Repair of Mitochondrial DNA Damage as Potential Treatment for Cardiac Aging
Mitochondrial DNA damage is a contributing cause of aging, and researchers here look at this issue in the context of the aging of heart tissue. Mitochondria are the power plants of the cell, a herd of bacteria-like structures that contain their own small genome, and work to produce the chemical energy store molecule adenosine triphosphate. This is an energetic process that produces oxidative molecules as a byproduct, capable of damaging cellular machinery and requiring maintenance and antioxidant processes as a defense. Mitochondria are destroyed by the quality control mechanism of mitophagy when damaged, and replicate to make up their numbers.
Some forms of mitochondrial DNA damage can subvert quality control and lead to problem cells overtaken by broken mitochondria, exporting harmful reactive molecules into the surrounding tissue. Ways to repair or replace damaged mitochondrial DNA will likely turn back aspects of aging by removing a source of damage and dysfunction, but the various approaches to this challenge are as yet still comparatively early in the development process.
Cardiac aging resulting in defects in cardiac mitochondrial function centers on the mitochondrial DNA (mtDNA) damage. The mechanisms of the alterations in the aging heart mainly involve mitochondrial dysfunction, altered autophagy, chronic inflammation, increased mitochondrial oxidative stress, and increased mtDNA instability.
Reactive oxygen species (ROS) play a pivotal role in healthy cellular and mitochondrial signaling and functionality. However, if unchecked, ROS can mediate oxidative damage to tissues and cells, leading to a vicious cycle of inflammation and more oxidative stress. Meanwhile, mitochondria, the major source of ROS, are thought to be particularly vulnerable to oxidative damage. Because of its richness in mitochondria and high oxygen demand, the heart is at high risk of oxidative damage. The most supportive evidence of the central role of mitochondrial ROS in the aged heart is that overexpression of catalase targeted to mitochondria attenuates cardiac aging.
A growing body of evidence suggests that there is increasing oxidative damage to mitochondrial DNA in cardiac aging. Because of the histone deficiency, limited DNA repair capabilities, and proximity of mtDNA to the site of mitochondrial ROS generation, mtDNA can suffer various types of damage, including mtDNA point mutations, mtDNA point deletions, and decreased mtDNA copy number (mtDNA-CN). The continuous replicative state of mtDNA and existence of the nucleoid structure render mitochondria vulnerable to oxidative damage and mutations.
DNA polymerase gamma (DNA Pol γ) plays a vital role in mtDNA replication. DNA Pol γ has two main functions: mtDNA synthesis and proofreading. Recent studies report that ROS reduces the proofreading ability of Pol γ, causing replication errors. Thus, oxidation aggravating mtDNA mutations causes replication errors, which indirectly cause mtDNA damage. This proves that mtDNA mutations are largely random, and Pol γ oxidation is likely to account for mtDNA mutations in aging. Therefore, mtDNA mutation may be highly associated with heart aging, and the repair of damaged mtDNA provides a potential clinical target for preventing cardiac aging.
Hi there! Just a 2 cents.
Though I really believein mitochondrial function improvement should improve health, the more I read about it the more I perplexed; because it is important for longevity (OXPHOS) in mitos and mitos are the main production/site of ROS; and mtROS equals MLSP in mammals. I now think it is more subtle and mitochondrial ROS are more towards health than actual maximal longevity. As seen in people with mitopathies and mitochondrial diseases. Oftenly, they just have mitos that are not doing correct respiration (oxphos), don't produce enough ATP, lower mtDNA copies number, increase mtDNA lesion and worse, mtDNA deletions, produce more ROS at ComplexI-III, yet overall their lifespan is not That changed; But, their health is (leading to organ dysfunction) and so is their possibility to reach the maximum lifespan of human. But, the latter, still stands, even, in these unhealthly people. If they did not have these mitochondrial pathologies they Would Still live to the human MLSP (122) no more. The other thing is mitochondria are sources of ROS, which diminish lifespan, due to it affecting telomeres shortening rate; and because mitochondria produce ROS, they make MDA/TBARS from their PUFA phospholipid destruction (homeovicous membrane/pacemaker theory); and Polyunsaturated Fatty Acids Peroxidation (at innner mitochondrial membrane phosphospholipids' polyunsat.fatty acids content) cause lipofuscin formation and MDA/TBARS. The longest lived animals had, generally, the lowest PI/DBI (Peroxidation Index and Double Bond Index); which means reordering of mitochondial membrane lipid composition towards Saturated/small-chain lenght PUFAs instead...of long-chain PUFAs (mainly the DHA/EPA which cause over 50% of all the damaging peroxidations by Their own peroxidation when ROS attack them; this cause macro-molecular damage and makes mtDNA frag/lesions (mt 8-oxodG')/deletions 1000-bp deletions (literally, chunks of mitochondrial DNA, is gone of mtDNA)).
''We compare damage levels in old and young animals and also between wild-type animals and long-lived mutant strains or strains with modifications in ROS detoxification or production rates. We confirm an age-dependent increase in mtDNA damage levels in C. elegans but found *that there is no simple relationship between mtDNA damage and lifespan.*''
'' Despite causing a significant elevation in mtDNA damage, γ-radiation did not shorten the lifespan of nematodes at any of the doses tested. When mtDNA damage levels were elevated significantly using UV-radiation, nematodes did suffer from shorter lifespan at the higher end of exposure tested. *However, surprisingly, we also found hormetic lifespan and healthspan benefits in nematodes treated with intermediate doses of UV-radiation, despite the fact that mtDNA damage in these animals was also significantly elevated.* Our results suggest that within a wide physiological range, the level of mtDNA damage does not control lifespan in C. elegans.''
It's more subtle, albeit they saw this in C. elegans; in mammals, the relationship is tighter, than in C.elegans....plus, they saw 'hormesis' at intermediate dose of ROS;;; which means priming of the redox at intermediate ROS level.
While, in flies, it did increase lifespan when they targeted mitos by mitochondrial antioxidants such as Catalase/SOD or SkQ1
male flies live up to 140 days on SkQ1...while female flies did not change anything...they Already lived 140 days with or without SkQ1.
''We hypothesize that in vivo SkQ1 is capable of alleviating the probable negative effects of increased mitochondrial reactive oxygen species production on longevity but *is not effective when reactive oxygen species production is already reduced by other means.*''
It means, in females, the ROS levels are lower Already (and that is due to estrogen/telomerase) so female flies already get the benefit without neededing SkQ1...males on the otherhand benefit because higher mtROS levels....
This means, Beating, the Already established Maximum 120 year lifespan by Mitochondrial Tinkering because a harder/less good' proposition simply because it is 'at the best it could be'; when for most people they have it worse...right now, if they WON'T live to 120. For those becoming centenarians, they Already have low mtROS and better preservation of mtDNA copies/content/quality/function...
''Dwarf hamsters and mole-voles kept in outdoor cages or under simulated natural conditions lived longer if treated with SkQ1. The effect of SkQ1 on longevity of females is assumed to mainly be due to retardation of the age-linked decline of the immune system. For males under LP or SPF conditions, SkQ1 increased the lifespan, affecting also some other system(s) responsible for aging.''
This is interesting, dwarf animals generally Already live longer (because low IGF/mTOR/small body/low GH/low insulin signaling in them), thus there a benefit; up until it becomes (pathways) redundant; but this is like trying to combine CR + Dwarfism; there is possible redundancy (in same pathways usage) but you could still see some improvements...as such dwarf mice On CR still live bit longer than fullfed dwarf mice. The less calories will also affect a long living animal, somewhat, mostly in health; but here they saw longevity improvement when combining
SkQ1 + dwarfism.
While in mtDNA mutator mice that have mitochondrial dysfunction/mitopathy they saw increase in life, though not much...
''The SkQ1-treated mice live significantly longer (335 versus 290 days).''
''These effects of SkQ1 are suggested to be related to an alleviation of the effects of an enhanced reactive oxygen species (ROS) level in mtDNA mutator mice: the increased mitochondrial ROS released due to mitochondrial mutations probably interact with polyunsaturated fatty acids in cardiolipin, releasing malondialdehyde and 4-hydroxynonenal that form protein adducts and thus diminishes mitochondrial functions. SkQ1 counteracts this as it scavenges mitochondrial ROS. As the results, the normal mitochondrial ultrastructure is preserved in liver and heart; the phosphorylation capacity of skeletal muscle mitochondria as well as the thermogenic capacity of brown adipose tissue is also improved''
It means that PUFA destruction in mito membranes is large element of longevity; they say malondialdehyde/MDA and 4-hydroxynonenal/4-HNE are changed because SkQ1 affects cardiolipin's PUFAs...albeit cardiolipin is a very small amount (despite its very obvious sensitive function; like the heart needing cardiolipin for function); while phosphatidyethanolamine and phosphatidylcholine (The 2 main phospholipid (that house the PUFA fatty acids) in mito's inner membrane) are in far higher amounts in mitos. They are the most consequential.
While, another study had showed that mitochondrial changes made HUGE changes in the longevity of the Same C. elegans species...
'' These worms self-fertilize (C. elegans reproduction being primarily hermaphroditic), to yield roughly one-quarter of total progeny homozygous for the age-1 mutation. These age-1 homozygotes may be loosely termed the "F1" generation, and their progeny would then be "F2" homozygotes. F2 mutants for these nonsense alleles, although genetically identical to their F1 parents, are clearly quite different in many respects. They develop very slowly at 15° or 20°C, and their development arrests completely at 25°C [44]. The adults are far more resistant to both electrophilic and oxidative stresses, and live *10-fold longer* than normal, wild-type worms under benign condition''
''two lipid structural properties correlated extremely well with lifespan in these worms: fatty-acid chain length and susceptibility to oxidation both decreased sharply in the longest-lived mutants (affecting the insulinlike-signaling pathway). This suggested a functional model in which longevity benefits from a reduction in lipid peroxidation substrates, offset by a coordinate decline in fatty-acid chain length to maintain membrane fluidity. ''
The reduction in PI/DBI meant that there was less mitonchondrial destruction/macromolecular damage. Other studies in birds and mammals have been conflictual (about seeing longevity extension with reduce PI); membrane fluidity is important for cell kinetics; but there are other ways to body can compensate for higher PI/DBI; which are consumation/consumption of ROS (Catalase, SOD)...or, likwise, SkQ1 doing same thing in mitos...as targetted mito anti-oxidant.
Mitochondrial reparation, I fear, is more muddied/ambiguous than we thought and will thus not make extreme lifespan (probably); it will contribute to healthspan mostly; but if there is little changes in PI/DBI I don't see any changes from it; animals that have healthspan improvement (such as mice living 800 vs 1000 days); generally have minimal changes in PI/DBI...one study had reduced the PI/DBI in mouse...and they barely lived longer/only had health improvement...it's very muddied. While, Queen bees live 3 years and have lower PI/DBI than worker bees...same for humans we have lower PI/DBI and some studies in centenarian's children showed lower PI/DBI too...so it's really not 'all' there is to it; it is contributory but not the whole thing about aging; that is far more the epigenome domain (nuclear DNA/chromosome tabs) and the telomerse (cell cycles/hayflick).
Just a 2 cents.
Mitochondrial DNA Damage Does Not Determine C. elegans Lifespan
1.https://www.frontiersin.org/articles/10.3389/fgene.2019.00311/full
The Mitochondria-Targeted Plastoquinone-Derivative SkQ1 Promotes Health and Increases Drosophila melanogaster Longevity in Various Environments
2. https://www.ncbi.nlm.nih.gov/pubmed/27166099
Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents
3. https://www.ncbi.nlm.nih.gov/pubmed/22166671
Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361666/
Extreme-Longevity Mutations Orchestrate Silencing of Multiple Signaling Pathways
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885961/
Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082008/
PS: ''This was mainly due to decreases in 22:6n-3 and increases in 18:1n-9 fatty acids. The atenolol treatment also lowered visceral adiposity (by 24%), decreased mitochondrial protein oxidative, glycoxidative, and lipoxidative damage in both organs, and lowered oxidative damage in heart mitochondrial DNA.''
''We conclude that it is atenolol that failed to increase longevity, and likely not the decrease in membrane unsaturation induced by the drug.''.
Lifelong treatment with atenolol decreases membrane fatty acid unsaturation and oxidative stress in heart and skeletal muscle mitochondria and improves immunity and behavior, without changing mice longevity
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326892/
PPS: After much more research, it is now seemingly clear/less ambiguous that it is what we knew and said all along...telomeres are the driver of aging...not their initial length/length...not really their actual 'short telomere' number count (though that is important for sure and is consequential);
it is their rate of shortening that is the penultimate decider of longevity. Because they sit right on the chromosomes, they are themselves full of DNA/TTAGGG repeats and as others stated, the genes are activated Depending on the size/length of the telomeres; but the Speed/Rate of telomere shortening makes SSBs (single strand breaks) appear at telomeres and this activates signal for senescence - p21, the most major one in replicative senescence (p53 is called...and then it activates p21...and then senescence ensues). Oxidative stress Accelerates telomere shortening rate, this causes demethylation is sub-telomeres regions; which cause epigenetic drifting/demethylation in epigenes; while also contributing to hypermethylation of pocket genes contributory to cancer/inflammation. So it is like a castle losing its foundations...or like a jenga tower losing its bottom pieces..until it wobbles... and then it falls once too many bits removes... like a castle/house of cards, that you pull the cards under at bottom...
mitochondrialROS are causal for that; but not so much what is hapepning IN the mitochondrialDNA...but IN the nDNA (nuclear DNA)/telomere/chromosome...oxidative stress caused by elevation of mitochondrial ROS - ABOVE - the redox balance (of Antioxidation VS Oxidation) means that now ROS will be detrimental..it's why ROS is only Benefitial at 'mid-level'...Hormesis; a small stress is benefitial; the minute you Increase ROS Too Much, now it is detrimental and Upsets the Careful Balance/Fine Line between Too Little ROS and Too Much ROS; and this balance is what causes diseases to happen when the balance tips towards excces accumulation of ROS - and Not Enough ROS Consumption/Quenching via redox antioxidant systems (CAT, SOD, GSH, ALBUMIN, BILE, ASC, TOCOPHEROL/VIT.E, CAROTENOID, etc...)l when these systems are exhausted or overwhelmed - at the 'Tipping point' Above Hormesis effect/'mild ROS'...then you see actual damage appear at telomeres (mostly Telomere Foci/y-H2AX and SSBs Single Strand Breaks) plus you also start to see SAHF (Senescence Associated Heterochromatic Foci)...with the accompanying SASP of same senescent cells...contributing to all that. This will make Weak/Fragile telomeres that will absolutely Uncapp and cause fusion/fission of telomeres (T-SCE/ Telomere -Sister Chromatid Exchanges...and Homologous Recombination; where the whole thing is 'chunking out' bits here and there trying to Elongate Telomeres - Because the Telomeres are Losing Stability...and there will be Accelerated Telomere Shortening Rate at that exact moment; while the cell will try to use ALT/alternate lenghtening of telomers to try to mitigate the extensive acceleration of telomere shortening....
Telomeres (being DNA/nucleus/chromsome) is what drives aging and is what DETERMINES maximum lifespan IN ALL animals.... with said when you see ambiguous results with telomeres it's because they never Follow for A FULL life...if you plot it over a full life..telomeres, not their length matter, but -The Speed at which they shorten...
I plotted using a French/German studies animals over telomere length and its crystal clear that telomeres' shortening speed/rate is the ultimate decider of maximum lifespan potential in All animals (mammals or not)...including the Longest Living Animals - like the Iceland Quahog...
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Rates of Loss (of telomeric DNA; kb/kilobase; bp/basepair; 1kb = 1000bp):
Mouse, (4 year lifespan max.)
Telomere (T): 7000bp/per year loss - Initial telomere length at birth (50kb), final telomere length at death (~37kb), mouse did not lose whole 50kb, only 14kb or so; but at a 7000bp/year Rate.
Dogs, ~15 years lifespan avg, (T) ~500 bp/y, initial telomere size (10-60kb-rare; 10-25; 20kb avg)
Reindeer, 15~20 years lifespan, (T), ~530 bp/y, initial telomere size (20kb)
Goat, ~20 years lifespan, (T), ~360 bp/y, initial telomere size (10kb)
HGPS people, ~15 years lifespan, (T) ~500 bp/y, initial telomere size (~18kb)
Flamingo Bird, ~50-80/65 avg. years lifespan, (T) ~110 bp/y, init. telom. size (20kb)
Elephant, ~50-90/70 avg. years lifespan, (T) ~100 bp/y, init. tel. size (~38kb)
Dolphin, ~15-50/35 avg. years lifespan, (T) ~150bp/y (50y) - 600bp/y (15y), init. tel. size (~90kb)
Seagull Bird, ~20-25/22.5 avg years lifespan, (T) ~770 bp/y, init. tel. size (~40kb)
Vulture Bird, ~35-45/40 years avg lifespan, (T) ~210 bp/y, init. tel. size (20kb)
Healthy Human, 60-90y/~122 years max. lifespan,(T) ~70 bp/y avg, init. tel. size (18kb)
Temperate Clam/Scallop (Baltic Sea), ~10-40/ 25 years avg lifespan,(T)~400 bp/y, ini. t. s. (15kb)
Polar Clam/Quahog (Iceland), ~100 - 530 years / 200 years avg. lifespan, init. tel. size (15kb)
(T) ~70 bp/y (100 years life), (T) ~35 bp/y (200 years life),
(T) ~14 bp/y (530 years max. life)
@Reason
It seems the site comments become complex enough to warrant rich text formatting. Is there a way to add markdown, or at least allow some html tags in the comments ?
I'm glad you realized the negative impact of PUFAs on longevity. However, there are several types of aging accelerators. If you continue to eat foods that accelerate aging, you have little hope of staying young for long.
SKQ1 is a bad antioxidant. Skulachev focused too much on mitochondrial concentrations and did not address the antioxidant effect. A mitochondrial antioxidant could be made many times more effective.