Shifting the balance of C/EBPβ isoforms extends healthspan in mice

 

In order to develop anti-aging pharmaceuticals, we need targets—proteins (or other macromolecules) whose functions influence longevity, and whose activities can be modulated by drugs in order to enhance lifespan.

One of the most well-known targets identified to date is mTORC1 (“mechanistic target of rapamycin complex 1”; “TOR” to its friends), which is targeted by the small-molecule drug rapamycin. Inhibition of the TOR pathway by rapamycin extends lifespan and exerts a variety of other beneficial effects in mice. The results to date are so promising that a large-scale test of the drug’s effects is currently underway in domestic dogs. As any dog lover would tell you, extension of canine lifespan is a worthy goal in its own right, but the Dog Aging Project has another selling point: if we can show that rapamycin prolongs life in two fairly diverged mammalian species, we would be much more confident that the drug would work in humans.

Despite the promise of rapamycin, however, there is also a risk of side effects. The compound was originally approved for use as an immune suppressant, albeit at much higher concentrations than those used for lifespan experiments, and it is conceivable that chronic low-dose use could have immunological consequences. Moreover, rapamycin may inhibit the formation, consolidation, and preservation of long-term memory (though again, it’s not certain it would have this effect at lower doses); I don’t have to point out the irony of a longevity-enhancing drug that eroded the memory.

Therefore, it makes sense to identify the specific effectors of TOR (a multifunctional signaling integrator hat influences a great many cellular processes) that govern lifespan and inhibit those.

One attractive candidate for this purpose is the dominant-negative LIP isoform of the transcription factor C/EBPβ. We’ve known for a while that calorie restriction (CR), which extends lifespan, upregulates C/EBPβ but shifts translation from LIP to the beneficial isoform LAP.  Conversely, TOR activity (which is negatively associated with lifespan) increases the relative abundance of LIP, which is also upregulated with age.

TOR does this via a very cute form of translational regulation that requires an upstream open reading frame (uORF) in the Cepb mRNA — the details are a bit beyond the scope of this post, but for now all we need to know is that when the uORF is present, TOR activity boosts synthesis of C/EBPβ-LIP. On the other hand, when the uORF is absent, LIP synthesized is dramatically reduced and LAP is comparatively more abundant..

In previous work, the Calkhoven group at ERIBA showed that elimination of the uORF (causing a decrease in LIP production) in mice mimics the metabolic effects of CR without requiring any reduction in caloric intake. This makes a very strong prediction…which turns out to be true. In their most recent paper, the same group showed that in addition to being more metabolically healthy, the ∆uORF mice also develop fewer tumors, have a more youthful physiology, and live longer than wild-type controls.

The molecular data in the study strongly imply that TOR-induced production of LIP plays a causative role in aging…making LIP  (and more broadly, the regulation of C/EBPβ isoforms) a promising target for anti-aging medicine. This is not lost on the authors, who have already developed a high-throughput screen for compounds that suppress LIP production—potentially enabling identification of CR mimetics that confer the lifespan-extending properties of TOR suppression without risking the side effects of chronic rapamycin exposure.

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Müller et al. “Reduced expression of C/EBPβ-LIP extends health- and lifespan in mice.” eLife 2018;7:e34985. DOI: 10.7554/eLife.34985