Longevity Briefs: What Regenerating Super-Fish Can Teach Us About 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.

Why is this research important: Ageing is a natural process that affects all living organisms, including humans. As we age, our bodies and brains undergo various changes that can impair our health and functioning. One of these changes is the accumulation of senescent cells, which are cells that have stopped dividing and secrete harmful substances that damage the surrounding tissue. Among other detrimental effects, senescence prevents stem cells from self-renewing. These are cells capable of developing into multiple different cell types, and they are vital for repairing damage in tissues throughout our bodies. This is one of the reasons we become more frail as we age.

Research suggests that senescent cells can be selectively eliminated by drugs called senolytics, which cause these cells to self-destruct. Senolytics have been shown to improve health and lifespan in various animal models of ageing, but their effects in humans remain uncertain despite a few promising studies.

What did the researchers do: In this study, researchers wanted to investigate the potential of senolytics to enhance brain regeneration. To do this, they chose a unique animal model: the African turquoise killifish. This fish is unusual because, while it only lives 4 to 6 months, it also exhibits many features of human brain ageing. Furthermore, like starfish and salamanders, killifish have a remarkable ability to regenerate from damage when they are young, but completely lose this ability in old age, much like humans do.

The researchers analysed proteins in the brains of young and aged killifish in order to figure out exactly what changed in their brains during ageing. After identifying cellular senescence as one of the pathways associated with brain ageing, they then treated aged killifish with a senolytic drug combo called dasatinib and quercetin (D+Q). They administered three injections of D+Q over one week, and choosing to give them when fish were already very old (17 weeks), meaning senescent cells would already be abundant in the brain. 

Key takeaway(s) from this research:

• D+Q reduced cellular senescence in the brains of aged killifish by around 30%.
• D+Q improved brain regeneration capacity but did not restore it to youthful levels.
• D+Q boosted the division of neural stem cells but not glial cells.
• Glial cell shifted to a less inflammatory state in fish treated with D+Q.
• The authors did not report an effect on lifespan.

The researchers found that D+Q treatment reduced cellular senescence in the aged killifish brains by an estimated 30%. Moreover, D+Q treatment did enhance the brain’s ability to regenerate, but only partially. The fish were able to regenerate brain matter after an injury more effectively, but still sustained scarring, whereas younger fish do not scar at all following injury.

D+Q boosted the division of non-glial progenitors , which are neural stem cells that produce new neurons, but didn’t affect division of glial cells, which are the immune cells responsible for clearing toxic debris. It did, however, appear to shift them away from a more inflammatory state, which should have a positive effect on neuroregeneration. The authors’ goal was not to study killifish lifespan, and data concerning lifespan was not reported.

The parallels between killifish and human ageing, and the fact that the treatment worked in very old killifish, are both encouraging from the point of view of human trials. It’s also worth noting that the researchers used much lower doses of D+Q than most animal studies (0.5 – 5mg/kg), which puts it more in line with typical human doses. Ultimately, however, we still need to wait for those human trials to be completed.