VCAM1 as a Potential Harmful Signal in Old Blood

Heterochronic parabiosis, linking the circulatory systems of an old and a young mouse, benefits the old mouse in that it reduces some measures of aging. Researchers initially focused on possible beneficial signals in young tissues and blood, but more recent research suggests that the outcome may occur because harmful signals present in old tissues and blood are diluted. If this is the primary mechanism, it would explain why transfusion of young blood to old individuals does not appear produce similar effects in animal studies. Here researchers claim evidence for one such harmful signal:

The effects of blood on ageing were first discovered in experiments that stitched young and old mice together so that they shared circulating blood. Older mice seem to benefit from such an arrangement, developing healthier organs and becoming protected from age-related disease. But young mice aged prematurely. Such experiments suggest that, while young blood can be restorative, there is something in old blood that is actively harmful. Now researchers seem to have identified a protein that is causing some of the damage, and have developed a way to block it.

The researchers found that the amount of a protein called VCAM1 in the blood increases with age. In people over the age of 65, the levels of this protein are 30 per cent higher than in under-25s. To test the effect of VCAM1, researchers injected young mice with blood plasma taken from older mice. Sure enough, they showed signs of ageing: more inflammation in the brain, and fewer new brain cells being generated, which happens in a process called neurogenesis. Blood plasma from old people had the same effect on mice. When researchers injected plasma from people in their late 60s into the bodies of 3-month-old mice - about 20 years in human terms - the mice's brains showed signs of ageing. These effects were prevented when researchers injected a compound that blocks VCAM1. When the mice were given this antibody before or at the same time as old blood, they were protected from its harmful effects.

Some teams have begun giving plasma from young donors to older people, to see if it can improve their health, or even reduce the effect of Alzheimer's disease. But for the best chances of success, we'll also need to neutralise the damaging effects of old blood. Other researchers comment that it is "surprising that a single protein seems to have such a huge effect," but the results need to be replicated by another lab. A drug that protects people from the effects of old blood would be preferable to plasma injections. Should transfusions from young donors turn out to be effective, it would be difficult to scale this up as a treatment for all. Drugs that block harmful proteins in our own blood would be cheaper, safer and more accessible.



Sounds interesting, and would be consistent with the Rebo/Conboy work showing that the parabiosis effect is mostly about eliminating bad stuff rather than delivering good stuff. And as they say, there are a lot fewer problems with delivering an antibody (or, eventually, a cocktail thereof, to include eg. beta-2 microglobulin and CCL11) than eking plasma out of young donors. However, they don't seem to have actually taken the step of testing its in real, aged mice:

Yousef injected young mice with blood plasma taken from older mice. Sure enough, ... fewer new brain cells being generated ... Blood plasma from old people had the same effect on mice. ...

These effects were prevented when Yousef injected a compound that blocks VCAM1. When the mice were given this antibody before or at the same time as old blood, they were protected from its harmful effects.

This is confirmed by the SfN conference abstract:

systemic injections of aged human blood into young immunodeficient (NSG) mice- acutely over 4 days or spread over 3 weeks- increased [brain endothelial cell]-specific VCAM1 expression, increased brain inflammation as assessed by microglial activation, and inhibited hippocampal neurogenesis. Blocking VCAM1 signaling systemically with a neutralizing monoclonal antibody rescued neurogenesis and prevented aged plasma induced microglial activation. This study suggests that preventing BEC-immune cell crosstalk through VCAM1 may be a therapeutic target for ameliorating aged blood induced decline in brain function.

That bit about this being brain endothelial cell-specific VCAM1 also explains that bit about not needing to cross the BBB in the New Scientist piece:

While the identity of systemic inhibitory factors from aged plasma are beginning to be elucidated, the question of how and if these factors cross the blood brain barrier (BBB) and act directly on brain tissue to inhibit neurogenesis, or whether they act through their direct contact with brain endothelial cells (BECs) of the vasculature remain unanswered. BECs upregulate expression of vascular adhesion molecules as a result of increased systemic inflammatory signaling resulting from multiple diseases that afflict the CNS. We discovered that BEC-specific VCAM1 increases in the hippocampus during normal aging. Exposure of young BECs to an aged systemic environment induces BEC activation and upregulation of VCAM1 both in vitro and in vivo.

So, possibly not even a factor directly borne in the blood (tho' there has to be something - or a mixture of things - upstream, of course). Cf. the similar story on B2M in the recent Rebo-Conboy report, which shows no increase in circulating B2M in aged blood but that exposure to same induces the young animal to generate more, to its detriment.

This is consistent with evidence of an inflamed BBB in aged brain, and with this being a Bad Thing for all kinds of reason, including making it more permeable to the systemic circulation and inhibiting Abeta efflux.

But first they need to replicate the result in real, normally-aging, WT rodents. And as ever, better to repair the damage at the root of it all, but clearly a lot less risky than shooting oneself up with putative youth juices.

Posted by: Michael at January 17th, 2017 5:14 PM

If there is something bad in old blood then removing it should atleast slow down aging.

Posted by: RS at January 18th, 2017 6:32 AM

warfarin helps too

Posted by: steve at January 12th, 2018 1:35 PM

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