Torin1 as an Example of the Search for Better Rapalogs, with a Focus on Autophagy

A sizable portion of the research community interested in intervening in the aging process searches for ways to mimic naturally occurring stress responses, those linked to a slowing of aging in animals. Much of this research in some way involves TOR, the target of rapamycin, and attempts to improve upon rapamycin as a drug candidate to inhibit TOR. TOR is connected to the regulation of autophagy, a cellular housekeeping process known to influence the pace of aging, but also to many other areas of cellular biochemistry relevant to aging. The relevant mechanisms and networks of protein interactions are only partially mapped, and are very complex - progress on that front is slow and expensive.

I point out the open access paper here as an illustrative example, representative of the work of many other scientific groups whose members aim to find and evaluate TOR inhibitors, also known as rapalogs, in search of drug candidates that are better than rapamyin. Better or not, however, it is still the case that this sort of thing is marginal in the grand scheme of what is possible - look at the survival curves in the paper to see how small the effect is in flies, and bear in mind that the effect size for stress response mechanisms diminishes greatly as species life span increases, where the data exists to compare directly. When it comes to what can be gained in terms of increased human life span, modestly slowing aging by activating cellular stress responses compares very unfavorably with rejuvenation strategies based on periodic repair of the molecular damage that causes aging.

Down regulation of the protein kinase TOR is reported to increase lifespan. TOR is highly conserved across eukaryotes and controls several fundamental cellular functions including autophagy - an important and highly conserved cellular repair mechanism. TOR is a major regulator of cellular growth and proliferation and is comprised of two differentially regulated protein complexes TOR complex 1 (TORC1) and TOR complex 2 (TORC2). TORC1 and 2 have distinct substrate specificities and are differentially sensitive to the TOR inhibitor rapamycin. TORC1 promotes anabolism and inhibits catabolism by blocking autophagy. TORC2 is known to be insensitive to rapamycin. Its role in protein synthesis isn't yet clear, though it plays roles in many cellular processes via the AGC kinases and is implicated in keratinocyte survival and cancer development.

The effects of TOR on autophagy are of interest in the context of ageing. It is known for example, that autophagy is naturally down-regulated as a result of normal ageing. The function of autophagy is to repair cellular damage, leading to the suggestion that manipulations that activate autophagy might increase lifespan by maintaining damage surveillance and increasing cellular repair. Consistent with this, over-expression of specific autophagy genes has been shown to extend lifespan in yeast, flies, and human cells. In general, manipulations involving changes to autophagy or autophagy genes are increasingly being reported to be associated with lifespan. Linking the two processes, it has been shown that the specific inhibition of TOR, which in turn activates autophagy, results in extension of lifespan in various species.

The TOR pathway can be inhibited, and hence autophagy activated, by inactivating TORC1 through treatment of cells with rapamycin or via nitrogen starvation. This increase in lifespan due to inhibition of TOR could potentially be via TOR's effects on protein synthesis. However, research on C. elegans suggests a more direct role of autophagy in the modulation of longevity, because inactivating autophagy genes specifically prevents the inhibition of TOR activity from extending lifespan. This finding suggests that the TOR pathway and autophagy act via the same signalling pathway to influence lifespan. However, it should also be noted that inhibition of TOR leads to decreased translation as well as increased autophagy, hence it can be important to distinguish whether either or both pathways are most associated with lifespan effects.

Torin1 is a well-established activator of autophagy via inhibition of the TOR pathway, which inhibits TOR with a higher degree of selectivity than other previously used pharmacological activators, e.g. rapamycin. Part of the mechanism of action of Torin1 is reported to be to suppress the rapamycin-resistant functions of TORC1 that are necessary to reduce autophagy. In addition, unlike rapamycin, Torin1 is reported to inhibit kinase function in both TORC1 and TORC2 complexes potentially giving it greater effectiveness. Torin1 inhibits cell growth and proliferation to a much greater degree than rapamycin and may represent a more effective and specific inhibitor.

In this study we initiated an investigation into the effects on lifespan and reproductive success of Torin1 supplied via the diet, in once-mated and continually mated D. melanogaster females, and on the lifespan of once-mated males. The main finding was that the addition of Torin1 to the diet activated autophagy and led to significant lifespan extension in both sexes. Elevated egg production was observed in females fed Torin1, but overall this did not result in higher overall fertility, owing to higher egg infertility in these females. Hence, there was no evidence for a trade-off between longevity and total fecundity, or between longevity and fertility. Elevated reproduction can lead to damage, which may result in reduced lifespan. Our hypothesis is that the activation of autophagy by dietary administration of Torin1 repairs damage caused by elevated reproduction, potentially minimising trade-offs between lifespan and reproductive rate.

Link: https://doi.org/10.1371/journal.pone.0190105

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