Possible intervention targets for age-related degeneration are always welcome, particularly when they come bearing experimental evidence, and even more so when they relate to the central nervous system. That’s the case with this new paper, from a multicenter team led out of Stanford. Interestingly, this also ties in with the well-publicized (and from what I can see, well-established) evidence that infusing young blood into aged rodents improves their brain function (among other things), while infusing elderly blood into young ones impairs them. That’s inspired a great deal of work to figure out what the blood factors are that are causing all this, on both sides.
This work makes the case for vascular cell adhesion molecule 1 (VCAM1). The group started out by looking at brain endothelial cells (BECs) from young and old mice, using RNAseq for expression profiling. There are plenty of differences (people have done this sort of analysis before, naturally), and these tend to show up in pathways that are known to be associated with the aging phenotype: immunity and inflammation, stress responses, the vascular system, cell adhesion, and more. The inflammation component really stands out, as has been noted for many years, and it makes sense: age-related damage to cellular systems is interpreted as, well, damage, and it sets off a response as with any other injury. But the persistent activation of the inflammation pathways probably ends up causing further damage on its own.
The group had already searched for age-related plasma protein differences in previous work, and correlating those with the BEC data showed that the soluble form of VCAM1 really stood out. That one is cleaved off the membrane-bound VCAM protein and circulates throughout the body, encouraging leukocyte tethering to cell surfaces via the integrin receptor system. Not every BEC cell is positive for VCAM1, though, so the team zeroed in with single-cell expression profiling on the ones that were. And even those, on detailed analysis, cluster into groups based on their gene regulation signatures, and that isn’t all due to age, either. But there was still enough of a definite age-related signature for Vcam1 mRNA and expression of VCAM protein correlated strongly with it, too. Interestingly, two of the clusters that could be differentiated, from the herd and from each other, were from venous and from arterial endothelial cells.
And plasma from aged mice, it turns out, sets off VCAM1 expression very noticeably (human plasma from aged subjects does it, too). Brain-specific deletion of VCAM1, on the other hand abolishes the effects of aged plasma on the brain. Not that this is dialyzed plasma, so the small molecules and metabolites should be largely removed (which argues for many of the bad effects to be mediated by proteins). There was still plenty of soluble VCAM1 protein out in the plasma, since they didn’t delete things out in the other tissues, but aged plasma treatment had no effect on BEC cells, on microglia, or on hippocampal activity, as opposed to mice that still had their cerebrovascuar VCAM intact. Similarly, treatment of the rodents with an anti-VCAM antibody also prevented aged plasma from having brain effects. In fact, old mice, when treated over several days in this way, significantly improved their cognitive function (in the sort of find-the-hole tests you run on mice), in some cases back to the levels of their younger peers.
This looks like important evidence. It’s not only very interesting that VCAM1 has been identified as a player in these processes, but even more so that there seems to be an opportunity for therapy (I honestly would not have been optimistic about the latter, but I’m glad to be wrong). It’s also worth noting that circulating VCAM1 is increased in many other chronic disease states in humans, as well as with aging in general, and it’s exciting to consider that this might be one of the too-much-inflammation bad actors that can be targeted. There’s still a lot to be unraveled – for example, what’s happening downstream of VCAM signaling to cause the trouble? You’d figure that it’s leukocyte-related, but there’s a lot to find out (and that may reveal additional ideas for intervention). How do the microglia and hippocampal cells know what’s going on, and by what pathways do they react? All this is well worth study – but another thing that’s well worth study is the effect of VCAM inhibition in the brains of more animal models, and if those bode well, in humans too. Here’s hoping that something comes of it!