Longevity Briefs: A Way To Reverse Tooth Ageing?

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:

The mental image of the ‘toothless old person’ is not entirely the consequence of poor dental hygiene. Of course dental hygiene helps keep teeth healthy into old age, but some deterioration is inevitable. Enamel and dentin (the hard layer below the enamel) become more brittle and prone to fracturing with age. This occurs when the pulp, which contains odontoblasts (cells responsible for maintaining the dentin), loses its self-renewal capacity. Dental pulp stem cells (DPSPs) that give rise to new odontoblasts enter a state called senescence in which they are no longer able to divide, and are therefore unable to maintain the odontoblast population.

Senescence can occur as a result of telomere shortening – each time a cell divides, these protective caps on the ends of the chromosomes become a little shorter, eventually preventing further division from occurring after around 60 divisions. However, DPSPs divide very infrequently, and it appears that their senescence is mainly caused by other factors. What are those factors? That’s what researchers set out to uncover in this study.

The discovery:

Researchers first studied the pulp from wisdom teeth that had been removed from younger (18–40 years) and older (60+ years) humans. After confirming that aged pulp had reduced regenerative capacity, researchers looked at the levels of a specific protein called NFATC1 (Nuclear Factor of Activated T-cells, Cytoplasmic 1). NFATC1 is a transcription factor, meaning that it regulates the activity of different genes. They were interested in this protein because their previous research had suggested that NFATC1 was linked to dentin formation by DPSPs. When comparing DPSPs from old and young wisdom teeth, they found that NFATC1 was undetectable in old DPSPs that had stopped dividing, suggesting a possible link with senescence.

To investigate whether this relationship was causal, researchers then genetically deleted NFATC1 in mice. They observed that the teeth of mice lacking NFATC1 aged rapidly: their DPSPs became senescent, their pulp resembled that of much older mice, and they had reduced dentin deposition compared to mice that did not lack NFATC1.

Researchers then treated mice with Dasatinib plus Quercetin, which is a combination of drugs that selectively kills senescent cells (drugs that kill senescent cells are known as senolytic). They found that this treatment significantly improved dentin regeneration in response to injury in mice lacking NFATC1, suggesting that eliminating senescent cells may restore the pulp’s dentin-maintenance capacity.

The implications:

This study suggests that NFATC1 depletion may be a contributing factor in human tooth ageing that could be targeted using senolytic treatments. Senescent cells don’t just stop dividing, but also release a cocktail of harmful signalling molecules that can impact the function of nearby cells and drive them to senescence as well. This is partly why ‘pruning’ these cells can have benefits despite there being no change in the number of non-senescent cells.

The researchers acknowledge that while their study demonstrates that NFATC1 depletion can cause DPSP senescence and pulp ageing, it doesn’t prove that it is the cause of pulp ageing because they did not test their hypothesis in naturally ageing mice. Of course if you create a problem (mice lack NFATC1, driving senescence in pulp stem cells) and then deliver a solution (remove the senescent cells) then you are likely to see some benefits. The next step will therefore be to determine if senolytics can actually impact normal tooth ageing.