Aging and Multiple Sclerosis: How Growing Older Impacts Disease Progression and Treatment

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of the central nervous system (CNS), characterized by a highly variable disease course. While MS often begins in early adulthood, the influence of aging on disease progression and treatment efficacy is becoming increasingly recognized. The review by Zeydan and Kantarci (2020) highlights the multifaceted impact of aging on MS, emphasizing how aging contributes to disease progression, disability accumulation, and the declining efficacy of treatment strategies.

Transition from Relapsing-Remitting to Progressive MS
MS commonly presents in two phases: the relapsing-remitting phase (RRMS) and the progressive phase (either secondary progressive MS (SPMS) or primary progressive MS (PPMS)). The transition from RRMS to SPMS typically occurs in the fifth decade of life. Importantly, this transition seems independent of the initial severity or activity level during the RRMS phase, suggesting that aging itself is a primary factor driving the onset of the progressive phase. The review points out that, on average, individuals enter the progressive phase at approximately 45 years of age, regardless of their clinical presentation during the RRMS phase​.

CNS Reserve and Aging
As individuals age, their CNS reserve—the capacity of the brain and spinal cord to compensate for damage—naturally declines. This decline is more pronounced in people with MS, as both gray and white matter integrity are compromised. White matter integrity, which is essential for efficient neural communication, begins to degrade after the third decade of life, correlating with the typical age of transition to progressive MS. The authors also note that physical fitness may help preserve white matter integrity, indicating that lifestyle factors can mitigate some of the impacts of aging on MS progression​.

Immune Senescence and MS
Aging also affects the immune system, a phenomenon known as immune senescence, which occurs prematurely in MS patients. In both MS and its animal model, experimental autoimmune encephalomyelitis (EAE), early alterations in immune cell populations—such as a reduced CD4+/CD8+ ratio, increased memory T cells, and expanded pro-inflammatory B cells—reflect a senescent immune system. These changes likely contribute to the variability in disease progression, with older individuals showing more neurodegeneration and less immune-mediated inflammation​.

The role of microglia, the resident immune cells of the CNS, becomes particularly important in the aging MS brain. While microglia are involved in immune surveillance and neuroprotection, their function shifts with age, contributing to chronic inflammation and neurodegeneration. This altered microglial activity exacerbates the neurodegenerative aspects of MS, particularly in the progressive phase, and underscores the interplay between aging and the immune system in driving disease progression​.

Recovery from Relapses and the Impact of Aging
One of the key observations discussed by Zeydan and Kantarci is the age-dependent decline in the ability to recover from MS relapses. In younger patients, recovery from relapses is typically more complete, but as individuals age, their capacity for recovery diminishes. This is a critical concern for older MS patients, as even a single relapse can lead to long-term disability. The authors highlight that delayed initiation of disease-modifying treatments (DMTs), particularly after a poorly recovered relapse, is associated with an increased risk of entering the progressive phase earlier than expected​.

Declining Efficacy of Disease-Modifying Therapies (DMTs)
The efficacy of DMTs, which are primarily aimed at reducing inflammatory activity, tends to decline with age. This reduction in efficacy may be due to several factors, including the natural decline in CNS repair mechanisms and the reduced inflammatory activity seen in progressive MS. As patients age, the neurodegenerative aspects of MS become more prominent, and inflammation-driven relapses become less frequent. Since most DMTs target immune-mediated inflammation, they are less effective in older patients, especially those in the progressive phase of the disease. The authors call for the development of therapies that target neurodegeneration and repair mechanisms, which are critical in the aging MS population​.

Reference:
Zeydan, B., Kantarci, O.H. Impact of Age on Multiple Sclerosis Disease Activity and Progression. Curr Neurol Neurosci Rep 20, 24 (2020).