Reduced IGF-1 Signaling Fails to Extend Life in Mitochondrial Mutator Mice
The activities and interactions of insulin, growth hormone, and insulin-like growth factor 1 (IGF-1) signaling are collectively one of the better studied influences on the pace of aging in animal models. Impaired IGF-1 signaling slows aging and extends life, affecting pathways known to be involved in the calorie restriction response, such as those involving mTOR. Sabotaging growth hormone signaling has even more dramatic effects. Here, researchers link these benefits to mitochondrial quality by showing that mice with impaired mitochondrial function due to excessive mitochondrial DNA mutations do not benefit from reduced IGF-1 signaling. The positive influences on pace of aging deriving from reduced IGF-1 signaling require intact and functional mitochondria. Since mitochondria become damaged and dysfunction with age, this is an interesting finding.
A large body of evidence supports the idea that instability of the mitochondrial genome (mtDNA) leads to a progressive decline in mitochondrial function, which accelerates the natural aging process and contributes to a wide variety of age-related diseases, including sarcopenia, neurodegeneration, and heart failure. A similar body of work describes the role of IGF-1 signaling in the aging process. IGF-1 regulates the growth and metabolism of human tissues, and reduced IGF-1 signaling can not only extend mammalian lifespan, but can also confer resistance against various age-related diseases, including neurodegeneration, metabolic decline, and cardiovascular disease. However, how mitochondrial mutagenesis and IGF-1 signaling interact with each other to shape mammalian lifespan remains unclear.
We found that reduced IGF-1 signaling fails to extend the lifespan of mitochondrial mutator mice. Accordingly, most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the pro-longevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome and that mitochondrial mutations may impose a hard limit on mammalian lifespan. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.
does anyone know if cell reprogramming gets rid of mito mutations?
@erasmus: the answer is likely complex. It appears that the process of producing iPSCs is known to shift the preexisting mutational heteroplasmy in the starting population of somatic cells, but it seems unclear as to whether severe mutations would be treated differently by reprogramming: https://doi.org/10.1016/j.tcb.2020.12.009