Progeria

Принимая во внимание сведения о том, что более половины территории России характеризуется экологически неблагоприятными условиями окружающей среды (ОС), что около 60% источников питьевого водоснабжения не соответствуют нормативным требованиям, а более 60% населения постоянно проживает на экологически загрязненных территориях, следует признать более справедливыми расчеты, определяющие долевой вклад экологического фактора в нарушение состояния здоровья и развитие основных форм патологии человека в пределах 40-60%.
В случае сложившихся промышленных центров мы имеем дело с проявлением особого рода очаговости экологической патологии человека, имеющей свои границы и специфику в различных регионах, свои особенности комплексного воздействия на здоровье, особенности формирования патологических процессов и заболеваемость постоянного и пришлого населения, что представляет собой весьма актуальную антропоэкологическую проблему.
Экологическая составляющая изменения и патоморфоза патологических процессов, несмотря на ее несомненную в большом числе случаев очевидность, до сих пор выпадает из поля зрения медицинской статистики заболеваемости населения и современных трактовок и объяснений особенностей патологии человека.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements. Recently, we identified Remodelin, a small-molecule agent that leads to amelioration of HGPS cellular defects through inhibition of the enzyme N-acetyltransferase 10 (NAT10). Here, we show the preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances the healthspan in a Lmna HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS.

A syndrome characterized by progeroid facies, multiple nevi, mild mental retardation, skin hyperextensibility, bruisability, moderate skin fragility, joint hypermobility principally in digits, is described in two unrelated patients. Electron microscopy of the skin showed some fragmentation of the elastic fibers' fibrous portion and moderate electrodensity in the amorphous portion. Since a practically identical constellation of clinical features was previously reported in three patients, the individualization of a distinct connective tissue disorder, probably autosomal dominant, with variable expressivity is concluded.

Scientific understanding of the genetic components of aging has increased in recent years, with several genes being identified as playing roles in the aging process and, potentially, longevity. In particular, genes encoding components of the nuclear lamina in eukaryotes have been increasingly well characterized, owing in part to their clinical significance in age-related diseases. This review focuses on one such gene, which encodes lamin A, a key component of the nuclear lamina. Genetic variation in this gene can give rise to lethal, early-onset diseases known as laminopathies. Here, we analyze the literature and conduct computational analyses of lamin A signaling and intracellular interactions in order to examine potential mechanisms for altering or slowing down aberrant Lamin A expression and/or for restoring the ratio of normal to aberrant lamin A. The ultimate goal of such studies is to ameliorate or combat laminopathies and related diseases of aging, and we provide a discussion of current approaches in this review.

Ancient Greek and Roman accounts of accelerated ageing fall into two main groups. The first group consists of mythological accounts of entire races born with grey hair, and these accounts generally obtain metaphorical or allegorical meanings about man's degenerate nature. The second group is comprised of literal accounts of real individuals who have aged astonishingly early, displaying such traits as baldness, wrinkled skin, bleary eyes, drooping ears, and muscle atrophy. The Greeks and Romans, completely unaware of any natural causes for such deformities, viewed such races and individuals as monstrous. Early Greek ethnographic accounts of grey-haired races placed them at the edges of the known world, in keeping with the ethnocentric desire to equate the monstrous with the uncivilised. Later, the Romans embraced the monstrous, deliberately seeking out such “freaks” for show and profit. Both types of account are most probably based on observations of the then unknown disease progeria. Persons suffering from progeria, a rare genetic mutation with no known treatment, display the signs of premature ageing described above.

Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16(INK4a), SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16(INK4a) associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16(INK4a) was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16(INK4a) and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression...

Ancient Greek and Roman accounts of accelerated ageing fall into two main groups. The first group consists of mythological accounts of entire races born with grey hair, and these accounts generally obtain metaphorical or allegorical meanings about man's degenerate nature. The second group is comprised of literal accounts of real individuals who have aged astonishingly early, displaying such traits as baldness, wrinkled skin, bleary eyes, drooping ears, and muscle atrophy. The Greeks and Romans, completely unaware of any natural causes for such deformities, viewed such races and individuals as monstrous. Early Greek ethnographic accounts of grey-haired races placed them at the edges of the known world, in keeping with the ethnocentric desire to equate the monstrous with the uncivilised. Later, the Romans embraced the monstrous, deliberately seeking out such “freaks” for show and profit. Both types of account are most probably based on observations of the then unknown disease prog...

Mutations in the lamin A/C gene that cause Hutchinson-Gilford progeria syndrome lead to expression of a truncated, permanently farnesylated prelamin A variant called progerin. Blocking farnesylation leads to an improvement in the abnormal nuclear morphology observed in cells expressing progerin, which is associated with a re-localization of the variant protein from the nuclear envelope to the nuclear interior. We now show that a progerin construct that cannot be farnesylated is localized primarily in intranuclear foci and that its diffusional mobility is significantly greater than that of farnesylated progerin localized predominantly at the nuclear envelope. Expression of non-farnesylated progerin in transfected cells leads to a redistribution of lamin A and lamin C away from the nuclear envelope into intranuclear foci but does not significantly affect the localization of endogenous lamin B1 at nuclear envelope. There is a similar redistribution of lamin A and lamin C into intranucl...

Have you ever noticed a small child playing with its fellows looking like an old man? This happens very rarely and the child looking like an old man is suffering from a genetic disease termed as 'Progeria'. The common name of progeria is Hutchinson-Gilford Progeria Syndrome and Hutchinson-Gilford syndrome. Actually speaking progeria is a very rare genetic disorder that occurs to one individual in eight million children born alive. The process of ageing is hastened in children suffering from progeria. The maximum life span of the children suffering from this genetic disorder is thirteen only although some reach to the age of twenties also. Individuals having progeria rarely complete their forties. The major cause of progeria is a genetic mutation that is not inherited. Progeria resembles another premature ageing disorder named as Dyskeratosis Congenita (DKC) which is inheritable and also occurs in the history of families. Scientist are very keen to understand the aspects of progeria as it will open the hidden mysteries of normal process of ageing. Progeria was first described by Jonathan Hutchinson in 1886 and independently by Hastings Gilford in 1897. Later on the disorder was names as Hutchinson-Gilford Progeria Syndrome (HGPS).

Age-related changes in splice-forms of LMNA, which encodes the nuclear lamina proteins lamin A/C, have not been investigated in skeletal muscle. In the rare premature ageing disease, Hutchinson-Gilford progeria syndrome (HGPS), de novo point mutations in LMNA activate a cryptic splice site in exon 11, resulting in a 150 base deletion in LMNA mRNA and accumulation of a truncated protein isoform, progerin. The LMNA Δ150 progerin transcript has also been found in trace quantities in tissues of healthy people and its implication in 'natural' ageing has been proposed. We therefore investigated the expression of progerin and lamin A/C in normal human and mouse skeletal muscles of different ages. LMNA Δ150 was detected in most muscle samples from healthy individuals aged 16-71 years, but was not present in any mouse muscle samples up to the age of 18 months. Real time qPCR of human muscle samples showed that there was an age-related increase in both the full length lamin A and LMNA...

Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-d...

The nuclear lamina is a complex reticular structure that covers the inner face of the nucleus membrane in metazoan cells. It is mainly formed by intermediate filaments called lamins, and exerts essential functions to maintain the cellular viability. Lamin A/C provides mechanical steadiness to the nucleus and regulates genetic machinery. Laminopathies are tissue-specific or systemic disorders caused by variants in LMNA gene (primary laminopathies) or in other genes encoding proteins which are playing some role in prelamin A maturation or in lamin A/C function (secondary laminopathies). Those disorders in which adipose tissue is affected are called laminopathic lipodystrophies and include type 2 familial partial lipodystrophy and certain premature aging syndromes. This work summarizes the main clinical features of these syndromes, their associated comorbidities and the clues for the differential diagnosis with other lipodystrophic disorders.

Анализ собственных результатов комплексных медико-экологических исследований в различных промышленных регионах страны и многочисленных литературных сведений последних десятилетий позволяет заключить, что повсеместно регистрируемые особенности течения, хронизации и патоморфоза основных  заболеваний населения промышленно загрязненных регионов,  изменение характера и структуры патологии и все большее распространение дистрофических, дегенеративных и опухолевых процессов в настоящее время определяются не столько климато-географическими, ландшафтными и геохимическими особенностями селитебных территорий, сколько антропогенными экологическими нарушениями и интенсивным загрязнением всех компонентов окружающей человека среды.