Sooraj Shah ’24
Aging is a natural process by which cells are progressively unable to divide as efficiently as before, causing cell death and lysis as the functions of the cell slowly begin to decline. The main contributor to this are the telomeres at the end of our chromosomes. Telomeres get shorter as cells divide because replication cannot copy the “lagging end” of the chromosome. However, regenerative biology is an area rapidly progressing to find a way to repair and replace old cells in order to combat aging. In 2007, a method called Yamanaka programming, which turned normal cells into stem cells that could take on any biological function over a course of 50 days, was a center of great attention for age related cell repair. A study led by Dr. Diljeet Gill, a former Ph.D. student at Babraham Institute’s epigenetics research program, focused on improving the efficiency of this method by shortening the growth period. Gill used a new method called maturation phase transient reprogramming or MPTR, which stops the reprogramming of cells before they reach maturation.
For the study, dermal fibroblast cells from donors aged 38-53 were utilized. The cells were regularly checked for mycoplasma infection, in order to prevent contamination. Four Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc) were inserted into the fibroblast cells, which made the cells temporarily lose their ability to express fibroblastic genes. Cells were then cultured and monitored over a short period of 17 days to see if the cells recovered their fibroblast identity.
The results showed that MPTR caused a temporary loss of identity but gradually regained their fibroblast qualities. This observation was found using the epigenetic clock, which is a way to determine the age of cells by counting how many methyl groups are attached to DNA molecules. In conjunction with the epigenetic clock, analysis of the transcriptome (genes expressed from an organism) found that comparison with baseline cells 30 years younger showed similarities. This can be supported by the observed reverse-regulation of the APBA2 and MAF proteins, associated with Alzheimer’s disease and cataract formation in old age, respectively. In addition, 13 days of MPTR treatment resulted in optimal rejuvenation in comparison to longer periods of treatment. The study also hinted that using MPTR may be more efficient than pluripotency, which is the differentiation of stem cells into cells with a specified function. Future research will focus on finding the specific genes responsible for this reverse-aging process, eliminating the need for reprogramming, and possibly applying these methods to the treatment of neurological diseases like Alzheimer’s.
- Gill, Diljeet, et al. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming. ELife, 11, (2022), doi: https://doi.org/10.7554/elife.71624.
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