Researchers at UC Berkeley have discovered a small molecule drug that could make aging tissues throughout the body act youthfully once again.
The molecule — an Alk5 kinase inhibitor already undergoing trials as an anti-cancer agent — interferes with the activity of a growth factor called transforming growth factor beta 1, or TGF-beta1. When injected into the blood of old mice, the molecule renewed stem cell function in their brain and muscle tissue.
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 to depress stem cell activity when present at high levels, according to the lead author of the study, Hanadie Yousef, a former UC Berkeley graduate student.
Aging is attributed to the failure of adult stem cells, which generate replacements for damaged cells and thus repair the body’s tissues. The TGF-beta1 pathway is a major factor in the tissue aging process, according to David Schaffer — campus professor of chemical and biomolecular engineering, bioengineering and neuroscience — who supervised the research.
“By correcting the chemical atmosphere around the tissues, the body could be rejuvenated,” Schaffer said.
Five years ago, Schaffer worked with campus assistant professor of bioengineering Irina Conboy to use a viral vector that Schaffer developed for gene therapy. They 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 youthfully, generating new nerve cells.
In the last 10 years, Conboy showed that the growth factor depresses the ability of various types of stem cells to renew tissue. In 2005, Conboy and her colleagues infused old mice with blood from young mice in a process called parabiosis, which reinvigorated stem cells in the muscle, liver and hippocampus, showing that the chemicals in young blood can actually rejuvenate the chemical environment of aging stem cells.
Schaffer said the entire process of the study took about three-and-a-half years to complete.
The next step, according to Schaffer, is tracking down the specific chemicals that can be used safely and sustainably for maintaining the youthful environment of stem cells in many organs, as well as identifying additional signals that would become misregulated with age.
Yousef said that because other biochemical cues also regulate adult stem cell activity, the study is only a first step.
“Right now, the study is more a proof of concepts,” Yousef said. “But people should still be pretty excited that now we’ve found it is possible to hinder processes in aging.”
Schaffer and Conboy’s research groups are collaborating to see which modulation of two key biochemical regulators might lead to safe restoration of stem cell responses in multiple aged and pathological tissues.