The Degeneration of Axons in Aging
This open access review discusses what is known of the way in which the function and structure of axons in nerve tissue decline over the course of aging, walking through evidence linking this degeneration to the various pillars of aging defined a few years back. Axons are fibers connecting nerve cells, usually those in close proximity to one another, but over distances of up to a few feet in cases such as the spinal cord cells that communicate with nerve cells in the feet. That connectivity is of course vital to the operation of the nervous system, and especially the brain. Axonal degeneration is one of many well-studied items that appear to be a downstream consequence of fundamental causes of aging, such as as those outlined in the SENS proposals for rejuvenation research projects. That downstream consequence then expands out to cause many more forms of failure in the brain and other systems.
The effects of aging on the brain are multiple and importantly, age constitutes the main risk factor for the development of neurodegenerative disorders (NDs), characterized by progressive neuronal death and loss of specific neuronal populations. For a better comprehension of the molecular and cellular changes that occur during aging, seven pillars of aging were defined, which are common processes involved in most chronic disorders that take place in an aging organism. These seven pillars are proteostasis, adaptation to stress, inflammation, stem cells and regeneration, epigenetics, metabolism, and macromolecular damage. Notably, changes in these cellular events are common to most NDs, suggesting that similar mechanisms might at least partially explain different age-related diseases.
Axonal degeneration, which occurs at early stages of NDs, also takes place as a consequence of normal aging. Indeed, many cellular processes that are altered with advanced age have shown to contribute to axonal pathology. Importantly, the degeneration of axons represents an early event during the development of NDs, preceding both cell death and the onset of clinical symptoms, which has important therapeutic implications. Although, the molecular basis of the transition that makes an individual to develop neurodegeneration with advanced age is currently unknown, increasing evidence support the potential role of axonal degeneration in this transition.
The process of axonal degeneration is an essential developmental event that consists in the selective destruction of axons. It is an evolutionary conserved process that can be activated by different stimuli including mechanical damage, axonal transport defects or by drugs used for chemotherapy. Although, the exact molecular and cellular pathways by which axonal degeneration occurs remain to be fully clarified, key contributing factors have been identified in the last decade. After nerve transection, axons undergo three phases: a latent phase, axonal fragmentation and axonal disintegration. The latent phase stills poorly understood but it is known that axons remain apparently normal for 1-2 days in mice after nerve injury, and can still conduct action potential. In the last stage, all the structures inside the axon are degraded. Disintegration of axonal cytoskeleton is followed by myelin degradation and macrophage infiltration that clear cell debris.
We have demonstrated that mitochondrial dysfunction is a key process associated to axonal degeneration. The degeneration of axons was shown to be associated to the formation of the mitochondrial permeability transition pore (mPTP) between the inner and outer mitochondrial membrane. mPTP formation triggers the mitochondrial permeability transition (mPT), which leads to an increase in axonal reactive oxygen species (ROS) followed by intra-axonal calcium release. Interestingly, blocking mPTP either pharmacologically or genetically, by removal of the mPTP component Cyclophilin D (CypD), significantly delays axonal degeneration. Notably, formation of the mPTP has been linked to the pathogenesis of NDs.
Increasing evidence suggest that axonal degeneration occurs before cell body loss and notably, prior to the onset of clinical symptoms in different age-related diseases. Hence, the understanding of the molecular and cellular mechanisms underlying this potentially reversible phase is critical for the development of therapeutic strategies aimed at the prevention and intervention of these disorders.