Putting Old Stem Cells Back to Work: Another Drug Target Emerges From Parabiosis Research

Heterochronic parabiosis is one of the research success stories of recent years. By linking the circulatory systems of an old and a young individual, usually laboratory mice, researchers have learned that levels of signal proteins circulating in blood and tissue change with age, and that these signals are the proximate cause of a great deal of the characteristic decline in stem cell activity that occurs with aging. The full story likely involves reactions to low-level cell and tissue structure damage that in turn change the balance of proteins generated and circulated, and stem cells react to this information by damping down their activity.

The consensus view in the research community is that this and other similar changes over the course of aging exist because they reduce the risk of cancer. Cancer is a game of chance, awaiting the right combination of mutations and cell damage. The more that damaged cells undertake activity such as replication then the higher the odds of spawning the seeds of a tumor. But if cells, and stem cells in particular, are less active then tissues and organs malfunction and weaken. Life span then is an evolved balance between death by cancer on the one hand and death through loss of tissue maintenance on the other, with natural selection favoring a balance that achieves a life span that produces success for the species in its niche.

The stem cell and parabiosis fields of research have produced a range of ways to spur greater activity in old and damaged cell populations. Many forms of simple stem cell transplant appear to work because the transplanted cells deliver signals that instruct native cells to be more active, for example. Interestingly, these lines of work have largely shown much less of a cancer risk in the laboratory and the clinic than was expected at the outset. It may well be that the evolved balance in mammals can be favorably adjusted towards greater stem cell maintenance of tissues, and extended healthy life as a response, but it is still a little early to be more than modestly optimistic on this front, I think. A way to activate dormant stem cells doesn't do much at all to revert the levels of cellular and molecular damage that cause aging. It only partially solves one problem, the diminished numbers in useful and necessary cell populations. Beyond that there are metabolic wastes inside and outside cells, lingering senescent cells, high levels of stochastic DNA damage, cells taken over by malfunctioning mitochondria, and more. Aging is a lot more than just stem cell dysfunction.

There was considerable excitement over the last drug target to emerge from parabiosis research, GDF-11. Increased levels of GDF-11 in the bloodstream put stem cells back to work in old mice and produced meaningful benefits in measures of health. This latest research is similar in nature, but involves a very different mechanism, possibly connected to regulation of chronic inflammation and its effects on stem cell activity:

Drug perks up old muscles and aging brains

Aging is ascribed, in part, to the failure of adult stem cells to generate replacements for damaged cells and thus repair the body's tissues. Researchers have shown that this decreased stem cell activity is largely a result of inhibitory chemicals in the environment around the stem cell, some of them dumped there by the immune system as a result of chronic, low-level inflammation that is also a hallmark of aging.

In 2005, researchers infused old mice with blood from young mice - a process called parabiosis - reinvigorating stem cells in the muscle, liver and brain/hippocampus and showing that the chemicals in young blood can actually rejuvenate the chemical environment of aging stem cells. Last year, doctors began a small trial to determine whether blood plasma from young people can help reverse brain damage in elderly Alzheimer's patients. Such therapies are impractical if not dangerous, however, so researchers are trying to track down the specific chemicals that can be used safely and sustainably for maintaining the youthful environment for stem cells in many organs. One key chemical target for the multi-tissue rejuvenation is TGF-beta1, which tends to increase with age in all tissues of the body and which depresses stem cell activity when present at high levels.

Researchers showed that in old mice, the hippocampus has increased levels of TGF-beta1 similar to the levels in the bloodstream and other old tissue. Using a viral vector developed for gene therapy, the team inserted genetic blockers into the brains of old mice to knock down TGF-beta1 activity, and found that hippocampal stem cells began to act more youthful, generating new nerve cells. The team then injected into the blood a chemical known to block the TGF-beta1 receptor and thus reduce the effect of TGF-beta1. This small molecule, an Alk5 kinase inhibitor already undergoing trials as an anticancer agent, successfully renewed stem cell function in both brain and muscle tissue of the same old animal, potentially making it stronger and more clever. "The challenge ahead is to carefully retune the various signaling pathways in the stem cell environment, using a small number of chemicals, so that we end up recalibrating the environment to be youth-like. Dosage is going to be the key to rejuvenating the stem cell environment."

Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age. Exploring the hypothesis that youthful calibration of key signaling pathways may enhance regeneration of multiple old tissues, we found that systemically attenuating TGF-β signaling with a single drug simultaneously enhanced neurogenesis and muscle regeneration in the same old mice, findings further substantiated via genetic perturbations.

At the levels of cellular mechanism, our results establish that the age-specific increase in TGF-β1 in the stem cell niches of aged hippocampus involves microglia and that such an increase is pro-inflammatory both in brain and muscle, as assayed by the elevated expression of β2 microglobulin (B2M), a component of MHC class I molecules. These findings suggest that at high levels typical of aged tissues, TGF-β1 promotes inflammation instead of its canonical role in attenuating immune responses. In agreement with this conclusion, inhibition of TGF-β1 signaling normalized B2M to young levels in both studied tissues.

Comments

Irina and Michael do excellent work and have helped track down a number of key pathways which when combined could significantly effect aging. It is still early days but in time it will lead to greater understanding of aging and interventions.

Posted by: Steve H at May 14th, 2015 3:29 AM

IMPORTANT: BMP-7 (bone morphogenetic protein 7) is an inhibitor of TGF-B1. Recently, news came out about an as-of-yet unnamed drug that inhibits TGF-b1, a major cause of aging and suppression of stem cell growth, mentioned in the article above.

BMP-7 seems to have incredible benefit in light of this TGF-b1 inhibition, as well as the ability for BMP7 to assist in kidney health, osteoblast activity, and brown fat activation/promotion of brown fat (BAT).

Posted by: Friend at May 14th, 2015 11:44 AM

CORRECTION: In my comment above I assert that BMP-7 is an inhibitor of TGF-b1. I actually don't know if that's true. However, sodium butyrate is an inhibitor of TGF-1 and will promote BMP-7 levels.

Posted by: Friend at May 14th, 2015 12:55 PM

Correction 2: Pirfenidone most likely doesn't inhibit ALK5. GW788388 is most likely the small molecule alluded to, as it inhibits TGF-b1, TGF-b2, ALK5, etc.

Posted by: Friendo at May 14th, 2015 1:10 PM

Further progress in the understanding of Epigenetic re-programming which Irina and Michael are basically doing. Synthetic in this case but opens the door to further understand cellular programming.

http://www.nanowerk.com/news2/biotech/newsid=40085.php

Posted by: Steve H at May 15th, 2015 7:38 AM

If you look in the experimental procedures, then you will see the following:

Aged (24 month old) C57BL6/J male mice were injected intraperitonially (IP) with TGF-β1 Type I Receptor Kinase Alk5 inhibitor 2-(3-(6-Methylpyridin-2-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine (Enzo Life Sciences) diluted in sunflower seed oil to a concentration of 57.4 μM.

http://www.enzolifesciences.com/ALX-270-445/alk5-inhibitor-ii/

This molecule has a different CAS # and is structurally different than GW788388.

Posted by: aaron at May 15th, 2015 11:09 AM

Aaron thank you I wish my previous comment would be deleted in regards to naming that other drug. All my comments, even. In addition, that drug's company had acknowledged a conflict of interest. There's also a number of different inhibitors of both TGF-1b and ALK5. I apologize.

Posted by: friendo at May 17th, 2015 9:44 AM

there have been reports that modified citrus pectin will "inhibit" TGF-beta. I don't have a reference readily available.

Posted by: Patrick Stanley at July 12th, 2015 9:41 AM

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