Longevity Briefs: A Breakthrough For Rewinding The Ageing Clock?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

‘Resetting’ the ageing process in human cells is not actually that hard. Expose a cell to the four Yamanaka factors (aka reprogramming factors), and age-related epigenetic changes (modifications to the DNA that affect which parts are expressed and to what extent) will be reset, reverting the cell to a younger state. This process also happens naturally in reproductive cells and is the reason that biological age is reset at each generation. Unfortunately, epigenetic alterations also determine cellular identity – they are what make heart, brain and kidney cells different despite containing the same genetic material. If we want to use epigenetic reprogramming to reverse ageing in humans, we need to separate these two components – otherwise target cells will revert to being stem cells.

Carefully controlling the level of exposure to Yamanaka factors can allow for cells to be rejuvenated without completely reprogramming them (this is called partial reprogramming), but doing this for human tissues and organs is challenging and potentially dangerous. Ideally, we would identify the individual pathways that Yamanaka factors affect, and single out those responsible for epigenetic rejuvenation specifically.

The discovery:

In this preprint study, researchers claim to have identified a single gene that can rejuvenate cells with similar efficacy to Yamanaka factors. They call their gene intervention SB000, but do not reveal which gene was targeted as this research was conducted by a corporate group.

To identify the gene, researchers developed a new machine learning algorithm to measure cellular rejuvenation based on the transcriptome (how the DNA is expressed), rather than epigenetic changes (which alter DNA expression). This allowed them to screen for pathways related to epigenetic rejuvenation with much higher throughput. After identifying SB000, they used a viral vector to express it in two types of human cell: fibroblasts (which lay down the molecular ‘mesh’ that holds tissues together) and keratinocytes, which produce keratin in the skin. They found that SB000 expression rejuvenated both cell types, at least in terms of epigenetic and transcriptomic age, and also reduced the expression of some genes associated with senescence (the state in which cells can no longer divide). However, SB000 was able to achieve reprogramming without de-differentiation (the identity of these cell types was not altered).

The implications:

This paper hasn’t been peer-reviewed and the identity of the gene in question remains known only to the authors, so it’s too early to get excited. It’s also possible that this method only works well in some cell types. However, if verified, this finding could have significant implications for our progress in the fight against ageing. Activating a single gene in a specific organ or tissue would be a lot easier and safer than trying to tightly control the expression of the four Yamanaka factors within a narrow range. While SB000 will not be the first single gene shown to have this effect, no previous single gene has been able to rival the full rejuvenating effect of Yamanaka factors.