WARNING WARNING: Cell Danger Response - Part 1

Written by Anil Bajnath, MD
Posted October 26, 2021

Dear Longevity Insider,

The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. 

Here's how it works: The cell senses that it is being attacked, and then uses specialized proteins to monitor our metabolism. When CDR is activated, the body will use available energy sources and switch its focus to self-defense rather than growth and reproduction. CDR is a mechanism that allows cells to sense "danger" that may be caused by viruses or bacteria. This danger can also come in the form of molecules such as DNA, RNA, and proteins – all of which are components found inside our cells. When these substances get leaked into the extracellular environment, CDR kicks into gear.

The activated CDR will then enter into a cascade – this is where it gets its name, the danger response cascade (DRC). The danger response cascade can be broken up into five steps that occur in succession: 

  1. Detection: Detection of PAMPs (e.g., pathogen-associated molecular patterns like lipopolysaccharides) or damage-associated molecular patterns (DAMPs). PAMPs are substances that can be recognized by specialized receptors, such as Toll-like receptor (TLR), NOD-like receptor (NLR), and RIG-I like helicases (RLH). DAMPs refer to the cellular debris or damage that results from being attacked. 

  2. Activation of MAPKs, IKKɛ, TBK1, PKA, and PKR. Next, these activated enzymes activate transcription factors (which refers to a biochemical process by which a particular gene’s instructions are copied into RNA) that then activate or suppress inflammation-promoting genes while suppressing other essential genes involved in repair pathways. When we discuss activated enzymes, this refers to enzymes that have been phosphorylated, which means a phosphate group has been added to the enzyme.  

  3. Activation of transcription factors such as NF-kB, FOXO3a and HIF1α. These transcription factors then go on to stimulate or suppress the transcription of genes that regulate inflammation and also cell survival. 

  4. Activation of MDA5 & RIG-I: MDA5 and RIG-I are critical to the CDR response because they activate an antiviral pathway known as type I interferon production. Type I interferon production is a pathway that allows our body’s immune system to help fight infections. 

  5. Secretion of inflammatory cytokines to induce downstream immune cells to take action against the infection. Inflammatory cytokines are a group of signaling proteins that trigger inflammation at sites of infection. The cells which release these cytokines are called antigen-presenting cells (APCs) and include monocytes, macrophages, dendritic cells, and B lymphocytes. This cascade is what allows CDR to induce inflammation – yet it can have negative consequences if activated over and over again.

In addition, CDR can also occur in response to non-infectious stresses such as heat, UV irradiation, and oxidative stress. These stresses have been shown to activate IKKɛ (which is one of the last components in the cascade) and cause it to activate NF-κB (Nuclear factor-kappa B). When activated, this protein moves into the nucleus where it works with other transcription factors to promote the expression of genes that trigger inflammation. It is important to note that these events happen within minutes of your body detecting CDR triggers. 

Your cells do a lot more than just detect danger.

To your longevity,

Anil Bajnath MD
CEO/Founder, Institute for Human Optimization
Chief Medical Officer, Longevity Insider HQ