The open access review paper I'll point out today covers numerous areas of cellular biochemistry relevant to aging wherein the nucleolus may have a role - though as is always the case, cause and effect in relationships with other aspects of aging are hard to pin down. As one might guess, this largely relates to stress responses, quality control, and damage repair within the cell. These line items are important in the way in which the operation of cellular metabolism determines natural variations in the pace of aging between species and between individuals within species. While the nucleolus is primarily responsible for building the ribosome structures where proteins are assembled, it has been found to play a part in a wide range of other cellular activities. Evolution tends to generate systems in which any given component has many and varied functions, and everything within a cell is connected to everything else.
This is an example of the broad, dominant class of aging research that is purely investigative. Most research into the detailed mechanisms of degenerative aging is very far removed from any thought of application, and it is lucky happenstance when such an opportunity does arise. Systems very closely tied to cellular housekeeping, or responses to stress, or replication seem unlikely to result in the foundations of truly effective therapies. We can look at calorie restriction or exercise, both of which alter all of the above items quite profoundly and throughout the body, to see the plausible benefits that might be attained through manipulation of these fundamental aspect of cellular behavior. Searching for means to adjust metabolism to modestly slow aging is not a winning strategy; the expected benefits are just not large enough. We must find ways to add decades of vigorous life, not just a few few healthy years.
The nucleolus is an intranuclear organelle primarily involved in ribosomal RNA (rRNA) synthesis and ribosome assembly, but also functions in the assembly of other important ribonucleoprotein particles that affect all levels of information processing. Recent evidence has highlighted novel roles of the nucleolus in major physiological functions including stress response, development, and aging. Due to its crucial role in ribosome biogenesis, the nucleolus actively determines the metabolic state of a cell. In fact, the size of the nucleolus positively correlates with rRNA synthesis, which in turn is governed by cell growth and metabolism.
The nucleolus has been regarded as a housekeeping structure mainly known for its role in ribosomal RNA production and ribosome assembly. However, accumulating evidence has revealed its functions in numerous cellular processes that control organismal physiology, thereby taking the nucleolus much beyond its conventional role in ribosome biogenesis. Indeed, the nucleolus has been implicated in a number of other important functions including signal recognition particle (SRP) assembly, pre-transfer-RNA (tRNA) maturation, RNA editing, telomerase assembly, spliceosome maturation, and genome stability maintenance, thus more generally serving as a critical control site for ribonucleoprotein maturation as well as genome architecture.
There is also growing evidence ascribing a key role for the nucleolus in aging. Since the discovery of various genes and signaling pathways that regulate lifespan, there has been a dramatic expansion in the research on understanding the biology of aging. A number of hallmarks of aging, including genomic instability, telomere attrition, epigenetic modifications, and perturbations in proteostasis have been well established. Recent literature also highlights the crosstalk of different nucleolar functions with some of these hallmarks.
The target of rapamycin (TOR) pathway is a major pathway that integrates inputs on nutrients, growth factors, energy, and stress. When food is plentiful, it promotes cell growth and suppresses recycling processes like autophagy. When food is scarce it suppresses growth and promotes autophagy. Notably, TOR inhibition extends lifespan. Active TOR signaling has also been associated with elevated rRNA transcription in multiple studies. The TOR complex stimulates rRNA synthesis in the nucleolus. As nucleolar size correlates with rRNA synthesis, the TOR signaling pathway has correspondingly been shown to regulate nucleolar size.
Ribosome biogenesis is one of the most energy demanding processes in the cell. It is estimated that almost 80% of cellular energy reserves are required for ribosome biogenesis. Major perturbations in the cell have repercussions at the level of ribosome biogenesis and conversely, factors involved in ribosome biogenesis can regulate other processes. A number of studies have highlighted the role of ribosomal factors in regulating the lifespan of an organism. Downregulation of genes encoding multiple ribosomal proteins has been shown to extend lifespan in yeast and C. elegans. Though it remains to be tested if single ribosomal protein knockdown can have lifespan benefits in vertebrates, there is evidence suggesting that this might be the case.
The highly repeated structure of the ribsosomal DNA (rDNA) locus and its high rates of transcription make it particularly vulnerable to genome instability and damage. Multiple studies have reported a link between rDNA stability and cellular aging, as well as the association of proteins involved in genome integrity transiting the nucleolus. Aging in yeast is accompanied by nucleolar enlargement and fragmentation, suggesting a mechanism of cellular aging that may be related to nucleolar structure. Concordantly a recent study reported that the premature aging disorder Hutchinson-Gilford progeria syndrome leads to nucleolar expansion and increased ribosome biogenesis. Furthermore, there is evidence suggesting an association of replication stress on rDNA loci with the aging of hematopoietic stem cells, adding more evidence to the general function of the nucleolus in genome integrity and aging.
The nucleolus also impacts other vital cellular processes like the cell cycle and the response to cellular stress. One of the major tumor suppressor proteins central to regulating cell cycle is p53. The nucleolus acts as a platform connecting a cellular stress response with cell cycle through the central tumor suppressor p53. Interestingly multiple studies have implicated p53 in aging in different organisms. The nucleolus has also been associated with regulation of cell senescence. Alterations in nucleolar morphology have been reported in aging cells. In particular, presenescent cells exhibit multiple small-sized nucleoli compared to senescent cells which possess a single enlarged nucleolus.
The perception that the nucleolus is simply the place where ribogenesis takes place has clearly evolved. We now know that it is a highly dynamic organelle that coordinates signals from growth, energy, and stress to the balanced production and assembly of multiple ribonucleoprotein particles and the maintenance of genome integrity. This has ramifications for essentially all levels of molecular organization from genome architecture, RNA metabolism, protein synthesis and quality control to metabolism.