Previously, we’ve discussed autophagy as being on the side of the angels in the fight against cellular deterioration (see On the benefits of eating oneself). The accumulation of unwanted molecules contributes to age-related decline in function, and autophagic pathways help remove and recycle the built-up junk. Autophagy seems to become less efficient with age, potentially leading to a garbage catastrophe as exponentially higher levels of malfolded proteins and other perpetrators further compromise the cell’s homeostatic mechanisms (see Better living through self-destruction).

A new article in BioEssays, however, takes a different perspective on autophagy. Takács-Vellai et al. review the evidence that in C. elegans, autophagy is responsible for the ultimate demise of neurons — the last holdouts against age-related decline, and themselves responsible for many aspects of genetic control of lifespan.

… Analysing major cellular changes in the ageing nematode Caenorhabditis elegans has revealed a gradual, progressive deterioration of different tissues except for the nervous system, which remarkably preserves its integrity even in advanced old age. In addition, genetic data have shown that, in C. elegans and in the fruit fly Drosophila melanogaster, lifespan is controlled by signals derived from neurons and acting throughout adulthood. Organismal death thus seems to be a consequence of the decline of specific neurons. Accumulating evidence demonstrates that late onset of neuronal cell loss generally occurs via autophagy, a process in which eukaryotic cells self-digest parts of their contents during development or to survive starvation. Here we suggest that overactivation of autophagy in the cells of the nervous system is the eventual cause of “physiological” death.

Let us for the moment accept the idea that autophagy is an anti-aging force in mid-life, per the articles cited in the intro paragraph of this posting, but a pro-death force in late life, per the neuronal death mechanism described in the paper. (Antagonistic pleiotropy, anyone?)

By the former premise, it’s tempting to think that in order to decrease age-related accumulation of cellular trash, we ought to increase autophagy (by CR, CR mimetics, anti-lipolytic drugs, or some other pharmaceutical mechanism) — however, by the latter premise, broad acceleration of autophagy could have deleterious consequences on the nervous system via activation of cell death pathways. (“We have some good news and bad news: You have the heart of a sixteen-year-old, but a brain made out of swiss cheese.”)

Which is not to say that we should throw the autophagic baby out with the bathwater. It’s quite conceivable that tissue targeting, timing of treatments, and other steps could be taken in order to make interventions based on autophagy an effective way to treat age-related decline.

Rather, this is a reminder that too much of a good thing can be bad for you, and that autophagy is not always an angel. The devil is (as always) in the details.

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