A Potential Oxidative Biomarker of Aging in Urine

Since aging is caused by a collection of distinct, interacting processes of damage accumulation and reactions to that damage, it is unlikely that there will ever exist one, unified, undisputed measure of biological age. All present candidate measures of aging are composites of many individual metrics, even the epigenetic clock, which is a specific pattern of many different DNA methylation locations in the genome. New, simple biomarkers of aging that reflect one process or aspect of age-related degeneration are still of interest, however, as they might turn out to improve existing combined measures of aging if added into the mix. So researchers continue to work in this area of development, turning out results such as the data presented in this open access paper.

The rate of aging differs among individuals due to variations in the genetic and environment background. Chronological age, which is simply calculated according to birth date, is an imprecise measure of biological aging. The disconnection between chronological age and lifespan has led to a search for effective and validated biomarkers of aging. A good aging biomarker should be based on mechanisms described by major theories of aging, which mainly include oxidative stress, protein glycation, DNA methylation, inflammation, cellular senescence and hormonal deregulation. The current consensus is that aging is driven by the lifelong gradual accumulation of a broad variety of molecular faults in the cells and tissues.

Any error occurring on a DNA template or in messenger RNA will eventually lead to the production of abnormal proteins. However, the exposure of a double-stranded DNA chain or single-stranded RNA chain to free radicals, which are by-products of normal metabolism, can cause oxidative damage to biomolecules. 8-Oxo-7,8-dihydro-2′-deoxyguanine (8-oxodGsn) is by far the most studied DNA oxidative product. Similarly, mismatch of 8-oxo-7,8-dihydroguanine (8-oxoGsn) in RNA leads to transcriptional errors and produces abnormal protein. These excision products can be transported across the cell membranes and excreted into cerebrospinal fluid, plasma, and urine without any further metabolism.

Under the free radical theory of aging, urinary 8-oxodGsn and 8-oxoGsn are molecules that may reflect the oxidative state of the whole body rather than a specific organ, and these are promising biomarkers of aging. We previously established a liquid chromatography-mass spectrometry system and determined the oxidized nucleosides in senescence-acceleration-resistant mouse 1 (SAMR1), demonstrating that the measurement of 8-oxoGsn in urine had potential as a novel means of evaluating the aging process. In the present study, we applied this procedure to human urine samples to see if such samples can be used to estimate the physiologic age.

We have taken a keen interest in the relationship between oxidation markers and age. Most previous studies have reported a rise in the urinary 8-oxodGsn level with age. Our previous study showed an age-dependent increase in the two biomarkers in mice, rats and monkeys. In the present study, the same trend was noted in humans. Compared with other studies, the current studies covered larger range of ages, from neonates to 90-year-olds. The lowest 8-oxodGsn and 8-oxoGsn levels appeared in the young adults (11-30 years of age). As people age, the antioxidant defense systems degenerate, and the levels of 8-oxodGsn and 8-oxoGsn increase gradually until the end of life.

To date, most studies have dealt with urinary 8-oxodGsn, and a very limited number of studies have focused on 8-oxoGsn. Our study demonstrated that 8-oxoGsn is a better aging marker than 8-oxodGsn in two respects. First, the level of 8-oxoGsn was higher (approximately 2-fold) than 8-oxodGsn in age-matched counterparts. Second and more importantly, the levels of 8-oxoGsn correlated better with the rate of aging. The 8-oxoGsn content does not always correlate with chronological aging but instead reflects the actual physiological stage of aging.

Link: https://doi.org/10.3389/fnagi.2018.00034

Comments

Hi there ! Just a 2 cent.

Epigenetic aging clock (Horvath) is a solid one. Epigenetic reprogramming is our future. For example, cancer is still not yet solved and OncoSENS WILT is a solution but less a guarantee. What is a (more) guarantee is Epigenetic reprogramming.
Cancer cell can evade immunity and could outwit WILT or use ALT homologous recombination and telomere exchange/fusion.

But Epigenetic reprogramming , no cancer cell survives that if the reprogramming was successful and its epigenome put back.
It's impossible or very unlikely that it thrives :

Methylation of its genes would never allow it, it would be instantaneous growth arrest senescence and/or apoptosis.

Chromosome Epigenetic signature controls tumor cell fate.

Still no epigenetic reprogramming therapy for cancer or aging as a pathway to follow.

8-oxodG is aVery Good damage marker, mostly mtDNA 8-oxodG not ntDNA 8-oxodG, nuclear DNA is far less susceptible than mitochondrial DNA to oxidative 8-oxodG lesion.

Currently what determines specie individual MLSP is basal mtROS emission and mitochondrial thiolate pool.The redox controls this, evolution twarthed aging via mitochondrial membrane fatty acid peroxidizability susceptibility by desaturation and poly/monounsaturation. I am amazed there is little done to improve mtROS, mitoSENS should help, but it must target basal mtROS, only the redox or fatty acid changes can alter it, mitoSOX, astaxanthin, ROS scavengers help a little, it's enough. There are Quadrillions of mitos, and mtROS rises with age. Centenarian have lifelong lower mtROS
Just a 2 cent.

Posted by: CANanonymity at February 28th, 2018 7:20 AM

"Any error occurring on a DNA template or in messenger RNA will eventually lead to the production of abnormal proteins. However, the exposure of a double-stranded DNA chain or single-stranded RNA chain to free radicals, which are by-products of normal metabolism, can cause oxidative damage to biomolecules. 8-Oxo-7,8-dihydro-2′-deoxyguanine (8-oxodGsn) is by far the most studied DNA oxidative product."

I thought DNA damage didn't matter in aging?

Does this mean that if DNA damage occurs, but is irrelevant to aging, then this measure of DNA damage is only somewhat correlated with the actual damage underlying aging, and hence will not be a useful measure of whether a treatment has made someone biologically younger?

Posted by: Jim at March 1st, 2018 1:38 AM

"I thought DNA damage didn't matter in aging?"

In the view of some researchers. However, the more popular view is that it is important. See Hallmarks of aging for example.

Posted by: Steve Hill at March 1st, 2018 2:22 AM

The forces at play "above the mutations" is a more exciting topic, as it pertains to aging, cancer, regeneration, etc.

I suggest everyone watch this quite recent presentation by Mike Levin at Tufts on flipping the software/hardware theme in terms of DNA:

https://www.youtube.com/watch?v=HwtOZ_WfMw0

Posted by: Ira S. Pastor at March 1st, 2018 4:44 AM

@Jim

Hi Jim ! Just a 2 cent.

I think, it's because there is ambiguity in the types of damages that actually relate to aging. For example, one study saw that protein carbonyls and glycation had risen in a mouse that had a health improvment while lipid peroxidation products had reduced (MDA). Like a temporary increase in glycoxidation and reduction in lipid peroxidation. Thus, it means not all damages are 1 and the same thing in regards to their contribution to maximal specie lifespan; thus 'intrinsic aging'.

The way I see it, is there are different 'levels' of damage,
some damages are only temporary and are repaired;
while Other damages become a part of you (just like the Junk accumulated over time), and are permanent/irreversible.

8-oxodG lesions are that kind, but, specifically, in the mitochondrias. One study had found that heart, brain and liver 8-oxodG lesions correlated inversely to maximal lifespan in mammals; but only in the mitochondrias, not the nuclear lesion ones. This is explaiable :

Mitochondrais are the ATP producers, the mitochondrials DNA is very close to the Complex I-V where the mtROS happens. The ROS damage the inner membrane Inside the mito. And it's why you see a reduction of peroxidizable fatty acids Inside these membranes' phospholipids. Evolution solved the mitochondrial ROS emission problem by making more 'sturdy' lipids that do not contribute to lipoxidation/lipid peroxidation products that harm the close mtDNA and create 8-oxodG lesions in it. It's a double whammy, the mtROS itself, and the chain effect of it : MDA mainly (malondialdehyde being the major one), DHA/EPA lipid peroxidation 'End'-products - all of them harm - two things, the innermembrane itself and the mtDNA closeby. This maens mitos because weak much quicker and ATP insufficient over teh decades.
It's why we can see 'aging' correlate (And be causated) by resting 'normal daily rate' mtROS emission of any healthy animal (because even healthy animals have mtROS; the ones who live short but healthy lives - have FAR more mtROS and especially much more susceptibility; and, the milieu is just oxidized all along rather then 'reduced'). One study foudn that mitochondrial ROS determines maximal lifespan in nearly all major organs of mammals (thus in the mitos/mitos'DNA). It was even a near 1:1 correlation, for example P.leucopus mice live 8 years - Double the lifespan of a mice/rat living a Long 4 years...ok not as long as Naked mole rats (35 y), but still 8 years - no life extension study has been capable of reproducing that in a regular mouse. Most CR studies, autophagy/HSPs, antioxidants, SIR/DAF...etc have only boosted mice life by like 20-40% tops, which means most mice lived from 2 years average, and some reaching 3 years by these interventions. A bit better but notthing compared to living 8 years. Not even AMes Dwarf mice can reach that, the best they can is like 5-6 years and they are growth hormone KO + CR + a ton of other things to make them reach this age.

Why would a P.Leucopus mouse live twice longer than a mouse and still longer than a dwarf one...mtROS. One study verified mtROS of P.Leucopus and regular mouse; it was a perfect 2x mtROS between mice and P.Leucopus for all their lifespan. The fact that P.Leucopus had half the mtROS emission of mice meant Something Very important, mitochondria are a major source of the problem in aging because they are the 'weak link/point' where damage occurs (via constant basal O2 created mtROS every second we breathe) and makes mitos weakn with age; until can't make ATP energy anymore and animal dies.

And, of course, mtDNA lesions 8-oxodG Hasten the speed of aging because the mitos are 'Under attack' by the mtROS (as a normal process of oxygen respiration/mito respiration releaseing ROS in mtETC/Complexes). Mitos become faulty, weak ATP-producing. Plus they 'clog' the autophagosome/proteasome - a recipe for problems. Proteasome can Not be clogged forever, game over otherwise once reach 'too clogged'; lipofuscin and effete mitos will clog it if mtROS is too high.

Animals that have been capable of living long lifespans - have Protected their Mitos like the pitts of their eyes, it was extremely important; and what mainly controls this are two things, the innermembrane fatty acid composition and the redox milieu in it.
Epigenetic/epigenome communicates with these elements and is capable of making sure it is kept correctly by gene activation/expression/transcription/translation/silencing in mitos.
But it needs these elements that protect mitochondrias, which are its composition and its 'state' (with age the mitos become oxidized milieu and this accelerates 8-oxodG mtDNA lesions also). There is no other place where the damage is so crucial (weak link/vulnerable point) as mitos because mitos themselves Create that damage (by mtROS emission in first place)). Nuclear DNA is 10-times less suseptible than mitochondria to oxidative lesions production and indeed, there is Far more lesions in the mitochondrias; nDNA is protected more and has less ROS 'hanging around' to damage it; mitos are in constant atatck (and hence require constant protection via redox/inner mitochondiral membrane lipid reordering. The redox is our 'oxidative stress' barometer, with age it declines towards a more 'positive' voltage (-250mV to -150mV) which means an oxidized milieu)), cells mitos that 'live in a oxidized' milieu accumulate more 8-oxodG over the years; this has Direct Correlation and Causation to MLSP of mammals).

Just a 2 cent.

Posted by: CANanonymity at March 1st, 2018 5:13 AM

@Jim: Yeah, probably so. One of the things that influence DNA damage is immunosenescence, so this could be a proxy measure of the health of the immune system.

Posted by: Antonio at March 1st, 2018 9:25 AM

@Ira

Thanks for the link to the presentation; it was just what I needed today (something to watch while doing dishes on a dreary day).

Posted by: CD at March 1st, 2018 11:41 AM

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