Restoration of Impaired Cellular Housekeeping in Intestinal Stem Cells in Aging Flies Improves Function and Extends Life

In aging flies, we can consider degeneration of intestinal tissue and function as the primary cause of mortality, in much the same way as we can consider cardiovascular dysfunction as the primary cause of mortality in humans. It isn't the whole story, but it is a sizable portion of the story. Whenever reading research about intestinal function and life span in flies it is worth bearing this in mind: flies are not people, and while it is likely that similar processes operate in both species, their details and relative importance are likely different. Those preliminaries out of the way, today's open access paper is a recent example of extending life span in flies via improved intestinal stem cell function. The authors have discovered a faltering in cellular housekeeping that impairs stem cells in older flies, and which can be overridden via a suitable upregulation of the appropriate proteins.

Stem cell function in general declines with age, in all tissues. Stem cells and the cells of their supporting niche become damaged, their numbers diminished, and stem cells react in inappropriate ways to changes in the surrounding environment, such as by remaining quiescent rather than generating daughter cells to support the surrounding tissue. Numerous lines of work in regenerative medicine and the new longevity industry involve ways to put stem cells back to work, even damaged as they are. In animal studies this appears beneficial and less likely to induce cancer than was originally suspected. Present methods are not all that effective, however: we can hope that future therapies are more effective.

Of late, there has been a growing interest in the role of age-related changes in gut bacteria populations in disrupting tissue function in the intestine, generating chronic inflammation and other undesirable consequences. It is possible that gut bacteria have an influence on long-term health that is in the same ballpark as that of exercise. Thus it is perhaps interesting to compare work on this topic in flies with work on intestinal stem cells. There isn't all that much overlap at the present time, in terms of specific mechanisms examined, but little in any given tissue happens in isolation. There will be connections.

Loss of a proteostatic checkpoint in intestinal stem cells contributes to age-related epithelial dysfunction

Protein homeostasis (proteostasis) encompasses the balance between protein synthesis, folding, re-folding and degradation, and is essential for the long-term preservation of cell and tissue function. This balance is perturbed in aging systems, likely as a consequence of elevated oxidative and metabolic stress, changes in protein turnover rates, decline in the protein degradation machinery, and changes in proteostatic control mechanism. The resulting accumulation of misfolded and aggregated proteins is widely observed in aging tissues. The age-related decline in proteostasis is especially pertinent in long-lived differentiated cells, which have to balance the turnover and production of long-lived aggregation-prone proteins over a timespan of years or decades. But it also affects the biology of somatic stem cells (SCs), whose unique quality-control mechanisms to preserve proteostasis are important for stemness and pluripotency.

Common mechanisms to surveil, protect from, and respond to proteotoxic stress are the heat shock response (HSR) and the organelle-specific unfolded protein response (UPR). When activated, both stress pathways lead to the upregulation of molecular chaperones that are critical for the refolding of damaged proteins and for avoiding the accumulation of toxic aggregates. If changes to the proteome are irreversible, misfolded proteins are degraded by the proteasome or by autophagy. While all cells are capable of activating these stress response pathways, SCs deal with proteotoxic stress in a specific and state-dependent manner.

While these studies reveal unique proteostatic capacity and regulation in SCs, how the proteostatic machinery is linked to SC activity and regenerative capacity, and how specific proteostatic mechanisms in somatic SCs ensure that tissue homeostasis is preserved in the long term, remains to be established. Drosophila intestinal stem cells (ISCs) are an excellent model system to address these questions. ISCs constitute the vast majority of mitotically competent cells in the intestinal epithelium of the fly, regenerating all differentiated cell types in response to tissue damage. Advances made by numerous groups have uncovered many of the signaling pathways regulating ISC proliferation and self-renewal. In aging flies, the intestinal epithelium becomes dysfunctional, exhibiting hyperplasia and mis-differentiation of ISCs and daughter cells. This age-related loss of homeostasis is associated with inflammatory conditions that are characterized by commensal dysbiosis, chronic innate immune activation, and increased oxidative stress.

ISCs of old flies also exhibit chronic inactivation of the Nrf2 homologue CncC. CncC and Nrf2 are considered master regulators of the antioxidant response. In both flies and mice, this pathway controls SC proliferation and epithelial homeostasis. Whether and how Nrf2 also influences proteostatic gene expression in somatic SCs remains unclear. Here, we show that Drosophila CncC links cell cycle control with proteostatic responses in ISCs via the accumulation of dacapo, a p21 cell cycle inhibitor homologue, as well as the transcriptional activation of genes encoding proteases and proteasome subunits. We establish that this program constitutes a transient 'proteostatic checkpoint', which allows clearance of protein aggregates before cell cycle activity is resumed. In old flies, this checkpoint is impaired and can be reactivated with a CncC activator. This limits age-related intestinal barrier dysfunction and can result in lifespan extension.