Possible Molecular Mechanisms of Ageing

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We have studied the age-related modifications of endogenous phosphorylations and protein kinases in seven different strains of cultured human cells (two fibroblastic and five human liver-derived strains). Endogenous phosphorylation of phosphopeptides by cells incubated in the presence of [³²P]orthophosphate constantly changed with aging; these modifications could not be explained only by loss of replicative capacity of these cells. Total casein and phosvitin kinase activity did not change in the course of in vitro cell aging. Gel filtration chromatography and autophosphorylation of partially purified kinase preparations, however, seemed to indicate some age-related modifications of protein kinases. Electrophoresis of active enzymes demonstrated that some histone/protamine kinases decreased with aging while a new 3′:5′-cyclic AMP-independent histone kinase band appeared progressively. It is proposed that new protein kinase isozymes could correspond to new genes progressively activated during cell aging and could be closely related to cell senescence and death.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Modifications of Phosphoproteins and Protein Kinases Occurring with in vitro Aging of Cultured Human Cells

Kahn¹,

Meienhofer²,

Cottreau³

et al. 1982

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“…The concept of terminal differentiation being coupled to a loss of proliferative ability (Dreyfus et al, 1977) could explain the limited proliferative capacity of cells in vitro. Subsequent degeneration of the cultures could then be due to the lack of adapt ability of differentiated cells to tissue culture conditions (Wigley, 1975).…”

Section: Discussionmentioning

confidence: 99%

“…It is a difficult task to sort out primary from secondary changes, although this may be approached by studying the temporal sequence of biological changes. In addition, as pointed out by Orgel (1973) and Dreyfus et al (1977), if the cou pling between different molecular processes is sufficiently strong, one may not be able to describe changes in one process as primary and changes in others as secondary. Instead, a more general description may have to be used in which each of a set of significant processes is dependent on the others.…”

Section: Future Prospectsmentioning

confidence: 99%

<i>In vitro</i> ‘Ageing’ and Nuclear Template Function

Whatley¹,

Hill²

1980

The fundamental cause(s) of senescent deterioration remain(s) to be established. Numerous attempts have been made to relate changes found at the cellular level with altered or failing functional changes occurring at the molecular level. However, the apparently contradictory published data often make it very difficult if not impossible, to decide whether any conclusive evidence has been provided. In this article, we have reviewed the attempts to relate in vitro ‘ageing’ with alterations in nuclear template function and have made brief mention of the few complementary in vivo experiments. Results from studies of chromatin function during in vitro ‘ageing’ in general favour the suggestion that the reduction in template activity with increasing ‘age’ may result from the loss of cellular division potential, so being an effect rather than a cause of in vitro ‘ageing’. However, nuclear control of ‘ageing’ via specific transcript ional mechanisms cannot be excluded by these data. It is possible that minor or discrete species of RNA are involved, but their investigation and detection await the development of new or more sensitive methodologies. Therefore, published data are consistent with theories of genetically programmed cellular senescence and terminal differentiation, but they do not allow us to decide firmly in favour of one or the other.

“…compare Baird et al, 1975, andHolliday, 1975). However, there is still some dispute on how important these changes are in bringing about senescence (Dreyfus et al, 1977). Much of the debate has centred around a single theory, the idea that if errors arise in the transcription-translation machinery of DNA they become self-perpetuating, leading to a gradual but irreversible and accelerating breakdown in the Fidelity of protein synthesis and ultimately leading to an error-catastrophe (Orgel, 1963).…”

mentioning

confidence: 99%

Bidder’s Hypothesis Revisited

Calow

1978

In this paper I consider three major difficulties associated with the general molecular theory of ageing, namely: (1) How can molecular damage accumulate in the face of the constellation of repair mechanisms that is found in cells? (2) How can the obvious programmatic nature of ageing be reconciled with underlying stochastic processes? (3) How do some organisms avoid ageing? As a solution to points 1 and 2, I propose that the repair mechanisms themselves deteriorate in a programmed fashion with age. However, I argue that this programming is unlikely to be a result of direct selection for life-shortening but, rather, is more likely to be a result of an indirect selection for other characters. This idea is very similar to the theory of senescence first formulated by Bidder. The solution to point 3 is that the repair mechanisms in systems which avoid ageing, in particular cellular and molecular turnover, are not impaired with age. The rejuvenating capacities of sexual and asexual reproduction are also discussed.