003 Apr 30;2003(17):PE9.
Butler RN, Austad SN, Barzilai N, Braun A, Helfand S, Larsen PL, McCormick AM, Perls TT, Shuldiner AR, Sprott RL, Warner HR. Longevity genes: from primitive organisms to humans. J Gerontol A Biol Sci Med Sci. 2003 Jul;58(7):581-4.