Social scientists frequently refer to the 'greying' of the population in the west, the extension of the average lifespan to around the age of 76, and the projected increases in the numbers of people aged 85 and over, with the ensuing problems of chronic illness and disability that often accompany very old age. Increasing interest is being expressed in positive aspects of ageing: given the increases in life expectancy during this century, is it resulting in a life worth living?
Cellular senescence is a state of irreversible cell cycle arrest in which normal cells at the end of their lifespan fail to enter into DNA synthesis upon serum or growth factor stimulation. We examined whether proteins required for G1/S cell cycle progression were irreversibly down-regulated in senescent human fibroblasts. Both the 44- and 42-kDa forms of the MAP-kinase protein were expressed at similar levels in young and senescent cells.
For several decades simian virus 40 (SV40) early region genes have been used as a means of generating immortalized human cell lines; however, the molecular mechanisms of this process have begun to be understood only recently. SV40-induced immortalization proceeds via two phases. In the first phase ("lifespan extension"), cells continue proliferating for a limited number of population doublings beyond the point at which normal cells undergo senescence.
We have examined the effects of the naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) on the growth, morphology, and lifespan of cultured human diploid fibroblasts. With human foreskin cells, HFF-1, and fetal lung cells, MRC-5, we have shown that carnosine at high concentrations (20-50 mM) in standard medium retards senescence and rejuvenates senescent cultures. These late-passage cultures preserve a nonsenescent morphology in the presence of carnosine, in comparison to the senescent morphology first described by Hayflick and Moorhead.
It has been recognized that the remarkable decline in infant mortality and the extension in human lifespan involving both developing and developed countries alike, has been influenced by social and economic developments and public health orientated measures (such as clean water and sewerage) rather more than by developments in medical research. However, the identification of important disease risk factors for a number of common conditions such as smoking, solar exposure, dietary fat and alcohol has led to further reductions in disease prevalence and mortality, at least in some countries.
Normal human breast epithelial cells were transfected with expression vectors containing the p53 gene mutated at either codon 143, 175, 248 or 273, or by infection with a recombinant retroviral vector containing the p53 gene mutated at codons 143, 175, 248, or 273. The breast epithelial cells were monitored for extension of in vitro lifespan and immortalization. Expression of some, but not all, p53 mutants resulted in an extension of in vitro lifespan.
BACKGROUND: Among patients with well differentiated papillary thyroid carcinoma who generally have an excellent prognosis and a near-normal lifespan, there exist subsets of patients who have significant risk for morbidity and mortality from this disease. It is important to define the patterns of disease progression and the clinical outcome of such patients to develop effective surveillance and treatment strategies.
This study addresses the question of whether loss of p16INK4 expression contributes to the immortalization of human cells. In vitro immortalization usually proceeds through two phases. In the first phase (lifespan extension), cells continue proliferating and their telomeres continue shortening beyond the point at which normal cells become senescent. In the second phase (immortalization), the cells activate a telomere maintenance mechanism and acquire an unlimited proliferative potential.
European Journal of Cancer (Oxford, England: 1990)
This article reviews the current understanding of the involvement of telomerase in in vitro immortalisation of human cells. In vitro immortalisation with DNA tumour viruses or chemicals usually occurs in two phases. The first stage is an extension of lifespan beyond that at which cells would normally senescence, after which the culture enters a period of crisis. The second stage involves the escape from crisis of a rare cell in the culture, which goes on to proliferate indefinitely.
Telomere loss has been proposed as a mechanism for counting cell divisions during aging in normal somatic cells. How such a mitotic clock initiates the intracellular signalling events that culminate in G1 cell cycle arrest and senescence to restrict the lifespan of normal human cells is not known. We investigated the possibility that critically short telomere length activates a DNA damage response pathway involving p53 and p21(WAF1) in aging cells.