To test the causative role of mtDNA mutations in aging we have developed the mtDNA mutator mouse that accumulates high levels of point mutations due to a proofreading deficiency of the mitochondrial DNA polymerase (POLG) [ 12].
Development of the mtDNA mutator mouse, an animal with mutated mtDNA polymerase γ, highlighted the strong potential for mtDNA mutations in aging.
Extended longevity is also observed in C. elegans with mutations in age-1 and daf-2, which encode the catalytic subunit of the worm PI3K and the insulin/IGF-1 receptor, respectively (Garsin et al., 2003; Murakami et al., 2005).
Mutations in this pathway, such as inhibitory mutations in age-1 (a homologue of the mammalian phosphatidylinositol 3-OH kinase) or daf-2 (a homologue of the mammalian insulin receptor) result in the relocalization of the transcription factor DAF-16 into the nucleus where it regulates a plethora of downstream genes [2], [13], [14], [15], [16].
All tissues from adult subjects show the presence of mitochondrial DNA molecules with deletions [24], and the accumulation of mtDNA mutations in aging contributes significantly to the decline of mitochondrial energy production that characterizes the aging process in many tissues [25] [26].
Reduction-of-function mutations in AGE-1, the C. elegans Class IA phosphoinositide 3-kinase (PI3K), increase lifespan and stress resistance in a daf-16 dependent manner.
Loss of function mutations in age-1 mg44), age-1 mg449) akt-1 tm399k393) akt-1 tm399ed for defects in and akt-2 ok393 akt-2 ok393formation.
Mutations in age-1 have high potential to induce broad regulatory effects that affect fitness even beyond its well-studied role in stress response and aging.
Mutations in age-1 or daf-2, for example, slow degenerative processes occurring throughout life, thereby constantly lowering mortality rates (Johnson, 1990; Kenyon et al., 1993; Taylor et al., 2014).
Loss of function mutations in age-1 not only affect overall kinase activity but also down-regulate the transcription of several genes in the IS pathway as well as in other signaling-pathways (Tazearslan et al. 2009).
Indeed, the insulin-signaling pathway satisfies the structural expectations of the antagonistic pleiotropy model of aging as longevity mutations in age-1 and daf-2 show a fitness cost under nutrient stress (Walker et al. 2000; Jenkins et al. 2004).
