Increased intrinsic neuronal vulnerability and decreased beneficial reaction of macrophages on axonal regeneration in aged rats

Previously we showed that macrophage activation in the eye by intravitreal application of zymosan increased retinal ganglion cell (RGC) survival and axonal regeneration after optic nerve injury. It is known that the intrinsic ability of CNS neurons to survive and to regrow axons after optic nerve injury differs between developing and adult mammals. However, whether aged animals also differ in their ability to survive and regrow injured axons are not known. In this study we investigated whether the abilities of RGCs to survive and to regrow injured axons differed between rats aged 6-8, 60 and over 96 weeks, and whether macrophage responses in the eye were different at different ages. We found that the intrinsic viability of RGCs, as shown in vitro, was reduced in aged rats, but RGC viability after optic nerve injury in vivo was similar among rats of the different ages. The ability of RGCs to regrow injured axons into a peripheral nerve graft also remained similar between young and aged rats. Macrophage activation in the eye was confirmed to be beneficial and provided the basis for zymosan treatment-dependent RGC protection. However, reduced activation of macrophages in zymosan-treated eyes was seen in aged rats. Importantly, this reduced macrophage activation in aged rats led to a decreased level of RGC axonal regeneration when compared with that in young rats of the same treatment. Thus age influences the intrinsic viability of RGCs and the beneficial impact of macrophages on RGC axonal regeneration after optic nerve injury.