by Josephine Machado

Graphic design by Yu-Wen Jan

Between the knowledge dissemination we see in the daily news and the lifestyle influencers that flood our social media feed, we’ve all come to understand the impacts that inflammation can have in the latter stages of life. From matcha lattes to incorporating ice-rolling into one’s skincare regime, individuals have sought out a variety of methods to reduce inflammation on a smaller scale. However, in the world of medicine, inflammation has been known to evoke more detrimental effects. The term “inflamm-aging” has been coined to describe the chronic, sterile, low-grade inflammation that individuals experience as they age.¹  

Inflamm-aging has been thought to contribute to the pathogenesis of a variety of age-related diseases throughout the body as we advance into adulthood.¹ It’s important to be aware of the variety of ways in which age-related inflammation can affect our health as a result of its systemic nature. Conditions such as osteoarthritis and inflammation-related joint concerns are known issues in the aging population, but inflamm-aging transcends this. Scientists have come to dedicate significant time to evaluating the impact of inflammation on the aging of the brain. We’ve all heard of dementia or Alzheimer’s disease, but what is the role of inflammation in the development of these conditions? 

Inflamm-aging & The Brain

Brain-aging refers to a decline in the structure and, consequentially, the function of the brain with age. This includes decreased nerve cells, a loss of neural network connections, cognitive decline, mood swings, and behavioural changes.² In terms of impact on functionality, the effects of brain-aging are vast. Brain-aging can significantly contribute to the decline of a variety of cognitive functions. This includes speed of information processing, as well as plasticity—which refers to the brain’s ability to adapt and create new connections between neurons in response to learning or injury. Brain-aging can also affect one’s capacity of working memory and spatial memory, which refer to the brain’s ability to temporarily hold and process information for tasks, and remember the arrangements of objects in one’s environments respectively.³ The brain-age gap can be defined as the difference between a person’s estimated biological brain-age and their chronological age (better known as their “actual” age). Current advances have used machine learning models to calculate this gap using MRI scans.⁴ 

Recent research has named neuroinflammation as the primary cause of brain-aging. The aging of brain cells leads to the upregulation of inflammatory pathways, causing issues with brain-function and increased inflammation damage.³ When too intense, immune responses can damage surrounding tissues and cause autoimmune pathologies, especially within the brain where neuronal regeneration is poor.⁵ Additionally, as individuals age, their microglia—the resident immune cells of the brain—lose the ability to clear misfolded proteins, which are linked to neurodegeneration. This dysfunctional protein clearance significantly contributes to the neuroinflammatory response observed in the brain.³ Brain-aging and neuroinflammation exist as a feedback loop, where aging processes such as protein misfolding cause inflammation, and inflammation can in turn accelerate brain-aging.

As mentioned, brain-aging has been linked to neurodegeneration; a serious issue in the realm of geriatric health. Neuroinflammation is significantly enhanced by the accumulation of amyloid beta plaques, which are clumps of neurotoxic proteins that disrupt signals, damage brain cells, and accelerate the progression of Alzheimer’s disease through several pathways. Additionally, chronic inflammation is associated with a wide array of neurodegenerative diseases of aging. This isn’t limited to Alzheimer’s disease—Parkinson’s disease and amyotrophic lateral sclerosis are included as well.⁶

Brain-aging in Action: The Study of Brain-aging in Autoimmune & Inflammatory Conditions

The computation of one’s brain-age gap has been an up-and-coming measure in the fields of neuroscience and behaviour. The link between brain-aging and neuroinflammation is a topic of concern for not only elderly populations, but individuals with inflammatory conditions as well. Thus, brain-aging has become an emerging topic of interest in rheumatology and autoimmune disorders across both pediatric and adult populations.

Brain-age has been computed in several studies evaluating patients with multiple sclerosis (MS), a chronic, inflammatory, autoimmune disease which damages the central nervous system.⁷ This inflammation is caused by an abnormal immune response that attacks myelin—a fatty, protein-rich material that coats neurons, which acts to insulate them and speed up electrical impulses.⁸ A recent multi-center study used a machine learning model to compute biological brain-age in 195 patients with relapsing remitting MS. The results revealed accelerated brain-aging and a larger brain-age gap in patients with MS, with a mean of +6.98 years, in comparison to healthy subjects, with a mean brain-age gap of +0.23 years. The study concluded that the brain-age gap is a viable surrogate marker of disease progression in MS patients.⁹

Similarly, another study used a machine learning model to predict biological age in 70 females with systemic lupus erythematosus (SLE), an autoimmune condition in which the body’s immune system attacks its own tissues, leading to systemic inflammation and possible multi-organ damage. The study found that individuals with SLE had brains that appeared 3.6 years older than healthy controls. They also found that SLE individuals with a high brain-age exhibited neuropsychological deficits including significantly longer reaction times, and decreased psychomotor speed and flexibility.¹⁰

Overall, the study of autoimmune disorders—where inflammation is an inherent issue—can continue to provide insights into the impacts of neuroinflammation on brain-aging and cognition. 

Age-related inflammation has historically held significant meaning in a variety of medical specialties, however, the link between neuroinflammation and brain-aging is a novel field that has shown great promise for both clinical and research-based purposes. Continuing to invest time and resources in deepening our knowledge on this connection can lead to significant advances in our understanding of the neurological effects of autoimmune conditions, as well as normal inflamm-aging. Understanding these processes is the first step in mitigating neuroinflammation and developing interventions that can act to prevent or even reduce its negative effects.

References 

1. Franceschi C, Garagnani P, Parini P, et al. Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576–90. https://doi.org/10.1038/s41574-018-0059-4

2. Aging Biomarker Consortium, Jia YJ, Wang J, et al. A framework of biomarkers for brain aging: a consensus statement by the Aging Biomarker Consortium. Life Medicine. 2023;2(3):lnad017. https://doi.org/10.1093/lifemedi/lnad017.

3. Li X, Li C, Zhang W, et al. Inflammation and aging: signaling pathways and intervention therapies. Sig Transduct Target Ther. 2023;8(1);239. https://doi.org/10.1038/s41392-023-01502-8.

4. Soumya Kumari LK, Sundarrajan R. A review on brain age prediction models. Brain Research.  2024;1823:148668. https://doi.org/10.1016/j.brainres.2023.148668. 

5. Kip E, Parr-Brownlie LC. Healthy lifestyles and wellbeing reduce neuroinflammation and prevent neurodegenerative and psychiatric disorders. Front Neurosci. 2023;17:1092537  https://doi.org/10.3389/fnins.2023.1092537.

6. Balestri W, Sharma R, Da Silva VA, et al. Modeling the neuroimmune system in Alzheimer’s and Parkinson’s diseases. J Neuroinflam1mation. 2024;21(1):32.  https://doi.org/10.1186/s12974-024-03024-8.

7. Ghasemi N, Razavi S, Nikzad E. Multiple sclerosis: pathogenesis, symptoms, diagnoses and cell-based therapy. CellJ. 2017;19(1);1-10.https://doi.org/10.22074/cellj.2016.4867.

8.Morell P, Quarles RH. The Myelin Sheath: molecular, cellular and medical aspects. In: Siegal GJ, Agranoff BW, Agranoff RW, Fisher SK, Uhler MD, editors. Basic neurochemistry: molecular, cellular and medical aspects. 6th ed. Philadelphia: Lippincott-Raven Publishers; 1999. 

9. Romme CJA, Stanley EAM, Mouches P, et al. Analysis and visualization of the effect of multiple sclerosis on biological brain age. Front Neurol. 2024;15:1423485. https://doi.org/10.3389/fneur.2024.1423485.

10. Kuchcinski G, Rumetshofer T, Zervides KA, et al. MRI BrainAGE demonstrates increased brain aging in systemic lupus erythematosus patients. Front Aging Neurosci. 2023;15:1274061. https://doi.org/10.3389/fnagi.2023.1274061.