Fight Aging!

Axons that connect neurons in the nervous system are sheathed in structures largely made of myelin. This myelin sheath is necessary for the correct function of nerves and the brain, as demonstrated by the unpleasant consequences of demyelinating conditions such as multiple sclerosis. In normal aging there is a lesser degree of loss of myelin over time, and a weight of evidence points towards this loss providing a meaningful contribution to age-related cognitive decline. Therefore it is worth keeping an eye on this area of research, and the development of therapies for demyelinating conditions, as some approaches might also be applicable to age-related myelin loss.

Myelin is maintained by the population of cells called oligodendrocytes. Like all cell populations, there is a drift away from youthful function with age. Numerous causes exist, including the usual suspects of increased inflammatory signaling and diminished stem cell and progenitor cell activity, but as is usually the case it is challenging to assign a relative importance to the many identified processes of oligodendrocyte aging. Cellular biochemistry remains an interconnected web of incompletely understood processes, only slowly mapped.

Oligodendrocytes in the aging brain

Although the exact mechanisms of cognitive decline are not yet known, it is understood that progressive breakdown of the intricate communication between neurons and glial cells, reduced efficacy of action potential conduction and processes such as neuroinflammation lead to a non-autonomous and gradual loss of cognitive function. White matter tracts functionally connect various areas of the central nervous system (CNS), and are predominantly populated by myelinated axons.

This has led to a growing field of interest and understanding of brain aging as a network deterioration, such that the loss of myelination in white matter tracts which connect cortical regions underlies the loss of cognitive functions which rely on this network connectivity and efficient neuronal transmission. Non-human primate work has found direct links between reduced myelination index, of specific corticocortical and corticobasal tracts and cognitive performance in normal aging.

Myelin is a lipid-rich membrane structure, which wraps concentrically around axons. In the CNS, myelin is provided by terminally differentiated cells of the oligodendrocyte lineage, which hereafter will be referred to as mature oligodendrocytes. Developmental myelination of the CNS takes place largely within the first 2 years of life, but white matter volume increases up until around mid-life as new axonal projections become myelinated. Adult myelination is highly plastic, modifiable by experience, and seems to have important roles in learning and memory and normal cognitive function. Oligodendrocytes are derived from specific neural progenitor cells; oligodendrocyte progenitor cells (OPCs). OPCs populate the CNS, and proliferate throughout life to self-renew, and differentiate to provide a continuous source of new mature oligodendrocytes.

It is widely accepted that there is an overall loss in white matter volume with age in non-pathologically aging human brains. Considering the widespread and specialised roles of myelin, it follows that myelin degradation leads to cognitive decline during 'normal' aging, that is in the absence of clinical age-related pathology such as dementia. This is not least as a result of leaving axons exposed and vulnerable to damage, as is well documented in demyelinating conditions such as multiple sclerosis. Longitudinal data shows that age-related myelin degeneration largely contributes to loss of cognitive function through disconnection of cortical regions, due to slowed processing speeds, which in fact appears to be independent of axonal degeneration. White matter loss and degeneration may result in age-related cognitive decline via several independent mechanisms.

The chronology of neuronal loss and myelin damage is not yet understood. Therefore, it could be hypothesised that a good understanding of the health of oligodendrocytes in the aging brain and how white matter might be protected in aging is ever more important as a potential prophylactic approach to age-associated disease.