Many of the methods by which aging can be modestly slowed in laboratory species are characterized by increased cellular housekeeping: more repair, more clearance of broken molecular machinery, more removal of metabolic waste. The extended life span produced by calorie restriction appears to depend on this increase: it doesn't happen in mice in which housekeeping processes are disabled. Most of the work on cellular housekeeping in aging is focused on autophagy, responsible for removing protein aggregates and cellular structures. The proteasome is a part of a separate system of housekeeping that deals with broken or otherwise unwanted proteins. (Though it can be debated as to just how separate these two systems actually are in practice - everything inside a cell connects to everything else in some way).
With this in mind, I'll point out a paper that caught my eye today, in which researchers genetically enhance proteasomal activity in a mouse model of retinal degeneration. They show that the mice are better able to resist the loss of retinal cells: the cells are more robust in the face of damaged and harmful proteins that accumulate either with age or because of inherited mutations that disrupt correct cellular function. This is more interesting for the demonstration of the possibility rather than the results in this particular case. Absent side-effects, permanently improved cellular housekeeping would be a desirable enhancement technology, something that might reproduce many of the long-term health benefits of calorie restriction and exercise.
The work in this paper for the proteasome is analogous to the LAMP2A gene therapy used in mice to enhance autophagy in the liver some years ago. That slowed the impact of aging on tissue function by making cells more resilient and capable of carrying out their assigned tasks. Both that and this proteasomal enhancement involve increasing the production of one of the component parts of the housekeeping system, and that is apparently enough to boost overall activity and efficiency. All forms of cellular housekeeping decline with age, an outcome that is caused by fundamental forms of damage, such as the buildup of forms of metabolic waste that our biochemistry cannot effectively break down. Enhancing housekeeping operations without dealing with that damage is essentially compensatory, an approach of limited effectiveness, given that the damage remains to cause all of its other consequences. It may still be cost-effective enough to pursue, provided it isn't pursued to the exclusion of addressing the underlying cell and tissue damage that causes aging and all of its issues.
More than 2 million people worldwide live with inherited and untreatable retinal conditions, including retinitis pigmentosa, which slowly erodes vision. Developing treatments is challenging for scientists, as these conditions are caused by more than 4,000 different gene mutations. But many of these mutations have something in common - a propensity for creating misfolded proteins that cells in the eye can't process. These proteins build up inside cells, killing them from the inside out.
Now scientists have shown that boosting the cells' ability to process misfolded proteins could keep them from aggregating inside the cell. The researchers devised and tested the strategy in mice, significantly delaying the onset of blindness. Their approach potentially could be used to prevent cell death in other neurodegenerative diseases, such as Huntington's, Parkinson's and Alzheimer's.
The researchers focused on the proteasome: machinery inside all cells that eliminates misfolded proteins. You can compare the barrel-shaped structure to a paper shredder, with the cutting elements hidden inside. Misfolded proteins must pass through a "lid" on the shredder to be processed, but cells in diseased mice do not have enough lids, enabling the buildup of the damaged proteins. Instead of trying to alter the shredders, researchers genetically increased the quantities of lids for the shredders, allowing cells to process more misfolded proteins. In trials, mice with added proteasome lids retained four times the number of functional retinal cells by adulthood than mice with the same form of retinitis pigmentosa, which went blind as adults.
Studies of animal models of retinitis pigmentosa (RP) have revealed a number of common pathological conditions: oxidative stress, unfolded protein response, retinoid cytotoxicity, iron toxicity, and aberrant phototransduction. Our recent work demonstrated that another major cellular stress factor prevalent in a broad spectrum of mouse RP models is the insufficient capacity of the ubiquitin-proteasome system to process misfolded or mistargeted proteins in affected cells. We further demonstrated that the severity of photoreceptor retinal degeneration correlates with the degree of misfolded protein production. Conversely, genetic manipulation reducing the proteolytic capacity of proteasomes evoked RP-like pathology in otherwise normal retinas.
The goal of the present study was to determine whether survival of degenerating photoreceptors could be supported by enhancing the proteolytic capacity of their proteasomes. We aimed to increase the proteasome activity in these cells using two independent genetic strategies and found that the strongest effect was achieved by overexpressing the PA28α subunit of the 11S proteasome cap. We also show that the underlying mechanism is based primarily on the stimulation of ubiquitin-independent protein degradation. Breeding PA28α-overexpressing mice with two mouse models of photoreceptor degeneration results in a delay of disease progression.