Inflammatory Mediators in Elderly People

Introduction

Older bodies often experience increased levels of inflammatory substances like cytokines and acute phase proteins, possibly two to four times higher than younger ones. Various factors contribute to this mild inflammation, including more fat tissue, lower production of sex hormones, smoking, subtle infections, and chronic conditions like heart disease or Alzheimer's (a progressive neurodegenerative disorder that affects memory, cognition, and behavior). Aging might also lead to an imbalanced response to stimuli, with certain substances potentially worsening the risk factors for age-related issues. These inflammatory substances could act as a link between lifestyle, infections, and natural aging processes on one side and the risk factors for age-related diseases on the other. Studies show that these substances are strong predictors of mortality in the elderly, even independently of other known risk factors. This article will focus on various inflammatory mediators affecting the elderly population.

What Are Inflammatory Mediators?

The body's way of dealing with infection or injury involves inflammation. This happens when special cells in the immune system sense danger signals, like those from harmful germs or stressed-out cells. To fight the danger, the body releases substances (inflammatory mediators) that cause classic signs of inflammation - redness, heat, pain, swelling, and sometimes loss of function. Various inflammatory mediators are:

• Cytokines: Signaling proteins produced by various cells, including immune cells, that regulate inflammation. Examples include interleukins (IL-1, IL-6, IL-8), tumor necrosis factor-alpha (TNF-alpha), and interferons.

• Chemokines: These molecules attract immune cells to the site of inflammation. Examples include IL-8, monocyte chemoattractant proteins (MCPs), and macrophage inflammatory proteins (MIPs).

• Prostaglandins: Lipid compounds derived from arachidonic acid that have diverse effects on inflammation. Prostaglandin E2 (PGE2) is a notable example.

• Leukotrienes: Another group of lipid mediators derived from arachidonic acid, involved in the recruitment and activation of leukocytes. Leukotriene B4 (LTB4) is an example.

• Histamine: Released by mast cells and basophils, histamine increases vascular permeability and promotes vasodilation.

• Bradykinin: A peptide that induces vasodilation and increases vascular permeability, contributing to inflammation and pain.

• Complement System: A group of proteins that enhance the immune response. Complement activation leads to inflammation through various pathways.

• Reactive Oxygen Species (ROS): Molecules like superoxide and hydrogen peroxide produced by activated immune cells, contribute to oxidative stress and inflammation.

• Acute Phase Proteins: Proteins whose levels increase during inflammation. Examples include C-reactive protein (CRP) and serum amyloid A.

• Matrix Metalloproteinases (MMPs): Enzymes that degrade extracellular matrix components and play a role in tissue remodeling during inflammation.

• Nitric Oxide (NO): A signaling molecule produced by various cells, including macrophages, with diverse effects on inflammation.

What Are the Roles of Inflammatory Mediators in Elderly People?

Inflammatory mediators play a significant role in the health of elderly individuals, influencing various aspects of the aging process. Here are some key points related to inflammatory mediators in elderly people:

Immunosenescence and Inflammation:

• Immunosenescence refers to the age-related deterioration in immune system function and is often associated with chronic low-grade inflammation in the elderly.

• Increased levels of circulating inflammatory mediators characterize this chronic inflammation.

Cytokines and Ageing:

• Interleukin-6 (IL-6) is a prominent cytokine associated with aging and is often considered a cytokine for gerontologists.

• Studies commonly report elevated plasma or serum levels of IL-6 with advancing age, although results can vary.

Factors Contributing to Inflammation:

• Various factors contribute to increased low-grade inflammatory activity in elderly populations.

• These factors include decreased sex steroid production, smoking, subclinical disorders such as atherosclerosis and asymptomatic bacteriuria, and higher amounts of fat tissue, which produces cytokines like TNF-alpha and IL-6.

What Is the Clinical Importance of Inflammatory Mediators?

• The clinical importance of circulating inflammatory mediators in elderly individuals has gained attention in recent studies.

• Elevated levels of these mediators are associated with high mortality risk, independent of pre-existing morbidity.

• Inflammatory mediators may play a vital role in the development and progression of age-associated chronic diseases.

• Studies, such as the longitudinal study of Danish centenarians, highlight the prevalence of cardiovascular disease (CVD) and dementia (forgetfulness) in individuals with extreme lifespans, emphasizing the potential link between inflammation and chronic conditions.

• Inflammatory markers in the elderly may serve as sensitive indicators of subclinical disorders, allowing for early detection and intervention.

What Is the Connection Between Inflammatory Mediators and Aging?

The connection between inflammatory mediators and various diseases in the elderly are:

• Cancer: The aging process amplifies cancer risk with environmental toxins, compromised immunity, and deficient DNA (deoxyribonucleic acid) repair mechanisms playing pivotal roles. Chronic inflammation, triggered by infections, emerges as a key mediator at various stages of tumor development. Various associations exist between bacterial or viral infections and specific malignancies.

• Rheumatoid Arthritis (RA): Elderly individuals facing RA ( chronic autoimmune disease that primarily affects the joints) encounter an intricate interplay of inflammatory mediators. Genetic and environmental factors converge to fuel chronic tissue inflammation. The NLRP3 (Nucleotide-binding domain, Leucine-rich repeat, Pyrin domain) inflammasome is involved in joint destruction, with biologics targeting pro-inflammatory cytokines, such as TNF and IL-6, proving effective in treatment strategies.

• Atherosclerosis: Aging's impact on atherosclerosis (gradual buildup of plaque in arteries) reveals a dynamic relationship with inflammatory mediators. Cellular senescence, cytokine modulation, and NLRP3 inflammasome activation respond to cholesterol crystals and oxidized LDL (low-density lipoprotein). Therapeutic interventions targeting IL-1beta show promise in reducing cardiovascular events.

• Aging Brain: In neurodegenerative diseases like Alzheimer's and Parkinson's, inflammatory mediators orchestrate a complex symphony. Microglia activation, cytokine release, and the involvement of sphingolipid metabolites contribute to disease progression. Genetic, lifestyle, and epigenetic factors intricately influence neuroinflammation in aging brains.

What Are the Future Implications of Inflammatory Mediators in the Elderly?

The research underscores the role of various factors, such as genetics, diet, and lifestyle, in modulating inflammation through pathways like NF-κB (nuclear factor-kappa B) signaling. Therapeutic opportunities may arise from understanding senescent cell induction, using monoclonal antibodies, and developing novel drugs targeting kinases controlling senescence and inflammation pathways. Repurposing old medications like Metformin and exploring histone-deacetylating drugs are currently subjects of clinical studies. Despite progress, research on inflammation resolution mechanisms in aging and age-related diseases is underexplored but holds promise. The development of synthetic resolvins for inflammation resolution may offer advantages over traditional anti-inflammatory methods. Ongoing studies on centenarians suggest that aging may be modifiable, with an enhanced anti-inflammatory status potentially contributing to their longevity.

Advancements in genomic technologies and bioinformatics present opportunities to identify key players in the inflammation pathway. Integrating large global datasets through artificial intelligence methods could unlock physiological, genetic, and molecular pathways, leading to novel therapeutic approaches for age-related diseases. Understanding and modifying the pro-inflammatory aging phenotype holds significant promise for achieving a better quality of aging and a longevity dividend for all.

Conclusion

In older adults, inflammatory mediators significantly impact health and aging. Immunosenescence and chronic low-grade inflammation, influenced by cytokines and other mediators, play a pivotal role. Elevated inflammatory levels are strong predictors of mortality, independent of existing health issues. These mediators also contribute to age-related diseases, including cardiovascular disease and dementia. Recognizing inflammatory markers as sensitive indicators allows for early detection and intervention, potentially enhancing elderly health outcomes.