Enhancing axonal myelination in seniors: A review exploring the potential impact cannabis has on myelination in the aged brain

Abstract

Consumption of cannabis is on the rise as public opinion trends toward acceptance and its consequent legalization. Specifically, the senior population is one of the demographics increasing their use of cannabis the fastest, but research aimed at understanding cannabis' impact on the aged brain is still scarce. Aging is characterized by many brain changes that slowly alter cognitive ability. One process that is greatly impacted during aging is axonal myelination. The slow degradation and loss of myelin (i.e., demyelination) in the brain with age has been shown to associate with cognitive decline and, furthermore, is a common characteristic of numerous neurological diseases experienced in aging. It is currently not known what causes this age-dependent degradation, but it is likely due to numerous confounding factors (i.e., heightened inflammation, reduced blood flow, cellular senescence) that impact the many cells responsible for maintaining overall homeostasis and myelin integrity. Importantly, animal studies using non-human primates and rodents have also revealed demyelination with age, providing a reliable model for researchers to try and understand the cellular mechanisms at play. In rodents, cannabis was recently shown to modulate the myelination process. Furthermore, studies looking at the direct modulatory impact cannabis has on microglia, astrocytes and oligodendrocyte lineage cells hint at potential mechanisms to prevent some of the more damaging activities performed by these cells that contribute to demyelination in aging. However, research focusing on how cannabis impacts myelination in the aged brain is lacking. Therefore, this review will explore the evidence thus far accumulated to show how cannabis impacts myelination and will extrapolate what this knowledge may mean for the aged brain.

Keywords: aged brain; astrocyte; cannabis; microglia; myelin repair; myelination; oligodendrocyte; oligodendrocyte progenitor cell.

Figure 1

The complex glial interactions that promote proper myelination and the general impact aging has on the myelin sheath | The process of myelination is extremely complex and is constantly evolving to our experiences and various environmental insults throughout the lifespan. Myelination is highly adaptive and is fine-tuned to these experiences through neuronal activity. Proper functioning of the myelinating glial cells of the CNS—oligodendrocytes—and their precursor cells—oligodendrocyte progenitor cells (OPCs)—is essential, but the process also heavily relies on astrocytes and microglia. The top half of this figure depicts the complex arrangement that exists between the various glial cells and neurons that all contribute to proper myelination and circuit formation. The inset depicts the internodes of a myelinated axon and the nodes of Ranvier that they create. Lastly, the bottom of this figure shows the general alterations and ultimate degeneration that many myelinated axons face with increasing age. Typically, myelin sheaths become thinner, shorter and less compact (shown by the axon cross-section at the bottom) with age, although many other abnormalities also occur. These abnormalities also contribute to the disorganization of ion channels at the paranode and at the nodes of Ranvier. Created with BioRender.com.

Figure 2

The transitional relationship between myelination and aging and the possible therapeutic advantage of cannabinoids | As emphasized throughout this review, the process of myelination is an intricate undertaking that involves all glial cells in the brain and is mainly driven by experience induced neuronal activity in adulthood and during aging. (A) The top panel of this figure shows some of the general contributions glial cells and neurons make to the overall process of myelination. With increasing age, a switch in cell state takes place in glial cells and neurons, ultimately leading to improper myelination and impairments in cognition. (B) The bottom panel showcases some of the benefits that cannabis (mainly focusing on THC and CBD) can have on myelination, as found in animal studies; with the majority looking at younger time points. Although evidence suggests improved myelination and cognition from cannabis use in aging animals, the paucity of studies focusing on this time point translates to relatively unknown overall effects of cannabis on myelination. This question mark indicates that topic, which is in need of increased research. Not only will this help fill in the gap of knowledge as to how cannabis impacts myelination across the lifespan, but will also better inform researchers on the effects of the endocannabinoid system on the aged brain. With this understanding, we are also better able to inform the public and health authorities on the impact cannabis use has on the senior population, who at the moment show increasing levels of consumption. Created with BioRender.com.