Increased Levels of Progerin Observed in Overweight Individuals

Progerin is the malformed version of LMNA, a protein vital to the structure of the cell nucleus. It is the cause of progeria, a rare condition that has the superficial appearance of greatly accelerated aging. It isn't aging, however, but rather an enormous burden of cellular damage and dysfunction resulting from structural issues in the cell nucleus that affect near all forms of function. In normal aging, there is also an enormous burden of damage and dysfunction, but this arises from a completely different mix of issues. Some of the end results, such as cardiovascular disease, are somewhat similar, but one can't compare the two if interested in first causes.

In the case of patients with progeria, the LMNA gene is mutated, resulting in large amounts of progerin. One of the interesting observations made over the past decade is that some tiny fraction of LMNA is malformed in older people without progeria, however, and it has been suggested that this may contribute to the aging progress. As for many such mechanisms, the question is whether or not its contribution is significant in comparison to that resulting from the various other forms of disarray in aging tissues. That question has not been resolved. The easiest way to do so would be to find an efficient way to remove or block the activity of all progerin and observe the results, but that has yet to take place.

In the open access paper noted here, researchers report on the interesting observation that overweight individuals have higher levels of progerin. Being overweight does in fact accelerate most of the processes of aging. Visceral fat tissue is metabolically active, and generates chronic inflammation through a range of different mechanisms, from increased numbers of senescent cells through to inappropriate signaling on the part of normal fat cells. Inflammation drives the progression of many forms of age-related disease. Again we might ask the question: given this sizable contribution, is the presence of progerin in the observed amounts significant? Answers will remain speculative until such time as the progerin can be removed.

High Body Mass Index is Associated with Elevated Blood Levels of Progerin mRNA

Excess weight is growing in frequency globally. Obesity is associated with morbidity and premature mortality and represents a major risk factor for many diseases especially cardiovascular disease. It is linked to a significant decrease in life expectancy of 5-10 years in comparison to persons with Body-Mass-Index (BMI) between 22.5 to 24.9. An elevated BMI, adipose tissue and muscular fat depositions, respectively, have been associated with aging. Aging is defined as deterioration of cellular and organ function with time related to many physiologic and phenotypical changes and represents the strongest risk factor for myocardial infarction, stroke, diabetes, and cancer. Therefore, premature aging-like syndromes such as Hutchinson-Gilford progeria syndrome (HGPS) are of particular interest in exploring pathophysiological changes of aging processes related to cardiovascular disease.

HGPS is based on mutations influencing the precise encoding and processing of lamin A (LMNA) an important filament protein in the nucleus of eukaryotic cells. LMNA is involved in the correct forming of a filamentous meshwork between chromatin and the nuclear membrane, keeping the nuclear envelope upright, which is essential to regulate processes like DNA replication, DNA repair, and RNA transcription. Individuals suffering from HGPS exhibit early cardiovascular atherosclerosis and often die due to heart attack and stroke as teenagers. Toward the end of life, HGPS patients also suffer from heart failure due to cardiac fibrosis and cardiomegaly.

In most HGPS cases, a single point mutation activates a cryptic splicing site causing the production of 50 amino acids truncated prelamin A called progerin. Progerin lacks the cleavage site for zinc-metalloproteinase (ZMPSTE24) resulting in accumulation in the nucleus, leading to disturbed lamina, telomere and DNA damages, apoptosis, early cellular senescence, and finally to deterioration of organ function. Astonishingly, it was shown that low amounts of progerin mRNA derived by alternative splicing are also expressed in healthy individuals leading to the discussion of the role of progerin in normal aging by various groups. Since obesity and premature aging are both accompanied with an increased cardiovascular morbidity and mortality, we aimed to investigate the association of BMI with respect to progerin mRNA expression in the blood of individuals with known cardiovascular disease.

This study shows that mRNA levels of the aging related lamin A splice variant progerin, associated with premature aging in HGPS, were significantly upregulated in subjects with BMI ≥ 25 kg/m2. Moreover, our data revealed a significantly positive correlation of BMI with progerin mRNA. These data provide to our knowledge for the first-time evidence for a possible involvement of progerin in previously observed accelerated aging of overweight and obese individuals potentially limiting their longevity. Our results also showed that progerin mRNA was positively correlated with C-reactive protein (CRP). This might suggest an association of progerin with an inflammatory response triggering accelerated aging. Moreover, we found an increase of the acute phase protein CRP in patients with BMI ≥ 25, indicating a higher systemic inflammatory status in the overweight group. This is consistent with prior findings where obesity was considered to predispose to local and systemic inflammation with ongoing activation of immune cells.