Multi-Omic Rejuvenation Turns Back the Clock for Mouse Organs

Scientists from the Cellular Plasticity and Disease lab at the Institute for Research in Biomedicine (IRB Barcelona) have successfully “rejuvenated” mouse organs and tissues via cell reprogramming. By studying molecular marks in DNA, gene expression, and cell metabolism, they were able to observe and reverse some of age-related changes in the pancreas, liver, spleen and blood.

“This work sought to identify the initial processes of in vivo reprogramming and cell rejuvenation and pinpoint those that can be modified in future studies, whether by drugs or at a nutritional level,” says Dr. Manuel Serrano, researcher with IRB Barcelona and Catalan Institution for Research and Advanced Studies (ICREA).

All tissues in our bodies are characterized by having highly specialized cells, such as neurons or muscle cells. The identity of these cells was considered fixed and inflexible until the Nobel Prize-winning researcher Shinya Yamanaka found a way to reprogram them by introducing high levels of four proteins—OCT4, SOX2, KLF4 and MYC (OSKM). Although these proteins, dubbed Yamanaka factors, can be found in some of our cells, it is the simultaneous presence of high levels of all four that can alter cell identity.

Now, a consortium of researchers from 20 institutions led by IRB Barcelona have examined the effects of a single cycle of Yamanaka factor stimulation in order to better define the mechanisms involved. To this end, they have probed the changes in metabolism, gene expression and cellular DNA status that occur during ageing and how these changes are partially reversed by reprogramming.

They found that a single period of transient OSKM expression was sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, they observed reversal of transcriptional changes, especially regarding biological processes known to change during aging. Some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming.

“We wanted to study the initial effects of the rejuvenation process, and it was a pleasant surprise to see such evident improvements at the molecular level, above all in the pancreas,” says Dr. Dafni Chondronasiou, of IRB Barcelona.

Many diseases, including cancer, are associated with ageing and are becoming more prevalent as life expectancy increases. The findings, published recently in the journal Aging Cell, also suggests a method for easy-to-access cells from a patient to be taken and converted into other cells that are difficult or impossible to collect, like heart cells or neurons, that can then be used for cell therapy applications.