Seminar in Biological Mechanisms of Aging and Cancer/Loss of Proteostasis

The Hallmarks of Aging review, authored by López-Otín et. al, summarizes the major components that scientists, up to 2013, had known to be the underlying causes of aging at the cellular level. In this extensive review published in the scientific journal Cell, one of the nine hallmarks that the authors highlight is the loss of proteostasis. The loss of proteostasis means that over time, as an organism ages, the number of damaged proteins increases in the cell. The loss of proteostasis can also mean that over time, once-abundant proteins become less abundant. This can impact a cell's ability to carry out reactions needed for proper function because these proteins are key components of such reactions.

Attempt at a graphical abstract showing a summary of the major findings of the Zhang and Cuervo article presented.

The authors of the review divide this big area of research into three key categories including: authophagy, proteosomal degradation, and protein folding. Authophagy is the cellular mechanism for the removal of bad proteins and waste. Proteosomal degradation is the elimination of proteins by other proteins whose function is to keep a stable environment with no too-little or too-much of a specific protein. Protein folding goes into the cell's way of fixing the many errors that occur on a daily-basis. Often times, proteins misfold. Thankfully, there are several mechanisms that allow for these misfolded proteins to get folded correctly. The review uses these three categories to explain how, over time, these mechanisms become less accurate. The lack of accuracy ultimately leads to a build-up of bad proteins, which in turn result in aging.

Scientists can study how stable the cellular environment is when it comes to its many proteins. By comparing the protein environments of young organisms as compared to old organisms, researchers can make conclusions as to what kind of environment is characteristic of aged organisms. From these observations, they can also study how keeping these environments constant as an organism ages impacts their overall health and performance. An example of one of these experiments is shown in the article published in the journal Nature Medicine in 2008 and titled Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function.

In this study, Zhang and Cuervo focused on the mechanism known as chaperone-mediated autophagy. Like previously state, autophagy is the way in which cells drive waste and oxidized proteins to the lysosome for their degradation. Over time, a protein known as LAMP-2A (lysosomal membrane associated protein-2A), which is a key component of chaperone-mediated autophagy, decreases in abundance. This leads to a build up of oxidized proteins in the cell because even though the non-functioning proteins are being driven to the lysosome, the LAMP-2A is not as abundant and not as many proteins are getting to the inside of the lysosome.

Knowing such pattern in which abundance of LAMP-2A decreases with time, the researchers wanted to know what would happen if LAMP-2A is kept at constant levels of abundance throughout the lifetime of a mouse. To answer this question, they created a double-transgenic mouse, which is a mouse that has had a gene implanted in its genome that makes it different than the normal, wild-type, organism. This gene created a copy of the LAMP-2A protein and was specifically controlled by the presence of an antibiotic in the food that was fed to the mouse. If the antibiotic was present, the extra copy of LAMP-2A was not made. If the antibiotic was absent, the extra copy of the LAMP-2A was made. Having this ability allowed the cellular biologists to have a pathway to keeping the amount of LAMP-2A abundant throughout the lifespan of the mouse.

When compared to the wild-type, the transgenic mouse at twenty-two months of age showed the very similar cellular maintenance and liver function than that of a mouse at six months of age. They also found out that even if the gene is turned on in later stages of the life of the mouse, there are still improvements in the cellular stability.

The scientists were then able to make an educated explanation that if LAMP-2A is kept abundant throughout life, then the cell is able to carry out chaperone-mediated autophagy at the same rate as a young organism, which then leads to better liver function and cellular stability for older organisms.