Killifish Lose Central Nervous System Regeneration with Age
Killifish are one of the species capable of scar-free regeneration of organs following injury, a capability that researchers suspect exists in humans and other mammals, suppressed after early development, but accessible given the right manipulation of genetic controls, yet to be discovered. The study here notes that killifish appear to lose this capability in later life. Having a species that exhibits both proficient and limited regeneration under different circumstances may point the way towards specific genes and mechanisms relevant to the goal of enabling proficient regeneration in human patients. Or it may be entirely irrelevant to inter-species differences, a peculiarity unique to killifish. The only way to find out is to follow the thread and see where it leads.
Over the recent years, the fast-aging African turquoise killifish (Nothobranchius furzeri) has emerged as an excellent biogerontology model, Despite having a lifecycle of only a few months, killifish do age. They even age in a similar way as humans, presenting many of the well-described aging hallmarks, yet often magnified and occurring within a much shorter time frame. Interestingly, killifish appear to pay a price for their fast growth and aging. In contrast to zebrafish - that maintain their neuroreparative ability albeit regenerate less efficiently at old age - killifish completely lose their regeneration capacity at old age and are unable to fully recover from central nervous system (CNS) injury.
Using an optic nerve crush injury model in killifish of different ages, we indeed revealed that, in contrast to young fish, aged animals do not regain vision following damage. An inadequate intrinsic capacity of aged retinal ganglion cells (RGCs) to revert to a "regenerative state" as well as a growth-inhibiting neuron-extrinsic environment seem to contribute to this impairment, similar to what has been described for (young) adult mammals. We postulate that age-associated changes within neurons and their glial environment - already manifesting before damage occurs- negatively affect the regeneration potential of the killifish CNS, which then leads to a mammalian-like regenerative response upon injury.
With increasing age, we revealed reduced expression levels of growth-associated genes in retinal neurons, thereby affecting the intrinsic ability of RGCs to regrow their axons. Additionally, oxidative stress was shown to pile up in the aged killifish retina, which is known to lead to mitochondrial dysfunction and therefore very likely contributes to failure of the energy-demanding regenerative process. Next to neuron-intrinsic changes, we observed signs of astrogliosis, inflammaging, and a senescence-associated secretory phenotype upon aging, which might sensitize the old killifish CNS and result in growth-unfavorable glial reactivity upon injury.
The onset of astrogliosis and a chronic inflammatory status in the killifish CNS during physiological aging seems to result in a more extensive and extended glial reactivity upon nerve injury, which is known to be detrimental for regeneration in mammals. Strikingly, the exaggerated neuroinflammatory events then result in the formation of a long-term glial scar. In summary, it seems that explosive growth and/or fast aging eventually turns the killifish CNS into a regeneration-incompetent organ. By shifting its regenerative potential from high to low with increasing age and forming a glial scar following CNS injury, the killifish puts itself in the exceptional position of resembling (young) adult mammals when at old age.