Aging, lipofuscin formation, and free radical-mediated inhibition of cellular proteolytic systems

Szweda, Pamela A.; Camouse, Melissa; Lundberg, Kathleen C.; Oberley, Terry D.; Szweda, Luke I.

doi:10.1016/s1568-1637(03)00028-x

Cited by 113 publications

(68 citation statements)

References 136 publications

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“…In mammals, this process is associated with decrements in cellular and physiological functions and a major incidence of degenerative diseases. The alterations that happen are the result of an interaction between many factors and aging is therefore a very complex phenomenon (Szweda et al, 2003). In the nervous system, the effects of aging are evidenced by a functional decline that involves the central and peripheral nervous system.…”

Section: Introductionmentioning

confidence: 99%

Postnatal‐related changes in the size and total number of neurons in the caudal mesenteric ganglion of dogs: Total number of neurons can be predicted from body weight and ganglion volume

et al. 2005

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Aging is mostly characterized by a progressive decline of neuronal function that involves both the central and the peripheral nervous system. The aging process is accompanied by changes in either the number or the size of neurons. However, these data are controversial and not very well known in the sympathetic ganglia of large mammals. Hence, the present investigation aimed to study the dog's caudal mesenteric ganglion (CMG) in three different periods of postnatal development, searching for qualitative and quantitative alterations. The CMG is responsible for the large intestine, internal anal sphincter, and partially the urogenital system innervations. Nine dead male dogs from the Veterinary Hospital of the College of Veterinary Medicine at University of São Paulo were divided into three well-defined age groups (1-2 months old, 1-2 years old, and 5-10 years old). The stereological study was pursued using the physical disector method combined to the Cavalieri principle. The postnatal development was accompanied by an increase in the nonneuronal tissue amount and in ganglion volume. Additionally, the total number of neurons also increased during aging (from 70,140 to 1,204,516), although the neuronal density showed an opposite trend (from 29,911 to 11,500 mm Ϫ3 ). Due to the interrelation between either body weight or ganglion volume and aging in the dogs investigated in this study, it was possible to predict the total number of neurons in CMG using both body weight and ganglion volume in an attempt to verify whether or not size and total number of neurons are both allometrically and aging ruled, i.e., if either the animal's body weight and ganglion volume or aging influence these parameters. The prediction of the total number of neurons was very close to the initially estimated values.

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Section: Introductionmentioning

confidence: 99%

Postnatal‐related changes in the size and total number of neurons in the caudal mesenteric ganglion of dogs: Total number of neurons can be predicted from body weight and ganglion volume

et al. 2005

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“…For example, the yeast Saccharomyces cerevisiae accumulates extrachromosomal ribosomal DNA circles (ECR) and depolarized mitochondria with age (Sinclair and Guarente 1997;Hughes and Gottschling 2012), while old Caenorhabditis elegans nematodes accumulate lipofuscin (Klass 1977), an insoluble aggregate of oxidized proteins and lipids (Toth 1968;Porta 1991), in their intestinal cells. In higher eukaryotes, damaged organelles and proteins accumulate in long-lived postmitotic tissues, such as skeletal muscles, heart, liver, and brain (Schmucker 2005;Chaudhary et al 2011;Szweda et al 2003). Cells in these aging organs contain increased levels of damaged and dysfunctional cellular components with age: for example, neurons, astrocytes, microglia, hepatocytes, and cardiomyocytes accumulate lipofuscin deposits and other protein aggregates (Landfield et al 1981;Salminen et al 2011;Vaughan and Peters 1974;Frenzel and Feimann 1984;Schmucker and Sachs 2002); rhabdomyocytes accumulate mitochondria with oxidized bases in their DNA, reduced activity, and increased production of reactive oxygen species (Mansouri et al 2006); and cardiac myocytes accumulate impaired mitochondria with increased fragmentation of mitochondrial DNA (Frenzel and Feimann 1984;Ozawa 1998).…”

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confidence: 99%

p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

AGE

122

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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“…However, as clarified by Porta (2002), such assumptions are ultimately based on unwarranted extrapolation of the influential early in vitro studies of Chio et al (1969) and Chio & Tappel (1969) to diverse animal tissues in studies such as Fletcher et al (1973), upon which Ettershank's pioneering, but methodologically questionable attempts to develop LF as an ecological tool were subsequently based (Ettershank 1983, Sheehy & Ettershank 1988, Sheehy & Roberts 1991. Recent molecular analysis suggests that lipid peroxidation products are indeed a component of LF (Schutt et al 2003, Szweda et al 2003 but they are unlikely to be the source of extractable autofluorescence. Dissolution of isolated neurolipofuscin granules results in a complete loss of fluorescence (Palmer et al 2002).…”

Section: Extracted Fluorescence Remains Unidentifiedmentioning

confidence: 99%

Questioning the use of biochemical extraction to measure lipofuscin for age determination of crabs: Comment on Ju et al. (1999, 2001)

Sheehy¹

2008

Mar. Ecol. Prog. Ser.

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In recent years, there has been considerable progress in the application of the cellular ageing biomarker, lipofuscin (LF), to age determination in crustacean fisheries in cases where no other reliable ageing methods exist. Two general approaches are available for LF measurement, the first involving fluorescence microscopy and image analysis of histological sections, and the second employing spectrofluorimetery of crude tissue extracts. However, for many years, controversy raged, mainly within the gerontological arena as to the validity of the second approach. Marine and fisheries ecologists may not be as aware of the problem. For example, Ju et al. (1999, Mar Ecol Prog Ser 185:171-179; 2001, Mar Ecol Prog Ser 224:197-205 and elsewhere) report application of the LF ageing method to demographic analysis of the economically important blue crab Callinectes sapidus using biochemical quantification procedures. This is an important issue because useful conclusions about valuable bioresources cannot be drawn where analysis techniques are flawed. In the present paper I discuss the main concerns regarding past attempts to quantify LF biochemically for age determination of crabs: (1) extracted fluorescence remains unidentified; (2) no correlation between extracted fluorescence and in situ LF concentration has ever been demonstrated; (3) there is no evidence that normalization to cellular protein produces a reliable LF assay; (4) dependence of fluorescence intensity on extracted tissue mass can be misleading; and (5) high throughput biochemical measurement does not compensate for absence of specificity. Despite the inherent challenges associated with devising a reliable biochemical quantification method for neurolipofuscin, there remains little doubt that such a development will be a significant advance both in marine-and fisheries ecology and in the wider arena of gerontology.

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Aging, lipofuscin formation, and free radical-mediated inhibition of cellular proteolytic systems

Cited by 113 publications

References 136 publications

Postnatal‐related changes in the size and total number of neurons in the caudal mesenteric ganglion of dogs: Total number of neurons can be predicted from body weight and ganglion volume

Postnatal‐related changes in the size and total number of neurons in the caudal mesenteric ganglion of dogs: Total number of neurons can be predicted from body weight and ganglion volume

p62/SQSTM1 at the interface of aging, autophagy, and disease

Questioning the use of biochemical extraction to measure lipofuscin for age determination of crabs: Comment on Ju et al. (1999, 2001)

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