If you thought that there was a lot of noise and action in the GLP-1 drug area before (medical, financial, societal), just wait. I think that this new paper at Nature is a preview of what’s to come. We’ve already been seeing a good bit of evidence that these compounds have what seem to be beneficial effects well outside of their primary effects on appetite and weight, but this work (building on some previous signals) goes straight for a very big target indeed.
Semaglutide (Ozempic, Wegovy) administered to aging mice (starting at 20 months) shows a whole range of useful effects. It reduced age-associated inflammation, improves a wide variety of metabolic processes, reduces markers of cellular senescence, improves overall genomic stability, reduces the levels of reactive oxygen species and improves the mitochondrial stress response, ER stress and stress in the unfolded protein response pathways. Markers of adaptive immune response improved, as did insulin response.
Overall, the effects were quite similar to caloric restriction (CR) in aged mice, which has been shown many times to improve lifespan. And indeed, GLP-1 treatment also lengthened the lives of these mice, and (like caloric restriction) also seemed to increase “healthspan”. Measures of total movement, ability to solve maze tests, to perform on the “rotarod” device, and the ability to run a treadmill test all improved notably versus control animals. A head-to-head test of CR versus GLP-1 demonstrated this well, but it also showed that GLP-1 treatment was actually superior in several categories, such as real improvements in total exploratory behavior, spatial memory, and glucose control. By contrast, caloric restriction just maintained these at the previous levels (as compared to falling off at the rate of control mice). Another interesting change: calorically restricted mice show constant behavioral signs of hunger, as well they might, but these effects did not occur with GLP-1 treatment. As the authors note, this is “raising the possibility that GLP-1 medicines may not only slow but also reverse aspects of ageing-associated functional decline”.
Well, there is a market for that. This is the place to note that yes, this is a mouse study, with all that that entails. But the wide variety of mRNA and proteomic changes that are detailed in this paper are in pathways that are very much shared between mice and humans, and caloric restriction itself works in a variety of small-animal systems and also seems to work in primates (although those are complicated studies to run). I would have to rate the chances of this work translating as rather high.
Toxicology, though, is another factor and it always gets the last word. We do not really know what the effects of multiyear GLP-1 dosing would be on an elderly population, and there’s no good way to model your way to a conclusion, either. We are perhaps conducting a large natural experiment on these and other populations right now, but not in a very controlled fashion. I think that work in this area is going to excite enough interest that actual trials will be worth running, and as a 64-year-old I certainly hope that this is the case. I have never taken any GLP-1 drug myself, but who knows. Perhaps it’s in my future? I will be watching with more-than-usual interest as this story unfolds.