A recurrent theme on this page is the idea that human aging is driven by a combination of proteins circulating in the blood. Blood is not just red cells and white cells; there is the blood plasma which contains thousands of dissolved proteins (and RNAs), signal molecules which regulate all aspects of metabolism, on time scales ranging from minutes to decades. As we get older, the mix of these protein signals changes in ways that are relatively subtle, with less of some proteins and more of others. It has been pretty well established that the mix of proteins is characteristic of your age. My bet is that the mix of proteins actually determines your age, in the sense that changing the blood plasma of an old person to that of a young person will, to a significant degree, transform the metabolism toward a younger state.

The promise of this work came to prominence in parabiosis experiments with mice, beginning about 2005 out of Stanford. Old mice were surgically paired with young mice, so their circulation was tied together. The old mice become younger and the young mice became older. In the intervening years, we have learned that blood plasma (no cells) from young animals has a rejuvenating effect on old animals.

But giving old people frequent transfusions from young donors sounds like an experimental procedure for aging tycoons, not a practical plan for population-wide life extension. Alternatively, to reproduce the full suite proteins in young blood artificially is a daunting task. Are all the proteins necessary for rejuvenation, or, perhaps, might the same success can be achieved with just a small number of proteins? Some would be added, others effectively subtracted from the blood by blocking their receptors with an inhibitor.

So the race is on to find candidates for proteins in the blood that could be part of this small subset, a handful of proteins that might, if we’re lucky, stand in for the thousands whose concentrations change with age. The Stanford students from 2005 have graduated and now have labs of their own at Berkeley and Harvard In the last few years, Mike and Irina Conboy of Berkeley identified oxytocin as a key protein, and Amy Wagers at Harvard identified GDF11, both proteins that we lose with age, and concentrations might be beefed up for rejuvenation. Oxytocin is holding up; there is controversy about GDF11.

But more effective than adding “youth factors” to old blood may be removal of pro-aging factors. This was the preliminary finding put out by the Conboys a few months ago. Right around this time, from the lab of Tony Wyss-Coray at Stanford, came the first report of anti-aging benefits from blocking a circulating protein. VCAM-1 is a protein that increases with age, but has not previously been identified as a bad actor of primary import. The “CA” in the middle of VCAM stands for cell adhesion, an essential cell function which in itself is not good or bad. Cells stick together for many reasons. But VCAM-1 has been loosely linked in the past to cardiovascular disease and to arthritis.

Hanadie Yousef, a post-doc at Wyss-Coray’s Stanford lab, presented preliminary results at a Neuroscience meeting in November, indicating that

VCAM-1 increases by only about 30% in blood of the elderly, but this is enough to make a difference.

Higher levels of inflammation and lower nerve growth in brains of older mice were linked to VCAM-1

An antibody that binds to VCAM-1 and pulls it out of circulation was successfully used to prevent these effects. Inflammation and nerve growth were both restored to levels typical of young mice.

Of course the findings are preliminary, and yet unpublished [Yousef abstract]. No anti-aging has been demonstrated in normal, living mice, but the benefit of intravenous antibody injections has been demonstrated in mice that are served up artificially with too much VCAM-1, and the molecular mechanism has been validated in cell cultures.

I find it promising that the research is being done on brain function. The central timekeeper that coordinates change in blood chemistry through a lifetime has not yet been identified, but neuroendocrine regions of the brain are a promising place to look for it. Human clocks are built on feedback loops, and if evolution’s engineering immitates human arts, then we might look for an epigenetic aging clock based on secretions from the brain that feed back to act indirectly on the brain.

Other blood proteins that increase with age, and which presumably could be targets for antibody therapies include the pro-inflammatory signals NFkB and TGF-ß, also the reproductive hormones LH and FSH.

I believe that the work of these three groups is the best prospect we have for powerful human anti-aging interventions in the medium term. In the short term, I think that senolytic agents will be the Next Big Thing. In the long term, we will learn how to reprogram our epigenetics. For the next decade or two, keep an eye on ciculating blood signals

Three previous posts with background on this subject:

How does the body’s hormonal signaling change with age?

Signal molecules in the blood: what do we have too much as we age?

Signal molecules in the blood: what do we lose with age?