Calorie Restriction Mimetics as an Approach to Slow Demyelination
Myelin sheathes axons, the connections between neurons. This sheath is essential to nervous system function, and a range of unpleasant diseases result from loss of myelin, such as through the autoimmune activity of multiple sclerosis. Demyelination occurs to a lesser degree over the course of aging, the standard problem of a complex system becoming disarrayed as the result of various forms of molecular damage and maladaptive reactions to that damage. Here, as elsewhere, chronic inflammation appears to be a contributing cause. Calorie restriction is known to dampen chronic inflammation and favorably alter the behavior of cells such as microglia and astrocytes that might otherwise be promoting inflammatory signaling. Thus the panoply of calorie restriction mimetic drugs is also a topic of interest - though none of these recaptures more than a fraction of the effects of the actual practice of calorie restriction, more is the pity.
The dysfunction of myelinating glial cells, the oligodendrocytes, within the central nervous system (CNS) can result in the disruption of myelin, the lipid-rich multi-layered membrane structure that surrounds most vertebrate axons. This leads to axonal degeneration and motor/cognitive impairments. In response to demyelination in the CNS, the formation of new myelin sheaths occurs through the homeostatic process of remyelination, facilitated by the differentiation of newly formed oligodendrocytes. Apart from oligodendrocytes, the two other main glial cell types of the CNS, microglia and astrocytes, play a pivotal role in remyelination. Following a demyelination insult, microglia can phagocytose myelin debris, thus permitting remyelination, while the developing neuroinflammation in the demyelinated region triggers the activation of astrocytes.
Modulating the profile of glial cells can enhance the likelihood of successful remyelination. In this context, recent studies have implicated autophagy as a pivotal pathway in glial cells, playing a significant role in both their maturation and the maintenance of myelin. In this review, we examine the role of substances capable of modulating the autophagic machinery within the myelinating glial cells of the CNS. Such substances, called caloric restriction mimetics, have been shown to decelerate the aging process by mitigating age-related ailments, with their mechanisms of action intricately linked to the induction of autophagic processes.