Unifying model of the programmed (intrinsic) and stochastic (extrinsic) theories of aging: The stress response genes, signal transduction-redox pathways and aging

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Abstract

Eukaryotic organisms possess natural defense mechanisms triggered by injury, inflammation, infection and oxidative stress. The response to many stress stimuli is mediated by a small number of trans-acting factors that initiate a cascade of events characterized by the activation of families of stress response genes. The functions of some of these genes are altered by aging, i.e., either attenuated or hyperactivated. This is due, in part, to age-associated changes in activity of the specific trans-acting factors. We propose that these trans-acting factors are key regulatory proteins that respond to changes in both intrinsic (biological mediators) and extrinsic (pollutants) factors. Thus, biological mediators such as cytokines, H2O2, oxygen radicals, nitric oxide, and extrinsic environmental factors such as pollutants act as second messengers that target the same signalling molecules thus regulating the activity of trans-acting proteins that activate stress response genes. Homeostatic levels of biological mediators (intrinsic factors) arc altered by aging and the extrinsic factors (pollutants) accelerate the action of these biological mediators. Thus, we propose a unifying model which states that the intrinsic and extrinsic factors that mediate the characteristics of aging target the trans-acting factors of stress response genes via the signal transduction-redox processes. We present the following model in an attempt to unify the Intrinsic and Extrinsic models of aging. (a) Age-associated declines in tissue function occur because of changes in the structure and function of regulatory proteins. (b) The structure, function and interactions of these proteins with their respective cis-acting DNA sequences are the intrinsic processes whose alteration(s) contribute to the development of biological characteristics of aging. (c) These age-associated changes occur in the absence of disease or extrinsic factors, but are accelerated by these factors. (d) Thus, trans-acting factors of families of stress response genes are intrinsic factors whose activities are affected by aging and are, therefore, a basis for age-associated increase or decrease in gene expression. (e) These intrinsic regulatory proteins are equally sensitive to the extrinsic factors such as pollutants via components of signal transduction and redox pathways. (f) The biological mediators and extrinsic mediators of stress response initiate, or regulate gene activity via these signaling pathways. (g) Through this mechanism extrinsic factors accelerate the age-associated characteristics of stress response gene activity, and the resultant over- or under-expression of these gene products contributes to the gradual decline in tissue function. Models are presented for NFκB and AP-1 (fos, jun) which are the trans-acting factors that regulate stress response genes and respond to homeostatic and stochastic factors. The models attempt to show that these transacting factors are targets of components of the same transduction and redox pathways and how these processes may be affected by aging, thus establishing the age-associated changes in gene expression and regulation.

Original languageEnglish (US)
Pages (from-to)195-211
Number of pages17
JournalAnnals of the New York Academy of Sciences
Volume719
StatePublished - 1994

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Signal transduction
Oxidation-Reduction
Trans-Activators
Signal Transduction
Genes
Aging of materials
Intrinsic Factor
Gene expression
Proteins
Gene Expression
Tissue
Intrinsic
Transduction
Extrinsic
Pathway
Gene
Age Factors
Transcription Factor AP-1
Gene Expression Regulation
Second Messenger Systems

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

@article{6a7a5c26a4584f308d2a40c21687cc07,
title = "Unifying model of the programmed (intrinsic) and stochastic (extrinsic) theories of aging: The stress response genes, signal transduction-redox pathways and aging",
abstract = "Eukaryotic organisms possess natural defense mechanisms triggered by injury, inflammation, infection and oxidative stress. The response to many stress stimuli is mediated by a small number of trans-acting factors that initiate a cascade of events characterized by the activation of families of stress response genes. The functions of some of these genes are altered by aging, i.e., either attenuated or hyperactivated. This is due, in part, to age-associated changes in activity of the specific trans-acting factors. We propose that these trans-acting factors are key regulatory proteins that respond to changes in both intrinsic (biological mediators) and extrinsic (pollutants) factors. Thus, biological mediators such as cytokines, H2O2, oxygen radicals, nitric oxide, and extrinsic environmental factors such as pollutants act as second messengers that target the same signalling molecules thus regulating the activity of trans-acting proteins that activate stress response genes. Homeostatic levels of biological mediators (intrinsic factors) arc altered by aging and the extrinsic factors (pollutants) accelerate the action of these biological mediators. Thus, we propose a unifying model which states that the intrinsic and extrinsic factors that mediate the characteristics of aging target the trans-acting factors of stress response genes via the signal transduction-redox processes. We present the following model in an attempt to unify the Intrinsic and Extrinsic models of aging. (a) Age-associated declines in tissue function occur because of changes in the structure and function of regulatory proteins. (b) The structure, function and interactions of these proteins with their respective cis-acting DNA sequences are the intrinsic processes whose alteration(s) contribute to the development of biological characteristics of aging. (c) These age-associated changes occur in the absence of disease or extrinsic factors, but are accelerated by these factors. (d) Thus, trans-acting factors of families of stress response genes are intrinsic factors whose activities are affected by aging and are, therefore, a basis for age-associated increase or decrease in gene expression. (e) These intrinsic regulatory proteins are equally sensitive to the extrinsic factors such as pollutants via components of signal transduction and redox pathways. (f) The biological mediators and extrinsic mediators of stress response initiate, or regulate gene activity via these signaling pathways. (g) Through this mechanism extrinsic factors accelerate the age-associated characteristics of stress response gene activity, and the resultant over- or under-expression of these gene products contributes to the gradual decline in tissue function. Models are presented for NFκB and AP-1 (fos, jun) which are the trans-acting factors that regulate stress response genes and respond to homeostatic and stochastic factors. The models attempt to show that these transacting factors are targets of components of the same transduction and redox pathways and how these processes may be affected by aging, thus establishing the age-associated changes in gene expression and regulation.",
author = "John Papaconstantinou",
year = "1994",
language = "English (US)",
volume = "719",
pages = "195--211",
journal = "Annals of the New York Academy of Sciences",
issn = "0077-8923",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Unifying model of the programmed (intrinsic) and stochastic (extrinsic) theories of aging

T2 - The stress response genes, signal transduction-redox pathways and aging

AU - Papaconstantinou, John

PY - 1994

Y1 - 1994

N2 - Eukaryotic organisms possess natural defense mechanisms triggered by injury, inflammation, infection and oxidative stress. The response to many stress stimuli is mediated by a small number of trans-acting factors that initiate a cascade of events characterized by the activation of families of stress response genes. The functions of some of these genes are altered by aging, i.e., either attenuated or hyperactivated. This is due, in part, to age-associated changes in activity of the specific trans-acting factors. We propose that these trans-acting factors are key regulatory proteins that respond to changes in both intrinsic (biological mediators) and extrinsic (pollutants) factors. Thus, biological mediators such as cytokines, H2O2, oxygen radicals, nitric oxide, and extrinsic environmental factors such as pollutants act as second messengers that target the same signalling molecules thus regulating the activity of trans-acting proteins that activate stress response genes. Homeostatic levels of biological mediators (intrinsic factors) arc altered by aging and the extrinsic factors (pollutants) accelerate the action of these biological mediators. Thus, we propose a unifying model which states that the intrinsic and extrinsic factors that mediate the characteristics of aging target the trans-acting factors of stress response genes via the signal transduction-redox processes. We present the following model in an attempt to unify the Intrinsic and Extrinsic models of aging. (a) Age-associated declines in tissue function occur because of changes in the structure and function of regulatory proteins. (b) The structure, function and interactions of these proteins with their respective cis-acting DNA sequences are the intrinsic processes whose alteration(s) contribute to the development of biological characteristics of aging. (c) These age-associated changes occur in the absence of disease or extrinsic factors, but are accelerated by these factors. (d) Thus, trans-acting factors of families of stress response genes are intrinsic factors whose activities are affected by aging and are, therefore, a basis for age-associated increase or decrease in gene expression. (e) These intrinsic regulatory proteins are equally sensitive to the extrinsic factors such as pollutants via components of signal transduction and redox pathways. (f) The biological mediators and extrinsic mediators of stress response initiate, or regulate gene activity via these signaling pathways. (g) Through this mechanism extrinsic factors accelerate the age-associated characteristics of stress response gene activity, and the resultant over- or under-expression of these gene products contributes to the gradual decline in tissue function. Models are presented for NFκB and AP-1 (fos, jun) which are the trans-acting factors that regulate stress response genes and respond to homeostatic and stochastic factors. The models attempt to show that these transacting factors are targets of components of the same transduction and redox pathways and how these processes may be affected by aging, thus establishing the age-associated changes in gene expression and regulation.

AB - Eukaryotic organisms possess natural defense mechanisms triggered by injury, inflammation, infection and oxidative stress. The response to many stress stimuli is mediated by a small number of trans-acting factors that initiate a cascade of events characterized by the activation of families of stress response genes. The functions of some of these genes are altered by aging, i.e., either attenuated or hyperactivated. This is due, in part, to age-associated changes in activity of the specific trans-acting factors. We propose that these trans-acting factors are key regulatory proteins that respond to changes in both intrinsic (biological mediators) and extrinsic (pollutants) factors. Thus, biological mediators such as cytokines, H2O2, oxygen radicals, nitric oxide, and extrinsic environmental factors such as pollutants act as second messengers that target the same signalling molecules thus regulating the activity of trans-acting proteins that activate stress response genes. Homeostatic levels of biological mediators (intrinsic factors) arc altered by aging and the extrinsic factors (pollutants) accelerate the action of these biological mediators. Thus, we propose a unifying model which states that the intrinsic and extrinsic factors that mediate the characteristics of aging target the trans-acting factors of stress response genes via the signal transduction-redox processes. We present the following model in an attempt to unify the Intrinsic and Extrinsic models of aging. (a) Age-associated declines in tissue function occur because of changes in the structure and function of regulatory proteins. (b) The structure, function and interactions of these proteins with their respective cis-acting DNA sequences are the intrinsic processes whose alteration(s) contribute to the development of biological characteristics of aging. (c) These age-associated changes occur in the absence of disease or extrinsic factors, but are accelerated by these factors. (d) Thus, trans-acting factors of families of stress response genes are intrinsic factors whose activities are affected by aging and are, therefore, a basis for age-associated increase or decrease in gene expression. (e) These intrinsic regulatory proteins are equally sensitive to the extrinsic factors such as pollutants via components of signal transduction and redox pathways. (f) The biological mediators and extrinsic mediators of stress response initiate, or regulate gene activity via these signaling pathways. (g) Through this mechanism extrinsic factors accelerate the age-associated characteristics of stress response gene activity, and the resultant over- or under-expression of these gene products contributes to the gradual decline in tissue function. Models are presented for NFκB and AP-1 (fos, jun) which are the trans-acting factors that regulate stress response genes and respond to homeostatic and stochastic factors. The models attempt to show that these transacting factors are targets of components of the same transduction and redox pathways and how these processes may be affected by aging, thus establishing the age-associated changes in gene expression and regulation.

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