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PubMed1980

Fidelity of protein synthesis does not decline during aging of cultured human fibroblasts.

To ascertain whether the fidelity of protein synthesis declines during cellular aging in vitro, we have developed a cell-free protein synthesizing system from cultured human fibroblasts which actively incorporates phenylalanine into acid-insoluble material upon addition of poly (U). The accuracy of poly (U)-directed protein synthesis was determined by comparing the ratio of leucine to phenylalanine incorporation in extracts of early- and late-passage fibroblasts derived from normal persons and from subjects with two genetic disorders of premature aging, progeria, and Werner syndrome. The results show no decline in translational fidelity at late passage or in prematurely aging cells, and thus fail to support the error catastrophe theory of cellular aging.

Cell Survival↗
PubMed1975

Repair of DNA strand breaks in progeric fibroblasts and aging human diploid cells.

The rate of rejoining of DNA strand breaks induced by 10 krad of gamma-irradiation has been studied in normal human diploid skin fibroblasts and in skin fibroblasts from six patients with symptoms of progeria. Although slightly more rapid in very early passage, the repair rate in normal cells was similar throughout most of their life span in vitro. The appearance of cells with reduced repair capacity was evident as the cultures became senescent. The progeric fibroblasts varied greatly in their response to irradiation. The rate of repair was greatly reduced in two strains, whereas in two others extensive DNA degradation was consistently observed in unirradiated cells. Degradation was apparently related to the radiation received from the incorporated radiolabel. Normal repair was seen in progeric fibroblasts transformed by SV40 virus.

Aging↗
PubMed1987

Skeletal abnormalities of acrogeria, a progeroid syndrome.

We report the skeletal abnormalities in a 4 1/2-year-old boy with acrogeria, a progeroid syndrome of premature aging of the skin without the involvement of internal organs seen in Hutchinson-Gilford progeria syndrome. Acro-osteolysis of the distal phalanges, delayed cranial suture closure with wormian bones, linear lucent defects of the metaphyses, and antegonial notching of the mandible are the predominant skeletal features of the disorder. The skeletal features described in 21 other reported cases of acrogeria are summarized.

Bone and Bones↗
PubMed1979

An unidentified neonatal progeroid syndrome: follow-up report.

Two male infants with a pseudo-hydrocephalic progeroid syndrome with natal teeth are compared with two very similar female cases reported in the literature and interpreted as congenital progeria. All these cases may represent a separate entity, a previously unrecognized genetic progeroid syndrome.

Adolescent↗
PubMed2007

Human progeroid syndromes, aging and cancer: new genetic and epigenetic insights into old questions.

Disorders in which individuals exhibit certain features of aging early in life are referred to as segmental progeroid syndromes. With the progress that has been made in understanding the etiologies of these conditions in the past decade, potential therapeutic options have begun to move from the realm of improbability to initial stages of testing. Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, and Hutchinson-Gilford progeria syndrome, which is characterized by aberrant processing of the nuclear envelope protein lamin A. Although best known for their causative roles in these illnesses, Werner protein and lamin A have also recently emerged as key players vulnerable to epigenetic changes that contribute to tumorigenesis and aging. These advances further demonstrate that understanding progeroid syndromes and introducing adequate treatments will not only prove beneficial to patients suffering from these dramatic diseases, but will also provide new mechanistic insights into cancer and normal aging processes.

Aging↗
PubMed1986

Analysis by high-performance liquid chromatography of hyaluronic acid and chondroitin sulfates.

The use of high-performance liquid chromatography for the quantification of glycosaminoglycan disaccharides has been hampered by the inability to isocratically resolve the chondroitinase digestion products 2-acetamido-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-D-glucose (delta Di-HA) and 2-acetamido-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-D-galactose (delta Di-OS). To overcome this limitation, we have developed a solvent system capable of resolving delta Di-HA, delta Di-OS, 2-acetamido-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-6-O-sulfo-D-galactose (delta Di-6S), and 2-acetamido-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-4-O-sulfo-D-galactose (delta Di-4S). Integrator responses were linear from 1 microgram down to 25 ng for delta Di-HA, delta Di-OS, and delta Di-4S and down to 100 ng for delta Di-6S. This method was used to examine changes in the content of urinary hyaluronic acid and chondroitin sulfates isolated from normal individuals and from patients with Lowe Syndrome, Werner Syndrome, and Hutchinson-Gilford Progeria Syndrome. We confirmed that the HPLC method gave results comparable to colorimetric methods.

Chondroitin↗
PubMed1979

Human mutations affecting aging--a review.

A review of human genetic mutations that affect aging and their potential contribution to help understand normal aging processes is presented. The lifespans of most animal species, including man, have a genetically determined maximum. The lifespan of man appears to have evolved exceedingly rapidly, which suggests that relatively few genes may determine longevity. Analysis of biochemical evolution suggests that the regulation of enzyme levels may underlie most evolutionary changes. There is a wide spectrum of human genetic mutations. Some, such as progeria and Werner's syndrome, produce a phenotype resembling premature aging and may involve genes related to the aging process. Certain human chromosomal abnormalities, such as Down's syndrome, produce an appearance of premature aging and may be due to abnormal gene regulatory mechanisms. Progress in understanding the genetic mechanisms underlying aging is likely to come from elucidation of the molecular defects that result in the premature aging syndromes and from insights gained regarding the regulatory mechanisms governing eukaryotic genetic expression.

Aging↗
PubMed1983

Changes in NAD levels in human lymphocytes and fibroblasts during aging and in premature aging syndromes.

NAD levels markedly increase upon mitogen stimulation of lymphocytes from young subjects. In contrast, lymphocytes from old subjects do not increase NAD levels upon stimulation. A survey of 35 individuals aged 18-79 years revealed a significant age-dependent decrease in the NAD response to mitogen stimulation. No significant differences were noted in lymphocytes from age-matched individuals with Down's syndrome or diabetes mellitus. On the other hand, cultured skin fibroblasts showed elevated NAD levels with age. However, this effect appears to be due to increased size of the cells since the NAD/protein ratio is unchanged. Skin fibroblasts from patients with progeria exhibit much higher levels of NAD and protein per cell than age-matched controls.

Adolescent↗
PubMed1986

An altered response in the induction of cell membrane (Na + K)ATPase by thyroid hormone is characteristic of senescence in cultured human fibroblasts.

There have been numerous investigations of thyroid function during senescence in humans. However, very little information is available on thyroid hormone action at the cell level during senescence. Therefore, we have investigated thyroid hormone induction of cell membrane (Na + K)ATPase during human senescence using three experimental fibroblast cell culture systems: (1) cells from premature aging syndrome, progeria; (2) aging in vitro; and (3) early passage cells from aged patients. In all cases senescence is associated with a dramatic alteration from the normal dose-dependent thyroid hormone induction of (Na + K)ATPase. Senescent cells depleted of thyroid hormones demonstrated an elevated activity of (Na + K)ATPase, while non-senescing cells exhibit the characteristic basal enzyme activities in the hypothyroid state. These results indicate that human senescence is associated with extreme alterations in thyroid hormone regulation of (Na + K)ATPase; and may suggest a more general change in thyroid hormone action at senescence. These changes may be associated with important alterations in cell metabolism and intracellular ionic environment during senescence.

Adolescent↗
PubMed2005

Gene expression and DNA repair in progeroid syndromes and human aging.

Human progeroid syndromes are caused by mutations in single genes accelerating some but not all features of normal aging. Most progeroid disorders are linked to defects in genome maintenance, and while it remains unknown if similar processes underlie normal and premature aging, they provide useful models for the study of aging. Altered transcription is speculated to play a causative role in aging, and is involved in the pathology of most if not all progeroid syndromes. Previous studies demonstrate that there is a similar pattern of gene expression changes in primary cells from old and Werner syndrome compared to young suggesting a presence of common cellular aging mechanisms in old and progeria. Here we review the role of transcription in progeroid syndromes and discuss the implications of similar transcription aberrations in normal and premature aging.

Aging↗
PubMed2006

Extended longevity mechanisms in short-lived progeroid mice: identification of a preservative stress response associated with successful aging.

Semantic distinctions between "normal" aging, "pathological" aging (or age-related disease) and "premature" aging (otherwise known as segmental progeria) potentially confound important insights into the nature of each of the complex processes. Here we review a recent, unexpected discovery: the presence of longevity-associated characteristics typical of long-lived endocrine-mutant and dietary-restricted animals in short-lived progeroid mice. These data suggest that a subset of symptoms observed in premature aging, and possibly normal aging as well, may be indirect manifestations of a beneficial adaptive stress response to endogenous oxidative damage, rather than a detrimental result of the damage itself.

Aging↗
PubMed1975

Older paternal age and fresh gene mutation: data on additional disorders.

Older paternal age has previously been documented as a factor in sporadic fresh mutational cases of several autosomal dominant disorders. In this collaborative study, an older mean paternal age has been documented in sporadic cases of at least five additional dominantly inheritable disorders; the basal cell nevus syndrome, the Waardenburg syndrome, the Crouzon syndrome, the oculo-dental-digital sysdrome, and the Treacher-Collins syndrome. It was also found to be a factor in acrodysostosis and progeria, suggesting a fresh mutant gene etiology for these two conditions in which virtually all cases have been sporadic and the mode of genetic etiology has been unknown.

Age Factors↗
PubMed2003

p53 and a human premature ageing disorder.

It has been shown that enhanced levels of p53 activity contribute to reduced cancer susceptibility in mice, however longevity is compromised due to the onset of an early-ageing phenotype. The effects of enhanced levels of p53 in these in mice could therefore have implications for human premature ageing disorders. We examined the DNA damage response of p53 and its target p21(WAF1) to UV and ionising radiation in fibroblasts from patients with the premature ageing disorder Hutchinson-Gilford Progeria (HGP). We report a normal p53 response to these DNA damaging agents suggesting that, in this particular human disorder, the premature ageing phenotype does not arise from an enhanced p53 response.

Aging, Premature↗
PubMed1997

A hypothesis that aging results from defects in genetically produced proteins.

The hypothesis is presented that our life span is genetically programmed and that it is possible that a defect in produced proteins encoded by the 'longevity' gene is a cause of aging. A study of correlations between defective enzyme activity in two diseases characterized by premature aging (progeria and Werner's syndrome) could assist in elucidating the common mechanism for all aging processes.

Adult↗
PubMedDate not supplied

Smooth muscle cell depletion and collagen types in progeric arteries.

Review of two autopsy cases of progeria confirms severe smooth muscle cell (SMC) depletion in the atherosclerotic aortic media and the presence of collagen types I, III, IV, V, and VI in the aorta and renal vessels as is consistent with atherosclerotic disease.

Adult↗
PubMed1997

Lysyl oxidase, cellular senescence and tumor suppression.

Replicative senescence may provide a mechanism of tumor suppression and tumor suppressor genes of the extracellular matrix, like lysyl oxidase, may play a role in cellular senescence. To test this hypothesis and determine whether the extracellular matrix may serve as a marker, the steady-state levels of human lysyl oxidase, alpha-I type III collagen and beta-actin transcripts were assessed in various cell lines during in vitro passage. Northern hybridization analysis showed a significant increase in the levels of progeria fibroblast extracellular matrix mRNAs immediately preceding senescence. The levels of these mRNAs were unaffected in age-matched normal fibroblast and fetal fibroblast cell lines.

Actins↗
PubMed2006

Therapeutic intervention based on protein prenylation and associated modifications.

In eukaryotic cells, a specific set of proteins are modified by C-terminal attachment of 15-carbon farnesyl groups or 20-carbon geranylgeranyl groups that function both as anchors for fixing proteins to membranes and as molecular handles for facilitating binding of these lipidated proteins to other proteins. Additional modification of these prenylated proteins includes C-terminal proteolysis and methylation, and attachment of a 16-carbon palmitoyl group; these modifications augment membrane anchoring and alter the dynamics of movement of proteins between different cellular membrane compartments. The enzymes in the protein prenylation pathway have been isolated and characterized. Blocking protein prenylation is proving to be therapeutically useful for the treatment of certain cancers, infection by protozoan parasites and the rare genetic disease Hutchinson-Gilford progeria syndrome.

Animals↗
PubMedDate not supplied

[Neonatal progeroid syndrome (Wiedemann-Rautenstrauch). A follow-up study].

The diagnostic criteria of the neonatal progeroid syndrome (NPS) are: intrauterine and postnatal growth failure, hydrocephalic appearance, prominent scalp veins, old-looking face, absence of subcutaneous fat and neonatal teeth. Until now altogether nine cases have been reported, which were predominant diagnosed in infant age. The NPS is in general assigned to the autosomal recessive trait. With increasing age the outward appearance stays unchanged. The in 1977 under diagnose progeria presented patient is now 16 years old. With her a considerable atactic movement disturbance developed next to a psychomotoric retardation. The change in metabolism of proteoglycane that was remarkable in infant age is now no longer provable.

Adolescent↗