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Longevity Briefs: Can This Small Molecule Reverse Ageing?

Posted on 13 June 2023

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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.

Why is this research important: Cellular reprogramming is a way of turning specialised cells, such as muscle or brain cells, into unspecialised stem cells with the ability to become many different types of cell. Scientists can reprogram cells in a dish using four special factors called Yamanaka factors. Yamanaka factors not only turn specialised cells into stem cells, but also rejuvenate them, essentially turning old cells young again. It is possible to rejuvenate a cell without turning it into a stem cell by exposing it to Yamanaka factors for only a brief period of time. Scientists think this might one day allow us to reverse ageing, but we cannot simply give Yamanaka factors to living humans – we will need to create molecules or gene therapies to activate the production of Yamanaka factors by our own cells.

What did the researchers do: In this study, researchers used high-throughput screening techniques to search for small molecules that could activate OCT4, one of the four Yamanaka factors necessary to reprogram cells. Such small molecules have been identified in the past, but none of them are capable of fully activating OCT4. By studying how these molecules were being metabolised by cells, the researchers attempted to engineer a small molecule that would be a more effective activator of OCT4. 

Key takeaway(s) from this research:

  • Researchers identified a group of small molecules called O4I2s that were able to activate OCT4
  • Based on these compounds, researchers created a more stable molecule called O4I4
  • O4I4 was able to fully activate OCT4 and reprogram human fibroblasts in the presence of the three other Yamanaka factors
  • O4I4 alone extended average and maximum lifespan in worms and fruit flies
The effects of O4I4 on lifespan in C.elegans worms (left) and fruit flies (right). Some flies received O4I4 throughout life, while others were only treated for part of their lifespans.
Development of a next-generation endogenous OCT4 inducer and its anti-aging effect in vivo

The researchers identified a group of OCT4 activators called O4I2s (OCT4-inducing compounds 2). By altering these molecules to make them more stable, they were able to create a compound that would be more resistant to breakdown by the cellular metabolism – they called this compound O4I4. They then took human cells called fibroblasts that had been genetically engineered to express the three Yamanaka factors besides OCT4, and exposed them to O4I4. This was enough to reprogram the fibroblasts into stem cells, suggesting that O4I4 can fully activate OCT4.

They then tested whether O4I4 had an effect in animal models. They found that O4I4 increased both average and maximum lifespan in C.elegans worms (about 45 worms per group) and in fruit flies (about 300 flies per group), though was less effective in the latter. So long as fruit flies received O4I4 in early adulthood, their average lifespan increased by about 5%, and the longest living flies lived about 10% longer in the O4I4 group than in the control group. Flies that received O4I4 in late adulthood, however, received no significant benefit. The researchers also repeated these experiments with O4I2s (the unmodified, less stable molecules that were first identified) and found no significant benefit on lifespan.

So, it seems like we now have the first small molecule that can fully activate OCT4, potentially delaying the ageing process and extending lifespan. The advantages of such a molecule over genetically manipulating a cell to express OCT4 are numerous, but we are still a long way from being ready to test this kind of therapy in humans. This and other similar molecules will be used to generate stem cells for regenerative medicine long before humans are taking them for anti-ageing purposes.

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    Development of a next-generation endogenous OCT4 inducer and its anti-aging effect in vivo

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