Lifespan mechanisms

The aging process involves a trade-off between growth and reproduction on the one hand and maintenance and repair on the other. In times of plenty, organisms must take advantage of the availability of nutrients for growth and reproduction. However, the utilization of resources for anabolic needs occurs at the expense of maintenance processes necessary to maintain homeostasis. When nutrients are scant, cells switch from growth to stress resistance and repair. In eukaryotes, the Target of mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">Rapamycin(definition) (TOR) has a central role in controlling this switch. TOR is responsive to nutrient availability as well as growth factor signaling. IGF-1 and Insulin-like signaling, stimulates TOR kinase activity to regulate protein translation and cell growth. Reduced TOR activity or IGF-1 signaling are features of several models of increased longevity. Our mice are hypomorphic for the IGF-1 allele. These mice are smaller in size and exhibit increased lifespan. The precise mechanism by which reduced Insulin-like signaling affects the state of the cell and supports an increased lifespan is not well understood. Using IGF-1 deficient mice and primary human fibroblasts, we have observed that reduced IGF-1 or impairment of mTOR activity with rapamycin slows growth and enhances autophagy(definition). Under conditions of reduced TOR activity by rapamycin, mitochondrial function is improved along with an increase in mitochondrial mass and mitochondrial gene expression. Furthermore, the expression and turnover of the adaptor protein p62/SQSTM1 appears to be required for the stability and expression of Nrf2(NEF2L) and Tfam, two factors important for mitochondrial homeostasis. Rapamycin treated cells are also resistant to oxidative stress, likely due to increased Nrf2 activity and do not accumulate mitochondria with impaired membrane potential, an effect which is dependent on autophagy. These results suggest that reduced signaling through TOR benefits mitochondrial function and homeostasis, and reveals a new role for p62 as a factor in the mammalian retrograde response.