Immune Aging, Inflammation, and Vitamin D

As with most things in life, the immune system does not get better with age. As we get older and fall into bad dietary and lifestyle habits, while failing to take the time to properly care for our body, things naturally start to break down. We generally do not feel as spry as we once did, and problems arise. These can be achy joints after exercise, less energy than we had when we were younger, or more serious things like the onset of conditions associated with age like memory loss, blood sugar issues, and cholesterol levels creeping up. Similarly, as our immune systems age, they also start to break down. Cells do not function as well or in some cases at all, the immune response can be over- or underactive, chronic inflammation increases, and the occasional bacterial or viral infection seems to take longer to overcome.

As it turns out, this is a real issue and some scientists have dubbed these changes “inflamm-aging”.  As we age, and as the immune system malfunctions, chronic inflammation results. When we are young, the immune system’s production of cytokines (chemical messengers released by immune cells) is balanced between those that cause inflammation and those that reduce it. With aging, however, there is a dramatic shift to excessively high production of the pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines. This leads to direct changes in how the immune system reacts to external insults from bacteria and viruses. Since the immune system is unable to effectively balance its reactivity by producing enough anti-inflammatory cytokines, the pro-inflammatory cytokines become predominant in a phenomenon called the “cytokine storm”.

While this may not sound detrimental or ominous, the results of uncontrolled inflammation are not just destructive to the virus or bacteria; rather, the effect of this highly inflammatory state is felt throughout the body, leading to tissue and organ damage, and is likely a bigger contributor to being unable to overcome the symptoms of an infection than the infectious agent itself. In other words, our own immune system’s reaction to an infection can be worse than the infection itself!

The immune response that results from the “cytokine storm” is extremely destructive and is a leading contributor the development of age-associated diseases such as diabetes, Alzheimer’s, atherosclerosis and more. There are several factors involved in the development of a malfunctioning immune system with age. Some of the key changes that researchers have identified are described below.

Decreased ACE2 activity

ACE2 is short for angiotensin converting enzyme type 2 receptors. From a biochemical point of view, promoting the ACE2 pathway leads to anti-inflammatory effects. The highest levels of ACE2 are in the lungs, kidney, heart, and blood vessels. In young, healthy individuals, ACE2 is highly expressed, indicating a balanced inflammation response. However, in an aging immune system, ACE2 expression is significantly reduced. Because of ACE2’s high levels in lung tissue, an outcome of its decreased expression on the immune system’s ability to fight off infections is that individuals may be more susceptible to developing lung and breathing symptoms associated with viruses known to affect the respiratory system. When these receptors are highly under-expressed during immune aging, it can lead to cytokine storm symptoms and ultimately shut down lung function.

Excess Free Radical Production

While free radicals at low levels function as signaling molecules for the immune system and can support its enhanced functionality, at high levels they cause inflammation and result in cell damage. When the immune system functions properly, the free radicals that are generated can be effectively neutralized. However, in the “inflamm-aging” condition during immune system aging, excessive free radicals signal the immune system to turn on the inflammation machine and result in increased release of pro-inflammatory cytokines, or cytokine release syndrome. They activate several transcription factors involved in increasing inflammation, including nuclear factor kappa B (NF-κB) and peroxisome proliferator-activated receptors (PPARs). These pro-inflammatory transcription factors can encourage the immune system to unleash the “cytokine storm” by producing TNF-α, Interferon-gamma, IL-6, and COX-2, among other inflammation-related cytokines. So uncontrolled free radical generation acts as a trigger for chronic inflammation in an aging immune system.

What is Autophagy? Removal of Dead Cells

Autophagy is the process the body uses to clean up damaged cells and their components to allow for the generation of newer, healthier cells. Research shows that during aging, the efficiency of the body’s autophagy process decreases, leading to the accumulation of dead or decaying cells. This impacts mitochondrial function in cells, affecting cellular energy, as well as causing free radical production to increase. Furthermore, lowered autophagy and the high level of free radicals generated because of it can lead to direct detrimental effects on the immune system by over-stimulating Nod-like receptors (NLRs), which are pathogen-recognition receptors. Overactivation of NLRs increase the release of pro-inflammatory cytokines, leading to uncontrolled cell damage and death. The result of this is imbalanced immune system activity with age.

Aging Cells lead to an Aging Immune System

As we age, cells are constantly being regenerated and renewed; however, with an aging immune system, these refresh-and-renewal processes are not as efficient, leading to the accumulation of aging cells. It is one thing to age and a separate thing to have a high number of aged cells circulating in the body. While these aged cells are alive, they have lower function and viability compared to young, healthy cells. They malfunction, leading to the release of cytokines that promote high levels of inflammation, increasing susceptibility to infections and a higher likelihood of complications of viral and bacterial infections. The increased release of inflammatory cytokines by aging immune cells leads to increased risk of the “cytokine storm”. Furthermore, aging cells lead to an aging immune system, where the processes of innate and adaptive immunity are compromised, and do not work. Immune aging leads to constantly elevated inflammation, an inability of immune cells to properly identify and neutralize infections, and an elevated risk of more severe disease.

Vitamin D, the Immune System’s Fountain of Youth?

Vitamin D is a key cog for the immune system’s ability to function optimally. While research shows that more than 60% of the general population are at risk for some level of vitamin D deficiency, the risk is elevated with age. For several reasons, aging decreases the body’s ability to effectively use vitamin D, increasing its requirement over time. Some of these factors include decreased pre-vitamin D production by the body, decreased ability of the skin to synthesize vitamin D, lower intake of vitamin D through the diet, increasing weight and obesity, decreased kidney function, and less time spent outdoors in the sun, which is a key factor for vitamin D production. Several chronic diseases have been linked to vitamin D deficiency, so it comes as no surprise that the sunshine vitamin plays a critical role for immune health and the body’s ability to counteract viral and bacterial infections.

The good news is that vitamin D counters several of the common issues associated with “inflamm-aging” and plays a significant role in preventing the “cytokine storm”. When vitamin D levels are adequate, the body’s immune system returns to balance and functions at a high level, even with increased age. Research shows that vitamin D deficiency during aging correlates with an overexpression of pro-inflammatory cytokines; however, adequate vitamin D levels are associated with the suppression of inflammatory markers including TNF-α, IL-1, and others. Vitamin D decreases the generation of pro-inflammatory mediators and increases the production of the anti-inflammatory ones. Simultaneously, vitamin D boosts the innate immune system while decreasing overactivation of the adaptive immune system, leading to an effective immune response to viral infections and a stronger first line of defense.

In terms of immune cell aging, vitamin D deficiency leads to dysfunctional and malfunctioning immune cells. Since nearly all immune cells express vitamin D receptors on their surface, providing adequate vitamin D levels can restore proper cellular function. Furthermore, vitamin D normalizes the expression of ACE2, an anti-inflammatory factor that is dysregulated in immune system aging and is associated with the severity of respiratory symptoms that result from some viral infections. By fixing the imbalance in ACE2, adequate vitamin D levels may be protective against the more severe respiratory symptoms associated with specific viruses. Sufficient levels of vitamin D are also required to maintain epithelial junction and endothelial vascular permeability, serving to minimize damage in the lungs.

Vitamin D further restores immune system balance by normalizing free radical production from immune cells and restoring the body’s autophagy function by impacting the ability of immune cells to clear out dead cells and tissue. This allows for the renewal and rejuvenation of the immune system, keeping it functioning at its prime.

Since vitamin D deficiency is so prevalent and research indicates that it plays a key role in immune function, maintaining optimal levels of the sunshine vitamin throughout the year is critical for overall health. A good supplemental dose of vitamin D to start with is 2,000 IU per day for general health. However, it is imperative to monitor blood levels as higher amounts may be required in those with specific conditions as well as those with decreased immune function. Also keep in mind that most of the vitamin D3 used in supplements is animal-derived; look for supplements that contain vegan vitamin D3 if this is a concern for you and your loved ones.

References

• Kalia V et al. Journal of Leukocyte Biology. 2021
• Meftahi GH et al. Inflammation Research. 2020
• Daneshkhah A et al. Aging Clinical and Experimental Research. 2020

Tags: Cytokine storm, Inflamm-aging, Immune, Immunity, Cytokines, Vitamin D3, Inflammation, Autophagy, Free radicals, Cytokines, Lungs, Respiratory, Virus, Bacteria, Infections