LOSS OF PROTEOSTASIS – The Breach of our DNA Security

Cells need protein to grow and repair. Our bodies have safety measures in place to keep the production of proteins stable and without defects. However, sometimes these measures fail. This can lead to a cascade of errors that contribute to one of the primary causes of aging.

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The biological definition of aging is the many processes of cellular damage accumulation in the body and these are known in the scientific literature as the Nine Hallmarks of Aging. The first four hallmarks are considered primary since they are believed to be actual causes of aging and have a definitively negative effect on DNA. The fourth hallmark, and the last of the primary, is loss of proteostasis.

Loss of proteostasis happens when the protein-building processes in the body go awry and the systems that eliminate damaged proteins malfunction. This leads to the accumulation of excess proteins, where they begin to cluster and cause disease, such as Alzheimer’s.

Transcribing the code

In our previous blog on genomic instability, we illustrated how our DNA contains the genetic instructions for making proteins. And our telomere attrition blog described the smaller units of DNA called nucleotide bases. In a process called transcription, when a cell is ready to copy its information, an enzyme called RNA polymerase binds to the DNA in a region known as the promotor.

In a manner similar to unzipping, RNA polymerase moves along the DNA making an exact, but opposite single strand of messenger RNA. The order of the bases is determined by the DNA code. The DNA continues to unwind ahead of the messenger RNA and rewinds behind it. The RNA polymerase enzyme helps to stabilize the molecules while the DNA is open, or unzipped.

Translating the code

Once the whole gene has been read, the messenger RNA travels out of the nucleus into the cytoplasm, a gel-like substance inside the cell membrane. Protein factories called ribosomes then bind to the messenger RNA. The ribosome reads the code in blocks of three bases at a time, known as codons.

Each codon contains instructions for one of 20 different amino acids. The ribosome then produces a chain where the corresponding amino acids are strung together. The sequence and chemical reactions along the molecule allow it to fold, twist or coil into elaborate structures called polypeptides, which create protein. Each structure has specific functions within the body.

The building blocks of life

Proteins do much of the work inside the cells and are responsible for the structure, function, and regulation of the body’s tissues and organs. They can be described according to their large range of functions in the body, listed in alphabetical order:

Examples of Protein Functions

Function	Description	Example
Antibody	Antibodies bind to specific foreign particles, such as viruses and bacteria, to help protect the body.	Immunoglobulin G (IgG)
Enzyme	Enzymes carry out almost all of the thousands of chemical reactions that take place in cells. They also assist with the formation of new molecules by reading the genetic information stored in DNA.	Phenylalanine hydroxylase
Messenger	Messenger proteins, such as some types of hormones, transmit signals to coordinate biological processes between different cells, tissues, and organs.	Growth hormone
Structural component	These proteins provide structure and support for cells. On a larger scale, they also allow the body to move.	Actin
Transport/storage	These proteins bind and carry atoms and small molecules within cells and throughout the body.	Ferritin

Proteostasis

Proteostasis, or protein homeostasis, is a balanced state in which the cellular pathways required to produce proteins works flawlessly. This state is maintained by a system that adapts to meet the requirements of the cell, known as the proteostasis network (PN).

A 2020 research review states that the PN “comprises the machineries for the biogenesis, folding, conformational maintenance, and degradation of proteins with molecular chaperones as central coordinators.” This means that from the creation of a protein to its maintenance to its deterioration and ultimate removal, the PN is intricately involved in upholding the integrity of the entire proteome.

The PN does this sophisticated work using the following elements:

·  Ribosomes – translate RNA into proteins.

·  Chaperones and folding factors – guide polypeptides into the appropriate structures.

·  Degradation components – direct lysosomes to digest and recycle unwanted proteins. They can also include ubiquitin, a medium-chain polypeptide that is involved in the synthesis of new proteins as well as the destruction of defective ones.

Loss of proteostasis

As we age, our ability to sustain the essential process of proteostasis dwindles. The complexity and importance of this cannot be overstated. Internal and external stress can cause the unfolding of proteins or the improper folding during protein synthesis.

This inevitably leads to clustering and clumping, and eventually the accumulation of damaged and harmful proteins. All of this results in proteotoxic effects, which Sandri and Robbins refer to as “the adverse effects of damaged or misfolded proteins and even organelles on the cell.”

The good news is that there are “promising examples of genetic manipulations that improve proteostasis and delay aging in mammals.”

Until then, I have an opportunity

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