Research On Progeria Reveals Important Insights Into The Aging Process

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New research on accelerated aging disease Progeria is reinforcing the damaging role genomic instability and cellular senescence play in the aging process

Progeria, also known as Hutchinson-Gilford progeria syndrome, affects around 1 in 4 million people and affected children exhibit an abnormally accelerated aging process. This results in a distinctive appearance and fatal complications including atherosclerosis which mirror conventional age-related disease - but decades earlier. The vast majority of patients die from complications in their adolescent years, despite being mentally acute.

What causes it?

Progeria is triggered by mutations that result in a mutant form of a protein called Lamin A called Progerin. Progerin contains a particular chemical group called farmesyl that can no longer be removed, and this permanently locks Progerin to the membrane of the cell nucleus. A fibrous layer called the nuclear lamina ordinarily provides support to the nucleus and plays an essential role in both DNA replication and keeping your chromosomes healthy. Lamin A usually plays a key role in this nuclear lamina, but the mutated Progerin results in a deformed lamina that has disastrous consequences for the cell.

Here you can see the distinctive progeroid appearance and a deformed nucleus of a progeroid cell (bottom right) Credit: The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises


"The length of the telomeres in these children is about the same as that of an 80 or 90 year old. Somehow, progerin is accelerating this aspect of the aging process. This study offers one of the best pieces of evidence that damaged telomeres and premature senescence is detrimental to the body"


The importance of your telomeres

While many researchers have focused on the unique appearance of the nucleus in progeria patients, a team a the A*STAR Institute of Medical Biology (IMB) decided to focus on telomeres in the disease. Using a model of progeria in fibroblast cells, they discovered that gradually inputting more and more progerin eventually creates the characteristic 'weirdly' shaped nucleus. Not only that, telomeres were displaying signs of damage and the cells were becoming senescent. Telomeres play a crucial role in protecting your chromosomes from fraying as cells divide, and any fraying leads to DNA damage and frequently cellular senescence. These senescent cells were bad news

"They just sit there. They are not dividing but are metabolically active and start to secrete all sorts of junk that breaks down the extracellular matrix"

Explaining progeria

It turns out accumulation of this progerin protein is the key factor here. Cells that accumulate progerin faster experience this failure earlier, explaining why children with the disease usually have no mental deterioration. Cells in blood vessels however quickly amass progerin in their nuclei - leading to cardiovascular issues.

A breakthrough

Telomere shortening and damage is strongly associated with normal aging

In a therapeutic effort, the researchers increased levels of telomerase in the cells; an enzyme that lengthens telomeres. This seemed to rescue many of the behavioural problems in progerin filled cells. They then introduced a protein called lamina-associated polypeptide-α (LAP2α). LAP2α which is an important protein in the nuclear lamina that usually associates with the correct form of Lamin A. Surprisingly, this helped cell growth, prevented DNA damage and crucially delayed senescence.

"I didn't think it would work, to be honest. We were looking for a needle in a haystack. We just couldn't believe it. We reproduced the experiment about seven times, but every time we did this, the cells grew better"

After further analysis they discovered this LAP2α protein is located much closer to the telomeres in normal cells, but is somehow moved further away in cells with accumulated progerin. The researchers theorise that this mis-localisation could perhaps explain the telomere defects observed in progeric cells.

These insights may reveal a way to save or at least delay problems in progeric cells - giving progeria victims a better quality of life and longer lives. They also reinforce how important your telomeres and nuclear integrity are to overall health, further implicating them in normal aging.  

Read more at MedicalXpress