Practice Points
- Understanding age-related changes in multiple sclerosis (MS) may help inform treatment decisions that address normal aging and MS-related aging processes.
- Clinicians should recognize and assess for earlier and more severe onset of age-related decline in physical function, compounding MS-induced neurological deficits.
- Cognitive domains, such as processing speed and attention, are more commonly affected in MS compared with other neurodegenerative disorders such as Alzheimer disease, which can affect language skills and executive function.
Disease activity in multiple sclerosis (MS) diminishes with age, with fewer relapses and decreased new T2 lesion formation on brain and spine MRI.1-4 Concurrently, age increases the risk and rate of developing nonrelapse-related disability accumulation.5 Age strongly correlates with declines in physical and cognitive function in MS, and there is overlap between MS progression and non-MS age-related changes. Older adults experience the combined effects of MS and age-related changes (Figure). Providers and patients often face challenges in distinguishing whether neurological symptoms are due to aging, MS-specific decline, or an interaction of the two. In this review, we discuss pathophysiological changes and biomarkers of aging in MS and describe age-related changes in physical and cognitive function in people with MS. Understanding aging processes and their role in the MS disease course may lead to improved markers of disease progression and uncover new targets for therapy.
Pathophysiological Changes of Aging and MS
Although chronological age is the greatest risk factor for MS disease progression, the age at which people experience progression or reach disability milestones varies. Individual differences in biological age may explain this variation. Biological age reflects the cellular, molecular, and genetic mechanisms of aging, and emerging evidence suggests accelerated biological aging in people with MS.6-8 Aging mechanisms are related to damage accumulation, response to damage, and loss of reserve and compensatory ability, which collectively drive the irreversible decline in function from accumulation of cellular and molecular damage over time.9
Aging is associated with cellular senescence and age-related immune exhaustion and dysregulation, referred to as immunosenescence.10 When cells permanently exit the cell cycle and become senescent in response to damage and stressors, the accumulation of senescent cells produces mediators of inflammation through the senescence-associated secretory phenotype (SASP).11,12 SASP mediators hinder remyelination and contribute to neurodegeneration and functional decline.13 In MS, particularly in progressive MS, senescent cells are in the tertiary lymphoid aggregates within the brain meninges and contribute to widespread microglial activation and SASP expression.14,15 In postmortem MS brain tissues, there is elevated expression of the senescence marker p16INK4a in MS lesions compared with normal white matter.16,17 One senotherapeutic approach is to try to remove senescent cells using senolytic agents that disrupt their antiapoptotic pathways. Studies in experimental autoimmune encephalomyelitis, the widely used animal model of MS, have shown that some senolytics lead to improved function and survival.18 A clinical trial of senolytics in MS is underway (NCT07270120).
Immunosenescence in MS results in a shift of immune cells toward terminally differentiated lymphocytes and activated microglia.19 Thymic involution occurs with aging and results in decreased naive T cells and increased memory T cells, which leads to decreased T-cell receptor repertoire and impaired antigen recognition.20,21 Compared with controls, people with MS tend to have a lower frequency of naive T cells and a higher frequency of terminally differentiated effector memory T cells.13,22 B cells also decline with age, with a decrease in naive B cells and an increase in dysfunctional antigen-experienced B cells.23 Microglia are activated in chronic active MS lesions and drive neuroinflammation by secreting SASP mediators.24
Other aging processes also play a role in MS progression. Aging-induced oxidative stress drives cellular senescence and mitochondrial dysfunction that damage neurons.25,26 Increased production of reactive oxygen species promotes oxidative stress and hinders energy production.27 Age-associated increases in gastrointestinal permeability lead to gut dysbiosis, resulting in the release of pathogen-associated molecular patterns, which are central nervous system penetrant and contribute to microglial activation.28 Aging also alters the gut microbiome, which may also contribute to MS progression.29
Measuring Biological Aging in MS
Aging biomarkers reflect mechanisms of aging and provide insights into the processes that drive the onset and progression of age-related diseases. There are a variety of biomarkers reflecting the different hallmarks of aging, and several have been studied in people with MS. Multiple studies have measured telomere length in people with MS, where the progressive shortening of the protective endcaps of genomic DNA contributes to genomic instability and the DNA damage response and, ultimately, to replicative senescence.30 Several studies, but not all, have found shorter telomere lengths in people with MS compared with a control group, and there appears to be an association between shorter telomere length and greater disability in MS.31-33
Aging has also been associated with epigenetic alterations. Epigenetic clocks have been derived from differential methylation patterns to predict life span (mortality) or health span–based outcomes.34,35 In people with MS, epigenetic age acceleration can be seen in both adults and children.36-38 As clinically accessible tools, composite biomarkers such as the National Health and Nutrition Examination Survey Biological Age Index (NHANES BAI), comprised of a 10-item clinical index of physiological measures and routine lab tests, may also be useful. The NHANES BAI has been shown to be elevated in people with MS compared with controls.39 Reproductive aging, marked by age-related decline in sex steroid hormones, has been shown to contribute to disability accumulation in women with MS, as measured by levels of anti-Müllerian hormone.40
Although the precise mechanisms by which biological aging drives MS disease activity and progression are unclear, measuring biological aging in MS may advance clinical practice by informing clinical trial design of drugs that target processes, referred to as gerotherapeutics, which are studied in age-related diseases. Aging biomarkers also have the potential to stratify disease severity in MS if strong associations can be determined between biological aging and MS disease outcomes.
Aging and Physical Function in MS
MS impacts overall physical function, neuromuscular performance, and physical activity levels, but there is only a modest understanding of the contribution of normal aging processes to these measures in older populations. Aging leads to reduced physiological reserve and performance,41 and there is overlap between MS disease-specific mechanisms and age-related health changes. The ability to identify and understand the similarities and distinctions between aging and the impact of MS on physical functioning may enable appropriate, targeted, and timely clinical interventions.
Physical Function
Physical function is divided into basic activities that are essential for independent living and complex activities that are discretionary and not required for independent living, but may affect quality of life.42,43 Many factors contribute to overall physical functioning beyond the presence or absence of disease, including perceptual, environmental, and behavioral considerations. The Short Physical Performance Battery (SPPB) is a tool that measures physical function and mobility in older adults.44 It includes assessments of balance, gait speed, and lower extremity strength, with a higher summary score indicating greater functional ability. The SPPB score typically declines with age in the general population.44,45 This tool has also been validated as a measure of lower-extremity physical function in people with MS across the life span.46 In a study that compared 345 people with MS and 174 controls across 6 age groups, SPPB scores declined along the life span in people with MS to a greater extent than those of controls.47 Strength was a robust component of physical functioning across most age groups.
Further support for the amplified decline of physical functioning in people with MS was demonstrated in a study that included 698 people with MS (aged 29-71 years) and 226 controls (aged 18-72 years).48 Performance tests were administered, including ambulation (Timed 25-Foot Walk Test) and upper extremity function (9-Hole Peg Test). The progression of motor decline increased synergistically in individuals with MS as they aged.
Accelerated decline in physical functioning during middle age was observed in people with MS in a longitudinal study. The 10-Item Physical Functioning Scale (PF-10) was used to assess various aspects of physical functioning in 733 women with MS over the course of 25 years.49 PF-10 scores declined in both the controls and in people with MS, but the decline was 3 to 4 times faster in midlife for those with MS. Specifically, a 45-year-old woman with MS exhibited physical function levels comparable to those of a 75-year-old woman without MS, suggesting a 30-year acceleration in functional decline due to the disease.
Physical Activity and Frailty
Physical activity declines with age in the general population, but this decline is more pronounced in people with MS.50 Recent study data confirm that older adults with MS are much less physically active than age-matched individuals without MS, and this can lead to compounding deleterious effects on physical function and worsening overall health.51,52 Older adults with MS exhibited lower step counts and greater sedentary time compared with controls without MS, despite adjusting for age, sex, and comorbidities. These differences may reflect not only the impact of aging but also MS-specific factors such as fatigue, balance issues, and reduced motor function.
Frailty is an age-related state characterized by decreased physiological reserve and increased vulnerability to adverse health outcomes. Common frailty measurements include the frailty phenotype, which assesses the presence of 3 or more out of 5 clinical manifestations, including weight loss, slow walking speed, low physical activity, exhaustion, and weak grip strength, and the Frailty Index, which evaluates the accumulation of deficits across a list of health-related variables that can be customized to the relevant clinical or research setting.53,54 In people with MS, frailty is associated with high disability, disease duration, and progressive MS.55 Although frailty may overlap with neurological disability in MS, its additional elements help capture the clinical complexity in MS and guide management and prognosis.
Neuromuscular Function
Muscle performance naturally declines with age due to physiological changes, such as decreased muscle mass, strength, and endurance.56 Neuromuscular function is the muscle’s ability to generate force and power, including the underlying neural and muscular determinants (such as voluntary activation and contractile properties). The combination of neural function (central) and muscular properties (peripheral) provides neuromuscular function, which then yields physical function and health-related outcomes, such as quality of life. In MS, age and the disease itself combine to reduce neuromuscular function.57 The rate of force development, which represents the ability to rapidly generate muscle force at the start of a maximal contraction, was up to 70% lower in people with MS than in controls across age groups. This becomes important in functional skills, where speed of contraction is essential, for example, a quick balance correction to prevent a fall.58 The study data also revealed that this decline begins early in the disease course and accelerates through middle age, with the most pronounced reductions seen in older adults with MS. An additional study investigated muscle power (work over time) and found a similar pattern of loss that was most evident in early to middle age, where changes in controls occurred later in the life span.59 The authors suggest that this should be an area of targeted therapy early in the disease trajectory.
People with MS experience more pronounced and complex alterations in muscle function. Research has shown that people with MS exhibit substantial impairment compared with controls in isometric and dynamic muscle strength, particularly in knee extensors and plantar flexors, with deficits ranging from 18% to 38%.60 Plantar flexors of the ankle were preferentially affected in people with MS vs age-matched controls, and these deficits are linked to limitations in walking and stair climbing. In addition, people with MS demonstrate an altered muscle oxidative mechanism, leading to impaired exercise tolerance at the muscle level.61
Aging and Cognitive Function in MS
Aging is associated with worsening cognition, specifically in executive function, prospective memory, learning and retrieval, information processing speed, shifting attention, and visuoperceptual judgment.62 Cognitive impairment (CI) in people with MS most commonly involves slowed cognitive processing speed and deficits in episodic memory, executive function, and verbal fluency.63 Visuospatial ability is affected less frequently.64 Aging results in increased prevalence of CI in people with MS, which, in one study, was seen in 77.4% of adults over age 55 compared with 42.8% of younger patients,65 and CI was found in 48% of people with MS who had 3 decades of disease duration.66
Only a few studies have directly examined the interaction between aging and cognitive decline in MS. For the most part, these studies have not demonstrated accelerated cognitive worsening or an interaction between the aging process and cognition in older people with MS.67,68 However, in late-onset MS, working memory and visuospatial memory (learning and recall) were more frequently and severely impaired than in people with earlier-onset MS, suggesting that MS-associated cognitive changes may be exacerbated by age-related brain changes, leading to reduced reserve and accelerated cognitive decline.69
CI usually presents differently in older people with MS than in people with other degenerative diseases, such as amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD). Studies have found there may be a similar decrease in semantic fluency in people with MS and people with aMCI.48 However, people with aMCI typically perform much worse on delayed memory measures than people with MS. In addition, people with progressive MS have greater deficits in attention, episodic memory, and information processing speed, whereas people with AD have impaired learning, memory, and verbal skills.68,70 CI in older people with MS, as well as the potential overlap with other neurogenerative diseases such as AD, is still understudied and poorly understood. Other age-related conditions, such as vascular comorbidities, further contribute to CI in MS.71 There is still much to learn regarding the impact of aging on the MS disease course, the risk of other causes of cognitive impairment in people with MS, and the impact of other common comorbidities.
Conclusions
With improved disease management and increased life span, more individuals with MS are entering older age and are experiencing the dual burden of MS-related impairments and age-related decline. MS introduces disease-specific impairments that often result in functional limitations earlier and more severely than those seen in typical aging. As the MS population ages, clinicians must consider the interaction between age and MS-related decline and incorporate assessments and interventions that address both processes.
