As cells age, they accumulate junk: cross-linked proteins, oxidized lipids, dysfunctional membrane-bound organelles, and other detritus. Such undesirables can interfere, directly or indirectly, with the proper functioning of the cell; therefore, it’s important for cells to have ways to take out the trash. One important class of garbage-disposal pathways is collectively termed autophagy (etymologically, “self-eating”); together, these mechanisms help to clear the cell of damaged macromolecules.

The rate of autophagy slows with age, making turnover of damaged components less efficient. This could conceivably set up a vicious cycle: slower autophagy –> more rapid accumulation of toxic protein aggregates –> further interference with cellular machinery, including autophagy itself –> even slower autophagy. This model has been termed the “garbage catastrophe” hypothesis, and is a prime contender for explaining age-related decline in cellular function.

The model makes a strong prediction: if one were able to prevent the age-associated decline in autophagy, one could delay or prevent this functional decline. That prediction was successfully put to the test by Zhang and Cuervo, who created a transgenic mouse whose autophagic activity can be experimentally modulated:

Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function

Chaperone-mediated autophagy (CMA), a selective mechanism for degradation of cytosolic proteins in lysosomes, contributes to the removal of altered proteins as part of the cellular quality-control systems. We have previously found that CMA activity declines in aged organisms and have proposed that this failure in cellular clearance could contribute to the accumulation of altered proteins, the abnormal cellular homeostasis and, eventually, the functional loss characteristic of aged organisms. To determine whether these negative features of aging can be prevented by maintaining efficient autophagic activity until late in life, in this work we have corrected the CMA defect in aged rodents. We have generated a double transgenic mouse model in which the amount of the lysosomal receptor for CMA, previously shown to decrease in abundance with age, can be modulated. We have analyzed in this model the consequences of preventing the age-dependent decrease in receptor abundance in aged rodents at the cellular and organ levels. We show here that CMA activity is maintained until advanced ages if the decrease in the receptor abundance is prevented and that preservation of autophagic activity is associated with lower intracellular accumulation of damaged proteins, better ability to handle protein damage and improved organ function.

To summarize: In normal mice, a lysosomal protein required for autophagy gradually disappears with age, resulting in downregulation of autophagic activity. In the transgenics, levels of that protein can be artificially maintained, resulting in long-term maintenance of autophagy and a significant delay in functional deterioration of at least one organ (the liver).

The data strongly support a causative role for diminishing autophagy in hepatic aging; the transgenic model thus points the way toward a therapeutic intervention against one of aging’s root causes. How that would translate into practical terms is another matter: We don’t have the technology to alter the cellular genome in every cell of the body (nor is it clear we’d want to try: as an exercise, multiply [the rate at which your favorite hypothetical delivery method would mistarget an integration to an oncogene] by [the number of cells in the human body], and count the number of raging tumors that emerge). It might be faster, not to mention safer, if we could develop a small molecule capable of stimulating cells to maintain chaperone-mediated autophagy on their own.

It will be important to determine whether these results will hold true in other organs besides the liver. I’m particularly concerned about the brain, where previous experiments involving pharmaceutical upregulation of autophagy have had worrisome results. I would also love to know whether this method is effective at reversing, rather than preventing, age-related damage (e.g., in mice that have aged normally for some time before the transgene is activated).

On a final note: It seems intuitive that accumulating detritus will be bad for cells, but I think it would be fruitful to consider the mechanisms involved. What are the rate-limiting cellular functions that are the first to go when autophagy begins to fail? Another strategy, complementary to the one outlined in this paper, might be to boost the pathways that are the most sensitive to rising levels of junk, thereby making cells more tolerant to a given level of garbage. (In the end, of course, one would still have to reactivate autophagy in order to take out the trash, but simultaneously boosting stress tolerance might buy the cell some extra time.)

P.S.: This story was reported in the press a few weeks ago. Here’s a particularly choice piece of coverage from Down Under: Scientists stop the ageing process — holy smokes, we’re out of a job! Note the bizarre non sequitur stock photo.

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