Aging, lipofuscin formation, and free radical-mediated inhibition of cellular proteolytic systems
Introduction
Aging is a multifaceted phenomenon associated with decrements in cellular and physiological function, increases in the incidence of numerous degenerative diseases, and a diminished capacity for responding to stress (Beckman and Ames, 1998). Research into the mechanisms at play in the aging process is of particular importance given that human lifespan has increased over the past several decades and, as a result, medical complications related to aging are becoming a major health concern world-wide. A large body of literature attests to various anatomical structures and cellular/physiological functions that are altered during aging (Beckman and Ames, 1998). It is therefore of interest to define molecular mechanisms that are responsible for and/or contribute to these changes, thereby aiding in the development of pharmacological, medical, and nutritional interventions for enhancing the health of the elderly. There is little doubt that, due to the complexity of living organisms, age-associated cellular and physiological alterations reflect changes in numerous interrelated biochemical processes. The current review focuses on the interplay between free radical-mediated modifications to protein structure/function, the activities of two major proteolytic systems within cells, lysosomes and the proteasome, and the age-dependent accumulation of fluorescent intracellular granules, termed lipofuscin. Evidence that free radicals mediate modifications to protein(s) that lead to the production of inhibitor(s) of cellular proteolytic systems will be presented. Results of in vitro studies will be summarized and related to in vivo findings, thus shedding light on potential consequences to cellular function. Finally, future research directions suggested by the available data will be discussed.
Section snippets
Aging and proteolysis
An apparently universal feature of aging is the accumulation of fluorescent, non-degradable material within intracellular granules, termed lipofuscin (Harman, 1989, Ames et al., 1993, Beckman and Ames, 1998, Porta, 2002). The build-up of lipofuscin is observed primarily in post-mitotic and long-lived cells from a wide variety of organisms, although its accumulation has also been documented in mitotic cells such as hepatocytes. The ultrastructural and histochemical properties of lipofuscin are
Free radical mechanism(s) and the production of inhibitor proteins
As determined in numerous in vitro studies, it is well known that free radicals can interact with proteins, lipids, and DNA, thereby altering the structure/function of these biomolecules (Esterbauer et al., 1991, Beckman and Ames, 1997, Berlett and Stadtman, 1997). Direct oxidation of amino acid residues results in the introduction of carbonyl groups on proteins and, for certain proteins, loss of enzyme activity (Berlett and Stadtman, 1997). Moreover, increases in overall protein oxidation
Oxidatively-modified proteins in lipofuscin
The intracellular levels of oxidatively-modified forms of protein reflect the rate with which proteins undergo free radical-induced modifications, the efficiency by which cells can repair such modifications, and the ability of cellular proteolytic systems to degrade altered forms of protein. Moreover, depending on the form and extent of modification, oxidatively-modified proteins may exhibit enhanced proteolytic susceptibility (Pacifici et al., 1993, Friguet et al., 1994b, Giulivi et al., 1994,
Future directions and physiological relevance
As summarized above, existing evidence suggests the possibility that, during the lifetime of a cell, proteins undergo continuous free radical-mediated cross-linking reactions thereby contributing to the formation of inhibitors of cellular proteolytic systems and, subsequently, lipofuscinogenesis. Further support for this possibility would be gained by demonstrating that specific proteins bearing distinct post-translational modifications act to inhibit cathepsin(s) and/or the proteasome in vivo.
Acknowledgements
We thank Joan Sempf for performing immunogold histochemical analyses. This work was supported in part by a grant from the National Institutes of Health (AG-16339).
References (140)
- et al.
Up-regulation of the lysosomal system in experimental models of neuronal injury: implications for Alzheimer’s disease
Neuroscience
(2000) - et al.
Protein oxidation and enzyme activity decline in old brown Norway rats are reduced by dietary restriction
Mech. Ageing Dev.
(1998) - et al.
Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow
J. Biol. Chem.
(1993) - et al.
Oxidative decay of DNA
J. Biol. Chem.
(1997) - et al.
Protein oxidation in aging, disease, and oxidative stress
J. Biol. Chem.
(1997) - et al.
Stress-inducible mechanisms of life-span extension in yeast, eubacteria, and metazoans
Trends Microbiol.
(1999) - et al.
Ubiquitin-mediated degradation of the proapoptotic active form of bid. A functional consequence on apoptosis induction
J. Biol. Chem.
(2000) - et al.
Lipofuscin: mechanisms of age-related accumulation and influence on cell function
Free Radic. Biol. Med.
(2002) - et al.
Oxidative modification and inactivation of the proteasome during coronary occlusion/reperfusion
J. Biol. Chem.
(2001) - et al.
Age-related alterations of proteasome structure and function in aging epidermis
Exp. Gerontol.
(2000)
Age-dependent declines in proteasome activity in the heart
Arch. Biochem. Biophys.
Carbonic anhydrase III. Oxidative modification in vivo and loss of phosphatase activity during aging
J. Biol. Chem.
Mitochondrial free radical generation, oxidative stress, and aging
Free Radic. Biol. Med.
Hydroxynonenal adducts indicate a role for lipid peroxidation in neocortical and brainstem Lewy bodies in humans
Neurosci. Lett.
Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer disease
Brain Res.
Gene expression and cellular content of cathepsin D in Alzheimer’s disease brain: evidence for early up-regulation of the endosomal-lysosomal system
Neuron
Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer’s disease and Down syndrome: differential effects of APOE genotype and presenilin mutations
Am. J. Pathol.
The protection of rat liver autophagic proteolysis from the age-related decline co-varies with the duration of anti-ageing food restriction
Exp. Gerontol.
Role of the proteasome in Alzheimer’s disease
Biochim. Biophys. Acta
Inhibition of adenine nucleotide translocator by lipid peroxidation products
Free Radic. Biol. Med.
Chemical characterization of a protein-4-hydroxy-2-nonenal cross-link: immunochemical detection in mitochondria exposed to oxidative stress
Arch. Biochem. Biophys.
Age-related decline in chaperone-mediated autophagy
J. Biol. Chem.
When lysosomes get old
Exp. Gerontol.
Degradation of oxidized proteins by the 20S proteasome
Biochimie
The proteasome, a novel protease regulated by multiple mechanisms
J. Biol. Chem.
Human heptocellular pigments and lysosomes
J. Ultrastruct. Res.
Chemistry and biochemistry of 4-hydroxynonenal malonaldehyde and related aldehydes
Free Radic. Biol. Med.
Inhibition of the multicatalytic proteinase (proteasome) by 4-hydroxy-2-nonenal cross-linked protein
FEBS Lett.
Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal. Formation of cross-linked protein that inhibits the multicatalytic protease
J. Biol. Chem.
Susceptibility of glucose-6-phosphate dehydrogenase modified by 4-hydroxy-2-nonenal and metal-catalyzed oxidation to proteolysis by the multicatalytic protease
Arch. Biochem. Biophys.
Exposure of hydrophobic moieties promotes the selective degradation of hydrogen peroxide-modified hemoglobin by the multicatalytic proteinase complex, proteasome
Arch. Biochem. Biophys.
The permeability transition pore complex: another view
Biochimie
Detection of lipofuscin-like fluorophore in oxidized human low-density lipoprotein. 4-hydroxy-2-nonenal as a potential source of fluorescent chromophore
FEBS Lett.
Leupeptin causes an accumulation of lipofuscin-like substances in liver cells of young rats
Mech. Ageing Dev.
Age-related changes in ultrastructural features of cathepsin B- and D-containing neurons in rat cerebral cortex
Brain Res.
Possible involvement of proteasome inhibition in aging: implications for oxidative stress
Mech. Ageing Dev.
Decreased levels of proteasome activity and proteasome expression in aging spinal cord
Neuroscience
Mitochondrial permeability transition and oxidative stress
FEBS Lett.
Oxidized low density lipoprotein is resistant to cathepsins and accumulates within macrophages
J. Biol. Chem.
Alzheimer’s disease-related overexpression of the cation-dependent mannose 6-phosphate receptor increases Abeta secretion: role for altered lysosomal hydrolase distribution in beta-amyloidogenesis
J. Biol. Chem.
Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson’s disease
Brain Res.
4-Hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress. Identification of proteasomes as target molecules
J. Biol. Chem.
Hydrophobicity as the signal for selective degradation of hydroxyl radical-modified hemoglobin by the multicatalytic proteinase complex, proteasome
J. Biol. Chem.
Ceroid lipofuscinosis in sheep. II. The major component of the lipopigment in liver, kidney, pancreas, and brain is low molecular weight protein
J. Biol. Chem.
Advances in age pigment research
Arch. Gerontol. Geriatr.
Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway
Proc. Natl. Acad. Sci. U.S.A.
Oxidants, antioxidants and the degenerative diseases of aging
Proc. Natl. Acad. Sci. U.S.A.
Dietary self-selection can compensate an age-related decrease of rat liver 20S proteasome activity observed with standard diet
J. Gerontol. A Biol. Sci. Med. Sci.
The free radical theory of aging matures
Physiol. Rev.
4-Hydroxynonenal, an aldehydic product of lipid peroxidation, impairs signal transduction associated with muscarinic acetylcholine and metabotropic glutamate receptors: possible action on Gaq/11
J. Neurochem.
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2018, Ageing Research ReviewsCitation Excerpt :With regard to oxidative stress, it was demonstrated that significantly lower levels of free radicals and ROS are generated in the brains of longer-lived animals (Bondy et al., 2004). The production of lipofuscin bodies and more importantly amyloid plaques, which are a major characteristic of Alzheimer’s disease, is an important feature of aged brain and contributes to deleterious effects in oxidative processes (Szweda et al., 2003). Based on what is known about the potent antioxidant and anti-inflammatory actions concluded from these studies, melatonin, a pineal secretory product is a candidate for exerting anti-ageing functions in the brain.