Rapidly Aging Cells May Contribute to Shorter Lifespan of Fabry Patients, Study Finds

Certain cells in patients with Fabry disease seem to age more rapidly than in healthy people, which may explain why patients have a shorter lifespan compared to the general population, a study has found.

By measuring “molecular clocks” linked to aging, called telomeres, researchers saw that cells from male patients looked “older,” a possible reason why men with Fabry disease typically don’t live as long as women.

The researchers suggested that testing for telomere markers may be a possible way to help identify patients at high risk of disease progression.

Their study, “Aging in Fabry Disease: Role of Telomere Length, Telomerase Activity, and Kidney Disease,” was published in the journal Nephron.

Generally, the lifespan of patients with Fabry disease is much shorter than the general population. On average, untreated male patients live about 58 years, which is nearly 20 fewer years than men without the disease, and female patients live up to age 75, or about five years less than women without Fabry.

Fabry patients accumulate sugar-fat molecules, specifically globotriaosylceramide (Gb3 or GL-3) and related molecules, in tissues throughout the body. This results in injury to several organs, most commonly to small blood vessels, heart, and kidneys, which can lead to chronic kidney disease (CKD) and kidney failure.

Fabry disease has been linked to increased levels of oxidative stress and inflammation, both of which are known to contribute to aging. Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species, are harmful to the cells and are associated with a number of diseases.

Accelerated aging due to widespread inflammation is common in chronic diseases, and particularly in people with CKD, which occurs frequently in patients with Fabry disease.

With this in mind, researchers were interested in investigating whether cells of patients with Fabry disease aged faster and if that had an impact on disease progression.

They focused on telomeres as potential biomarkers of aging. Telomeres are DNA sequences at the end of chromosomes that protect them from wearing down and getting scrambled — much like an aglet, the small sheath on the tip of shoelaces that keeps them from unraveling.

Each time a cell divides, telomeres grow shorter. When telomeres get too short, the cell can no longer divide and becomes inactive or dies — this is what accounts for some of the changes seen in aging.

Hence, telomere length can be used as a “molecular clock” of biological age, where longer telomeres are a sign of youth, and shorter ones mark older age, researchers say.

To prevent telomeres from getting dangerously short, cells produce an enzyme called telomerase which adds new pieces of DNA to telomeres from time to time. In this way, the level of telomerase activity can reflect the capacity of cells to resist aging.

To determine the biological age of cells from Fabry patients, the researchers measured the telomere length and telomerase activity (telomerase levels) in white blood cells, or leukocytes, of 33 patients (13 males and 20 females) and compared them against the white blood cells of 66 healthy subjects (median age of 45 years).

Nineteen of these patients were receiving enzyme replacement therapy (ERT) with Replagal (agalsidase alfa) or Fabrazyme (agalsidase beta).

The researcher found that telomeres were significantly shorter in people with Fabry disease than in healthy controls (0.69 vs. 0.73 relative units).

Conversely, telomerase was more active in those with Fabry than in healthy individuals (1.55 vs. 1.19, relative units), which the researchers believe could be the body’s response to counteract telomere shortening and avoid accelerated aging.

Male patients had shorter telomere lengths (“older” biological age) and appeared to lack enough telomerase to compensate for this loss. This “may explain the large difference in survival” between females and males with Fabry disease, the researchers noted.

To see if aging was linked to disease severity and complications, the researchers analyzed patients who were divided by kidney function or level of protein in their urine (proteinuria), which can also be a sign of kidney injury.

Telomere length was not influenced, but telomerase activity was significantly lower in those with poorer kidney health — suggesting that at advanced stages of kidney disease, cells can no longer cope with accelerate aging.

“Our study reports important new information on telomere shortening and compensatory [telomerase activity ] which, in addition to the permanent chronic inflammation and oxidative stress already described, supports accelerating aging leading to premature death in [Fabry disease],” the researchers wrote.

Therefore, testing for telomere parameters “could provide important information regarding high-risk patients and could serve as a marker of disease progression and affect disease-specific treatment,” they said.