Blood magic: old blood ages the young

“Our ancient countess was refused her desires will
To bathe in pure fresh blood
She'd peasant virgins killed

Elizabeth, in the chasm where was my soul
Forever young, Elizabeth Bathorii in the castle of your death
You're still alive, Elizabeth”

-“Elizabeth”, Ghost

As folklore has it, Elizabeth Bathorii, Countess of Hungary, often bathed in young virgins’ blood to keep her beauty and youth. Macabre, no? As repulsive as it sounds, she might actually be on to something.

When we age, our brain gradually looses the ability to give birth to new neurons (neurogenesis). This sad decline is linked to impairments in cognitive functions such as learning and memory. The brain, like any other organ, feeds off of nutrients and chemicals in the BLOOD to keep it going. This made researchers wonder: is something in the blood affecting neurogenesis as we age?

Villeda SA et al (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 447: 90-94

To explore this, researchers hooked up the circulation of young and old mice (with young-young & old-old pairing as control) so that their blood intermixed. This incredibly cool technique, called “heterochronic parabiosis”, has been around for over 150 years. It’s often used to look at circulatory factors in immunology, metabolism and aging.

Yellow is young, grey is old. Looks like an intense surgery!

Several weeks after the surgery, researchers examined the animals’ brains to look for changes in neurogenesis. Young mice, when linked with older mice, had significantly fewer newly born neurons and neural progenitor cells than young-young controls. This impacted their brains’ functionality: fewer neurons fired together after an electrical stimulus, and those that did refused to maintain their enhanced signal transmission for long. In stark contrast, old mice seemed rejuvenated from sharing blood with the young, with dramatically increased neurogenesis and neural stem cells than their old-old counterparts.

Vat is dis magic? Blood!

Further experiments (as pictured above) confirmed blood as the bearer of youth (and aging). Researchers isolated the liquid component (plasma) of young and old mice, and injected it multiple times into young mice. In 10 days, old plasma-receiving mice rapidly aged, showing lower neurogenesis and deteriorated memory. This is amazing, since it suggests that factors in old blood can overcome youth-promoting factors in young blood, ending in an aged phenotype.

The authors then worked some proteomics magic, and isolated a cytokine called CLL11 that seemed to be mediating the “aging” effect. CLL11, an obscure protein in neuroscience, is secreted from the intestine and smooth muscle and mostly involved in the allergic response. CLL11 increased with aging in mice and men, as well as in young mice that have been hooked up to old mice.

Is CLL11 the harbinger of aging? Researchers injected the protein into young mice, and indeed found decreased neurogenesis after 10days. This was blocked if an antibody against CLL11 (which neutralizes it) was also given. So the observations seemed specific to CLL11. This cellular-level decline in brain function paralleled a functional deterioration in memory. As seen below, when dropped into a big mater maze, young mice usually rapidly learn to find a hidden platform that they can rest on (training phase). However, young mice receiving multiple doses of CLL11 gradually forgot the location of their sanctuary, swimming around in circles, trying to find the platform in vain (testing phase - see how CCL11-injected mice make more mistakes?).

CLL11 is clearly promoting brain aging. But maybe the protein isn’t directly inhibiting neurogenesis, instead indirectly affecting the brain through primary effects on the body? In one last experiment, researchers amped up CLL11 in young mice through several abdominal injections. They then specifically neutralized CLL11 in the hippocampus, a part of the brain important for learning and memory. This was sufficient to rescue the decline in neurogenesis, suggesting CLL11 is directly linked to brain aging.

But...but!! No one wants to accelerate aging! What about eternal youth?
Source: SA Villedaa & T Wyss-Coraya (2013). The circulatory systemic environment as a modulator of neurogenesis and brain aging. Autoimmunity Reviews 12 (6): 674–677

 So science is saying old blood can age the young, but what about the other way around? Can young blood slow or stop aging? While premature and unpublished as of now, further studies from these researchers show that blood from the young can rejuvenate old mice, both in terms of neurogenesis and memory. However, they don’t yet know which proteins are driving the effect. In a recent published study, another group used the same “blood-to-blood” technique to identify a blood-borne factor that reversed aging of the heart. Finally, in a study in Nature, researchers identified gonadotropin-releasing hormone (GnRH), a circulating peptide decreased in old age, as an important factor in aging. Giving GnRH supplements to aged mice not only increased neurogenesis, but also slowed WHOLE BODY aging (covered astutely –as always- by Scicurious and Ed Young).

This (obviously) doesn’t give you free reins to hunt down and drink the blood of the young. Not that you would. Or want to. We’re not sure if the same anti-aging effect happens in humans. (However, there are cases of humans drinking human blood, such as “witches” in certain cultures who drink blood as part of rituals and ceremonies. I’d love to know if & how their brains are changed.) But scientists seem optimistic. To quote the study’s lead author: “Do I think young blood could have an effect on a human? I’m thinking more and more that it might.”

Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, & Wyss-Coray T (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, 477 (7362), 90-4 PMID: 21886162

Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, Sinha M, Dall'osso C, Khong D, Shadrach JL, Miller CM, Singer BS, Stewart A, Psychogios N, Gerszten RE, Hartigan AJ, Kim MJ, Serwold T, Wagers AJ, & Lee RT (2013). Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy. Cell, 153 (4), 828-39 PMID: 23663781

Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, & Cai D (2013). Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature, 497 (7448), 211-6 PMID: 23636330