Inflammation drives ageing and reduces longevity we discuss a key player.

<div class="intercom-container" style="margin:0 0 40px;"><img src="https://hsfiles.gorgias.help/gm/help-centers/22775/attachments/2a9bc70e-9f2c-4b67-b8ba-e99d51f02f98.jpg"></div> In the field of longevity research, a key area of focus is the phenomenon known as &quot;inflammageing,&quot; a term coined to describe the chronic low-grade inflammation that characterises aging [3]. 
Chronic inflammation was recently added as one of the 12 key hallmarks of ageing.

Persistent inflammation is believed to be a major risk factor for both morbidity and mortality in older adults, contributing to the development of age-related diseases such as cardiovascular disease, diabetes, cancer, and neurodegenerative diseases [3]. Therefore, managing this chronic inflammation is vital for promoting healthy aging and extending lifespan.
<h4 id="h_c6c4572dd9">Dealing with the chief of the body&apos;s inflammation fire department NF-&#x3BA;B</h4>
Think of NF-&#x3BA;B as one of the key players, if we think of inflammation in terms of a fire in a city then the chief of the body&apos;s inflammation fire department is NF-&#x3BA;B. This chief is responsible for overseeing the body&apos;s response to emergencies, like infections or injuries [1]. It&apos;s involved in how the body responds to various triggers such as stress, germs, or even free radicals (molecules that can cause damage to your body&apos;s cells) [1].

Now, when the chief (NF-&#x3BA;B) is working as it should, it calls in the fire department (the inflammation response) at the right time, with the right intensity [1]. That&apos;s when we see the firefighters (IL-6 and TNF-&#x3B1;) getting to work [1].

But sometimes, the chief can get a little too zealous and trigger the emergency response even when it&apos;s not needed, or keep it going for too long [1]. When this happens, the inflammation fire department can cause more harm than good, leading to what we call &apos;excessive inflammation&apos; [1]. 
This can be like a fire hose that&apos;s turned on full blast and left running &#x2013; it can end up causing more damage than the fire it was supposed to put out!

So, while NF-&#x3BA;B is crucial in our body&apos;s defense mechanism, it&apos;s important it doesn&apos;t overdo its role, as that can lead to problems down the line [1].

<h4 id="h_e53463d060">Normal response to stress or infection</h4>
<h4 id="h_206f0c5f17">Stress or infection &#x2192; Activation of NF-&#x3BA;B (The Chief) &#x2192; Increase in TNF-&#x3B1; and IL-6 (The Firefighters) &#x2192; Inflammation (Emergency Response) [1]</h4>
This is the usual process when the body is dealing with stress or infection. It&apos;s a necessary process to help the body recover. But if the chief (NF-&#x3BA;B) calls in the firefighters (TNF-&#x3B1; and IL-6) too much or too often, we end up with chronic inflammation, which can cause problems [1].
Now, enter our heroes CAT and SOD2. These guys are like the fire station&apos;s maintenance crew, they help to keep everything in balance [2]:
<h4 id="h_1c211ed9cd">Maintaining the balance of inflammation</h4>
<h4 id="h_da4203f7e8">High levels of TNF-&#x3B1; and IL-6 &#x2192; Activation of CAT and SOD2 (The Maintenance Crew) &#x2192; Reduction of excessive inflammation [2]</h4>
In a healthy body, when the chief (NF-&#x3BA;B) becomes too overzealous and inflammation gets out of hand, the maintenance crew (CAT and SOD2) step in to bring things back to balance [2]. They work to reduce the intensity of the inflammation and help prevent the damage that excessive inflammation can cause [2].

In summary, we can look at inflammaiton in this way:
<h4 id="h_7014e809f6">Stress or infection + NF-&#x3BA;B (overactive) &#x2192; Too much TNF-&#x3B1; and IL-6 &#x2192; Excessive inflammation + CAT and SOD2 &#x2192; Balanced inflammation [1, 2]</h4>
See our article on managing inflammation to understand how you can rebalance chronic inflammation when it gets out of check.
<h4 id="h_00e7544627">References:</h4>
[1] Lawrence, T. (2009). The Nuclear Factor NF-&#x3BA;B Pathway in Inflammation. Cold Spring Harbor Perspectives in Biology, 1(6), a001651. 
[2] Sies, H., Berndt, C., &amp; Jones, D. P. (2017). Oxidative Stress. Annual Review of Biochemistry, 86, 715-748.
[3] Franceschi C, Campisi J. (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 69 Suppl 1(Suppl 1), S4-S9.

Inflammation: dealing with the chief of the body's inflammation fire department- NF-κB

Managing the drivers of inflammation are the key ways to deal with inflammation. If you are easily overactivated some of these tips can help

<div class="intercom-container" style="margin:0 0 40px;"><img src="https://hsfiles.gorgias.help/gm/help-centers/22775/attachments/482c00bc-83f1-43b3-ac99-30ca7fbd8a91.jpg"></div>There are several strategies, including dietary, lifestyle modifications, and supplements, that have been shown to reduce the levels of IL-6 and TNF-&#x3B1;, thus helping to mitigate excessive inflammation [1].
A key strategy is to work at a level above IL-6 and TNF-a by reducing another messenger that activates both of these- NF-&#x3BA;B [1].
NF-&#x3BA;B is like the chief of the body&apos;s inflammation fire department [1]. This chief is responsible for overseeing the body&apos;s response to emergencies, like infections or injuries. It&apos;s involved in how the body responds to various triggers such as stress, germs, or even free radicals [1].
When NF-&#x3BA;B works properly, it calls in the inflammation response at the right time, with the right intensity, bringing into action IL-6 and TNF-&#x3B1; [1]. However, sometimes, NF-&#x3BA;B can trigger the emergency response even when it&apos;s not needed, or keep it going for too long. This can lead to what we call &apos;excessive inflammation&apos; [1].
The inflammation equation:
Stress or infection + NF-&#x3BA;B (overactive) &#x2192; Too much TNF-&#x3B1; and IL-6 &#x2192; Excessive inflammation + CAT and SOD2 &#x2192; Balanced inflammation [2]
Strategies to reduce inflammation:
<ol>
<li>
Reduce NF-&#x3BA;B, TNF-&#x3B1;, and IL-6 [1].
</li>
<li>
Increase CAT and SOD2 [2].
</li>
<li>
Reduce the stress or infection [1].
</li>
</ol><h4 id="h_36f55d3e69">Dietary Approaches:</h4>
<ol>
<li>
Mediterranean diet: Associated with lower levels of inflammatory markers, including IL-6 and TNF-&#x3B1; [3].
</li>
<li>
Omega-3 fatty acids: Anti-inflammatory properties, reduces levels of IL-6 and TNF-&#x3B1; [4].
</li>
</ol><h4 id="h_f67a901ef2">Lifestyle Modifications:</h4>
<ol>
<li>
Physical activity: Reduces levels of inflammatory markers, including IL-6 and TNF-&#x3B1; [5].
</li>
<li>
Adequate sleep: Poor sleep quality or insufficient sleep duration can increase inflammation [6].
</li>
</ol><h4 id="h_0dab4b6111">Supplements and adaptogens:</h4>
<ol>
<li>
Resveratrol: Inhibits NF-&#x3BA;B signaling, decreases levels of IL-6 and TNF-&#x3B1; [7].
</li>
<li>
Quercetin: Inhibits NF-&#x3BA;B activation, reduces IL-6 and TNF-&#x3B1; production [8].
</li>
<li>
Vitamin D: Modulates immune response, inhibits NF-&#x3BA;B activation, reduces levels of IL-6 and TNF-&#x3B1; [9].
</li>
<li>
Sulforaphane: Inhibits NF-&#x3BA;B and reduces inflammation [10].
</li>
<li>
Fish Oil (Omega-3 Fatty Acids): Inhibits NF-&#x3BA;B activation, reduces production of inflammatory cytokines like IL-6 and TNF-&#x3B1; [11].
</li>
</ol>Boosting SOD2 and CAT can also help to balance the inflammatory response [2].
Several supplements have been shown to modulate the NF-&#x3BA;B pathway, potentially reducing inflammation [7,8,9,10,11].

<h4 id="h_f36e62e5a1">References: </h4>
[1] Lawrence, T. (2009). The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harbor perspectives in biology, 1(6), a001651. 
[2] Handy, D. E., &amp; Loscalzo, J. (2012). Redox regulation of mitochondrial function. Antioxidants &amp; redox signaling, 16(11), 1323&#x2013;1367. 
[3] Casas, R., Sacanella, E., &amp; Estruch, R. (2014). The Immune Protective Effect of the Mediterranean Diet against Chronic Low-grade Inflammatory Diseases. Endocrine, Metabolic &amp; Immune Disorders Drug Targets, 14(4), 245-254.
[4] Calder, P. C. (2017). Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochemical Society Transactions, 45(5), 1105-1115. 
[5] Gleeson, M., Bishop, N. C., Stensel, D. J., Lindley, M. R., Mastana, S. S., &amp; Nimmo, M. A. (2011). The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nature Reviews Immunology, 11(9), 607-615. 
[6] Irwin, M. R., Olmstead, R., &amp; Carroll, J. E. (2016). Sleep Disturbance, Sleep Duration, and Inflammation: A Systematic Review and Meta-Analysis of Cohort Studies and Experimental Sleep Deprivation. Biological Psychiatry, 80(1), 40-52. 
[7] Berman, A. Y., Motechin, R. A., Wiesenfeld, M. Y., &amp; Holz, M. K. (2017). The therapeutic potential of resveratrol: a review of clinical trials. NPJ Precision Oncology, 1(1), 1-9. 
[8] Li, Y., Yao, J., Han, C., Yang, J., Chaudhry, M. T., Wang, S., ... &amp; Yin, Y. (2016). Quercetin, inflammation and immunity. Nutrients, 8(3), 167. 
[9] Aranow, C. (2011). Vitamin D and the immune system. Journal of Investigative Medicine, 59(6), 881&#x2013;886. 
[10] Heiss, E., Herhaus, C., Klimo, K., Bartsch, H., &amp; Gerh&#xE4;user, C. (2001). Nuclear factor &#x3BA;B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. Journal of Biological Chemistry, 276(34), 32008-32015.
[11] Calder, P. C. (2015). Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1851(4), 469-484.

Inflammation: nutrition, lifestyle and supplement hacks for IL-6, TNF-a and NF-κB

Two key genes affecting inflammation are IL-6 adnd TNF-a in some instances can be beneficial.

<div class="intercom-h2b-video"><iframe allowfullscreen frameborder="0" mozallowfullscreen src="https://www.loom.com/embed/9f6b6b55079e434bb1a002fd0284d45a" webkitallowfullscreen></iframe></div>Inflammation or chronic inflammation is a key driver of premature ageing but without inflammation we wouldn&apos;t survive.

inflammation is a bit like your body&apos;s own personal fire department. It&apos;s an essential part of your immune system&apos;s toolkit and it&apos;s what helps you heal when you&apos;re injured or fight off infections when you&apos;re sick. When a problem pops up, like a cut on your finger or a virus in your lungs, your body turns on the inflammation response. It sends in special cells and proteins (like IL-6 and TNF-&#x3B1;) to take care of the issue and start the healing process. It&apos;s a really effective system, but just like a fire hose, it&apos;s possible for it to get out of control. If your body&apos;s inflammation response is turned up too high or stays on for too long, it can end up causing damage instead of helping you heal. This is why it&apos;s so important for the body to maintain a balance in managing inflammation.

Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-&#x3B1;) are substances produced by our bodies, playing essential roles in our immune system. They act like messengers, sparking inflammation, which is a crucial defense mechanism against injury or infection. However, if they&apos;re produced in excessive amounts or at inappropriate times, they can cause harmful levels of inflammation and contribute to various health problems, including arthritis, cancer, and Alzheimer&apos;s disease [1][3].

Specifically, IL-6 is a versatile substance that coordinates immune responses and other reactions to injuries. When it&apos;s produced excessively, it can help cause diseases such as arthritis and certain cancers [1]. The gene that encodes IL-6 has a variant known as rs1800795, which can increase IL-6 production. As a result, people with this variant may have an amplified inflammatory response and a higher risk of certain inflammatory diseases [2].
Similarly, TNF-&#x3B1; is a substance that controls a variety of cellular activities, including inflammation. Like IL-6, it can contribute to disease development when it&apos;s produced excessively or inappropriately, leading to conditions like depression, Alzheimer&apos;s disease, and inflammatory bowel diseases [3]. There&apos;s a variant in the TNF-&#x3B1; gene, rs1800629, which is associated with increased TNF-&#x3B1; production. This variant can elevate disease risk, particularly for autoimmune and infectious diseases like arthritis, Crohn&apos;s disease, and severe malaria [4].

<h4 id="h_5879b3d782">The evolutionary benefits of producing a stronger inflammatory reponse</h4>
The evolution of genetic variants associated with heightened inflammatory response, such as those found in the IL-6 and TNF-&#x3B1; genes, can be understood within the context of the environment and challenges faced by our ancestors.

Increased production of inflammatory mediators, like IL-6 and TNF-&#x3B1;, might have conferred survival advantages in certain circumstances. For instance, a robust inflammatory response can help to effectively control and eliminate infections. During human evolution, when infectious diseases were a major cause of mortality, genetic variants that amplified the body&apos;s ability to fight off infections could have been beneficial and thus favored by natural selection [5].
However, these same genetic variations might also contribute to excessive or chronic inflammation under conditions of modern life, leading to a higher risk of various inflammatory and autoimmune diseases. This concept is known as the &quot;mismatch hypothesis&quot; or &quot;evolutionary discordance hypothesis&quot;, suggesting that our bodies are best adapted to the environment in which we evolved, and changes in that environment can lead to health issues [6].

Understanding how we respond allows us to adapt our environment appropriately.

<h4 id="h_e5e7d51af7">Keeping inflammation in check</h4>
<ol>
<li>
The antioxidants ie Catalase (CAT) and Superoxide Dismutase 2 (SOD2): These are like the body&apos;s cleanup crew. They go around mopping up harmful substances called reactive oxygen species (ROS), or &quot;free radicals,&quot; that can damage our cells if left unchecked.
</li>
<li>
IL-6 and TNF-&#x3B1;: These are like the body&apos;s alarm system. When there&apos;s an infection or injury, they send out signals that kickstart the body&apos;s immune response. This includes inflammation, which is a bit like calling the fire department: it&apos;s helpful for dealing with immediate threats, but can cause damage if it goes on for too long.
</li>
</ol>Now, the cleanup crew and the alarm system need to work together to keep things running smoothly:
<ul>
<li>
If there&apos;s too much damage from ROS, CAT and SOD2 work to clean it up. By doing so, they help to keep the body&apos;s alarm system from going into overdrive and creating too much inflammation.
</li>
<li>
On the other hand, if the body&apos;s alarm system (IL-6 and TNF-&#x3B1;) sends out signals for inflammation, this can lead to more ROS being produced. But our body is clever: these signals can also tell our cleanup crew (SOD2 in particular) to work harder, helping to keep things in balance.
</li>
</ul>In short, CAT and SOD2 help control the level of ROS, reducing potential damage and keeping inflammation in check. Meanwhile, IL-6 and TNF-&#x3B1; help coordinate the body&apos;s response to threats, but they also make sure our cleanup crew is ready to handle any extra ROS produced during this response. It&apos;s all about balance!

See our article on strategies to reduce these inflammatory messengers and the role of IL6 in exericse.

References:
<ol>
<li>
Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011 May;1813(5):878-88.
</li>
<li>
Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998 Oct 15;102(7):1369-76.
</li>
<li>
Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001 Feb 23;104(4):487-501.
</li>
<li>
Louis E, Franchimont D, Piron A, et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol. 1998 Jun;112(3):451-6.
</li>
</ol>

Major genes that affect inflammation: IL-6 (Interleukin-6) and TNF-α (Tumor Necrosis Factor-alpha) are key messengers (cytokines) involved in inflammation and immune response.

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