Sixty years in 50 days: how we’ll rejuvenate our neurons and better combat Alzheimer’s

Ponce de Leon’s fountain of eternal youth is still a long way off. Let’s not delude ourselves. But that doesn’t stop us from dreaming. Because the idea of turning back the clock on our cells – rolling them back by decades until they are young and fully functional once more – may not be impossible to achieve. At least in the laboratory. In fact, the red blood cell precursors of an octogenarian have been turned back in time and, thanks to reprogramming, have even been transformed into stem cells with a molecular age of under 20. All this in just under two months – 50 days – effectively gaining some sixty years. But that’s not all. There is further confirmation.

The stem cells obtained through this laboratory process can develop into neurons. And this is precisely the most fascinating aspect of the research coordinated by Oliver Brüstle, director of the Institute of Reconstructive Neurobiology at the University Hospital of Bonn and of the University itself, as published in Aging Cell. By reprogramming human cells in a test tube, they can be turned back into ‘infant-like’ cells and thus, thanks to ultra-fine-scale programming processes, even transform into nerve cells. And it is precisely this aspect that opens up fascinating prospects – for now merely working hypotheses – for finding new ways to combat the cognitive decline and neurodegeneration characteristic of Alzheimer’s disease.

Researchers at the Institute of Reconstructive Neurobiology at the University of Bonn have extracted red blood cell precursors from donors aged between birth and 101 years. Using just two genetic ‘switches’ – the transcription factors SOX2 and c-MYC – they transformed them directly into neural stem cells, i.e. the precursors of neurons. They did so without passing through the pluripotent cell stage, the stage capable of developing into any type of tissue. They then measured the cells’ age using an epigenetic clock. The surprise was that, at a molecular level, the cells from an 80-year-old were found to be under 20 years old. The principle of reconversion from blood is not new: the same team had already described it back in 2018.

The real novelty lies in the timescales. When a cell is reprogrammed to a pluripotent state, the clock is reset almost instantly. Here, however, the rejuvenation process unfolds over several weeks and continues even after the cells have stopped dividing. “The most interesting finding is not the sixty years gained, but the slow pace at which they are gained,” notes Matteo Pardini, a lecturer in the Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal-Paediatric Sciences (DINOGMI) at the University of Genoa and the Genoa Metropolitan Hospital Trust –. “It is a process that lasts for weeks and can be observed step by step, but above all, we can try to modify it. This is what makes the work so valuable for research.” Brüstle himself is moving in this direction: the model, he explains, will enable us to understand which factors and substances accelerate or slow down rejuvenation.

In short: a window opens. But onto what? “An epigenetic clock is an algorithm that estimates age by analysing certain chemical modifications of DNA – methylation – which change over the years,” explains Pardini. It is a powerful tool, but it tells us that certain molecular parameters have returned to youthful levels, not that the cell is ‘young’ in every respect. The authors also show that the cells do not display the typical signs of ageing and that the differences between young and elderly donors are diminishing, which reinforces the finding. However, this remains a finding obtained from cells in culture.” As for neurodegeneration linked to Alzheimer’s, the link exists, but it is indirect. Age remains the main risk factor for the disease, and understanding how the cellular clock is rewound is an important question. ‘There is a paradox here that is worth explaining,’ emphasises Pardini. ‘To study an age-related disease in the laboratory, we need neurons that retain their age-related characteristics. For this reason, when we want to replicate the brain of an elderly patient, we often prefer techniques that preserve the molecular signatures of the donor’s age. The cells from Bonn erase those signatures. They are therefore an excellent model for studying rejuvenation, but less so for studying the disease.”