Diseases of human aging have always been difficult to study in the lab. Stem cell technology always had promise, but when scientists reverted a skin cell from an 89-year-old woman back into a stem cell-like state, the cells became young again. Now, a new approach, presented October 8 in Cell Stem Cell, makes it possible to generate and grow cultures of neurons with gene expression reflecting a patient's age.
These aged neurons are ideal for studying the differences between the old and young brain. For example, older neurons were found to have defects in the transport of proteins into and out of the nucleus, a mechanism recently suggested to play an important role in neurodegenerative disorders.
"We describe for the first time that not only the person-specific genetic identity, but also aging-related signatures, can be studied in living human neurons in the laboratory," says senior author Fred Gage of The Salk Institute for Biological Studies. "We expect that the paradigm of direct conversion into age-equivalent cells can be very important for future studies of age-related diseases."
Scientists who research aging in the brain have traditionally relied on animal models such as worms and mice. More recently, they have been able to take cells from patients and turn them into induced pluripotent stem cells (iPSCs) that can be propagated to generate enough brain cells needed for experimental studies. But because iPSCs resemble the earliest stages of embryonic development, the age of the cells that usually come from elderly patients becomes erased, leaving researchers with rejuvenated neurons.
"As researchers started using these cells more, it became clear that during the process of reprogramming to create stem cells the cell was also rejuvenated in other ways," says Jerome Mertens, a postdoctoral research fellow and first author of the new paper.
The scientists collected skin cells from 19 people, aged from birth to 89 years old, and used them to generate brain cells using both the iPSC technique and the direct conversion approach. Then, they compared the patterns of gene expression in the resulting neurons with cells taken from autopsied brains.
In the cells generated using direct conversion, "the neurons we derived showed differences depending on donor age," says Mertens. "And they actually show changes in gene expression that have been previously implicated in brain aging."
Gage notes that the techniques used in this study might also be useful for assessing age-related changes in other tissues such as the heart and the liver.
The study was supported by the G. Harold & Leila Y. Mathers Charitable Foundation, the JPB Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, Annette Merle-Smith, CIRM, the German Federal Ministry of Education and Research, and the Glenn Foundation Center for Aging Research.
Cell Stem Cell, Mertens et al.: "Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects" http://dx.doi.org/10.1016/j.stem.2015.09.001
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