Rebooting neurorepair in the aged killifish pallium by targeting cellular senescence

The brain deteriorates with advancing age, halting our cognitive abilities and our intellectual growth. Because of the advancements made in medical care, the human population has gained an increased life expectancy, that is unfortunately mirrored by an elevated number of elderly that suffer from age-related neuropathology. The energy-demanding brain is specifically prone to aging stressors, what eventually causes a loss of neurons and hence, proper functioning of the brain. Compensation by growing new neurons from existing stem cells is possible, but very limited in the human brain, especially at old age. Up to date, age-related neuropathology thus remains uncurable, yet represents the second main cause of death in the world. The discovery of new strategies that can enhance regrowth of neurons, i.e. neuroregeneration, what can lead to better preservation of functional and cognitive capacity, is clearly needed. In search for innovative neuroregenerative strategies, biologists turn to animal research models that closely resemble human physiology. Teleost fish share about 60-70% of genes with humans, nevertheless have unprecedented regenerative capacities, with quite similar cellular mechanisms driving this effective neuroregeneration. Teleosts can regrow their central nervous system, and their fins, heart and kidneys so successfully that they can completely restore function of damaged organs. In addition, several teleost fish have gained momentum in biogerontology research as they seem to mimic human aging. Established teleost research organisms, such as the zebrafish, are however as long-lived as mice (3-5 years), making investigations on healthy aging slow. As an exemption, the African turquoise killifish (Nothobranchius furzeri), has a lifespan of 4-6 months in captivity and shows gradual aging during this compressed lifespan. Increasing research efforts have exposed the killifish' remarkable aging features to highly resemble human aging, including spontaneous age-related neurodegeneration. The two main research questions of this PhD dissertation comprised (1) how aging impacts neuroregeneration in the killifish dorsal telencephalon, and (2) whether we can identify effective strategies to reboot neuroregeneration in the aged killifish brain. I first devised a brain injury model in the killifish, so that neuroregeneration could be easily characterized and compared between adult and aged fish. The traumatic brain injury (TBI) model consisted of stab-wounding the dorsal telencephalon with a needle. The procedure allowed the creation of a standardized TBI model for young adult and aged killifish that caused cell death of the surrounding tissue. The dorsal telencephalon contains the killifish counterparts of the mammalian hippocampus and cortex. These brain regions are responsible for memory and learning, which are two abilities impeded by aging and neurodegenerative diseases. The stem cell zones of the telencephalon are homologous to the two existing stem cell zones in mammals. The telencephalon as a model brain region was thus chosen for its translational value. Using the established TBI model, I characterized the regeneration process in young, sexually mature, adult and aged killifish. From the existing literature, it remained unclear if the popular teleost model, zebrafish, completely lost its regenerative abilities upon aging. For killifish, I revealed that aging heavily blunts the killifish capacity for successful neurorepair. Specialized non-glial progenitors became unfit to generate new neurons that needed to replace the lost neurons at the injury site, while this went smoothly in young adult killifish. Intriguingly, the aged killifish seemed to have adopted several aspects of the restricted neurorepair process in mammals, including excessive inflammation and glial scarring. The young killifish in contrast, displayed full-blown regeneration without showing any visible persistent morphological damage to the telencephalon. Based on these results, I questioned if removal of the aging environment in brain tissue could reinstate complete neuroregeneration in the aged fish. In search for a rejuvenation strategy, I performed a proteomics study to identify relevant aging pathways that could be modulated pharmacologically. The study revealed a high senescent state in the aged killifish brain, as was confirmed by the high expression of senescent markers in gene expression studies and enzymatic stainings. Senescent cells are resistant to cell death and have a specialized secretory phenotype that creates a non-permissive environment for neuroregeneration. As such, I aimed to remove the senescent cells from the aged killifish via senolytic drug treatment. A very short treatment with senolytics was able to reduce the senescent cell burden and to ameliorate the neurogenic output in the aged fish, partly improving neuroregeneration. Eliminating the aged state of the brain can thus be used as a strategy to improve recovery after brain disease or injury. Longer senolytic treatment or a combination with other treatments will be revealing to elucidate if full-blown neurorepair can be reinstated in the aged brain. This dissertation has demonstrated the power of the non-canonical killifish biogerontology model to obtain a better understanding of aging and all its cellular and molecular manifestations. In addition, I have proven the validity of the short-lived killifish as a fast-track drug discovery platform. Exploiting the unique aging killifish biology can thus help in finding neuroregenerative strategies that could also apply to the aged diseased/injured mammalian brain.

Jaar van publicatie:2021

Toegankelijkheid:Embargoed