Fight Aging!

The protein Nrf2 shows up in a number of places in the study of aging and related aspects of cellular biochemistry. Higher levels of Nrf2 appear to correlate well with longer species lifespan, at least among mammals in the wild, but this is also arguably the case in the various genetically engineered lineages of mice, worms, and flies that exhibit longer lifespans. Until recently the main focus of research into the role of Nrf2 has been the regulation of antioxidants as a response to cellular stress, as occurs due to the metabolic demands of exercise, for example. Of interest here is that Nrf2 levels decline with age, which is probably a phenomenon that we'd be better off without; it is one of many, many candidates for the mechanisms of aging that float somewhere between the root causes and the final consequences in the long chain of cause and effect that produces degenerative aging as we know it.

In the research linked below, the authors expand the bounds of influence for Nrf2, linking it to some of the mechanisms of cellular housekeeping that strive to remove damaged proteins. In particular, it seems influential in the matter of a few proteins associated with neurodegenerative conditions, such as α-synuclein in synucleinopathies like Parkinson's disease. Greater cellular maintenance activity is a common theme in many of the methods that have been demonstrated to modestly slow aging in laboratory species. When cells have less damage at any given moment in time, that damage has less of a chance to cause further downstream harm. There are many researchers who place natural mechanisms of quality control and damage repair at the center of all methods of slowing aging via metabolic and genetic alteration discovered to date, and evidence such as calorie restriction requiring the maintenance processes of autophagy in order to extend healthy life makes this a fairly compelling argument.

If greater levels of Nrf2 indeed produce greater housekeeping efforts in the clearance of damaged proteins, then that new knowledge fits well into this bigger picture given what is known to date. Where is this all going, however? Despite a good many years during which numerous researchers have argued for the importance of increased cellular maintenance, there has been next to no concrete progress towards therapies based on this principle. I was noting calls to action on this topic a decade ago, and I am by now somewhat surprised at the continued lack of motion towards the clinic in this part of the field, despite a growing catalog of research very much like the results presented here.

Single Protein May Hold Secret to Treating Parkinson's Disease and More

At their root, neurodegenerative diseases, such as Parkinson's, Huntington's, Alzheimer's, and amyotrophic lateral sclerosis (ALS), are triggered by misbehaving proteins in the brain. The proteins misfold and accumulate in neurons, inflicting damage and eventually killing the cells. In a new study, researchers used a different protein, Nrf2, to restore levels of the disease-causing proteins to a normal, healthy range, thereby preventing cell death. The researchers tested Nrf2 in two models of Parkinson's disease: cells with mutations in the proteins LRRK2 and α-synuclein. By activating Nrf2, the researchers turned on several "house-cleaning" mechanisms in the cell to remove excess LRRK2 and α-synuclein. "Nrf2 coordinates a whole program of gene expression, but we didn't know how important it was for regulating protein levels until now. Overexpressing Nrf2 in cellular models of Parkinson's disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we've found."

In the study, the scientists used both rat neurons and human neurons created from induced pluripotent stem cells. They then programmed the neurons to express Nrf2 and either mutant LRRK2 or α-synuclein. The researchers tagged and tracked individual neurons over time to monitor their protein levels and overall health. They took thousands of images of the cells over the course of a week, measuring the development and demise of each one. The scientists discovered that Nrf2 worked in different ways to help remove either mutant LRRK2 or α-synuclein from the cells. For mutant LRRK2, Nrf2 drove the protein to gather into incidental clumps that can remain in the cell without damaging it. For α-synuclein, Nrf2 accelerated the breakdown and clearance of the protein, reducing its levels in the cell. "I am very enthusiastic about this strategy for treating neurodegenerative diseases. We've tested Nrf2 in models of Huntington's disease, Parkinson's disease, and ALS, and it is the most protective thing we've ever found. Based on the magnitude and the breadth of the effect, we really want to understand Nrf2 and its role in protein regulation better."

Nrf2 mitigates LRRK2- and α-synuclein-induced neurodegeneration by modulating proteostasis

The prevailing view of nuclear factor erythroid 2-related factor (Nrf2) function in the central nervous system is that it acts by a cell-nonautonomous mechanism to activate a program of gene expression that mitigates reactive oxygen species and the damage that ensues. Our work significantly expands the biological understanding of Nrf2 by showing that Nrf2 mitigates toxicity induced by α-synuclein and leucine-rich repeat kinase 2 (LRRK2), by potently promoting neuronal protein homeostasis in a cell-autonomous and time-dependent fashion. Nrf2 accelerates the clearance of α-synuclein, shortening its half-life and leading to lower overall levels of α-synuclein. By contrast, Nrf2 promotes the aggregation of LRRK2 into inclusion bodies, leading to a significant reduction in diffuse mutant LRRK2 levels elsewhere in the neuron.

Disruption of protein homeostasis is an emerging theme in Parkinson's disease pathogenesis, making mechanisms to reduce the accumulation of misfolded proteins an attractive therapeutic strategy. By identifying the stress response strategies activated by Nrf2, we also highlight endogenous coping responses that might be therapeutically bolstered to treat Parkinson's disease.