Heterochronic Genes Turn Back the Clock in Old Neurons

Although some neuron types regenerate better than others, all neurons lose the ability to regenerate with age. This intrinsic decline is the primary cause of regeneration failure even in permissive environments. This was shown in 1995 by comparing the regeneration ability of retinal neurons from different aged retinas growing into tectums of different ages ( 1 ). Embryonic retinal axons regrew into tectum of any age, including older tectum with an inhibitory glial environment, whereas postnatal day 2 or older retinal axons failed to regrow even into embryonic tectum. This indicated a “programmed” loss of axon regeneration ability with neuron age. Similarly, young hindbrain neurons transplanted into older spinal cords could regenerate axons into a normally inhibitory myelinated environment ( 2 ). Despite the clear therapeutic implications of these observations, the underlying molecular mechanisms controlling age-dependent regenerative capacity were unclear. On page 372 in this issue, Zou et al. ( 3 ) report that the highly conserved let-7 –LIN-41 heterochronic signaling pathway is responsible for part of the age-related decline in axon regeneration in the worm Caenorhabditis elegans .