Stem Cell-Derived "Young" Immune Cells Reverse Alzheimer's and Aging Signs in Preclinical Study

Researchers at Cedars-SinaiView company profile have developed "young" immune cells from human stem cells that successfully reversed signs of aging and Alzheimer's disease in mouse brains, according to findings published in Advanced Science. The preclinical study demonstrates that these laboratory-manufactured cells improved cognitive function and preserved critical brain structures associated with learning and memory.

Breakthrough in Stem Cell-Based Neurotherapy

The research team, led by Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute, addressed a key limitation in previous aging research. "Previous studies have shown that transfusions of blood or plasma from young mice improved cognitive decline in older mice, but that is difficult to translate into a therapy," Svendsen explained. "Our approach was to use young immune cells that we can manufacture in the lab—and we found that they have beneficial effects in both aging mice and mouse models of Alzheimer's disease."

The cells in question, known as mononuclear phagocytes, normally travel through the body clearing harmful material, though their effectiveness declines with age. To generate younger versions of these cells, the team reprogrammed human adult cells into induced pluripotent stem cells, which can be reset to an early embryonic state. From these, they produced new mononuclear phagocytes and infused them into aged mice and mice with Alzheimer's-like disease.

Significant Cognitive and Structural Improvements

Mice given the young cells performed significantly better on memory assessments compared with untreated mice. They also retained higher numbers of "mossy cells" in the hippocampus, a brain structure essential for learning and memory.

"The numbers of mossy cells decline with aging and Alzheimer's disease," said Alexendra Moser, PhD, a project scientist in the Svendsen Lab and lead author of the study. "We did not see that decline in mice receiving young mononuclear phagocytes, and we believe this may be responsible for some of the memory improvements that we observed."

Additionally, mice receiving the young mononuclear phagocytes had healthier immune cells, called microglia, in their brains. These microglia use long, thin branches to detect and clear debris and damaged cells. The branches shrink and retract due to aging and Alzheimer's disease, but they remained long and healthy in mice receiving the therapy.

Indirect Mechanism of Action

The mechanism behind the effects in the brain remains to be established. As the young mononuclear phagocytes did not appear to enter the brain, investigators believe the cells may have worked indirectly. The cells could have released antiaging proteins or even tiny particles called extracellular vesicles, which are small enough to enter the brain. Alternatively, they could have absorbed pro-aging factors from the blood to keep them out of the brain.

Clinical Translation Potential

The mechanism of protection is the focus of ongoing studies to determine the most effective way to turn these findings into a therapy that could be used in a clinical trial in patients. "Because these young immune cells are created from stem cells, they could be used as personalized therapy with unlimited availability," said Jeffrey A. Golden, MD, executive vice dean for Education and Research. "These findings show that short-term treatment improved cognition and brain health, making them a promising candidate to address age- and Alzheimer's disease-related cognitive decline."

The work was supported by the Universal Sunlight Foundation, the Cedars-SinaiView company profile Center for Translational Geroscience, and the Cedars-Sinai Board of Governors Regenerative Medicine Institute.