Hierarchical deterioration of body systems in Werner's syndrome: Implications for normal ageing

doi:10.1016/S0047-6374(97)00111-5

Mechanisms of Ageing and Development

Volume 98, Issue 3, December 1997, Pages 239-254

https://doi.org/10.1016/S0047-6374(97)00111-5 Get rights and content

Abstract

Normal human ageing is a complicated biological phenomenon. `Werner's syndrome (WS)', caused by mutations of RecQ type DNA helicase, has been recognized as a top ranking `segmental' progeroid syndrome. Patients with WS show a wide variety of clinical and biological manifestations in the four major self-assembly body systems (nervous, immune, connective tissue and endocrine-metabolic systems) similar to normal ageing at an early stage of their life, followed by death at an average age of 46. The sequential appearance of clinical and biological deterioration of the body systems observed in WS suggested that the disorder is more than a segmental progeroid syndrome, analysis of which may shed new light on the question `Why and how we age?'

Introduction

The human comes into being, grows to adulthood and ages, accompanied by an increased frequency of death [1]. Ageing is a complicated biological phenomenon consisting of (1) natural (physiological) ageing and (2) diseased (pathological) ageing. However, the two kinds of ageing are closely interrelated and cannot be completely separated. Normal ageing may be an appropriate term for ageing as a whole and ageing-related phenomena in the general population.

Werner's syndrome (WS), a genetically-determined (autosomal recessive inheritance) segmental premature ageing syndrome, has been viewed as a model of natural human ageing [2]. The patients with WS manifest relatively uniform signs and symptoms of a variety of elderly phenomena at an early stage of their life 3, 4. In addition to the early onset of age-related clinical manifestations and a short life span (average age at death is 46 years), the numerous in vitro experiments of WS cells and body fluids have suggested their striking similarity to the normal ageing process 5, 6, 7, 8, 9, 10, 11.

Despite the fact that much attention has been paid to this unique syndrome, the rarity of WS patients and the reduced proliferative potential of their cells have limited the opportunities for study. Worldwide, 1100 patients with WS have been reported since the first description by Otto Werner in 1904 [12], up to 1994 [11]. Seventy five percent were of Japanese descent. 70% of the patients are offspring of consanguineous marriage [4].

Extensive clinical investigation into over 800 Japanese patients with WS has suggested that their characteristic signs and symptoms appear in a sequence that can be grouped into four system-based clinical conditions; nervous, immune, connective tissue, endocrine-metabolic systems and a mixture of the four systems (NICE body system) (Table 1).

The phenomenon of hierarchical deterioration of the NICE body system in WS may shed new light on the analysis of the normal ageing process in man, though WS is a disease and most of the clinical features are of pathological ageing. WS is a state of deformed ageing with a wide variety of body system deterioration and may be more than a `segmental' progeroid syndrome.

Section snippets

Historical background

The landmark events and the number of case reports of WS by year of occurrence are indicated in Fig. 1. Werner, as a medical student in the Ophthalmology Clinic at the Royal Christian Albrecht University of Kiel, reported four siblings with scleroderma in association with cataracts as his doctoral dissertation [12]. He described several progeric manifestations observed in the patients in addition to the skin sclerosis and juvenile cataracts. He also assumed a genetic origin of the syndrome

Materials and methods

The literature has been searched for publications on WS since 1904 using Medline and through a citation index; Igaku-Chuo-Zasshi from 1917 (in Japan) to December 1994. Bibliographies of each report were examined for additional references. Care was taken to exclude multiple reports of the same patient, recognized by details of family and personal histories as well as demographic characteristics. The case reports in Japan were ascertained through a national citation index, whereas those from

Demographic distribution and genetics

A total of 1100 patients with WS have been described all over the world, as is depicted in Fig. 1, Fig. 2. Fig. 2 shows that Japan has the largest number, 810, followed by the U.S., 68 and Germany, 51. No Asians other than Japanese have been reported with WS (Chinese, Korean, Mongolian, other people in far-Eastern countries, Eskimos and American Indians). As shown in Fig. 3, several prefectures in Japan also have an aggregation of WS patients, where the frequency of consanguineous (mostly

Acknowledgements

The author wishes to thank Dr Robert W. Miller at NCI and Dr Haruo Sugano at the Cancer Institute for helpful discussions.

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Werner syndrome is a premature ageing disorder caused by biallelic variants in the WRN gene. WRN encodes a dual DNA helicase/exonuclease enzyme. Molecular diagnosis is commonly only made at a late disease stage in the third or fourth decade, when cardinal features have become apparent. We describe a 28 year-old woman who presented with early onset diabetes associated with partial lipodystrophy, severe dyslipidaemia and rapidly progressive liver fibrosis related to non-alcoholic steatohepatitis in the absence of progeroid features. Werner syndrome was diagnosed by trio exome analysis, which revealed compound heterozygous WRN mutations: the known variant c.1290_1293del (p.Asn430Lysfs*7) and the novel intronic splice site variant c.2732+5G>A. cDNA analysis demonstrated this to lead to in-frame skipping of exon 22, predicted to delete most of the zinc binding region of the helicase domain. We suggest that including the WRN gene in genetic analysis of early onset diabetes, lipodystrophy or dyslipidaemia would allow for the opportunity to diagnose some cases of Werner syndrome long before clinical criteria are met, thereby allowing early implementation of important primary prevention interventions.
General anesthesia for old Werner syndrome patient: a case report
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Werner syndrome (WS) is a rare autosomal recessive, premature aging disorder whose clinical manifestations include short stature, bilateral cataracts, diabetes mellitus, hypertension, and atherosclerosis. WS first manifests during adolescence and patients usually die at 40–50 years of age. Only symptomatic treatment options available according to clinical manifestations. In anesthetic management, they need to be considered to elderly patients. Difficult intubation is expected and the patients are regarded as a high-risk group for anesthesia, owing to the concomitant cardiovascular and cerebrovascular disorders. The anesthetic management of WS requires a meticulous preoperative history taking, physical examination, and preparation for cardiovascular events.
Ribosomal DNA and the nucleolus at the heart of aging
2022, Trends in Biochemical Sciences
The rRNA genes [ribosomal DNA (rDNA)] are organized in a prominent nuclear compartment, the nucleolus. It is now well established that the nucleolus functions beyond ribosome biosynthesis, regulating several physiological cellular responses. The nucleoli constitute dynamic genomic/nuclear hubs and demonstrate unique inherent characteristics, rendering them ideal to sense, signal, and respond to various intrinsic and environmental insults. Here, we discuss emerging findings supporting direct links between rDNA/nucleolar instability and cellular senescence/organismal aging from yeast to mammals. Moreover, we highlight evidence that nucleolar functionality and rDNA architecture impact on meiotic/transgenerational rejuvenation, thus revealing causality underlying connections between rDNA/nucleolar instability and aging.
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Aging is a central risk factor for many age-related pathologies including cancer, cardiovascular disease, and autoimmune disease. Therefore, a mechanistic understanding of the aging process promises great potential for discoveries of therapeutic measures that can relieve the burden of age-related pathologies. According to the “DNA damage accumulation theory of aging,” the accumulation of unrepaired DNA damage and resulting genomic instability plays a central role in promoting aging. In line with this, numerous DNA-repair diseases are characterized by increased genomic instability and recapitulation of several symptoms of normal aging. Numerous intrinsic and extrinsic factors contribute to age-dependent DNA damage accumulation, including oxidative stress, DNA replication errors, deteriorating genome-maintenance mechanisms, altered nuclear organization, and survival in presence of DNA damage. This negatively affects cell and tissue homeostasis through causing changes in gene expression profiles, or inducing cellular senescence or apoptosis, thereby promoting functional decline of tissue function, which is characteristic for aging.
Mutations in conserved functional domains of human RecQ helicases are associated with diseases and cancer: A review
2020, Biophysical Chemistry
RecQ helicases belong to a ubiquitous family of DNA unwinding enzymes that are essential to maintain genome stability by acting at the interface between DNA replication, recombination, and repair. Humans have five different paralogues of RecQ helicases namely RecQ1, BLM, WRN, RecQ4, and RecQ5. Germ-line mutations in these helicases give rise to distinct human genetic disorders, Bloom Syndrome, Werner Syndrome, Rothmund-Thomson, RAPADILINO, and Baller-Gerold syndromes. Other than distinct clinical symptoms, all these genetic disorders show a predisposition to cancer. While the three paralogues BLM, WRN, and RecQ4 are directly associated with syndromes, loss of function of RecQ1 and RecQ5 are also emerging to be causative of various types of cancer. This review summarizes the domain architecture of RecQ helicases and the mutations that are associated with various diseases. Here we observe the occurrence of disease-causing mutations mainly in the catalytic regions of the proteins, and that some of these mutations are common between the respective disorders and cancer. Furthermore, this review discusses the results of several reports that study the role of residues with disease-causing mutations. It also overviews the research focusing on RecQ helicases as potential targets for cancer therapy.
Nonfunctional mutant Wrn protein leads to neurological deficits, neuronal stress, microglial alteration, and immune imbalance in a mouse model of Werner syndrome
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Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter lifespan. Yet, little is known about the impact of WRN mutations on the central nervous system in both humans and mouse models of WS. In the current study, we have performed a longitudinal behavioral assessment on mice bearing a Wrn helicase deletion. Behavioral tests demonstrated a loss of motor activity and coordination, reduction in perception, increase in repetitive behavior, and deficits in both spatial and social novelty memories in Wrn mutant mice compared to age-matched wild type mice. These neurological deficits were associated with biochemical and histological changes in the brain of aged Wrn mutant mice. Microglia, resident immune cells that regulate neuronal plasticity and function in the brain, were hyper-ramified in multiple regions involved with the behavioral deficits of Wrn mutant mice. Furthermore, western analyses indicated that Wrn mutant mice exhibited an increase of oxidative stress markers in the prefrontal cortex. Supporting these findings, electron microscopy studies revealed increased cellular aging and oxidative stress features, among microglia and neurons respectively, in the prefrontal cortex of aged Wrn mutant mice. In addition, multiplex immunoassay of serum identified significant changes in the expression levels of several pro- and anti-inflammatory cytokines. Taken together, these findings indicate that microglial dysfunction and neuronal oxidative stress, associated with peripheral immune system alterations, might be important driving forces leading to abnormal neurological symptoms in WS thus suggesting potential therapeutic targets for interventions.

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Hierarchical deterioration of body systems in Werner's syndrome: Implications for normal ageing

Abstract

Introduction

Section snippets

Historical background

Materials and methods

Demographic distribution and genetics

Acknowledgements

Clin. Chim. Acta

Am. J. Med.

Exp. Cell Res.

Exp. Cell Res.

Exp. Cell Res.

Werner's syndrome. A review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process

Medicine

Werner's syndrome: analysis of 15 cases with a review of the Japanese literature

J. Am. Geriatrics Soc.

Family analysis of Werner's syndrome: a survey of 42 Japanese families with a review of the literature

Clin. Genet.

Replicative life-span of cultivated human cells

Lab. Invest.

Immunological abnormalities of aging: An analysis of T lymphocyte subpopulations of Werner's syndrome

J. Clin. Invest.

Reduced natural killer cell activity of lymphocytes from patients with Werner's syndrome and recovery of its activity by purified human leukocyte interferon

Scand. J. Immunol.

Hypercoagulable state indicates an additional risk factor for atherosclerosis in Werner's syndrome

Thromb. Haemost.

Excess of rare cancers in Werner's syndrome (adult progeria)

Cancer Epidemiol. Biomarker Prevention

A case of cataract associated with scleroderma

Nippon Gannka Gakkai Zasshi

Werner's syndrome—a heredo-familial disorder with scleroderma, bilateral juvenile cataract, precocious graying of hair and endocrine stigmatization

Trans. Ass. Amer. Physicians

Werner's syndrome, report of the first necropsy and of findings in a new case

Am. J. Med. Sci.

Precocious cataracts and scleroderma (Rothmund's syndrome; Werner's syndrome)

Arch. Ophthalmol.

Werner's syndrome associated with malignant melanoma

Jap. J. Clin. Dermatol.

Werner's syndrome (progeria of the adult) and Rothmund's syndrome: Two types of closely related heredofamilial atrophic dermatosis with juvenile cataracts and endocrine features; a critical study with five new cases

Ann. Intern. Med.