No abstract

Cellular senescence has long been used as a cellular model for understanding mechanisms underlying the ageing process. Compelling evidence obtained in recent years demonstrate that DNA damage is a common mediator for both replicative senescence, which is triggered by telomere shortening, and premature cellular senescence induced by various stressors such as oncogenic stress and oxidative stress. Extensive observations suggest that DNA damage accumulates with age and that this may be due to an increase in production of reactive oxygen species (ROS) and a decline in DNA repair capacity with age. Mutation or disrupted expression of genes that increase DNA damage often result in premature ageing. In contrast, interventions that enhance resistance to oxidative stress and attenuate DNA damage contribute towards longevity. This evidence suggests that genomic instability plays a causative role in the ageing process. However, conflicting findings exist which indicate that ROS production and oxidative damage levels of macromolecules including DNA do not always correlate with lifespan in model animals. Here we review the recent advances in addressing the role of DNA damage in cellular senescence and organismal ageing.

SYNOPSIS An immunoradiometric assay for human ferritin has been developed. Concentrations of ferritin in the serum of male and female controls and patients with iron deficiency and iron overload were measured.Male controls were found to have a significantly higher mean concentration of serum ferritin than females. Patients with iron deficiency had significantly lower levels than normals of either sex and patients with iron overload had greatly elevated serum ferritin concentrations. It is thought that the serum ferritin concentration may reflect the iron stores of the body. (Reissmann and Dietrich, 1956;Aungst, 1966).Previous methods for the estimation of ferritin have been relatively insensitive (Reissmann and Dietrich, 1956; Beamish, Llewellin, and Jacobs, 1971) and have been able to detect ferritin concentrations in the serum corresponding to about 2 5 ,ug of ferritin iron per 100 ml. Using these techniques it has not been possible to detect ferritin in normal or iron-deficient sera. The present paper describes a sensitive method for measuring ferritin protein and reports the concentration in the sera of normal subjects and those with iron deficiency and iron overload.Received for publication 13 January 1972. Materials and MethodsA horse ferritin immunoadsorbent was prepared as previously described (Miles and Hales, 1968). One hundred mg of diazocellulose and 200 mg of horse ferritin (Koch Light Limited) were reacted for 48 hr at 4°C in the dark. The immunoadsorbent was washed 10 times in 0-15 M phosphate buffer pH 7*4 containing 9 g per litre sodium chloride. After this washing the free ferritin, as measured by OD at 430 nm of the supernatant, fell to zero. However, on storing the immunoadsorbent for several days the OD at 430 nm of the supernatant increased and the horse ferritin immunoadsorbent was always rewashed three times before use: 22 5 mg (11 25%Y) of the horse ferritin was coupled giving an immunoadsorbent with 225 mg antigen per g cellulose.The antibodies from 1 ml of both rabbit antihorse ferritin serum and rabbit antihuman ferritin serum were extracted separately with the horse ferritin immunoadsorbent by incubation at 4°C for three to four days. After washing six times in the phosphatesaline buffer the protein uptakes were measured by the method of Lowry, Rosebrough, Farr, and Randall (1951)

Fetal growth and development is dependent upon the nutritional, hormonal and metabolic environment provided by the mother. Any disturbance in this environment can modify early fetal development with possible long-term outcomes as demonstrated by extensive work on 'programming'. Growth restriction resulting from a deficit in tissue/organ cell number (as measured by tissue DNA content) is irrecoverable. However, when the cell size (or cell protein content) is reduced, the effects on growth may not be permanent. Recent epidemiological studies using archival records of anthropometric measurements related to early growth in humans have shown strong statistical associations between these indices of early development and diseases in later life. It has been hypothesised that the processes explaining these associations involve adaptive changes in fetal organ development in response to maternal and fetal malnutrition. These adaptations may permanently alter adult metabolism in a way which is beneficial to survival under continued conditions of malnutrition but detrimental when nutrition is abundant. This hypothesis is being tested in a rat model which involves studying the growth and metabolism in the offspring of rat dams fed a low-protein diet during pregnancy and/or lactation. Using this rat model, it has been demonstrated that there is: (i) Permanent growth retardation in offspring nursed by dams fed a low-protein diet. (ii) Permanent and selective changes in organ growth. Essential organs like the brain and lungs are relatively protected from reduction in growth at the expense of visceral organs such as the liver, pancreas, muscle and spleen. (iii) Programming of liver metabolism as reflected by permanent changes in activities of key hepatic enzymes of glycolysis and gluconeogenesis (glucokinase and phosphoenolpyruvate carboxykinase) in a direction which would potentially bias the liver towards a 'starved' setting. We have speculated that these changes could be a result of altered periportal and perivenous regions of the liver which may also affect other aspects of hepatic function. (iv) Deterioration in glucose tolerance with age. (v) An increase in the life span of offspring exposed to maternal protein restriction only during the lactation period, and a decrease in life span when exposed to maternal protein restriction only during gestation. These studies show that hepatic metabolism and even longevity can be programmed by events during early life.