Aging, oxidative stress and degenerative diseases: mechanisms, complications and emerging therapeutic strategies.

Aging accompanied by several age-related complications, is a multifaceted inevitable biological progression involving various genetic, environmental, and lifestyle factors. The major factor in this process is oxidative stress, caused by an abundance of reactive oxygen species (ROS) generated in the mitochondria and endoplasmic reticulum (ER). ROS and RNS pose a threat by disrupting signaling mechanisms and causing oxidative damage to cellular components. This oxidative stress affects both the ER and mitochondria, causing proteopathies (abnormal protein aggregation), initiation of unfolded protein response, mitochondrial dysfunction, abnormal cellular senescence, ultimately leading to inflammaging (chronic inflammation associated with aging) and, in rare cases, metastasis. RONS during oxidative stress dysregulate multiple metabolic pathways like NF-κB, MAPK, Nrf-2/Keap-1/ARE and PI3K/Akt which may lead to inappropriate cell death through apoptosis and necrosis. Inflammaging contributes to the development of inflammatory and degenerative diseases such as neurodegenerative diseases, diabetes, cardiovascular disease, chronic kidney disease, and retinopathy. The body's antioxidant systems, sirtuins, autophagy, apoptosis, and biogenesis play a role in maintaining homeostasis, but they have limitations and cannot achieve an ideal state of balance. Certain interventions, such as calorie restriction, intermittent fasting, dietary habits, and regular exercise, have shown beneficial effects in counteracting the aging process. In addition, interventions like senotherapy (targeting senescent cells) and sirtuin-activating compounds (STACs) enhance autophagy and apoptosis for efficient removal of damaged oxidative products and organelles. Further, STACs enhance biogenesis for the regeneration of required organelles to maintain homeostasis. This review article explores the various aspects of oxidative damage, the associated complications, and potential strategies to mitigate these effects.

Oxidative stress, inflammation and hormesis: The role of dietary and lifestyle modifications on aging.

Oxidative stress (OS) is primarily caused by the formation of free radicals and reactive oxygen species; it is considered as one of the prominent factors in slowing down and degrading cellular machinery of an individual, and it eventually leads to aging and age-related diseases by its continuous higher state. The relation between molecular damage and OS should be particularized to understand the beginning of destruction at the cellular levels, extending outwards to affect tissues, organs, and ultimately to the organism. Several OS biomarkers, which are established at the biomolecular level, are useful in investigating the disease susceptibility during aging. Slowing down the aging process is a matter of reducing the rate of oxidative damage to the cellular machinery over time. The breakdown of homeostasis, the mild overcompensation, the reestablishment of homeostasis, and the adaptive nature of the process are the essential features of hormesis, which incorporates several factors, including calorie restriction, nutrition and lifestyle modifications that play an important role in reducing the OS. In the current review, along with the concept and theories of aging (with emphasis on free radical theory), various manifestations of OS with special attention on mitochondrial dysfunction and age-related diseases have been discussed. To alleviate the OS, hormetic approaches including caloric restriction, exercise, and nutrition have also been discussed.

Oxidative stress, antioxidants, hormesis and calorie restriction: The current perspective in the biology of aging.

Aging, in a large measure, has long been defined as the resultant of oxidative stress acting on the cells. The cellular machinery eventually malfunctions at the basic level by the damage from the processes of oxidation and the system starts slowing down because of intrinsic eroding. To understand the initial destruction at the cellular level spreading outward to affect tissues, organs and the organism, the relationship between molecular damage and oxidative stress is required to understand. Retarding the aging process is a matter of cumulatively decreasing the rate of oxidative damage to the cellular machinery. Along with the genetic reasons, the decrease of oxidative stress is somehow a matter of lifestyle and importantly of diet. In the current review, the theories of aging and the understanding of various levels of molecular damage by oxidative stress have been emphasized. A broader understanding of mechanisms of aging have been elaborated in terms of effects of oxidative at molecular, mitochondrial, cellular and organ levels. The antioxidants supplementation, hormesis and calorie restriction as the prominent anti-aging strategies have also been discussed. The relevance and the efficacy of the antiaging strategies at system level have also been presented.

Plasma protein hydroperoxides during aging in humans: correlation with paraoxonase 1 (PON1) arylesterase activity and plasma total thiols.

BACKGROUND AND AIMS: Oxidative stress is thought to play a major role in the development of several age-dependent diseases. Proteins are major targets for oxidative attack. Protein hydroperoxides are formed by hydroxyl and singlet oxygen attack on protein, forming relatively stable hydroperoxides on histidine, tyrosine and tryptophan residues. This study investigated the levels of plasma protein hydroperoxides and antioxidant potential of plasma during aging in humans. We correlated the protein hydroperoxide formation with plasma antioxidant potential, paraoxonase 1 (PON1) arylesterase activity and plasma total thiols. METHODS: The protein hydroperoxides and antioxidant potential were measured in plasma of human subjects aged between 20 and 81 years of both genders. RESULTS: Increase in plasma protein hydroperoxides and decrease in plasma antioxidant potential were observed as function of human age. CONCLUSION: This study provides strong correlation between plasma protein hydroperoxides formation and decrease in plasma antioxidant potential during aging. PON1 arylesterase activity and plasma total thiols levels were also found to show significant correlation with increasing levels of plasma protein hydroperoxides during aging. The plasma protein hydroperoxides provide a reliable marker of long-term redox balance and degree of oxidative stress during aging process.

N,N-Dimethyl-p-phenylenediamine dihydrochloride-based method for the measurement of plasma oxidative capacity during human aging.

N,N-Dimethyl-p-phenylenediamine dihydrochloride (DMPD) is a compound that is normally used to measure the antioxidant potential. In the presence of Fe(3+), it gets converted to DMPD(∙+) radical, which is scavenged by antioxidant molecules present in test samples. In plasma, due to the presence of iron, this method cannot be applied for the measurement of antioxidant potential. The modified DMPD method proposed by us measures with great accuracy the oxidant potential of plasma using the oxidizing effect of plasma to oxidize DMPD into producing a stable pink color. The method is fast and reproducible. We show that plasma oxidative capacity increases significantly during human aging.

Human plasma paraoxonase 1 (PON1) arylesterase activity during aging: correlation with susceptibility of LDL oxidation.

BACKGROUND AND AIMS: The role of free radicals has long been proposed as a cause for the aging process. Oxidative stress is considered a major factor for altering many physiological processes and enzymatic activities during aging and is also known to play a major role in the development of several age-dependent diseases. Paraoxonase 1 (PON1) is an anti-atherosclerotic enzyme that mainly prevents accumulation of lipoperoxides and inhibits the lipid oxidation in low-density lipoproteins (LDL). This study was undertaken to investigate the antioxidant behavior of PON1 by measuring its arylesterase activity. The susceptibility of LDL for oxidation and the radical scavenging activity of plasma were also measured during aging in humans. METHODS: Arylesterase activity of PON1 was measured in plasma of human subjects between 20 and 81 years of age of both genders. The susceptibility of LDL for oxidation and radical scavenging activity were measured in plasma. RESULTS: Decrease in plasma arylesterase activity of PON1, increase in susceptibility of LDL for oxidation and decrease in plasma radical scavenging activity were observed as a function of human age. CONCLUSIONS: The study provides evidence of a relationship between PON1 activity, LDL oxidation and free radical scavenging activity of plasma. The present results emphasize the dependency of PON1 activity to prevailing oxidative stress during human aging. Our findings assume significance in view of the possible categorization of PON1 as a longevity gene.

Erythrocyte sialic acid content during aging in humans: correlation with markers of oxidative stress.

Sialic acids are substituted neuraminic acid derivatives which are typically found at the outermost end of glycan chains on the membrane in all cell types. The role of erythrocyte membrane sialic acids during aging has been established however the relationship between sialic acid and oxidative stress is not fully understood. The present work was undertaken to analyze the relationship between erythrocyte membrane sialic acid with its plasma level, membrane and plasma lipid hydroperoxide levels and plasma total antioxidant capacity. Results show that sialic acid content decreases significantly (P< 0.001) in RBC membrane (r= -0.901) and increases in plasma (r=0.860) as a function of age in humans. Lipid peroxidation measured in the form of hydroperoxides increases significantly (P<0.001) in plasma (r=0.830) and RBC membranes (r=0.875) with age in humans. The Trolox Equivalent Total Antioxidant Capacity (TETAC) of plasma was found to be significantly decreased (P< 0.001, r=-0.844). We observe significant correlations between decrease of erythrocyte membrane sialic acid and plasma lipid hydroperoxide and TETAC. Based on the observed correlations, we hypothesize that increase in oxidative stress during aging may influence the sialic acid decomposition from membrane thereby altering the membrane configuration affecting many enzymatic and transporter activities. Considering the importance of plasma sialic acid as a diagnostic parameter, it is important to establish age-dependent reference.