Altered cellular responsiveness during ageing

Rattan, Suresh I. S.; Derventzi, Anastasia

doi:10.1002/bies.950131111

Cited by 54 publications

(19 citation statements)

References 60 publications

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“…42,43 The mitogenic and stimulatory effects of growth factors, hormones, and other agents are reduced significantly during cellular aging, and the sensitivity of aging cells to toxic agents including antibiotics, phorbol esters, radiation, and heat shock increases. 44 In normal wound healing, fibroblasts are recruited from the surrounding intact tissue into the granulation tissue to proliferate, and mitogenesis is critical for wound repair. Fibroblast proliferation is regulated by activation of the EGF-R, the levels of which in dermal fibroblasts have been seen to decline in aging related to alterations in receptor processing and reduced EGF-R mRNA transcription with this decline correlating with decreased mitogenic responsiveness to EGF.…”

Section: Discussionmentioning

confidence: 99%

Aging Fibroblasts Resist Phenotypic Maturation Because of Impaired Hyaluronan-Dependent CD44/Epidermal Growth Factor Receptor Signaling

Simpson

Wells

Thomas

et al. 2010

The American Journal of Pathology

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Fibroblast differentiation into myofibroblasts is a key event during normal wound repair. We have previously demonstrated an age-related defect in this process associated with impaired synthesis of hyaluronan (HA) synthase (HAS) 2 but failed to prescribe its role in a mechanistic sense. Here we demonstrate that in addition to HAS2 , there is loss of EGF receptor (EGF-R) in aged cells , and both are required for normal fibroblast functionality. Analysis of molecular events revealed that in young cells , transforming growth factor (TGF)-␤1-dependent phenotypic activation uses two distinct but cooperating pathways that involve TGF-␤ receptor/Smad2 activation and EGFmediated EGF-R/extracellular signal-regulated kinase (ERK) 1/2 signaling , and the latter is compromised with in vitro aging. Pharmacological inhibition of any of the five intermediates (TGF-␤ receptor , Smad2, EGF , EGF-R , and ERK1/2) attenuated TGF-␤1 induction of ␣-smooth muscle actin. We present evidence that the HA receptor CD44 co-immunoprecipitates with EGF-R after activation by TGF-␤1. This interaction is HA-dependent because disruption of HA synthesis abrogates this association and inhibits subsequent ERK1/2 signaling. In aged fibroblasts , this association is lost with resultant suppression of ERK1/2 activation. Forced overexpression of EGF-R and HAS2 in aged cells restored TGF-␤1-mediated HA-CD44/EGF-R association and ␣-smooth muscle actin induction. Taken together , these results demonstrate that HA can serve as a signal integrator by facilitating TGF-␤1-mediated CD44-EGF-R-ERK interactions and ultimately fibroblast phenotype. We propose a model to explain this novel mechanism and the functional consequence of age-dependent dysregulation.

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Section: Discussionmentioning

confidence: 99%

Aging Fibroblasts Resist Phenotypic Maturation Because of Impaired Hyaluronan-Dependent CD44/Epidermal Growth Factor Receptor Signaling

Simpson

Wells

Thomas

et al. 2010

The American Journal of Pathology

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“…Aging impacts the ability to respond to stressors. Cells of older people have poorer response to physiological stressors, 129 including lower heat shock protein response. In one study, immune cells from an elderly sample exposed to paraquat had an 8% mean increase in antioxidant response (superoxide dismutase or SOD), whereas those under 40 years had an 80% response.…”

Section: Stress Resistancementioning

confidence: 99%

Psychological and metabolic stress: A recipe for accelerated cellular aging?

Epel

2009

375

329

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Chronic stress can affect human health through a myriad of behavioral and biochemical pathways. Τhis review focuses on some key hormonal and metabolic pathways that appear important today. In modern society, we are faced with excessive psychological stress, as well as an epidemic of overeating, and the two together appear to have synergistic effects. Chronic stress can lead to overeating, co-elevation of cortisol and insulin, and suppression of certain anabolic hormones. This state of metabolic stress in turn promotes abdominal adiposity. Both the direct stress response and the accumulation of visceral fat can promote a milieu of systemic inflammation and oxidative stress. This biochemical environment appears to be conducive to several cell aging mechanisms, mainly dampening telomerase and leading to telomere length (TL) shortening and cell senescence. Immune cell telomere shortness is linked with many chronic disease states and earlier mortality. In this way, chronic stress may influence a variety of diseases through a biochemical cascade leading to immune cell senescence. Certain psychological temperaments at high risk of this stress cascade (mainly anxiety prone), gene-environment interactions, and potential interventions for interrupting the stress-aging cascade are discussed.

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“…A loss of one or a number of these mechanisms may be responsible for the changes in the acinar cells observed in this study. Altered cellular responsiveness to growth factors, hormones and other factors have been found to be reduced significantly during cellular ageing of cultured diploid cells (Cristofalo, Pignolo and Rotenberg, 1992 ;Rattan and Derventzi, 1991). This resulted in a significant reduction in both protein and DNA synthesis and reduced induction of several cell-cycle related genes.…”

Section: Discussionmentioning

confidence: 99%