Heterochronic parabiosis. credit: Bioscience Technology

Now, all you dirty old men as well as members of the PC Police – relax! I know what your fevered imagination is conjuring up. That’s not what I’m talking about. But before I plunge into a truly fascinating research, let me begin with a personal story.

In my early days as a researcher, I was struck by the phenomenon of thymus involution, meaning that as we age the thymus gland loses its volume, cell number, and function. Turning this statement on its head, could it be that as a consequence of thymus loss of function we undergo the aging process? The implication of that could be profound: aging may not be an unavoidable process if we could only keep the thymus gland fully functional.


The function of the thymus

The thymus has an important function: it is responsible for the “education” of T lymphocytes, a critical component of the immune response, to recognize “self” from “non-self,” thus endowing us with defense against foreign invaders, like parasites, bacteria, and viruses, while avoiding destruction of “self” tissues (autoimmunity). To test this hypothesis I selected a short-lived strain of mice (AKR strain) and periodically grafted thymus from young mice into the aging mice. There was only a slight problem: most of the older mice succumbed to the anesthesia; only about 5% survived, but they actually had a longer life span, and their T cell function was youthfully intact. It was impractical to pursue this research with such a high mortality, so I just moved on, abandoning this line of investigation.


New research

You can imagine my satisfaction when I read a Nature article by Amy Wagers and Irving Weissman of Stanford in which they hooked up young mice to old mice and rejuvenating the old mouse livers. A factor in the young blood prompted liver stem cell proliferation in the oldsters. Hooking up two blood circulations is called parabiosis, and when animals of two different ages are involved it is called heterochronic. This heterochronic parabiosis experiment wasn’t a one-off.

Amy Wagers, now at Harvard, followed up with a paper titled Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy showing that the pathological changes of the aging heart, such as thickening of the cardiac walls, are reversed by heterochronic parabiosis, and that the factor responsible for this effect is called DGF-11.

If that’s not exciting enough, read on.

One of the processes that slow down in aging is re-myelination. The axons (long branches) of our neurons are wrapped in a myelin sheath. This sheath serves as an insulator and ensures the rapid transmission of the electrical pulses traveling along the axon. When an axon is demyelinated, as occurs in aging, transmission is slowed down. In multiple sclerosis such de-myelination fails to repair itself, hence the loss of neurological functions characteristic of this disease.
In a January paper in Cell Stem, Wagers tackled the central nervous system. Here are the highlights of the paper, in the authors’ words:
“Remyelination is a regenerative process in the central nervous system (CNS) that produces new myelin sheaths from adult stem cells. The decline in remyelination that occurs with advancing age poses a significant barrier to therapy in the CNS, particularly for long-term demyelinating diseases such as multiple sclerosis (MS). Here we show that remyelination of experimentally induced demyelination is enhanced in old mice exposed to a youthful systemic milieu through heterochronic parabiosis. Restored remyelination in old animals involves recruitment to the repairing lesions of blood-derived monocytes from the young parabiotic partner, and preventing this recruitment partially inhibits rejuvenation of remyelination. These data suggest that enhanced remyelinating activity requires both youthful monocytes and other factors, and that remyelination-enhancing therapies targeting endogenous cells can be effective throughout life.”

How is demyelination/re-myelination regulated?

By the old Ying and Yang principle: blood macrophages and CNS oligodendrocytes, which are CNS cells whose function is similar to macrophages, are made up of two sub-populations: M1 are pro-inflammatory and M2 are anti-inflammatory. When the two populations are in balance -the myelin sheath is regenerated as soon as it is destroyed. When M2 is getting weaker, demyelination is slowed down (as in normal aging). When M2 is severally affected -the lesions fail to repair, as in multiple sclerosis.
I am sure you can readily see the implications of this work. If your vision of the future is “rejuvenation salons” or “heterochronic parabiosis clinics” where you get hooked up to a young specimen (male or female, your choice), I hate to disappoint. But if you see future drugs designed to mimic the action of GDF-11 to keep your heart young, or drugs that stimulate M2 oligodendrocytes to repair the lesions of MS, your vision of the future is right on. Which raises the question whether we really need or want a bunch of retired youthful oldsters clogging our beaches and coffee houses. But this is a subject for another day.
Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.


  1. Great article, but you may have one mistake. Oligodendrocytes don’t have macrophage like functions, so I believe you meant to write microglia. This article is exactly what I was looking for, thanks!


Please enter your comment!
Please enter your name here

This site uses Akismet to reduce spam. Learn how your comment data is processed.