Progeria syndromes and ageing: what is the connection?

One of the many debated topics in ageing research is whether progeroid syndromes are really accelerated forms of human ageing. The answer requires a better understanding of the normal ageing process and the molecular pathology underlying these rare diseases. Exciting recent findings regarding a severe human progeria, Hutchinson-Gilford progeria syndrome, have implicated molecular changes that are also linked to normal ageing, such as genome instability, telomere attrition, premature senescence and defective stem cell homeostasis in disease development. These observations, coupled with genetic studies of longevity, lead to a hypothesis whereby progeria syndromes accelerate a subset of the pathological changes that together drive the normal ageing process.

Senescent cells: SASPected drivers of age-related pathologies.

The progression of physiological ageing is driven by intracellular aberrations including telomere attrition, genomic instability, epigenetic alterations and loss of proteostasis. These in turn damage cells and compromise their functionality. Cellular senescence, a stable irreversible cell-cycle arrest, is elicited in damaged cells and prevents their propagation in the organism. Under normal conditions, senescent cells recruit the immune system which facilitates their removal from tissues. Nevertheless, during ageing, tissue-residing senescent cells tend to accumulate, and might negatively impact their microenvironment via profound secretory phenotype with pro-inflammatory characteristics, termed senescence-associated secretory phenotype (SASP). Indeed, senescent cells are mostly abundant at sites of age-related pathologies, including degenerative disorders and malignancies. Interestingly, studies on progeroid mice indicate that selective elimination of senescent cells can delay age-related deterioration. This suggests that chronic inflammation induced by senescent cells might be a main driver of these pathologies. Importantly, senescent cells accumulate as a result of deficient immune surveillance, and their removal is increased upon the use of immune stimulatory agents. Insights into mechanisms of senescence surveillance could be combined with current approaches for cancer immunotherapy to propose new preventive and therapeutic strategies for age-related diseases.

Acro-osteolysis, keloid like-lesions, distinctive facial features, and overgrowth: two newly recognized patients with premature aging syndrome, Penttinen type.

We report on two unrelated patients with a rare progeroid syndrome first described by Penttinen. Patients presented with prematurely aged appearance, delayed dental development, acro-osteolysis, diffuse keloid-like lesions, and ocular pterygia. Facial features are progressive but recognizable at birth. Premaxillary and maxillary retraction with pseudo-prognathism and palpebral malocclusion are characteristic. Thumbs and halluces are broad and spatulated. Linear growth is increased and intellectual functions are preserved. Skin retractions and joint contractures progressively developed during adolescence. Death occurred in the second decade in one of the patient due to restrictive respiratory insufficiency and cachexia. LMNA and ZMPSTE24 sequencing were normal. The molecular basis of the disorder remains unknown.

An accumulation of non-farnesylated prelamin A causes cardiomyopathy but not progeria.

Lamin A is formed from prelamin A by four post-translational processing steps-farnesylation, release of the last three amino acids of the protein, methylation of the farnesylcysteine and the endoproteolytic release of the C-terminal 15 amino acids (including the farnesylcysteine methyl ester). When the final processing step does not occur, a farnesylated and methylated prelamin A accumulates in cells, causing a severe progeroid disease, restrictive dermopathy (RD). Whether RD is caused by the retention of farnesyl lipid on prelamin A, or by the retention of the last 15 amino acids of the protein, is unknown. To address this issue, we created knock-in mice harboring a mutant Lmna allele (LmnanPLAO) that yields exclusively non-farnesylated prelamin A (and no lamin C). These mice had no evidence of progeria but succumbed to cardiomyopathy. We suspected that the non-farnesylated prelamin A in the tissues of these mice would be strikingly mislocalized to the nucleoplasm, but this was not the case; most was at the nuclear rim (indistinguishable from the lamin A in wild-type mice). The cardiomyopathy could not be ascribed to an absence of lamin C because mice expressing an otherwise identical knock-in allele yielding only wild-type prelamin A appeared normal. We conclude that lamin C synthesis is dispensable in mice and that the failure to convert prelamin A to mature lamin A causes cardiomyopathy (at least in the absence of lamin C). The latter finding is potentially relevant to the long-term use of protein farnesyltransferase inhibitors, which lead to an accumulation of non-farnesylated prelamin A.

Premature aging syndrome.

Hutchinson-Gilford progeria syndrome and Werner syndrome are two of the best characterized human progeroid diseases with clinical features mimicking physiological aging at an early age. Both disorders have been the focus of intense research in recent years since they might provide insights into the pathology of normal human aging. The chapter contains a detailed description of the clinical features of both disorders and then it focuses on the genetics, the resulting biochemical alterations at the protein level and the most recent findings and hypotheses concerning the molecular basis of the premature aging phenotypes. A description of available diagnostic and therapeutic approaches is included.

Progeroid syndromes and UV-induced oxidative DNA damage.

Progeroid syndromes are a group of diseases characterized by signs of premature aging. These syndromes comprise diseases such as Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford syndrome, Fanconi anemia, and ataxia-telangiectasia, as well as xeroderma pigmentosum, trichothiodystrophy, and Cockayne syndrome. Clinical symptoms of premature aging are skin atrophy with loss of cutaneous elasticity, dysfunction of cutaneous appendices, degeneration of the central nervous system and an increased susceptibility for malignant tumors. Genetic defects in the repair of DNA damage can lead to progeroid syndromes, and it is becoming increasingly evident that direct DNA damage and indirect damage by highly reactive oxygen species play central roles in aging. The clinical signs of progeroid syndromes and the molecular aspects of UV (ultraviolet radiation)-induced oxidative stress in aging are discussed.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 8-14; doi:10.1038/jidsymp.2009.6.

Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice.

How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age), including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPD(G602D/R722W)/XPA(-/-)) that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80(-/-) mouse. Specific (but not all) types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage.

Mouse models in modeling aging and cancer.

Mouse models have been widely used in the research of human diseases. Aging, just as cancer, is influenced by the interaction of various genetic and environmental factors. Currently, aging could be induced by many mechanism, including telomere dysfunction, oxidase stress, DNA damage and epigenetic changes. Many of these genetic pathways are also shared by aging and cancer. The mouse models generated to study these pathways might manifest either aging or cancer phenotypes, sometimes both, which in deed has worked as a good model system in understanding the correlation between aging and cancer. Here, we reviewed these mouse models that were generated to model aging or cancer. These mouse models might help us put those related pathways in context and discover essential interactions in cancer and aging regulation.

A Tissue Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome Using Human iPSC-derived Smooth Muscle Cells.

Hutchison-Gilford Progeria Syndrome (HGPS) is a rare, accelerated aging disorder caused by nuclear accumulation of progerin, an altered form of the Lamin A gene. The primary cause of death is cardiovascular disease at about 14 years. Loss and dysfunction of smooth muscle cells (SMCs) in the vasculature may cause defects associated with HGPS. Due to limitations of 2D cell culture and mouse models, there is a need to develop improved models to discover novel therapeutics. To address this need, we produced a functional three-dimensional model of HGPS that replicates an arteriole-scale tissue engineered blood vessel (TEBV) using induced pluripotent stem cell (iPSC)-derived SMCs from an HGPS patient. To isolate the effect of the HGPS iSMCs, the endothelial layer consisted of human cord blood-derived endothelial progenitor cells (hCB-EPCs) from a separate, healthy donor. TEBVs fabricated from HGPS iSMCs and hCB-EPCs show reduced vasoactivity, increased medial wall thickness, increased calcification and apoptosis relative to TEBVs fabricated from normal iSMCs or primary MSCs. Additionally, treatment of HGPS TEBVs with the proposed therapeutic Everolimus, increases HGPS TEBV vasoactivity and increases iSMC differentiation in the TEBVs. These results show the ability of this iPSC-derived TEBV to reproduce key features of HGPS and respond to drugs.

Protein modification in aging: an update.

Post-translational modifications of proteins are an important biologic tool for the production of various protein species from a single gene, which may vary in conformation, function, biologic half-life and complex formation with other proteins. The present minireview summarizes a few selected research observations important for the role of post-translational modifications in biologic aging and age-related diseases, including farnesylation, methylglyoxal-derivatization, transglutaminase pathways and the formation of 3-nitrotyrosine and 2-oxo-histidine in vivo.

Genetic alterations in accelerated ageing syndromes. Do they play a role in natural ageing?

The molecular mechanisms leading to human senescence are still not known mostly because of the complexity of the process. Different research approaches are used to study ageing including studies of monogenic segmental progeroid syndromes. None of the known progerias represents true precocious ageing. Some of them, including Werner (WS), Bloom (BS), and Rothmund-Thomson syndromes (RTS) as well as combined xeroderma pigmentosa-Cockayne syndrome (XP-CS) are characterised by features resembling precocious ageing and the increased risk of malignant disease. Such phenotypes result from the mutations of the genes encoding proteins involved in the maintenance of genomic integrity, in most cases DNA helicases. Defective functioning of these proteins affects DNA repair, recombination, replication and transcription. Other segmental progeroid syndromes, such as Hutchinson-Gilford progeria (HGPS) and Cockayne syndrome are not associated with an increased risk of cancer. In this paper we present the clinical and molecular features of selected progeroid syndromes and describe the potential implications of these data for studies of ageing and cancer development.

The accelerated occurrence of age-related changes of organism in Chernobyl workers: a radiation-induced progeroid syndrome?

The rate of aging was studied in 306 persons working at Chernobyl Atomic Power Station after the accident by means of integral and partial biological age assessment. An accelerated rate of aging was found in 81% of men and in 77% of women in comparison with a control random population sample of Kiev. Persons younger than 45 years appeared to be more vulnerable to radiation. The biological age of persons who worked in the contaminated zone immediately after the disaster exceeded the biological age in those who arrived in Chernobyl 4 months later. The biological age in the investigated persons exceeded its average populational value for 5 years (the integral biological and partial cardiopulmonary age) and for 11 years for the partial psychological age. These data may underlie the concept of radiation progeroid syndrome as the form of accelerated aging.

Gastrointestinal complications of spinal cord injury.

The incidence, nature, and radiographic features of gastrointestinal complications encountered in a group of 567 consecutive spinal-cord-injury patients are reported. Eighty-seven episodes of gastrointestinal complications developed in 63 (11%) patients. During the first month postinjury, these complications consisted of ileus, gastric dilatation, the body cast syndrome, peptic ulcer disease, and pancreatitis. More chronically these patients presented with fecal impactions, peptic ulcer disease, the superior mesenteric artery syndrome, hepatitis, amyloidosis, and the precocious appearance of diverticulosis, hiatus hernia, and gastroesophageal reflux. Radiographic findings were diagnostic in the majority of cases and aided in the early diagnosis of these potentially life-threatening complications.

The cell biology of aging.

It is only within the past ten years that biogerontology has become attractive to a sufficient number of biologists so that the field can be regarded as a seriously studied discipline. Cytogerontology, or the study of aging at the cellular level, had its genesis about 20 years ago when the dogma that maintained that cultured normal cells could replicate forever was overturned. Normal human and animal cells have a finite capacity to replicate and function whether they are cultured in vitro or transplanted as grafts in vivo. This phenomenon has been interpreted to be aging at the cellular level. Only abnormal somatic cells are capable of immortality. In recent years it has been found that the number of population doublings of which cultured normal cells are capable is inversely proportional to donor age. There is also good evidence that the number of population doublings of cultured normal fibroblasts is directly proportional to the maximum lifespan of ten species that have been studied. Cultures prepared from patients with accelerated aging syndromes (progeria and Werner's syndrome) undergo far fewer doublings than do those of age-matched controls. The normal human fibroblast cell strain WI-38 was established in 1962 from fetal lung, and several hundred ampules of these cells were frozen in liquid nitrogen at that time. These ampules have been reconstituted periodically and shown to be capable of replication. This represents the longest period of time that a normal human cell has ever been frozen. Normal human fetal cell strains such as WI-38 have the capacity to double only about 50 times. If cultures are frozen at various population doublings, the number of doublings remaining after reconstitution is equal to 50 minus the number of doublings that occurred prior to freezing. The memory of the cells has been found to be accurate after 23 years of preservation in liquid nitrogen. Normal human cells incur many physiologic decrements that herald the approach of their failure to divide. Many of these functional decrements are identical to decrements found in humans as they age. Thus it is likely that these decrements are also the precursors of age changes in vivo. The finite replicative capacity of normal cells is never seen to occur in vivo because aging and death of the individual occurs well before the doubling limit is reached.

[Werner syndrome. Apropos of a case]. / Le syndrome de Werner. A propos d'un cas.

A 26 year-old woman, whose parents were consanguineously married, was admitted to our center because of bilateral juvenile cataract. The patient exhibited short stature, sclerodermalike appearance of the skin with a typical bird-like facies, thinning and graying of hair, high pitched voice and hypogonadism. Werner's syndrome, was diagnosed. History, pathogeny, clinical features, diagnosis and cataract surgery are discussed.

TRF2 and lamin A/C interact to facilitate the functional organization of chromosome ends.

Telomeres protect the ends of linear genomes, and the gradual loss of telomeres is associated with cellular ageing. Telomere protection involves the insertion of the 3' overhang facilitated by telomere repeat-binding factor 2 (TRF2) into telomeric DNA, forming t-loops. We present evidence suggesting that t-loops can also form at interstitial telomeric sequences in a TRF2-dependent manner, forming an interstitial t-loop (ITL). We demonstrate that TRF2 association with interstitial telomeric sequences is stabilized by co-localization with A-type lamins (lamin A/C). We also find that lamin A/C interacts with TRF2 and that reduction in levels of lamin A/C or mutations in LMNA that cause an autosomal dominant premature ageing disorder--Hutchinson Gilford Progeria Syndrome (HGPS)-lead to reduced ITL formation and telomere loss. We propose that cellular and organismal ageing are intertwined through the effects of the interaction between TRF2 and lamin A/C on chromosome structure.

p.Pro4Arg mutation in LMNA gene: a new atypical progeria phenotype without metabolism abnormalities.

Hutchinson-Gilford progeria syndrome (HGPS) is a typical presenile disorder, with mutation in the LMNA gene. Besides HGPS, mutations in LMNA gene have also been reported in atypical progeroid syndrome (APS). The objective of the study was to investigate the phenotype and molecular basis of APS in a Chinese family. LMNA gene mutations were also reviewed to identify the phenotypic and pathogenic differences among APS. Two siblings in a non-consanguineous Chinese family with atypical progeria were reported. The clinical features were observed, including presenile manifestations such as bird-like facial appearance, generalized lipodystrophy involving the extremities and mottled hyperpigmentation on the trunk and extremities. A heterozygous mutation c.11C>G (p.Pro4Arg) of the LMNA gene was detected in the two patients. 28 different variants of the LMNA gene have been reported in APS families, spreading over almost all the 12 exons of the LMNA gene with some hot-spot regions. This is the first detailed description of an APS family without metabolism abnormalities. APS patients share most of the clinical features, but there may be some distinct features in different ethnic groups.

Biogenesis of the Saccharomyces cerevisiae pheromone a-factor, from yeast mating to human disease.

The mating pheromone a-factor secreted by Saccharomyces cerevisiae is a farnesylated and carboxylmethylated peptide and is unusually hydrophobic compared to other extracellular signaling molecules. Mature a-factor is derived from a precursor with a C-terminal CAAX motif that directs a series of posttranslational reactions, including prenylation, endoproteolysis, and carboxylmethylation. Historically, a-factor has served as a valuable model for the discovery and functional analysis of CAAX-processing enzymes. In this review, we discuss the three modules comprising the a-factor biogenesis pathway: (i) the C-terminal CAAX-processing steps carried out by Ram1/Ram2, Ste24 or Rce1, and Ste14; (ii) two sequential N-terminal cleavage steps, mediated by Ste24 and Axl1; and (iii) export by a nonclassical mechanism, mediated by the ATP binding cassette (ABC) transporter Ste6. The small size and hydrophobicity of a-factor present both challenges and advantages for biochemical analysis, as discussed here. The enzymes involved in a-factor biogenesis are conserved from yeasts to mammals. Notably, studies of the zinc metalloprotease Ste24 in S. cerevisiae led to the discovery of its mammalian homolog ZMPSTE24, which cleaves the prenylated C-terminal tail of the nuclear scaffold protein lamin A. Mutations that alter ZMPSTE24 processing of lamin A in humans cause the premature-aging disease progeria and related progeroid disorders. Intriguingly, recent evidence suggests that the entire a-factor pathway, including all three biogenesis modules, may be used to produce a prenylated, secreted signaling molecule involved in germ cell migration in Drosophila. Thus, additional prenylated signaling molecules resembling a-factor, with as-yet-unknown roles in metazoan biology, may await discovery.

Schizophrenia as segmental progeria.

Schizophrenia is associated with a variety of physical manifestations (i.e. metabolic, neurological) and despite psychotropic medication being blamed for some of these (in particular obesity and diabetes), there is evidence that schizophrenia itself confers an increased risk of physical disease and early death. The observation that schizophrenia and progeroid syndromes share common clinical features and molecular profiles gives rise to the hypothesis that schizophrenia could be conceptualized as a whole body disorder, namely a segmental progeria. Mammalian cells employ the mechanisms of cellular senescence and apoptosis (programmed cell death) as a means to control inevitable DNA damage and cancer. Exacerbation of those processes is associated with accelerated ageing and schizophrenia and this warrants further investigation into possible underlying biological mechanisms, such as epigenetic control of the genome.