Author: Varsha Pramod Rao
Artist: Irina Pirvu
Editor: Daniel Jacobson
As we all undergo the daunting and inevitable process of ageing, we acquire wear and tear on our genomes, associated with gradual decline and the loss of functioning. Ageing is a complex process with several markers that continue to elude our understanding, yet genetics may offer use for predicting an individual’s age. Age-related changes consist of measurable epigenetic and transcriptomic alterations which can be exploited to accurately predict the chronological age of cells, offering insight into what natural decline may look like.
A method of ‘de- ageing’ cells coined ‘maturation phase transient reprogramming’ (MTPR) by UK researchers including Dr Diljeet Gill of the Babraham Institute involves reversing the age of fibroblasts, a type of skin cell that provides structure to tissues, by 30 years whilst allowing them to retain their identity. It was administered to fibroblasts of middle-aged donors and the cells of younger donors were used to make comparisons. This method is novel because it is the first time that the age of cells has been reversed by so many years and without the loss of function.
This idea of tampering with the developmental clock is not new by any means. Shinya Yamanaka was awarded the Nobel Prize in 2012 for genetically reprogramming mature skin cells in mice to become the famous induced pluripotent stem cells (iPSCs), which are fundamental in the field of regenerative medicine research. These are cells that have been reprogrammed back to their pluripotent state and that are capable of becoming any type of human cell. This was achieved by manually reversing multiple factors, such as telomere attrition and oxidative stress.
MTPR follows the same principle as induced pluripotent stem cell reprogramming and utilises the four Yamanaka factors- Oct3/4, Sox2, Klf4, c-Myc, which are molecules that are highly expressed in embryonic stem cells. However, the crucial difference is that iPSC reprogramming takes much longer and is characterised by a loss of function. MTPR enables the cell to retain its original characteristics and behave as it originally would.
The key to the preservation of function is to not subject the cells to complete reprogramming. MTPR exposes the cell to Yamanaka factors for just 13 days until the point of rejuvenation. The cells were subsequently removed and grown in normal conditions, upon which the cells regained fibroblast markers. Thus, a fine balance is struck between restoring the cell’s youthfulness and allowing them to preserve their specialised cell function.
Whilst the mechanism by which this is achieved is not yet completely understood, it was observed that MTPR had positive effects on the APBA2 gene which is associated with Alzheimer’s disease. APBA2 codes for a protein that interacts with the precursor of Alzhemier’s disease called amyloid precursor protein (APP) and stabilises it. Further, the reprogrammed cells have been shown to be better at healing wounds as they produce higher levels of collagen, a property that can have many uses in clinical practice.
Even though this method cannot be used clinically at present, it will have widespread applications, especially if it can be replicated in other cell types. It could be used to potentially identify the genes involved in rejuvenation after which gene therapy can be used to target them directly. Several prolific people, including Bill Gates, have expressed their disapproval, claiming it to be an egocentric endeavour to try to prolong lives when there are infectious diseases that are yet to be eliminated from the more developing parts of the world. However, the wider consensus is that this technique must be harnessed for good, to prolong healthy lives and prevent neurodegenerative diseases that occur with age. Research is proceeding full-throttle to investigate therapeutic applications, albeit with caution. How would these partially reprogrammed cells behave in living organisms? Could there be adverse effects upon injecting these cells into the recipient? Could they be cancerous? There is much to be discovered in this arena but the implications of the discovery are enormous and will lay the foundation for many potential valuable discoveries.
kinesismagazine.com 