Hutchinson-Gilford progeria syndrome (HGPS), or simply progeria, is a rare genetic condition that presents the superficial appearance of greatly accelerated aging. It isn't in fact accelerated aging, but rather one specific form of molecular damage run amok, causing severe and increasing dysfunction in near all cells. Normal aging is a collection of many varied forms of molecular damage that eventually cause severe and increasing dysfunction in near all cells. The consequences of a failure of any given population of cells or an organ to function correctly can appear superficially similar even if the causes are not the same, but as soon as one digs in to the details, the different mechanisms become evidence and significant.
Soon after the turn of the century, the cause of progeria was identified: a mutation in the LMNA gene that gives rise to a broken protein now called progerin. The normal, unbroken form of this protein, lamin A, is a vital part of the internal structure of a cell, and once once that structural support falters, all of the other finely balanced mechanisms begin to fail as well. Soon thereafter, it was discovered that progerin can also be found in small amounts in older genetically normal individuals, and for many years it has been an open question as to whether progerin plays a significant role in the degeneration of normal aging. Given that it exists, it is certainly causing harm, but the size of the effect is key: there are plenty of areas in the biochemistry of aging where it might be argued that observed forms of damage and change do not rise to the level of being significant causes of dysfunction, disease, and mortality. We can worry about them after every other problem is fixed.
The paper here identifies a patient group suffering from an age-related disease in which progerin is elevated in comparison to their healthier peers. This is an intriguing addition to what is known of progerin in normal aging. It is still a long way from being able to assign numbers to the position of progerin in a hierarchy of cell damage, especially given that the research community has yet to achieve this for any of the other root causes of aging, but it is a small step along that road. It also suggests that a more careful survey of age-related disease might turn up other conditions in which progerin may be either a contributing factor, or a consequence of other disease processes.
Age is a major cardiovascular risk factor including cardiovascular disease. Therefore, elucidating aging-related processes might lead to the identification of novel treatment options for heart failure, which has a prevalence of 1-2% in the adult population in developed countries and is a growing health care problem worldwide. Premature aging-like syndromes like Hutchinson-Gilford progeria syndrome (HGPS) have been investigated to achieve a better understanding of pathophysiological aging processes. HGPS is based on mutations affecting the proper encoding and further processing of lamin A an important protein in the nucleus of eukaryotic cells resulting in misprocessed lamin A (progerin) which also plays an important role in normal ageing.
Lamin A is an intermediate filament protein which is involved in forming a filamentous meshwork between the chromatin and the nuclear membrane. It is very important to keep the nuclear envelope upright regulating important processes like DNA replication, DNA repair, and RNA transcription. In 90% of the cases in HGPS a point mutation in the LMNA A gene results in the production of a truncated prelamin A protein, also called progerin. Consequently, the protein cannot be processed to functional lamin A, causing structural and functional nuclear abnormalities.
With time proceeding progerin accumulates in the nucleus and not only alters the structure of the nuclear lamina but also negatively influences the stiffness and mechanochemical properties of the nucleus. Patients with HGPS develop severe cardiovascular morbidities like atherosclerosis and heart failure and die as teenagers due to stroke or myocardial infarction. Toward the end of life HGPS patients suffer from cardiomegaly and cardiac dilatation. It has been shown that low levels of progerin are expressed in non HGPS-cells and that a positive correlation exists between accumulation of progerin in the nucleus and the process of ageing. However, the role of progerin in human dilated cardiomyopathy (DCM), a major reason of severe heart failure, has never been investigated so far.
Here we provide first experimental evidence that progerin, associated with premature aging in HGPS is upregulated in human DCM. Progerin mRNA expression in the heart was strongly significantly correlated with left ventricular remodeling. Although there was a weak positive correlation between age and progerin mRNA expression, statistical testing revealed no significant differences. These data suggest that not the age of the heart per se but rather the process of "myocardial aging" defined by a progressive deterioration in cellular and organ function with time is associated with increased levels of progerin mRNA.
It is known that prelamin A accumulation plays a key role in aging in several tissues, including the vasculature and is discussed as a marker for vascular aging. However, it is currently unknown whether this is relevant in myocardial aging, too. Since LMNA gene mutations are causally involved in patients with idiopathic dilated cardiomyopathy (3.6%) and familial dilated cardiomyopathy (7.5%), we hypothesized that accumulation of progerin in non-HGPS individuals in the heart may as well be involved in the progression of DCM. To our knowledge we show for the first time that progerin is upregulated in human DCM hearts suggesting that accumulation of progerin (prelamin A) could be involved in the progression of DCM and myocardial aging.