The by-now famous experiments that have tied the circulations of young and old animals together, showing the rejuvenating effects of “young blood”, have also shown that the harmful effects of old blood may be greater than the rejuvenating effects of young blood. There’s something about old blood — likely many things — that cause a young animal to show signs of aging; I’ve speculated that two of the more important factors might be iron and bacterial lipopolysaccharides — or possibly the bacteria themselves. Here we’ll discuss the links among young blood, aging, and iron.
Of course, other elements in old blood differ in quantity from those in young blood, and scientists are studying a number of candidates that take the form the form of proteins, as Josh Mitteldorf discusses in his latest article. (See my review of Josh’s book, Cracking the Aging Code.) One of the proteins under investigation is VCAM-1, for vascular cell adhesion molecule, the level of which increases in old blood.
Exposure of young animals to old blood increases the expression of VCAM-1.
Studies from our lab and others have recently shown that brain function – specifically neurogenesis, synaptic plasticity and cognitive function in the hippocampus, a key center for learning and memory– is inhibited in young mice connected to aged mice through heterochronic parabiosis or aged plasma intravenous injections…. BECs [brain endothelial cells] 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. Specifically, systemic injections of aged human blood into young immunodeficient (NSG) mice- acutely over 4 days or spread over 3 weeks- increased BEC-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 preventing BEC-immune cell crosstalk through VCAM1 may be a therapeutic target for ameliorating aged blood induced decline in brain function.
To decipher: old blood injected into young mice → brain inflammation and ↑VCAM-1 production. Blocking VCAM-1 with an antibody abolished this effect, showing that VCAM-1 is the culprit, or one of them, in brain inflammation.
But, what is it about old blood that causes an increase in VCAM-1 expression?
These data suggest that iron plays a critical role in TNFα mediated VCAM-1 induction in HDMEC [human dermal microvascular endothelial cells], and the target for iron effects may be IRF-1, NF-kB, and potentially chromatin remodeling.
Iron could be one of the main factors in old blood that causes inflammation and damage.
NF-kappa B is another molecule that’s been suggested as a pro-aging factor in old blood; it’s a master regulator of factors that increase inflammation, which is a key characteristic of aging.
These results demonstrate that the iron chelator effectively blocks NF-kappa B activation and coordinate TNF-alpha and IL-6 gene upregulation by HM [hepatic macrophages] in cholestatic liver injury or under in vitro lipopolysaccharide stimulation. These findings support a pivotal role for iron in activation of NF-kappa B and cytokine gene expression by HM in vitro and in vivo.
Iron satisfies a few other requirements for evidence of being involved in aging:
Here we have an element, iron, which looks to me like a prime candidate in aging promotion. Why aging researchers generally don’t see this, I don’t know, but possibly iron just isn’t a sexy topic. Or, I could be wrong, but obviously I doubt it.
I’ll just leave you with one other item of interest.
Restored Vulnerability of Cultured Endothelial Cells to High Glucose by Iron Replenishment. When endothelial cells are serially cultured, they lose their sensitivity to damage by high glucose, which is normally toxic. It turns out that serial culturing causes them to lose their iron, to a level only 10% that of normal. When the cells were incubated with iron, they took it up, their iron levels were restored to normal, and high glucose once again became toxic to them.