The fact that neurons and other types of cells in the human body are rarely replaced raises the question of the genetic mechanisms that enable cells to function properly for decades and possibly 100 years or more. The popular “free-radical aging” and “rate of living” theories, and the Hayflick phenomenon, fail to adequately explain such extreme cellular longevity. Nevertheless, these ideas affect human behavior e.g. intake of antioxidant supplements and experimental rejuvenation therapy.
Our project will investigate a new direction that connects the efficiency of stress response to cellular and animal lifespan, and analyze a candidate genetic mechanism. We will create models of cells that are rarely replaced, e.g. neurons, and cells with limited lifespan, e.g. fibroblasts, from exceptionally long living, and short living mammals. We will expose cells to repeated stress stimuli while monitoring their viability by high throughput microscopy. Moreover, we will analyze the mammalian long noncoding RNA gene NEAT1 orchestrating the assembly of specialized stress-induced complexes, named paraspeckles. We identified key components of the paraspeckle-RNA-metabolism-protein quality axis (e.g. Mol. Cell 2019, BMC Biology 2020), and our preliminary analysis indicates high homology among long living mammals. Based on putative connections to lifespan, we will analyze the phylogeny of NEAT1, and overexpress paraspeckles to quantify stress protection effect in each species. To validate mechanisms, we will transfer NEAT1 from mammals with highly efficient stress protection to less efficient cells.
The project will deliver answers on the ability of cells to withstand prolonged stress in relation to animal lifespan, paraspeckles function, and their evolution. If successful, a new theory and model of cellular lifespan will be established, paving ways to investigate and prevent age-related frailty. The multispecies stem cell approach will open new avenues for evolution and genetics.