Edited by: Touqeer Ahmed, National University of Sciences & Technology, Pakistan
Reviewed by: Selva Rivas - Arancibia, National Autonomous University of Mexico, Mexico; Ian James Martins, Edith Cowan University, Australia
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Brain aging is the critical and common factor among several neurodegenerative disorders and dementia. Cellular, biochemical and molecular studies have shown intimate links between oxidative stress and cognitive dysfunction during aging and age-associated neuronal diseases. Brain aging is accompanied by oxidative damage of nuclear as well as mitochondrial DNA, and diminished repair. Recent studies have reported epigenetic alterations during aging of the brain which involves reactive oxygen species (ROS) that regulates various systems through distinct mechanisms. However, there are studies which depict differing roles of reactive oxidant species as a major factor during aging. In this review, we describe the evidence to show how oxidative stress is intricately linked to age-associated cognitive decline. The review will primarily focus on implications of age-associated oxidative damage on learning and memory, and the cellular events, with special emphasis on associated epigenetic machinery. A comprehensive understanding of these mechanisms may provide a perspective on the development of potential therapeutic targets within the oxidative system.
Aging involves the systemic loss of functioning in a time-dependent manner (
Cognition is the collective set of abilities that involves various information processing, storage, and retrieval. This envelopes the concept of intelligence or metacognition, which involves the capacity to learn from experience and the ability to adapt to the surrounding environment or situations (
Oxidative stress and its associated damage being involved in the age-dependent cognitive loss have been highlighted through numerous investigations to be the basis of pathogenesis. Comparison between young and aged animal brains showed higher levels of ROS and oxidative stress markers (
The conditions that prevail during aging are higher levels of oxidant species, oxidative stress and a shortfall in the antioxidant levels. To counter the effects of drop in antioxidant levels, the aged mice models that overexpress extracellular superoxide dismutase (EC-SOD) showed alleviation in spatial learning and memory related hippocampal long-term potentiation (LTP) that declines with age (
A prominent sign of an aging cell is the imbalance between the constantly produced reactive oxidant species and the diminishing antioxidant capacity (
DNA is an important carrier of heritable genetic information that faces the limitation of chemical stability that is constantly prone to changes (
DNA undergoes oxidative damage due to a series of sources reactive oxygen and nitrogen species (RONS), reactive carbonyl species, products of lipid peroxidation (
Oxidizing species – their targets and products.
Oxidizing species (source) | Target | Oxidative damage product | References |
Superoxide anions | Guanine | 5-Diamino-4 |
|
Singlet oxygen | Guanine | 8-Oxo-7,8-dihydroguanine and spiroiminodihydantoin | |
Hydroxyl radicals | Adenine/adenosine | 5-Formamido-6-aminopyrimidine type product (FAPy) adenine and adenosine; 8-hydroxyadenine or -adenosine | |
Cytosine | 5-Hydroxy-5,6-dihydrocytos-6-yl and 6-hydroxy-5,6- dihydrocytos-5-yl | ||
5-Methylcytosine | 5,6-Dihydroxy-5,6-dihydro-5-methylcytosine; 1-carbamoyl-4,5-dihydroxy-5-methyl-2-oxo-imidazolidine; aminocarbonyl[2-amino]-carbamic acid and |
||
Nitrous anhydride | Adenine | Hypoxanthine | |
Cytosine | Uracil | ||
5-Methylcytosine | Thymine | ||
Guanine | Xanthine | ||
Peroxynitrite | Deoxyguanosine | 8-Nitro-deoxyguanosine | |
Deoxyadenosine | 8-Oxo-7,8-dihydro-2′-deoxyadenosine | ||
Guanine | 8-Nitroguanine |
Oxidative damage causes profound effects on the genetic composition by affecting the nuclear and mitochondrial DNA. The relative amounts of such damages if quantified can give an idea regarding the levels of oxidative stress faced by the cell, especially during aging. This has been done previously by various groups using different techniques such as HPLC-EC or GC/MS (see
Relative amounts of oxidative damages on nucleic acids in aging.
Type of oxidative damage | Rate of production | Sample studied | Rate of repair required/hits on DNA | Technique used to measure oxidative damage | Species | Age groups | Source of oxidative stress | References |
8-Hydroxydeoxyguanosine (8OHdG) | 236 fmol/μg of DNA | Liver | 165 ± 66 pmol kg–1 day–1 | HPLC- electrochemical detection | Rat | 24 months | Naturally occurring | |
37.5 ± 3.2 fmol/μg of DNA | Kidney | |||||||
16.7 ± 1.1 fmol/μg of DNA | Intestine | |||||||
13.1 ± 2.5 fmol/μg of DNA | Brain | |||||||
13.2 ± 0.9 fmol/μg of DNA | Testes | |||||||
3.2 residues/106 bp | Liver | 20% cleavage per μg DNA | HPLC- electrochemical detection | Mouse | 4 months | Naturally occurring | ||
8–73 per 106 dG residues | Liver | Not mentioned | HPLC- electrochemical detection | Rat | 6 months | Naturally occurring | ||
8-Hydroxyguanosine (8OHG) | 3645 ± 1166 pmol kg–1 day–1 | Urine | Not mentioned | HPLC- electrochemical detection | Rat | 24 months | Naturally occurring | |
8-Oxoguanine (8-oxoG) | 76.2 ± 6.15 nmol/mmol creatinine | Urine | Not mentioned | HPLC and GC/MS | Rat | 14 months | Naturally occurring | |
84.99 ± 5.91 nmol/mmol creatinine | 34,000 repair events/cell/day | Mouse | 12 months | |||||
8.4 ± 1.21 nmol/mmol creatinine | 2,800 repair events/cell/day | Human | 40 years | |||||
8-Oxo-deoxyguanosine(8-oxodG) | 0.037 ± 0.004 per 105dG residues | Liver | 47,000 lesions/cell/day | HPLC- electrochemical detection | Mouse | 4–8 months | γ-Irradiation (0.5–50 Gy | |
0.012 ± 0.003 per 105dG residues | Brain | Not mentioned | ||||||
0.012 ± 0.004 per 105dG residues | Heart | Not mentioned | ||||||
0.033 ± 0.005 per 105dG residues | Liver | Not mentioned | Rat | 4–6 months | Naturally occurring | |||
0.012 ± 0.003 per 105dG residues | Brain | Not mentioned | ||||||
0.010 ± 0.002 per 105dG residues | Heart | Not mentioned | ||||||
0.064 ± 0.004 per 105dG residues | Prostate | Not mentioned | Human | 60–78 years | Naturally occurring | |||
8-Oxo-deoxyguanosine(8-oxodG) | 7.22 ± 1.05 nmol/mmol creatinine | Urine | Not mentioned | HPLC and GC/MS | Rat | 14 months | Naturally occurring | |
13.2 ± 1.23 nmol/mmol creatinine | 34000 repair events/cell/day | Mouse | 12 months | |||||
2.1 ± 0.44 nmol/mmol creatinine | 2800 repair events/cell/day | Human | 40 years | |||||
8-Oxo-deoxyadenosine(8-oxodA) | 59 per 105 nucleosides | Aqueous solution of DNA | Not mentioned | HPLC- electrochemical detection | – | – | Peroxynitrite solution |
The aging cell displays certain nucleocytoplasmic features which describe the events that precede and that follow the oxidative damage in various organelles as well as other subcellular compartments. As a part of the normal respiration, ROS such as superoxide is produced from the oxygen consumed, these reactive species interact with iron–sulfur clusters and release free iron, which triggers the downstream release of more reactive oxidant species (
In terms of energy metabolism, the metabolite NAD+ and its associated histone deacetylase (HDAC) enzymes- sirtuins show significant decrease in aging and associated increased oxidative stress, causing catabolic breakdown of NAD+ (
A longitudinal study on a sample size of 104, performed with data on episodic memory as a parameter for tests, showed that the epigenetic DNA-methylation age predicted dementia significantly when compared to the chronological age (
Prominent behavior changes in aging and underlying epigenetic code.
Epigenetic code/modification | Genes affected | Behavior changes/cognitive parameter affected | References |
DNA cytosine methylation (MeC) | Conditioned fear memory; long-term associative memory formation and consolidation | ||
Cytosine hydroxymethylation (OHMeC) | Long-term associative memory formation and consolidation | ||
H3 phosphorylation at Ser 10 and acetylation at K14 | Not mentioned | Conditioned fear memory- long-term memory consolidation | |
H4 acetylation at K12 | Associative learning, conditioned fear memory | ||
H3 and H4 acetylation | Contextual fear conditioned memory | ||
H3 acetylation at K9 and H4 acetylation | Not mentioned | Spatial learning and memory | |
H2B acetylation at Lys 5, 12, 15, 20 and H4 acetylation at Lys 12 | Spatial memory and consolidation |
DNA methylation is one among the epigenetic regulators of gene expression and is controlled through family of enzymes, DNMTs (DNA methyl transferases). They take part in establishing spatial memory and also in fear conditioning (
Upregulated histone acetylation post-treatment with HDAC inhibitors has been shown to enhance memory formation and LTP (
Oxidative stress in form of ROS induced DNA lesions can influence and alter the methylome landscape in a cell, by means of DNA oxidation and TET-mediated hydroxymethylation (
Studies showed that hippocampal cells from Alzheimer’s patients had decreased global methylation as well as hydroxymethylation (
The oxidative environment does seem to play an influence in regulating epigenetic machinery and the resulting epigenome of the aging cell. This affects certain characteristics of the cellular system in terms of plasticity and transmission efficacy that ultimately alter cognition to become prone to a gradual decline (
Changes exhibited by the aging neuron: increased reactive oxidant species production, mitochondrial and nuclear DNA damage, dysfunctional mitochondrial-endoplasmic reticular sites. These changes in the redox environment in the cytosol as well as nucleus trigger epigenetic changes leading to altered gene expression and further leading to changes in aging prone behaviors. Schematic parts of the figure were taken from Servier Medical art (
The long-established theory that was made to attempt explaining the mechanism underlying aging explains it as the accumulating cellular and molecular damage through reactive oxidant species, is well known as the Free radical theory (
The process of oxidative damage has opened avenues for probable targets that either aid in apoptotic inhibition, reducing ROS, modulate chromatin architecture to keep learning and memory associated genes active in transcription. Some of them have been listed below. Quinone reductase 2 is one among the many genes that undergo changes in their hippocampal expression pattern with aging. Its overexpression is reported to be involved in learning deficits that occur in the case of age-related memory impairment. Its selective inhibitors, S26695 and S29434, were able to protect against the toxin menadione-induced apoptosis, preserving and enhancing learning abilities. Similarly, knockout models showed improved motor learning skills (
Human TFAM protein was overexpressed in transgenic mice which suppressed ROS sourced from the mitochondria as well as the inflammatory IL-1β response. It increased the mean EPSP (excitatory postsynaptic potential) when compared to the wild-type aged mice, it ameliorated the working memory as well the hippocampal LTP (
Another possible target which could also bring about epigenetic regulation through HDAC sirtuins is NAD+. NAD+ is essential as a cofactor, a hydride donor in several metabolic functions necessary for cell’s survival, a key player in energy metabolism- glycolysis, tricarboxylic acid cycle, mitochondrial oxidative phosphorylation (OXPHOS) as well as fatty acid β-oxidation (
On the other hand, Sirt1 levels could be regulated by means of certain activators and inhibitors (such as bacterial lipopolysaccharides-LPS). Its activators such as resveratrol have applications in stabilizing cases of epilepsy as well as epilepticus (
Therapeutic strategies may be devised using multiple approaches to curb the effects of oxidative stress, this could be in the form of caloric restriction (
Possible therapeutic directions that could result in healthier aging of the brain. Schematic parts of the figure were taken from Servier Medical art (
When observing the cellular background of cognitive decline, various aspects come into the picture that seem to be the basis of pathogenesis- oxidative stress and its associated damage, vast changes in the metabolic landscape, epigenetic variations, all of which accompany organellar dysfunction and the shortfall in repair and recovery mechanisms. Most of the studies highlight the significant association between aging and oxidative stress; however, still more studies have to be conducted that can show a direct causal link between the two. There is an increasing number of studies that point toward the epigenetic regulation of cognition through several mechanisms that affect the genes involved in learning and memory. Such that there might be a histone code that is involved in the regulation of cognition that may be impacted during aging. All the studies converge to a point that highlight the presence of oxidative stress in the aging cells, cognition in particular is affected via various mechanisms at the gene, nucleocytoplasmic and mostly the epigenetic level. Each component could pose as targets for therapy for symptomatic therapy but for a holistic approach several strategies that also involve epigenetic machinery would prove to be ideal. There is a need for longitudinal studies
AK synthesized and generally organized the manuscript,
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We would like to thank Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal for the infrastructure and support.