As often mentioned here, cells and living organisms are built out of an enormous array of very complex subsystems, and those very complex subsystems are prone to dysfunction over the course of aging. As soon as any one part of a subsystem is sufficiently impacted by the mechanisms of aging to run awry, the whole subsystem starts to run awry. An army of scientists ten times the size of the one we have now would take a century to catalog every last important detail of the way in which aging causes disarray.
These mechanisms are all interesting in their own right, and the goal of science is full understanding. But the sheer scope of such a project is precisely why we should not focus on increased understanding of the fine details of the progression of aging as the primary near future path to the production of therapies. Instead, we should focus on attempting to repair and reverse the well-known mechanisms of aging, and then observe the outcomes. That is the practical path to longer, healthier lives over the course of the near future of the next few decades.
As an example of a complex system that may run awry with age for reasons that are poorly understood and have the look of being quite interesting, researchers here discuss whether or not there exists a form of stress response focused on maintaining the integrity of the cell cytoskeleton. That the upregulation of some associated regulatory proteins can increase life span in short-lived species is suggestive. One might also consider that disruption of the cytoskeleton, as in progeria, produces a dramatic shortening of life span and general dysfunction of cells and tissues. Stress responses in general have proven to be a reliable source of ways to modestly slow aging in short lived species, but not so great at extending life in long-lived species; it remains to be seen as to how a cytoskeletal stress response behaves.
Organelle-specific stress responses have evolved to preserve homeostatic function of each specialized organelle compartment within eukaryotic cells. These include the cytosolic heat shock response (HSR) and the unfolded protein responses of the mitochondria (UPRmt) and endoplasmic reticulum (UPRER), all of which contribute to homeostatic function of their designated organelle and have implications in longevity.
Despite major efforts in this field, the machineries dictating homeostatic function of the actin cytoskeleton during stress and aging are poorly understood. The actin cytoskeleton is a complex, dynamic network of protein filaments that provide structural support and shape to cells and has been implicated in many physiological age-related changes. For example, in multiple model systems, cytoskeletal form and function has been shown to decline with age, which can directly impact nutrient sensing and aging in S. cerevisiae and thermotolerance and longevity in C. elegans. Mechanistic function of the cytoskeleton is also important in mammalian systems, as dysfunctions in actin are implicated in age-associated diseases, such as Alzheimer's Disease (AD).
Despite the implications of the actin cytoskeleton contributing to aging physiology and disease, little is known about actin regulation throughout an organism's lifespan. To date, there are two known "master" regulators of actin function: heat shock transcription factor-1 (HSF-1), and serum response factor 1 (SRF1). Therefore, to identify additional conserved regulators of the actin cytoskeleton, we performed an unbiased, cross-species screen. A number of targets were identified from the consecutive screens; however, bet-1 was the only gene that showed correlations with lifespan in C. elegans. Specifically, bet-1 knockdown resulted in shortened lifespan, while overexpression was sufficient to drive longevity. bet-1 is a conserved (BRD4 in mammals) double bromodomain protein recognized for its role in cell fate determination with some links to actin function.
On a physiological level, our study found that BET-1 drives organismal health and longevity by promoting stability of muscle and intestinal actin, which maintained muscle motility and gut barrier function at advanced age. While our study did not identify mechanistically how BET-1 promotes actin health, transcriptome analysis revealed that overexpression of bet-1 induces expression of actin regulatory genes. Moreover, the increased stability of actin is required for the beneficial effects of bet-1 overexpression on organismal health and longevity.
It is worth investigating whether a true "actin cytoskeletal stress response" (ACSR) exists whereby in response to stress, actin integrity can be maintained as a mechanism to drive resilience and organismal health. An exciting area of research can be to investigate whether a BET-1/BRD4 driven ACSR - possibly in coordination with other stress regulators - can drive overall stress resilience and longevity.