Cellular Antioxidant Defenses Measured in Blood Samples Decline with Age

Cells are in a constant state of generating oxidative molecules, clearing those molecules via the use of antioxidant proteins, and repairing the damage caused by oxidative reactions. Researchers here show that aging is accompanied by declining amounts of the natural antioxidants involved in clearing oxidizing molecules from cells, preventing them from reacting with cellular machinery to cause damage. This is an unfortunate downstream consequence of the underlying causes of aging, one that will cause further dysfunction in cells. Exactly how and why this is a feature of aging, the exact chain of cause and effect that leads from the underlying damage to this result, remains to be determined. At the present time, the fastest approach to answering that sort of inquiry is likely to build rejuvenation biotechnologies that can repair specific forms of molecular damage thought to cause aging, and then see what happens when the therapies are applied in animal studies.

An integral part of aerobic metabolism is reactive oxygen species (ROS) generation which should be analyzed according to its two main functions. On the one hand, ROS plays an important role in biomodulating and regulating many cellular functions, such as defense against pathogens, signal transduction processes during transmission of intercellular information, and activation of specific transcription factors. On the other hand, an excessive quantity of ROS has a deleterious effect on cells, reacting with a variety of molecules and thereby interfering with cellular functions. To cope with the elevated generation of ROS, ROS-scavenging biochemical pathways have been developed in aerobic cells.

In recent years there have been a lot of studies supporting the role of ROS in molecular aging mechanisms. The confirmation of oxidative stress increase with age of diverse organisms, and the generation of transgenic invertebrates overexpressing the antioxidant enzymes with increased lifespan were among the most important results of these studies. Nevertheless, there were no alterations in the lifespan in most of the examined mouse models, which under- or overexpressed a wide variety of genes coding for antioxidant enzymes. Thus, the role of oxidative stress in aging mammals is not fully understood and still demands further inquiries.

In this study, analysis of antioxidant defense was performed on the blood samples from 184 "aged" individuals aged 65-90+ years, and compared to the blood samples of 37 individuals just about at the beginning of aging, aged 55-59 years. Statistically significant decreases of Zn,Cu-superoxide dismutase (SOD-1), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were observed in elderly people in comparison with the control group. Moreover, an inverse correlation between the activities of SOD-1, CAT, and GSH-Px and the age of the examined persons was found. No age-related changes in glutathione reductase activities and malondialdehyde concentrations were observed. These lower activities of fundamental antioxidant enzymes indicate the impairment of antioxidant defense in the erythrocytes of elderly people.

Link: https://doi.org/10.2147/CIA.S201250


Hi there ! Just a 2 cents.

It can be many things, but a couple of possibilities; like antagonistic pleiotropy. Loss of NAD+. Antioxidants enzymes have been both benefical and deleterious. That's because ROS abrogation is just as bad (no more ROS signaling). While ROS quenching is important to mitigate ROS-caused damage to mitos and surroundings. Certain enzymes with ages become ROS-producing instead of Anti-ROS. Certain studies showed very high levels of certain enzymes during disease state; demonstrating - compensatory protection; high levels do not mean healthier, it means it's try to 'quench/overquench' whatever excess ROS there is (ROS overload). Very high levels of SOD can be deadly. SOD is like your 'background' oxide quenching enzyme, it's fail-safe system and it must alwyas 'be there'...as a basis for 'minimal quenching' at the Complex I-III in mito membrane. SOD1, SOD2, SOD3; cytoplasm, mito, extra-cellular. Same thing of GPX, glutathione peroxidase, a peroxide quenching gsh-dependent enzyme of the redox. TRX, same thing (thioredoxin) and PRX, same thing (peroxiredoxin). In animals studies the results were very conflicting and you could very High levels of these enzymes in short-lived animals; demonstrating 'Compensatory' oxidative-stress hyperquenching. THe system can't overcome it but 'tries'. Whereas longer-lived animals had LESS antioxidative activity - no need for it, the mitomembranes are more sturdy and less ROS subsceptibility (they say that MDA (MalonDiAldehyde/TBAR (thiobarbiturate), an ALE/lipid peroxidation product) does not change in humans; but all this 'Accumulates' over time, and lipid peroxidation contributes to more lipofuscin formation (clogging the lysosomes/making autophagosome dynsfunctional 'clogged') and also contributes to telomere damage/which means telomere demethylation, and demethylation means epigenetic age advancing in methylome as you lose the DNA methyl content). Studies, basically, said the long lived animal could 'stress resistant' 'oxidative stress resistant'...like naked mole rats...that show higher levels of NRF2 (nuclear response factor) phase II detox enzymes (such as GPX, GST, Seleno enzymes, Gamma-GlutamylCysteine Ligase), yet the studies said they experience high level of oxidatives stress, have higher protein carbonyls...yet live much longer than mice (30 years vs 3 years). They have sturdier mito membranes (10-times less long-chain omega-3 PUFA DHA a highly suspectible fatty acid to peroxidation (causing MDA/TBAR formation)) and preserve their redox much longer than mice. Plus, their developmental growth is far more protracted/delayed than a mouse (they reach puberty muchh later and have replasticizing brain for the whole time (like us humans brain in our infant up to teen years), hence they are epigenetically youger than a mouse at all times points (proportionally speaking to mouse lifespan). This goes to show that oxidative stress is like an important 'added layer' of 'age acceleration'...not entirely the 'first one/layer'...that is the epigenetic. If you have more oxidative stress, it should hasten the process, as telomeres will dwindle down faster and accumulate lots of telomere foci; which causes nuclear DNA/SSB/DSBs strand breaks. But, if you mitigate this stress and keep your antioxidative systesm intact, you allow a full lifespan to be possible, up to the maximum.
With that said, I do not think (anymore) that antioxidants alone are sufficient to make someone go much beyond MLSP (maximum lifespan potential); because, there seems to be a certain disconnect and ambiguity between antioxidative systems and aging; antioxidants did not help to live much longer (in animals studies) and even if they were targetted (like MitoQ) to mito ROS...the results were always pretty small overall; like 20-50% lifespan extension in short-lived animals. That means ROS damage is just one explanation, the other one, I believe, is the epiclock, chromosomal integrity loss and telomeres loss and cell replicative 'passaging' to Hayflick; these are far more causal to the aging; damages contribute to them - and THEY also contribute to damages; inversely - both ways. Double whammy.

Studies in centenarians had shown that the ones who living the longest had the highest glutathione reductase (GR) activity, this means they kept the redox in check; GR is responsable for recycling oxidized glutathione (GSSG) back to reduced/unoxidized glutathione (GSH), thus by lowering GSSG content it increases total GSH; and the GSH:GSSG ratio determines 'oxidative stress' levels in cell. WIth age the ratio drops (GSH is lost, and GSSG accumulates...making a smaller ratio, meaning the cell is experiencing continuous oxidative stress; which will cause diseases later and the person won't be able to reach their maximum lifespan - the centenarian studies showed that their GSH:GSSG in blood was kept or rised - thus it did not lower like in blood erythrocytes and leukocytes of people in their 60-80 years old where things get drop around that specific time as diseases happen, this can hasten death as the disease would advance). To reach 100-120 you need stellar health, and thus, redox function, kept and not become 'oxidized' with time.

But, as said, this is just 'an extra layer'...at 120 you still die, because the rest ends (just look at the epigenetic studies on centenarians, they are Total Mutants...activating SO much stuff...to 'still' make it work...it means at a certain point, it'S just too much to 'function' anymore...threshold for function..and huamsn age..because they accumulate these mutations which cause loss of DNA/methyl/advancement of clock/advancement cell epigenetic age 'signature' becoming more and more 'differentiated/activation/accumulation of mutations/activation of genes' while young/immature cells, just like young stem cells, are more undifferentiated in appearance/gene 'Silenced'). Thus, by getting older - with 'Activate' tons of stuff, that should not be...activated - but remain silenced like a in young body, gene silenced. Methylation is creates gene silencing in gene areas that have strong implication in aging (inflammation/cancer/stress/deleterious mutations acquiry/DNA nucleotide errors, etc), demethylation causes gene DE-repression, thus (re)activation. This, in turn, allows the cell to continue dividing and restores function - thus, post-poning replicative senescence. Humans (and animals) are thus true mutants that 'acquire mutations' and make you somebody/thing totally different than what you were 'yesterday'...our body replaces itself millions of times, that we are not the same anymore; we accumulate these mutations and they cause aging advancement and loss of function once we accumulate too much of them/reach threshold, that is death point (around MLSP).

Just a 2 cents.

Posted by: CANanonymity at June 13th, 2019 12:52 AM

PS: I am willing to bet my 2 cents that if we ever live a 1000 years by LEV, the level of lipofuscin will be near-completely 'stalled', thus the accumulation of it will be slowed by almost 1 order of magnitude; this is visible in immortalized cancer cells or extremely-conserved ancient lotus seeds (of 1300 years old), who do not accumulate lipofuscin over time (FACS scans showed lipofuscin content Regressing in them, something like 600 PDs later (population doublings), if 1 passage would be a real-time of 1 year, that would mean 600 years before seeing any lipofuscin granule in lysosome), unlike normal cells that age regularly and accumulate it. With that said, there is still ambiguity about this pigment being simply a 'consequence' of the damages/aging...rather than a cause. Like an 'inert' residue showing up and cloggin lysosome...but not being the cause of aging. Though, it,s not helping for sure, mouse that have injection of synthetic lipofuscin in their cells have autophagy dysfunction (lysosome bottleneck/can't phage the crap anymore), and it causes premature senescence of the cells.It can be deadly and cause premature/sudden death of mice or ressemble progeria like accelerated aging (most likely, it causes, faster accumulation of progerin, as by product of lipofuscin; since progerin accumulates, albeit much slower, already in healthy humans than HGPS short-lived people).

This wil be a marker that we are indeed reversing or stalling aging completely, and post-poning death (far Beyond human MSLP). It would also manifest on the epigenome, progerin would lower, lipofuscin would lower/or freeze/drastically reduce in accumulation, and epiclock would accumulate much less mutations, much less transcriptome drifting, chromosomes would not lose histones or become decompacted, Much less DNA mutations accumulations/deletions/lesions/methyl loss...etc.

Imagine for a second being 50 years old (epibiologically)...but for 500 real-time years (in chronological time passing/real years)....'frozen' at that age..roughly. Yes, like dracula.

Posted by: CANanonymity at June 13th, 2019 1:21 AM

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