Proteolysis, free radicals, and aging1,2 1Guest Editor: Earl Stadtman 2This article is part of a series of reviews on “Oxidatively Modified Proteins in Aging and Disease.” The full list of papers may be found on the homepage of the journal.

The Free Radical Theory of Aging Matures

1998 • 3,846 citations

Protein Oxidation in Aging, Disease, and Oxidative Stress

1997 • 3,299 citations

Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules

1994 • 2,480 citations

STRUCTURE AND FUNCTIONS OF THE 20S AND 26S PROTEASOMES

1996 • 2,408 citations

Gene Expression Profile of Aging and Its Retardation by Caloric Restriction

1999 • 1,483 citations

Organelle-specific initiation of cell death pathways

2001 • 1,454 citations

Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease.

1991 • 1,290 citations

Degradation of CFTR by the ubiquitin-proteasome pathway

1995 • 1,285 citations

Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli.

1995 • 1,010 citations

Degradation of oxidized proteins by the 20S proteasome

2001 • 846 citations

Senescence-associated β-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells

2000 • 791 citations

Endocytic Pathway Abnormalities Precede Amyloid β Deposition in Sporadic Alzheimer’s Disease and Down Syndrome

2000 • 764 citations

Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone.

1991 • 734 citations

ER Degradation of a Misfolded Luminal Protein by the Cytosolic Ubiquitin-Proteasome Pathway

1996 • 704 citations

Four-Hydroxynonenal, a Product of Lipid Peroxidation, is Increased in the Brain in Alzheimer’s Disease

1998 • 677 citations

Age-related Decline in Chaperone-mediated Autophagy

2000 • 612 citations

Oxidative damage during aging targets mitochondrial aconitase

1997 • 612 citations

Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains.

1987 • 606 citations

Mitotic Misregulation and Human Aging

2000 • 592 citations

The Proteasome, a Novel Protease Regulated by Multiple Mechanisms

1999 • 540 citations

Protein oxidation in the brain in Alzheimer's disease

2001 • 495 citations

A macrophage receptor that recognizes oxidized low density lipoprotein but not acetylated low density lipoprotein

1989 • 480 citations

Cathepsin D protease mediates programmed cell death induced by interferon-gamma, Fas/APO-1 and TNF-alpha.

1996 • 467 citations

The glial glutamate transporter, GLT‐1, is oxidatively modified by 4‐hydroxy‐2‐nonenal in the Alzheimer's disease brain: the role of Aβ1–42

2001 • 458 citations

Comparative resistance of the 20S and 26S proteasome to oxidative stress

1998 • 442 citations

Bax degradation by the ubiquitin/proteasome-dependent pathway: Involvement in tumor survival and progression

2000 • 439 citations

Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway.

1995 • 438 citations

Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy.

1997 • 424 citations

Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis.

1997 • 388 citations

Gene expression and cellular content of cathepsin D in Alzheimer's disease brain: Evidence for early up-regulation of the endosomal-lysosomal system

1995 • 359 citations

Oxidative Modification and Inactivation of the Proteasome during Coronary Occlusion/Reperfusion

2001 • 349 citations

Increased Neuronal Endocytosis and Protease Delivery to Early Endosomes in Sporadic Alzheimer’s Disease: Neuropathologic Evidence for a Mechanism of Increased β-Amyloidogenesis

1997 • 348 citations

4-Hydroxy-2-nonenal-mediated Impairment of Intracellular Proteolysis during Oxidative Stress

1999 • 320 citations

The endosomal-lysosomal system of neurons in Alzheimer's disease pathogenesis: a review.

2000 • 314 citations

Age-related Macular Degeneration

2000 • 311 citations

Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal. Formation of cross-linked protein that inhibits the multicatalytic protease.

1994 • 311 citations

The ubiquitin conjugation system is required for ligand-induced endocytosis and degradation of the growth hormone receptor.

1996 • 307 citations

Proteasome inhibition by lipofuscin/ceroid during postmitotic aging of fibroblasts

2000 • 302 citations

Preferential degradation of the oxidatively modified form of glutamine synthetase by intracellular mammalian proteases.

1985 • 282 citations

The canine as an animal model of human aging and dementia

1996 • 269 citations

Inhibition of the multicatalytic proteinase (proteasome) by 4‐hydroxy‐2‐nonenal cross‐linked protein

1997 • 264 citations

Possible involvement of proteasome inhibition in aging: implications for oxidative stress

2000 • 264 citations

The proteasome activator 11 S REG (PA28) and Class I antigen presentation

1999 • 262 citations

Cardiac reperfusion injury: Aging, lipid peroxidation, and mitochondrial dysfunction

1998 • 260 citations

Hydrophobicity as the signal for selective degradation of hydroxyl radical-modified hemoglobin by the multicatalytic proteinase complex, proteasome

1993 • 252 citations

Age-Dependent Declines in Proteasome Activity in the Heart

2002 • 231 citations

When lysosomes get old☆

2000 • 220 citations

Protein oxidation and 20S proteasome-dependent proteolysis in mammalian cells

2001 • 216 citations

Protein oxidation and degradation during cellular senescence of human BJ fibroblasts: part I— effects of proliferative senescence

2000 • 216 citations

Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle

2000 • 215 citations

Ubiquitin-mediated Degradation of the Proapoptotic Active Form of Bid

2000 • 195 citations

Differential Impairment of 20S and 26S Proteasome Activities in Human Hematopoietic K562 Cells during Oxidative Stress

2000 • 191 citations

Recognition of Misfolding Proteins by PA700, the Regulatory Subcomplex of the 26 S Proteasome

2000 • 191 citations

Age-related alterations of proteasome structure and function in aging epidermis

2000 • 177 citations

Mechanisms of life span determination in Caenorhabditis elegans☆

1999 • 177 citations

Ligand-induced polyubiquitination of the platelet-derived growth factor beta-receptor.

1992 • 173 citations

Susceptibility of Glucose-6-Phosphate Dehydrogenase Modified by 4-Hydroxy-2-nonenal and Metal-Catalyzed Oxidation to Proteolysis by the Multicatalytic Protease

1994 • 172 citations

Protein Degradation by the Proteasome and Its Implications in Aging

2000 • 168 citations

Protein oxidation and degradation during cellular senescence of human BJ fibroblasts: part II—aging of nondividing cells

2000 • 160 citations

THE EFFECT OF AGE ON FORMATION AND ELIMINATION OF AUTOPHAGIC VACUOLES IN MOUSE HEPATOCYTES

1995 • 158 citations

Exposure of Hydrophobic Moieties Promotes the Selective Degradation of Hydrogen Peroxide-Modified Hemoglobin by the Multicatalytic Proteinase Complex, Proteasome

1994 • 153 citations

Ubiquitin Sorts Proteins into the Intralumenal Degradative Compartment of the Late‐Endosome/Vacuole

2001 • 151 citations

Oxidized low density lipoprotein is resistant to cathepsins and accumulates within macrophages

1991 • 147 citations

IκB Is a Substrate for a Selective Pathway of Lysosomal Proteolysis

1998 • 143 citations

Declines in mitochondrial respiration during cardiac reperfusion: Age-dependent inactivation of α-ketoglutarate dehydrogenase

1999 • 141 citations

Age-Related Changes in the Autophagic Proteolysis of Rat Isolated Liver Cells: Effects of Antiaging Dietary Restrictions

2001 • 140 citations

Studies on lipid peroxidation and protein oxidation in the aging brain

1995 • 140 citations

Oxidative Stress-Associated Impairment of Proteasome Activity during Ischemia–Reperfusion Injury

2000 • 138 citations

Effect of aging on intracellular Ca2+, pHi, and contractility during ischemia and reperfusion.

1992 • 120 citations

How do intracellular proteolytic systems change with age

1998 • 120 citations

Regulation of catabolism of microinjected ribonuclease A. Identification of residues 7-11 as the essential pentapeptide.

1986 • 117 citations

Protein oxidation and enzyme activity decline in old brown Norway rats are reduced by dietary restriction

1998 • 115 citations

Inactivation of lysosomal proteases by oxidized low density lipoprotein is partially responsible for its poor degradation by mouse peritoneal macrophages.

1994 • 115 citations

Proteasome inactivation upon aging and on oxidation-effect of HSP 90.

1997 • 112 citations

Ca2+-free Calmodulin and Calmodulin Damaged byin Vitro Aging Are Selectively Degraded by 26 S Proteasomes without Ubiquitination

2000 • 109 citations

Age-Related Changes in the Regulation of Autophagic Proteolysis in Rat Isolated Hepatocytes

2001 • 103 citations

Lipofuscin-Like Substances Accumulate Rapidly in Brain, Retina and Internal Organs with Cysteine Protease Inhibition

1990 • 100 citations

Lipofuscin and Ceroid Formation: The Cellular Recycling System

1990 • 99 citations

Increased left ventricular dysfunction in elderly patients despite successful thrombolysis: The GUSTO-I angiographic experience

1996 • 97 citations

Role of the proteasome in Alzheimer’s disease

2000 • 95 citations

The proteasome activator 11 S REG (PA28) and Class I antigen presentation

2000 • 93 citations

Ceroid/Lipofuscin-loaded human fibroblasts show increased susceptibility to oxidative stress

1999 • 92 citations

Relocalization of Cathepsin D and Cytochrome c Early in Apoptosis Revealed by Immunoelectron Microscopy

2001 • 92 citations

On the degradability and exocytosis of ceroid/lipofuscin in cultured rat cardiac myocytes

1998 • 77 citations

The protection of rat liver autophagic proteolysis from the age-related decline co-varies with the duration of anti-ageing food restriction

2001 • 73 citations

Oxidation of Aβ and Plaque Biogenesis in Alzheimer's Disease and Down Syndrome

2001 • 67 citations

Dietary Self-Selection Can Compensate an Age-Related Decrease of Rat Liver 20 S Proteasome Activity Observed With Standard Diet

1998 • 64 citations

Vulnerability of Synaptosomes from ApoE Knock-Out Mice to Structural and Oxidative Modifications Induced by Aβ(1−40): Implications for Alzheimer's Disease

2001 • 63 citations

Age-related changes in ultrastructural features of cathepsin B- and D-containing neurons in rat cerebral cortex

1999 • 47 citations

Interferon Regulatory Factor 1 Mediates the Interferon-γ Induction of the Human Immunoproteasome Subunit Multicatalytic Endopeptidase Complex-like 1

1999 • 43 citations

Dysfunction of the Islet Lysosomal System Conveys Impairment of Glucose-Induced Insulin Release in the Diabetic GK Rat*

1999 • 42 citations

Accumulation of Cardiac Lipofuscin Depends on Metabolic Rate of Mammals

1992 • 38 citations

Accumulation of cardiac lipofuscin in crab-eating monkeys (Macaca fasicularis): The same rate of lipofuscin accumulation in several species of primates

1993 • 20 citations

Age-related accumulation of lipofuscin in myocardium of Japanese monkey (Macaca fuscata)

1989 • 17 citations

Lysosomal Pathways of Protein Degradation

2001 • 13 citations

Dysfunction of the Islet Lysosomal System Conveys Impairment of Glucose-Induced Insulin Release in the Diabetic GK Rat

1999 • 13 citations

Ubiquitin and Alzheimerʼs amyloid ß precursor protein colocalize to endosomes-lysosomes in cultured human cells

1996 • 11 citations

Evaluation of the activities of eight lysosomal hydrolases in sera of humans, rats and pigs of different ages

1997 • 10 citations