Some long-lived proteins (such as components of nuclear pore structures) in some long-lived cells (such as neurons) may never be replaced across a normal life span, or at the very least have lifetimes of years. That suggests that damage to these molecules may be important in aging and age-related disease. Some research has taken place on this topic, but as noted here, issues of measurement ensure that damage to long-lived molecules remains a more speculative contribution to degenerative aging. It may be important relative to other mechanisms, or it may not.
Neurons, unlike most other cell types, do not divide and are not replaced over an organism’s lifetime. This lack of turnover necessitates robust mechanisms to maintain cellular integrity and function across prolonged periods of time, up to many decades. One key aspect of neuronal longevity is protein homeostasis, or proteostasis, which involves the balance between protein synthesis, folding, and degradation. Advances in metabolic labeling techniques have provided unexpected insights into protein turnover rates in neurons, and identified long-lived proteins (LLPs) in the brain. In addition to proteins, recent studies assessing the longevity of RNA have led to the identification of long-lived RNAs (LLRs) in the brain, challenging the prevailing consensus that RNA molecules are unstable.
Investigating the mechanisms underlying the long-term maintenance of these long-lived molecules – and the consequences of their dysfunction during brain aging or in the pathogenesis of age-related disease – is crucial to understanding their pathophysiological roles. However, due to limitations in measurement sensitivity and the lack of tools to selectively manipulate long-lived molecules, current proposals regarding their roles in brain aging remain largely speculative. In this opinion article, we discuss recent developments in characterizing LLPs and LLRs, as well as advances in emerging technologies to detect long-lived molecules in the brain. We also examine the mechanisms underlying the maintenance of long-lived molecules and these molecules’ potential physiological roles. We finally delineate future directions to improve current understanding of the biological roles of long-lived molecules in brain aging and longevity.
