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Aging and Lifespan

VCAM1 As a Player in the Aging Brain

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!


13 comments on “VCAM1 As a Player in the Aging Brain”

  1. a. nonymaus says:

    Very interesting effect, but I am reminded of Chesterton’s fence. Are there VCAM1 natural knockouts in the population, and what do they die of? Or do they immortally walk among us?

    1. still searching says:

      VCAM-1 knockouts in mice were embryonically lethal

  2. Pedantic says:

    I think you meant “Note”, not “Not”.

    1. Tim says:

      Ditto on “Not that this is dialyzed plasma”.

  3. Lane Simonian says:

    Here is one possibility (VCAM1 activation of protein kinase C alpha which can increase the possibility of some neurodegenerative diseases).

    This study is interesting but I doubt the one protein, one receptor, or one agent approach is going to work. For example, there are dozens of proteins/receptors/agents that can lead to protein kinase C alpha activation.

  4. dearieme says:

    “infusing young blood into aged rodents …”

    Golly, it’s back – approximately – to monkey glands.

    1. eub says:

      I *was* going to say I’m shocked nobody seems to be selling vampiric transfusions of virgin blood for Bitcoin, but

      It turns out it’s PayPal. Which makes sense since it’s for the olds. Presumably they Venmo to pay their donors.

  5. cynical1 says:

    Okay, since VCAM-1 is a ligand for VLA-4 and VCAM-1 is up-regulated in multiple sclerosis and Natalizumab inhibits the binding of VCAM-1 to the integrin AND Natalizumab also produces positive improvement in cognitive function in MS patients; then shouldn’t everyone be racing to the clinic with Natalizumab in age-related neurodegeneration??? Aside from the very small risk of dying from PML, it’s otherwise a pretty safe drug. I think they call that an off-the-shelf drug, right?

    With that said, I would agree with you that I’m not going to bet the (my) farm on it working but seems like a fairly straight forward proof of concept based on what you are summarizing above. Or am I missing something?

  6. imaging guy says:

    Another “target identification” article. I might be wrong, but I have a feeling that the findings will not be reproducible. In this study they used anti VCAM1 antibody [Rat monoclonal anti-VCAM-1 (BioxCell, BE0027, clone M/K-2.7)] to check the expression of VCAM1 on brain endothelial cells or isolate them. According to them they had to inject the antibody intravenously through retro-orbital vein since the expression is so low even in aged brains, young brains challenged with old age plasma or other inflammatory agents (lipopolysaccharide, TNFα and IL1β). This is highly unusual, and I think images shown were chosen in biased manner. Moreover, the first author of this article (Hanadie Yousef) is the CEO of a start-up for aging treatment (Juvena Therapeutics) and she has got a patent application for anti VCAM1 antibody (1) but none of this is reported in conflict of interest section of the paper. Very recently the last author published an article in Nature identifying CD 22 as another “target” involved in cognitive impairment in aged mice (2). I don’t think that study would also be reproducible. About 5 years ago Amy Wagers of Harvard identified GDF11 as the protein responsible for anti-aging effects seen in aged mice when they received young plasma (either through injection or parabiosis). That study was also found to be not reproducible (3). Finally, current reproducibility crisis became exposed when researchers from Bayer and Amgen reported that “drug targets” published in high impact journals were rarely reproducible in their labs (4, 5).
    1) “Vcam-1 mediated methods and compositions for treating aging associated impairments”, US 20170145105 A1
    2) “CD22 blockade restores homeostatic microglial phagocytosis in ageing brains”, Nature. 2019 Apr;568(7751):187-192. doi: 10.1038/s41586-019-1088-4. Epub 2019 Apr 3.

    1. Anon2 says:

      According to the Stanford press release, Juvena Therapeutics is not pursuing clinical use of VCAM-1 blocking agents, which probably explains the lack of any COI statement.

  7. jwskud says:

    I haven’t heard of VCAM-1 since I worked on it as a primary target for atherosclerosis with the now-defunct AtheroGenics. Things didn’t work out so well on that front…

  8. Uudon Rock says:

    VCAM-1 has upregulation has been noted in some cases of acute meyloid and lymphoblastic leukemias, as well as plasma cell meyloma.

    Generally speaking this is a not a good prognostic factor.

  9. 9-1=eight says:

    It’s worth noting that small-molecule prodrug antagonist of VCAM-1- Zaurategrast (CDP323) – failed in P2 for relapsing MS.

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