Cells continually accumulate damage in the form of metabolic waste products and broken or misfolded protein machinery. Several systems toil to remove this damage on an ongoing basis, and the efficiency of these systems is linked to longevity: more cellular housekeeping is a good thing. Unfortunately, and as is the case for all aspects of our biology, these housekeeping processes become less efficient with age, most likely overwhelmed by forms of damage and waste products that they cope poorly with.
You might be familiar with the lysosome and its role in recycling damaged cellular components, and know that lysosomal activity declines with aging due to a build up of hardy waste compounds that our biology isn't equipped to break down. There are other components of the housekeeping system in our cells, however, and they also fail with age. Just as there are potential means to restore lysosomal recycling to youthful efficiency, so too will there be ways to rejuvenate these other housekeeping systems. For example, here researchers demonstrate restoration of the effectiveness of the ubiquitin-proteasome system, important in the clearance of misfolded proteins:
Levels of damaged proteins increase with the age of different species, including fungi, flies, worms, bats, birds, rodents, and humans. Several principal possibilities have been suggested to explain this apparently universal accumulation of damaged/misfolded proteins, including a diminished capacity for protein quality control, which encompasses the removal of damaged and misfolded proteins by the proteasome. Indeed, the function of the 26S proteasome decreases during aging in several human tissues, senescent primary cultures, and whole organisms, pinpointing the proteasome as a possible malefactor behind age-related damage propagation.
Here, using yeast as a model system, we show that while the level and potential capacity of the 26S proteasome is maintained in replicatively aged cells, the UPS is not functioning properly in vivo. As a consequence cytosolic UPS substrates are stabilized, accumulate, and form inclusions.
By integrating a PGPD-HSP104 recombinant gene into the genome, we were able to constitutively elevate protein disaggregase activity, which diminished the accumulation of protein inclusions during aging. Remarkably, this elevated disaggregation restored degradation of a 26S proteasome substrate in aged cells without elevating proteasome levels, demonstrating that age-associated aggregation obstructs UPS function. The data supports the existence of a negative feedback loop that accelerates aging by exacerbating proteostatic decline once misfolded and aggregation-prone proteins reach a critical level.