Dysdifferentiation Hypothesis of Aging and Cancer: A Comparison with the Membrane Hypothesis of Aging

Abstract

Our laboratories have been testing the basic concept that the age-dependent deterioration of the molecular components of living systems may be due in part to the biochemical effects of active oxygen species. The dysdifferentiation hypothesis of aging and cancer (DHAC) as well as the membrane hypothesis of aging (MHA) are discussed and compared to each other. These two hypotheses consider cellular mechanisms through which free radical-induced alterations may lead to the aging process. DHAC emphasizes the importance of the instability of the differentiated state of cells and how active oxygen species may interact with the genetic apparatus of cells, leading to improper gene regulation. The evidence supporting this hypothesis includes an age-dependent increase in the expression of specific genes that normally are expected to be repressed. Such evidence now includes the c-myc oncogene as well as an age-dependent decrease in the average methylation level of the entire genome in liver tissue of mice. The central concept of DHAC is that aging is a result of gene regulatory instability and that lifespan is governed by mechanisms acting to stabilize proper gene regulation. MHA is based on the concept that all cellular components are exposed to free-radical attacks, and that the damaging efficiency of the radicals is density-dependent. Compact structures like membranes are consequently more susceptible to damage than cytosolic components. In addition, the cell plasma membrane is exposed to another damaging effect called residual heat damage, which is due to the depolarization-induced discharge of the membrane during the action potential. MHA predicts that a key process of normal differentiation as well as aging is a continuous, age-dependent loss of the passive permeability of the cell membrane for potassium and probably also for water. This is due to a constant difference between the rates of damage and replacement of the membrane components and results in a gradual dehydration of the intracellular mass from the embryonic state to the aging state. The increasing intracellular density will eventually become rate-limiting for many different cellular functions, resulting in the cessation of growth and the beginning of aging. MHA also predicts an overall decrease of gene expression and protein turnover rate during aging. Pharmacological interventions on the cell membrane have supported the validity of MHA and have indicated specific mechanisms of how aging and dysdifferentiation may occur.

Oxidative Stress Profiling:

“…Aging is largely a result of the natural limitation of the genetic apparatus of a cell to be able to maintain over time the proper state of differentiation of its cells. 2,[121][122][123][124][125][126][127][128] The proper state of differentiation in cells is taken to be that when the program of differentiation and development was completed.…”

Age and Organ Dependent Spontaneous Generation of Nuclear 8-Hydroxydeoxyguanosine in Male Fischer 344 Rats

“…However, the defense systems may be overcome, leading to the phenomenon known as "oxidative stress" (Ames et al, 1993;Anisimov, 1998;Harman, 1988). In recent years, this has become recognized or suggested as participating in the development of senescence, carcinogenesis, and a wide variety of diseases, either aging-dependent or independent (Ames et al, 1993;Ando et al, 1998;Anisimov, 1998;Busciglio et al, 1998;Facchinetti et al, 1998;Feher et al, 1998;Feig et al, 1994;Floyd, 1990;Harman, 1988;Hasselwander and Young, 1998;Hogg, 1998;Kaplowitz and Tsukamoto, 1996;Kasai, 1997;Minamoto et al, 1999;Peterhans, 1997;Reiter, 1998;Saugstad, 1998;Schenker and Montalvo, 1998;Singal et al, 1998;Stadtman and Berlett, 1998;Thomson et al, 1998;Zs-Nagy et al, 1988).…”

Model of human aging: Recent findings on Werner’s and Hutchinson-Gilford progeria syndromes

“…The studies by Kyng and Bohr (2005) and Csoka and colleagues (2004b) point to a shared mechanism of aging acceleration in PSs ie, misregulated transcription. The idea that aging is due to the loss of the proper transcriptional state of the cell followed by “dysdifferentiation” had been previously proposed by other investigators (Kator et al 1985; Zs-Nagy et al 1988; Fossel 2003; Prolla 2005). These findings that HGPS patients show inappropriate transcriptional patterns provides new evidence that transcriptional deregulation can contribute to the aging process in humans.…”