Imagine a pill that perks up “old” brain and muscle tissue

Whether you’re the one with the brain or the brawn, there’s good news from the science front. Researchers at the University of California, Berkeley, have discovered that a small-molecule drug, which is currently undergoing trials as an anti-cancer agent, perks up old stem cells in the brains and also in the muscles of mice.

The finding could lead to treatment for humans that would make ageing tissues throughout the body act young again.

“We established that you can use a single small molecule (called an ‘Alk5 kinase inhibitor’) to rescue essential function in not only aged brain tissue but aged muscle,” said David Schaffer, director of the Berkeley Stem Cell Center and a professor of chemical and biomolecular. “That is good news, because if every tissue had a different molecular mechanism for ageing, we wouldn’t be able to have a single intervention that rescues the function of multiple tissues.

Ageing is partially caused by the failure of adult stem cells to generate replacements for damaged cells and repair the body’s tissues. Researchers have shown 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 ageing.

Last year, doctors began a small trial to determine whether blood plasma from young people could help reverse brain damage in elderly Alzheimer’s patients. As this kind of therapy is impractical beyond the lab, 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 Conboy showed depresses stem cell activity when present at high levels.

“Based on our earlier papers, the TGF-beta1 pathway seemed to be one of the main culprits in multi-tissue aging,” said Irina Conboy, an associate professor of bioengineering. “That one protein, when upregulated, ages multiple stem cells in distinct organs, such as the brain, pancreas, heart and muscle. This is really the first demonstration that we can find a drug that makes the key TGF-beta1 pathway, which is elevated by aging, behave younger, thereby rejuvenating multiple organ systems.”

Five years ago, Schaffer, who studies neural stem cells in the brain, teamed up with Conboy to look at TGF-beta1 activity in the hippocampus, an area of the brain important in memory and learning. Among the hallmarks of aging are a decline in learning, cognition and memory. In the new study, they showed that in old mice, the hippocampus has increased levels of TGF-beta1 similar to the levels in the bloodstream and other old tissue.

When the team inserted genetic blockers into the brains of old mice to knock down TGF-beta1 activity, they found that hippocampal stem cells began to act more youthful, generating new nerve cells.

The team then injected into the blood the Alk5 kinase inhibitor molecule, known to block the TGF-beta1 receptor and thus reduce the effect of TGF-beta, which successfully renewed stem cell function in both brain and muscle tissue of the same old animal, potentially making it stronger and more clever, Conboy said.

“You can simultaneously improve tissue repair and maintenance repair in completely different organs, muscle and brain.”

This is only a first step toward an actual drug therapy as there are other biochemical factors involved in adult stem cell activity that need to be addressed. But the researchers are now collaborating to find a way to restore stem cell responses in multiple aged and pathological tissues.

“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,” Conboy said. “Dosage is going to be the key to rejuvenating the stem cell environment.”

Source: University of California Berkeley

Tell us, if you had to choose, would you go with brain, brawn or both?