UC San Diego

The connection between aging and metabolism seems obvious, but the particulars of this relationship remain obscure. Theories linking the two abound, centered on the fact that mitochondria are the location of much of the cell's free radical production and on the general correlation between lifespan and metabolic rate. The connection between longevity and mitochondrial function was strengthened by RNAi-based screens in the worm C. elegans, where RNAi knock-down of mitochondrial Electron Transport Chain (ETC) subunits of Complex I (nuo-2), Complex III (cyc-1), Complex IV (cco-1) and Complex V (atp-3) extended lifespan (Dillin et al., 2002b; Lee et al., 2002). The effects of ETC knockdown on life span appear to depend on a mechanism more complex than direct effects on mitochondrial metabolic rates. Instead, they point towards the existence of signaling programs emanating from the mitochondria and capable of regulating the life span of the entire organism. The identity of components and timing requirements of the mitochondrial ETC that influence longevity have led us to search for a mechanism imposed during early development that sets the rate of aging for the remainder of the animal's life cycle as well as the critical tissues required for the mitochondrial ETC to set the rate of aging. I have found that disruption of cco-1, in the neurons or intestine of the worm is sufficient to confer a longevity phenotype. This tissue-specific knockdown was able to uncouple some of the detrimental phenotypes of organism-wide knockdown, such as reduced brood size and slow movement. Furthermore, the long lifespan that results from ETC perturbance is dependent on the mitochondrial Unfolded Protein Response (UPRmt) gene, ubl-5. Knowing that there are tissues in which ETC function is critical as well as the necessity for a functional UPRmt might allow us to better understand the basis of mitochondria-mediated longevity.