Peering at the Proteasome

You might have noticed recent investigations into exactly how embryos generated by an old collection of cells - people like you and I - turn out to be made of young cells. After all, every other clump of cells we generate is also old.

Quite unexpectedly we found that the level of protein damage was relatively high in the embryo's unspecified cells, but then it decreased dramatically. A few days after the onset of cell differentiation, the protein damage level had gone down by 80-90 percent. We think this is a result of the damaged material being broken down.

If we're lucky there's a potent life-extending therapy in there somewhere, but of course the odds are good that the process by which the early embryo repairs most of its damage is tightly bound to the embryonic nature of its cellular machinery and will be somewhere between very challenging and next to impossible to safely apply to organized, differentiated structures of adult cells. The difference between "very challenging" and "next to impossible" is probably about twenty years of technological development in this era - but we shall see. This seems worth watching.

The researchers involved in this latest research into embryonic development think that the proteasome is the root of this profound embryonic damage repair process. This is a recycling mechanism in the cell that is separate and distinct from the lysosome that regular readers are probably sick of hearing about by now, focused on breaking down every errant protein that looks like it doesn't belong, is unwanted, or is somehow malfunctioning.

The rate of accumulation of damaged proteins and larger cellular components is important in determining the pace of aging, and this is illustrated by the degree to which the recycling processes of autophagy keeps turning up in investigations of various longevity-enhancing mutations and environmental circumstances. If a machine accumulates gunk and broken parts, then it tends to break down more rapidly and in more ways - and we are in effect very complex machines. Aging is damage. This model is somewhat complicated by the fact that we can repair ourselves, by those repair mechanisms - like the proteasome and lysosome - are also machines, and prone to damage. Once the spiral down starts it tends to accelerate, and eventually you wind up with the aptly named garbage catastrophe view of aging.

But here is an example of quite different research into aging and the activities of the proteasome - in yeast rather than people. Yet it still shows that, as for other forms of recycling mechanism, healthy life span lengthens as these cellular maintenance tool kits work harder.

Elevated Proteasome Capacity Extends Replicative Lifespan in Saccharomyces cerevisiae

The ubiquitin/proteasome system (UPS) is an integral part of the machinery that maintains cellular protein homeostasis and represents the major pathway for specific protein degradation in the cytoplasm and nuclei of eukaryotic cells. Its proteolytic capacity declines with age. In parallel, substrate load for the UPS increases in aging cells due to accumulated protein damage. This imbalance is thought to be an origin for the frequently observed accumulation of protein aggregates in aged cells and is thought to contribute to age-related cellular dysfunction.

In this study, we investigated the impact of proteasome capacity on replicative lifespan in Saccharomyces cerevisiae using a genetic system that allows manipulation of UPS abundance at the transcriptional level. The results obtained reveal a positive correlation between proteasome capacity and longevity, with reduced lifespan in cells with low proteasome abundance or activity and strong lifespan extension upon up-regulation of the UPS in a mechanism that is at least partially independent of known yeast longevity modulating pathways.

All told, the longevity science community hasn't devoted as much attention to the proteasome as to other housekeeping mechanisms, but that will probably change in the years ahead. All it takes is one widely noticed mouse study with an impact on aging to generate a great deal more attention.

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