Fight Aging!

The axons that connect neurons are sheathed in myelin, an insulator necessary to maintain normal electrochemical transmission through the nervous system. Demyelinating conditions such as multiple sclerosis produce profound dysfunction leading to death precisely because myelin is so fundamental to the correct operation of nerves and brain. With normal aging, a lesser degree of damage to myelin sheathing occurs, however, and this is thought to contribute to cognitive decline. As is the case for many aspects of aging, there are many possible interconnected mechanisms involved, and it isn't clear as to which are more or less important, or whether the list is complete.

Myelination is an active, ongoing process conducted by oligodendrocyte cells. Many of the possible mechanisms driving loss of myelin involve a reduced oligodendrocyte population size or activity, but in today's open access paper, researchers discuss how proteins that encourage or prevent phagocytosis, the engulfment and destruction of cells or debris in tissue by immune cells, might be involved in age-related demyelination. The researchers argue for the importance of a maladaptive increase in pro-phagocytosis decoration ("eat me" signals) near myelin structures combined with a maladaptive reduction in anti-phagocytosis decoration ("don't eat me" signals) near myelin structures and on oligodendrocytes. The result is damaged myelin and too little remyelination activity.

Dysregulated C1q and CD47 in the aging monkey brain: association with myelin damage, microglia reactivity, and cognitive decline

Although the cause of myelin pathology is not known, microglia are likely contributors as they play an important role in removing myelin debris that inhibits remyelination, a process which becomes dysregulated with age. Microglia become overburdened with degenerating myelin, and failure to clear the debris results in accumulation of damaged myelin that blocks remyelination and proper myelin maintenance. Moreover, the aging brain is characterized by chronic inflammation, which is especially elevated in white matter regions. This neuroinflammation puts microglia into a cycle of contributing to inflammation while also responding to proinflammatory signaling. Chronic neuroinflammation heightens microglia-mediated elimination of cellular components, which may become misdirected with excess pro-inflammatory signaling.

The timing and precision of microglia-mediated debris removal is regulated by immunologic proteins that either initiate or inhibit phagocytosis. Two such proteins are the "eat me" classical complement initiator, C1q, and the "don't eat me" immune-regulatory protein, CD47. Dysregulation in both C1q and CD47 have been implicated in age-related diseases such as multiple sclerosis (MS), a chronic demyelinating disease, synapse removal, and normal aging. Our previous study showed that C1q and CD47 expression are dysregulated in aging gray matter, likely contributing to age-related synapse loss.

Changes in C1q and CD47 in aging white matter may direct microglia towards chronic phagocytosis and inflammation and hinder efficient debris clearance and myelin maintenance. However, studies in white matter have mainly focused on either "eat me" or "don't eat me" proteins and not both, so the interaction between the two in white matter remains unknown even though both C1q and CD47 bind to myelin and proper balance between the two molecules is critical for phagocytosis. Since these signals have not been studied in aging white matter tracts in relation to myelin damage and related cognitive impairment, the present study aimed to assess changes in the balance of C1q and CD47 in the white matter of the aging cingulum bundle in cognitively assessed nonhuman primates.

Our findings showed significant age-related elevation in C1q localized to myelin basic protein, and this increase is associated with more severe cognitive impairment. In contrast, CD47 localization to myelin decreased in middle age and oligodendrocyte expression of CD47 RNA decreased with age. Lastly, microglia reactivity increased with age in association with the changes in C1q and CD47. Together, these results suggest disruption in the balance of "eat me" and "don't eat me" signals during normal aging, biasing microglia toward increased reactivity and phagocytosis of myelin, resulting in cognitive deficits.