Review of Nature paper: stem cell exosomes on the brain and aging

Is there a stem cell connection between the brain and aging?

Could a type of brain stem cell or the exosomes it secretes control whole body aging?

A recent big Nature article from the lab of Dongcheng Cai argues an emphatic “Yes” to these questions, at least in mice. In the Zhang, et al paper, entitled “Hypothalamic stem cells control ageing speed partly through exosomal miRNAs”, their team reports the claim that a narrow population of hypothalamic stem cells are directly fighting aging of the entire murine body via a mechanism involving exosomes, the brain and aging.

It’s a wildly exciting idea on many levels, but as with all such grant hypotheses, extraordinary evidence is needed to back it up. Does this paper have that level of evidence? So far I’m not convinced the research is there yet, but this team did a ton of work to support their big hypothesis.

What did they do to support their idea?

The paper first takes away those key stem cells in the brain and looks for what happens. It argues that via a thymidine kinase-based ablation of these hypothalamic stem cells, that they are necessary in the brain to maintain all kinds of bodily functions such as healthy skin. That is possible, but it’s a huge claim.

They also argue that these brain stem cells are required for many other things as the hypothalamic stem cell-ablated “mice displayed accelerated decreases in muscle endurance, coordination, treadmill performance, sociality and novel object recognition.” And some of these changes are giant in magnitude so if the authors are right about this then this is a rather giant discovery. In fact, in Figure 2n they report that mice lacking these brain stem cells die much younger than control mice. Some experiments were repeated using diphtheria toxin as well.

The first thing that crossed my mind when I read this part of the paper on the pleiotropic effects of hypothalamic stem cell depletion was the question, “Could their model system of toxic ablation of these cells have been somewhat leaky and led to more widespread toxic effects in other parts of the body?” Aberrant presence of toxin elsewhere could accelerate overall body aging and seems like a simpler mechanism that removing a small population of cells in the brain. There is evidence that the Sox2 gene (used to ideally target only the hypothalamic stem cells of the brain via virus in this paper) is expressed and important elsewhere including in skin. They did look at some other types of neurons in the brain and didn’t see effects in the ablation system. Also in support of their conclusions, they only injected their virus into a specific region of the brain so how would it have gotten to skin, muscle, etc.?

In additional support of the authors being on the right track with their specific hypothesis, they went beyond the ablation approach to test conversely what would happen if “young” hypothalamic stem cells were implanted into the region of the hypothalamus in aging mice. They reported that the stem cell transplant had the opposite effects of the toxin experiment. The transplants improved cognition, locomotion, and other performance of these mice, and the mice lived about 100 days longer than controls (see Figure 3d above).

If reproducible this is a tremendously important finding. These results are so amazing that they make me feel initially skeptical, but technically in the paper what is there to be skeptical about how this work was done? Not that much.

Unless I missed it they could have looked for their virus elsewhere and looked for the toxins and cell death elsewhere in the body. There are probably other things they could have done, but they did quite a mountain of work already. One thing to keep in mind here was that the stem cells used for these transplants were modified. These so-called IκBα-htNSCs have supercharged ability to engraft as described in the paper:

“Therefore, we asked whether inhibition of the inflammatory response in these cells might help to overcome this survival problem. To do so, we used htNSCs derived from newborn mice that stably expressed dominant-negative IκBα and GFP (IκBα-htNSCs). We have previously shown that these cells are resilient to NF-κB-mediated inflammation, compared to control htNSCs that stably expressed GFP (control-htNSCs)¹⁹.”

The rest of the paper is devoted to defining mechanisms of the anti-aging effect of the hypothalamic neural stem cells and the authors attribute it to exosomes and in particular exosomal miRNAs. Figure 6 reports the astounding finding that infusion of these exosomes alone (no cells) into the brains of mice had dramatic effects on many aspects of nervous system function, locomotion and more.

Are exosomes the main connection between the brain and whole body aging?  Could there be some other mechanism at work besides exosomes? Wouldn’t the stem cells in question also have positive effects via neurogenesis? Is this mechanism at “work” in human brain and aging?

This Nature paper is onto something and again it seems generally technically sound on first look, but the effect sizes on the whole organism attributable reportedly to such specific cells and sub cellular mechanisms again seem extraordinary to me. Will others be able to reproduce the phenomenal phenotypes described here attributable to these particular brain stem cells and remarkably largely just to their exosomes? I’m as excited as the next cell biologist about exosomes, but this particular finding seems of a rather mind-boggling magnitude.

The wildly risky, clinical extrapolation some may take from the current Nature paper reminds me somewhat of the whole “young blood” anti-aging narrative that is still bouncing around that invoked imagery of rich old folks getting the blood of young people to try to fight aging. You can pay $8,000 to participate in Jesse Karmazin’s biotech Ambrosia’s controversial trial to get young blood.

Will we start seeing Silicon Valley tycoons or aging politicians getting “young” exosomal infusions into their brains at $5 million a pop?

The brain definitely impacts aging and maybe these cells and their exosomes are major players, but let’s be sober about just one paper.