To address this question, we have investigated the role of nuclear pore proteins (Nups). Some Nups are long-lived proteins that constitute the stable nuclear pore complex, which organizes nuclear transport and also plays roles in epigenetic regulation. These long-lived proteins likely serve as stable platforms for cell type-specific gene regulation, but due to their extended half-life, they are also susceptible to damage during aging. Our ongoing research identified one of the Nups, Nup153, plays a critical role in the regulation neuronal gene expression and brain function.
Given the critical roles of Nup153 in brain function, we also explored Nup153-interacting proteins and identified lamin B1 as a regulator of adult neural stem cell (ANSC) aging. Lamin B1 is a nuclear lamin protein essential for maintaining nuclear membrane integrity and is also a long-lived protein. We found that lamin B1 is highly expressed in ANSCs within the hippocampus. Since ANSCs give rise to new neurons throughout life, this ongoing neurogenesis provides structural and functional plasticity to the adult hippocampus. However, lamin B1 levels in ANSCs decline with age, and premature reduction of lamin B1 in these cells leads to decreased neurogenesis and age-related mood dysregulation (published in EMBOJ, 2021). These findings suggest that both Nups and lamins are pivotal in maintaining brain plasticity, and the decline of these long-lived proteins may be a biological link to the initiation of age-dependent pathology. Intriguingly, lamin B1 expression patterns differ between mammals and anamniotes in the adult neurogenic regions, suggesting that lamin B1 may also contribute to the varying degrees of brain plasticity observed across evolution (published in Dev. Dyn 2025).
In parallel, beyond the roles of long-lived proteins, we sought other long-lived cellular components that could contribute to brain maintenance and aging. Although RNA is traditionally considered an unstable molecule, some evidence suggests that it can be retained for over a year in certain cell types, such as oocytes and plant seeds, which are both non-proliferating (quiescent) cells. As most brain cells, including neurons and ANSCs, are non-proliferating (post-mitotic or quiescent), we examined RNA turnover rates in the rodent brain. Strikingly, we discovered that some RNAs do not turn over for up to two years in certain brain cell types, including neurons and hippocampal ANSCs (published in Science, 2024). This finding challenges the current view of RNA stability and raises the possibility of unidentified roles for RNAs in brain ageing. While the functions of these long-lived RNAs remain unclear, our data suggest that they likely contribute to chromatin stability. These findings open up new avenues for research into brain ageing and RNA regulation.
Overall, our research has revealed the significant contributions of long-lived proteins and RNAs to neural plasticity and function. This has led to their identification as potential targets for addressing brain dysfunction associated with ageing.
