Considering GSK-3 in Aging

The two extremes of theorizing on the process of aging might be seen as (a) arguing that aging is damage that causes metabolism to react, alter its processes, and ultimately fail, and (b) arguing that aging is a harmful programmed change in the operation of metabolism, the result of evolved processes that are beneficial in youth continuing past the point at which natural selection operates strongly and progressively becoming ever more damaging to the individual. The views held by researchers tend towards one side of the aisle or the other, largely favoring aging as damage, but it's not a black and white thing: it's perfectly possible to think that some portions of aging are spawned by damage while other portions are programmed, or that the answer is different in different species.

This paper leans towards the programmed side of the house in discussing GSK-3 in the context of the biology of aging. It's a study that only shows accelerated aging, however. This is always less convincing as an argument that a particular gene or protein is related to longevity because researchers can create what appears to be accelerated aging by breaking any number of important biological mechanisms so as to cause more damage and dysfunction in an organism. Very few of those changes can be turned in the opposite direction and shown to extend life, however - and extending life rather than shortening it is the crucial test of relevance:

Very few enzymes exert as broad a regulatory influence on cellular functions as do the two isoforms of GSK-3(α and β). The substrates that are phosphorylated by GSK-3s can be classified into four categories: metabolic enzymes, signaling molecules, structural proteins, and transcription factors, typically involved in regulating cell proliferation and differentiation; cellular metabolism, cell survival and cell cycle regulation. Additionally, GSK-3 has been linked to several chronic diseases, including diabetes and Alzheimer disease. Nevertheless, it was not clear whether GSK-3 might regulate aging.

Our recent work seems to clearly implicate GSK-3, and specifically the α isoform, in aging. Through targeting GSK-3α in the mouse, we found accelerated development of age-related pathologies in multiple organ systems. These included accelerated aging in the bone/skeletal system, leading to severe degenerative joint disease that was accompanied by increased inflammatory cytokines. The gut and liver also showed clear signs of accelerated aging. But the most striking findings were seen in the heart and skeletal muscle (i.e. striated muscle). These organ systems developed profound hypertrophy and dysfunction.

Notably, [we] saw innumerable structurally abnormal organelles, in particular (but not limited to) disrupted mitochondria. The profound nature of this suggested that the [mice] were unable to clear these damaged organelles, possibly implicating dysfunctional autophagy. We confirmed that [knockout] of GSK-3α markedly activated mTOR, and knowing that mTOR suppresses autophagy, we asked if autophagy was dysregulated. We confirmed that it was.

The key remaining question was whether this dysregulation of autophagy was leading to (or at least contributing to) the abnormalities of striated muscle. We employed a second generation inhibitor of mTORC1, everolimus, and found that both cardiac contractile abnormalities and skeletal muscle abnormalities were largely corrected. It remains to be seen whether the numerous other organ systems that we found to be dysfunctional in the absence of GSK-3α will also be corrected by mTORC1 inhibition.

I'd be inclined to read this as simply a confirmation that GSK-3 sits in the same general set of aging-related mechanisms as mTOR, and that autophagy, once again, is shown to be a very important aspect of health and longevity.



Caution is probably in order since activating GSK-3α could possibly speed progression of Alzheimer's - See:

"GSK-3 is essential in the pathogenesis of Alzheimer's disease"

Posted by: Lou Pagnucco at June 21st, 2013 11:33 AM

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