Onset Of Age-related Diseases Research Articles

Aging-related decrease in liver peroxisomal fatty acid oxidation in control and clofibrate-treated mice. A biochemical study and mechanistic approach

Membrane fatty acid composition affects membrane structure and function. Alterations in membrane composition have been reported in old animals and it is now hypothesized that these alterations may contribute to the onset of age-related diseases. Previously, we proposed that peroxisomes might also be involved in these aging-related membrane alterations. In order to extend our previous work, we have assayed acyl-CoA oxidase activity and cyanide-insensitive fatty acid oxidation activity for both arachidonic 20:4(n-6) and docosa-hexaenoic 22:6(n-3) acids, catalase and urate oxidase activities, microsomal cytochrome P450 content and cytochrome P4504A1 laurate hydroxylase activity in the liver of young and old mice fed either a control or a clofibrate-supplemented diet. Our results suggest a progressive general decrease in peroxisomal function during aging, including a decrease in the fatty acid oxidation pathway that takes place via a specific decrease in acyl-CoA oxidase activity. The aging-related decrease in peroxisomal function is linked to a concomitant decrease in cytochrome P4504A laurate hydroxylase activity in control animals but not in clofibrate-treated mice. This suggests aging impairs a mechanism in peroxisome proliferation that is subsequent to the cytochrome P4504A step. Implications of the aging-related peroxisomal fatty acid oxidation decrease on health through possible alterations in membrane composition and function and very long chain fatty acid accumulation are discussed.

Oxygen radical detoxification processes during aging: the functional importance of melatonin.

That free radical destruction of macromolecules is a basis of aging and age-related diseases has considerable experimental support. Melatonin, a hormone produced in organisms as diverse as algae and humans, is believed to have evolved coincident with aerobic metabolism. In all organisms melatonin is produced primarily during the daily period of darkness, with only small amounts being synthesized during the day. In mammals including man, melatonin is produced by and secreted from the pineal gland during the night; however, the night-time production of melatonin falls markedly with aging such that in senescent animals a night-time melatonin rise is barely measurable. This may be significant in terms of aging in the light of recent observations which show that melatonin is a highly efficient free radical scavenger and antioxidant both in vitro and in vivo. In vitro, melatonin has been shown to directly scavenge both the hydroxyl and peroxyl radical, and it does so more efficiently than other known antioxidants. Furthermore, melatonin greatly potentiates the efficiency of previously-discovered endogenous and exogenous antioxidants. In vivo, both physiological and pharmacological levels of melatonin reportedly counteract the devastatingly destructive actions of free radical generating chemicals. For example, melatonin effectively combats DNA damage in rats given massive doses of the chemical carcinogen safrole, and the indole overcomes much of the genomic damage inflicted by ionizing radiation. Also, lipid peroxidation induced by either paraquat, bacterial lipopolysaccharide or H2O2 is highly significantly reduced by concurrent melatonin administration. Finally, cataracts produced in newborn rats by the depletion of the endogenous antioxidant glutathione are prevented by melatonin. These findings provide evidence that melatonin is operative in the cell nucleus, in the aqueous cytosol and in lipid-rich cellular membranes as an antioxidant. Considering this, the loss of this potent antioxidant during aging may be consequential in terms of cellular and organismal aging as well as the onset of age-related diseases. These experimental results from a variety of sources suggest that a more determined approach to the study of melatonin as an anti-aging factor is warranted.

The pineal gland and melatonin in relation to aging: A summary of the theories and of the data

Within recent years, many investigators have implicated the pineal gland and melatonin in the processes of both aging and age-related diseases. These theories stem from the importance of melatonin in a number of biological functions and the fact that melatonin production in the organism is gradually lost throughout life, such that in very old individuals of any species the circadian melatonin rhythm is bearly discernible. In most species, from algae to humans, where it has been investigated, melatonin has been shown to exhibit a strong circadian rhythm in production and secretion, with high levels of the indole always being associated with the dark period of the light:dark cycle. One theory states that when the melatonin rhythm deteriorates during aging, other circadian rhythms are likewise weakened and rhythms become dysynchronized. This dysynchronization is believed to contribute significantly to aging and to render animals more susceptible to age-related diseases. Another theory assumes that the waning melatonin cycle provides an important switch for genetically programmed aging at the cellular level; furthermore, because all cells in the organism are exposed to the same gradually dampening melatonin signal throughout life, all cells age more or less at the same rate. In this theory, it is presumed to be the duration of the nocturnally elevated melatonin (which, like the amplitude, is reduced during aging), which, when coupled to a time-gating signal, is consequential in determining the rate of aging. Another compelling argument that the reduction in melatonin with age may be contributory to aging and the onset of age-related diseases is based on the recent observation that melatonin is the most potent hydroxyl radical scavenger thus far discovered. A prominent theory of aging attributes the rate of aging to accumulated free radical damage. Inasmuch as melatonin can markedly protect macromolecules, especially DNA, against free radical attack, it could, indeed, be a major factor in determining the rate at which organisms age. Besides its ability to directly scavenge the highly toxic hydroxyl radical, melatonin also promotes the activity of the antioxidative enzyme glutathione peroxidase, thereby further reducing oxidative damage. These actions may be manifested more obviously in the central nervous system, which is highly susceptible to damage by oxygen-based radicals and, because of its inability to regenerate and its high vulnerability to oxidative attack, its deterioration may be especially important in aging.(ABSTRACT TRUNCATED AT 400 WORDS)

Slowing ageing by caloric restriction.

Dietary caloric restriction is the only intervention conclusively shown to slow ageing, delay the onset of age-related diseases, maintain function and extend both median and maximal life span in mammals.

Melatonin, hydroxyl radical‐mediated oxidative damage, and aging: A hypothesis

Melatonin is a very potent and efficient endogenous radical scavenger. The pineal indolamine reacts with the highly toxic hydroxyl radical and provides on-site protection against oxidative damage to biomolecules within every cellular compartment. Melatonin acts as a primary non-enzymatic antioxidative defense against the devastating actions of the extremely reactive hydroxyl radical. Melatonin and structurally related tryptophan metabolites are evolutionary conservative molecules principally involved in the prevention of oxidative stress in organisms as different as algae and rats. The rate of aging and the time of onset of age-related diseases in rodents can be retarded by the administration of melatonin or treatments that preserve the endogenous rhythm of melatonin formation. The release of excitatory amino acids such as glutamate enhances endogenous hydroxyl radical formation. The activation of central excitatory amino acid receptors suppress melatonin synthesis and is therefore accompanied by a reduced detoxification rate of hydroxyl radicals. Aged animals and humans are melatonin-deficient and more sensitive to oxidative stress. Experiments investigating the effects of endogenous excitatory amino acid antagonists and stimulants of melatonin biosynthesis such as magnesium may finally lead to novel therapeutic approaches for the prevention of degeneration and dysdifferentiation associated with diseases related to premature aging.

Effects of aging anf dietary restriction of DNA polymerase expression in mice

DNA polymerase α was isolated from livers of 6-month-, 16-month-, or 26-month-old mice fed ad libitum, or calorically restricted. The enzymes differed in chromatographic characteristics, binding affinity for DNA, and activity, with both total activity and specific activity of DNA polymerase α decreasing as a function of age. A positive correlation was observed between polymerase α specific activity and the affinity of enzyme binding to activated DNA template-primer. The age-associated decline in enzyme activity was modified by dietary restriction, with measureably higher activity seen for polymerases from dietary restricted animals compared with ad libitum animals of all ages. The data suggest that dietary restriction could act to delay the age-associated decrease in cellular capacity for DNA synthesis, which may play a significant role in prolonging the onset of age-related diseases in which decreased DNA synthesis is a potential component.

Effects of Surface Hydrophobicity, Net Charge and SH Groups on Thermal Coagulation and Gelation of Ovalbumin

Age-related cataracts, which probably form due to insolubilization of lens proteins, can lead to loss of vision. Although the exact reason is unknown, lens protein aggregation may be triggered by increases in PTMs such as d-β-, l-β- and d-α-Asp isomers. These isomers have been observed in aged lens; however, there have been few quantitative and site-specific studies owing to the lack of a quick and precise method for distinguishing between d- and l-Asp in a peptide or protein.We describe a new method for detecting peptides containing Asp isomers at individual sites in any protein by using an LC–MS/MS system combined with commercial enzymes that specifically react with different isomers. We also summarize current data on the effect of Asp isomerization on lens crystallins.The new technique enabled the analysis of isomers of Asp residues in lens proteins precisely and quickly. An extensive proportion of Asp isomerization was observed at all Asp sites of crystallins in the insoluble fraction of aged lens. In addition, d-amino acid substitutions in crystallin-mimic peptides showed altered structural formation and function. These results indicate that isomerization of Asp residues affects the stability, structure and inter-subunit interaction of lens crystallins, which will induce crystallin aggregation and insolubilization, disrupt the associated functions, and ultimately contribute to the onset of senile cataract formation.The mechanism underlying the onset of age-related diseases may involve isomerization, whereby d-amino acids are incorporated in the l-amino acid world of life.This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.

Central neurotransmitter substances and aging: a review.

Available evidence suggests that age is an important determinant of the levels of neurotransmitters and their associated enzymes and metabolites in some regions of the brain. Alterations at the synaptic level, or selective cell death in the brain, or both, may be implicated in progressive loss of function, behavioral changes and the onset of age-related diseases. Stimulation of hypothalamic neuroendocrine transducer cells by agents that alter neurotransmitter metabolism might provide some measure of control of the process of aging.