The MitoAge Database: Mitochondrial DNA and Longevity Compared Between Numerous Species
Here I'll point out a recent addition to the set of open data interfaces that are both interesting and relevant to aging research: the MitoAge database, cataloging mitochondrial DNA and longevity in a wide range of species. Mitochondria, the descendants of ancient symbiotic bacteria, swarm in herds inside our cells. The research of past years provides compelling data to suggest that the details of mitochondrial composition, particularly in respect to their resistance to oxidative damage, has a fair-sized effect on life span. Why is oxidative damage an important consideration? Because mitochondria work to create energy store molecules used to power the rest of the cell, a process that involves the generation of reactive oxidizing molecules as a side-effect. A cell is a fluid sack of structures and chemical reactions, all of these components moving around in close proximity, engaged in constant activity. Newly created oxidants don't have far to go in order to react with some important piece of molecular machinery in a way that causes damage and dysfunction. Some are rendered harmless by natural antioxidants, but damage is constant and ongoing, albeit usually repaired very rapidly.
The closest structure for mitochondrially generated oxidants to react with and harm is the mitochondrion itself, and in particular its DNA. Every mitochondrion has at least one copy of the left-over remnant genome from its bacterial ancestry, encoding necessary proteins used in its structure and energy store construction machinery. This DNA isn't as well protected and repaired as is nuclear DNA, and certain rare forms of damage can produce mitochondria that are both dysfunctional and more likely to replicate and survive within their cell. It isn't completely open and shut that this is the way in which cells become overtaken by broken mitochondria and go on to harm surrounding cells and tissues; this contribution to the aging process might have more to do with errors in mitochondrial replication than oxidative damage, for example. But there is certainly a good solid correlation in mammals between longevity and mitochondrial resistance to oxidative damage. When we look at birds and bats, the details of their mitochondrial biochemistry is entwined with the metabolic requirements of flight, and the comparatively long life spans in these species when considering their size may once again be a factor of adaptation to higher levels of oxidative stress generated during flight. Further, there are the studies showing modestly increased health or life span in mice due to increased levels of natural mitochondrial antioxidants, or mitochondrially targeted antioxidant drugs.
To my eyes all of this work and knowledge as a whole should really be taken as a big pointer to suggest that repair of damaged mitochondria is an important part of any future regenerative medicine to produce rejuvenation. The SENS Research Foundation has helped to pioneer the allotopic expression approach to maintaining undamaged mitochondria that is currently under clinical development for inherited mitochondrial disease at Gensight, and continues to work towards a more comprehensive version of the treatment that can be used to treat aging. Funding - as ever - is very limited for this line of research given the potential benefits, but the fastest path to results remains to get this working in mice and see what happens. Given what we know of the effects of more subtle and limited manipulations in mitochondrial biochemistry, we should probably expect the benefits to health and longevity to be sizable enough to draw attention.
The rapidly increasing number of species with fully sequenced mitochondrial DNA (mtDNA), together with accumulated data on longevity records, provide new fascinating opportunities for the analysis of the links between mtDNA features and longevity across animals. To facilitate such an analysis, and to support the scientific community in carrying it out, we developed MitoAge - a curated, publicly available database, containing an extensive collection of calculated mtDNA data records, and integrated it with longevity records. The MitoAge website also provides the basic tools for comparative analysis of mtDNA, with a special focus on animal longevity.Mitochondria are the most "hard-working" organelles and the only organelles in the animal cell that have their own genome. They have long been considered one of the major players in the mechanisms of aging, longevity and age-related diseases1. We and others have shown strong correlative links between mammalian maximum lifespan and mtDNA base composition. In particular, the mtDNA GC content appears to be an independent and powerful predictor of mammalian longevity.
The stability of the mitochondrial DNA (mtDNA) is vital for mitochondrial proper functioning; therefore, changes in mtDNA may have far-reaching consequences for the cell fate and, ultimately, for the whole organism. Not surprisingly, due to a key role in energy production, generation of damaging factors (ROS, heat), and regulation of apoptosis, mitochondria and mtDNA in particular have long been considered one of the major players in the mechanisms of aging, longevity and age-related diseases.We developed the MitoAge database containing calculated mtDNA compositional features of the entire mitochondrial genome, mtDNA coding (tRNA, rRNA, protein-coding genes) and non-coding (D-loop) regions, and codon usage/amino acids frequency for each protein-coding gene. MitoAge includes 922 species with fully sequenced mtDNA and maximum lifespan records. The database is available through the MitoAge website, which provides the necessary tools for searching, browsing, comparing and downloading the data sets of interest for selected taxonomic groups across the Kingdom Animalia. The MitoAge website assists in statistical analysis of different features of the mtDNA and their correlative links to longevity.
I don't know about DNA purine and pyrimidine nucleotides. It is a iffy field in terms of results (from telomere DNA results),
wether it be mitochondrial DNA restoration, nuclear DNA or telomeric DNA RNA. DNA composes us
and we must not lose it or we die, telomere studies show that one after the other, when we lose
our telomeres we make our chromosome dysfunctional and telomere loss removes its DNA content.
This lost DNA is the aging phenotype. It accelerates inflammation and the mitochondrial DNA gets fragmented during OXPHOS and mtETC leakage around Complex I.
Studies have shown mitochondrial membrane Complex I ROS production in the ETC is more than 70% responsible for mitochondrial DNA lesions; fly's that their
Complex I ROS producion is abrogate live longer, this means mitochondrial ROS creates a cascade of damage, lipid peroxidation products (4-HNE, Acrolein, MDA) and very far reaching aldehydes that destroy the mtDNA.
Evolution solve that problem that membrane composition reordering and lipid gene selection pression (for example, mouse have high PI Peroxidation Index in their mitochondrial membranes phospholipids (mostly PE phosphatidylethanolamine and PC phosphatidylcholine, PS Phosphatidylserine, PI Phosphatidilinositol)
evolution changes the type of fatty acids to alter membrane fluidity and reduce peroxidation products (such as reducing omega-3 DHA content and increasing monounsaturates Oleic acid by altering the double-bonds in the fatty acid chains thus rendering the lipid peroxidant-resistant; and thus stopping lipid hydroperoxide caused mostly by DHA 22:6 n-3 peroxidation from reaching the mitochondrial DNA and fracturing it/creating mtDNA deletions/lesions 8-oxo-dG)
Artica Islandica (the 500 year old clam, has lower PI and lived 500 years...it makes senses that its mtDNA is protected via lipid modulation)
You would think we should just eat or ingest DNA nucleotides and we would be immortal, that this would
increase our nucleotide pools and everything is ok.
Telomerase catalitic RNA + hTERT transcript that ADDS NUCLEOTIDES in the Telomere itself by adding TTAGGG repeats (Thymine, Adenine, Guanine DNA Nucleotides) thus ADDS DNA itself makes for immortality, yet so far it has failed. Showing DNA studies are iffy in results.
ATP (like AMP (Adenosine MonoPhosphate), ADP (Adenosine Diphosphate), GTP (Guanosine TriPhosphate), CTP (Cytosine TriPhosphate) is the energy created by the mitochondria (Adenosine Triphosphate, adenosine is a nucleotide
same goes NAD+ Nicotinamide dinucleotide....this one I am putting more my bets on,
as it is directly behind the REDOX and dictactes cell redox GSH/GSSG levels (antiox/oxidation levels),
NAD+ is used to create GSH. Still same thing there, feeding NAD or NAM (nicotinamide mononucleotide) does not make mouse become immortal either.
it does not seem to stop damage accumulation or regular aging programm (if there is one,
or let's say damage accrual by program dysfunction during telomere loss and death gene
activation of inflammation promoting the aging process and destruction of DNA nucleotides).
One study injected salmon sperm DNA in mice through blood stream or through intestinal absorption. It's ironic blood absorption was more mutagenic/cancerous than feeding nucleotides (most likely feeing damaged DNA, mice that are fed oxidized damaged DNA such as salmon or herring sperm nucleotide DNA that has been oxidatively stressed by UV exposure developp problems and have children congenital defects/that die young).
Bottom line, eating your own semen or sexual DNA is rejuvenating (though very repulsing and gross to take in your own body secretion some would say) but it does not stop aging all that much but slightly slow aging signs.
One very old study (in the mid-1800s describes the effect of a male scientist litterally ingesting his own sperm semen and seeing what it does to his body (thus effect on a human), (semen is elongated by testicular telomerase, that is why men can have children longer, telomerase in their testicules is the reason, it maintain higher spermatozoid telomeres as a man ages, and there is a positive correlation between paternal age and mature sperm telomere size). The man in question gives a detailed account in his journal of how he feels invigorated, energized (not taking the carriage, he now walks again to get there (aged in his 50s or so, in 1800s you can understand it's like a miracle) and 'young againg' (sure he's ingesting DNA nucleotides in his sperm that are breakdown to Uric Acid). He says his immune system is improved (no cold) and he defecates much faster/often (improved intestinal passage and vili size by nucleotides/improved immunity/bacterial change in colon). But he notices something, it lasts barely one two days in effect, he feels tired yet again if he stops taking in...he needs to take more every two days..he notices his skin becomes younger and his reverses aging (just for a day or two every time). It's not enough to stop aging, that's what we understand from his journal and thus shows sperm DNA nucleotides injection or ingestion (sperm) don't stop aging.
The study here says that GC DNA nucleotide repeats are correlated MLSP, Guanine + Cytosine nucleotide pairs content correlate to MLSP in 140 mammalian species.
It is a proof that DNA = MLSP (obviously DNA content loss is the big reason so is 5-methylcytosine loss, chromosomal telomere DNA loss being the first one), especially Guanine and Cytosine. In fact, it does not supprise me, Cytosine activates Telomerase to add nucleotides.
They are also called CpG site islands (Cytosine Guanine islands) and often in studies evolving in immortal cancer cell lines that increase their cytosine content and alter methylation and histone methylaion (H3) and in these CpG islands methyl content. The fact the loss of 5-methylcytosine = MLSP, shows methylation loss is a causative factor, so is Cytosine loss. When Guanine amount is increased it has a powerful effect on immune system, it is safety and genome stability mechanism (G-quadruplex, when G-Quads are increased in swine their immune system is boosted).
Same thing of demethylated short telomeres goes on in CpG islands, they become demethylated, methylation loss is big game changer in CpG islands.
STill studies showed that feeding oligonucleotides or DNA vaccines yield next to nothing in terms lifespan, only health span improves or immunity too (same thing as the study in 1800s the shows nucleotides are limited in effect).
If we could somehow increase our GC content, we could improve our MLSP.
But as shown...telomeres techincally already improve that by telomerase, TTA*GGG* that's 3 guanine nucleotide right there. They alerady rebuild DNA (repeats) in the telomeres. Has telomerase been a breakthrough so far ? No. Thus DNA tinkering is still iffy in results.
When we will be able to make our telomeres remain high and methylated, than we will be able to make for real rejuvenation.
I always put my fate in the Redox as the only real true capable thing to do that so far (SENS therapies, except for lipofuscin/AGEs removal, are unlikely to be capable to have such powerful reversal of aging by eradication of damages).
1. http://www.dailysquib.co.uk/most-popular/1092-semen-proven-to-increase-life-expectancy.html
2. http://www.ncbi.nlm.nih.gov/pubmed/22708840
3. http://www.ncbi.nlm.nih.gov/pubmed/23566066
4. http://jvi.asm.org/content/77/21/11471.full
5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725537/
6. http://www.ncbi.nlm.nih.gov/pubmed/17988355
7. http://www.ncbi.nlm.nih.gov/pubmed/24398830
8. http://www.ncbi.nlm.nih.gov/pubmed/8483468
9. http://www.ncbi.nlm.nih.gov/pubmed/8361495
10. https://en.wikipedia.org/wiki/CpG_site
11. https://en.wikipedia.org/wiki/G-quadruplex
@CANanonymity: You should come and help us with the Major Mouse testing project, we plan to rapid test some of these interventions eg, senescent cells removal, stem cell rejuvenation and AGE breakers. We plan to take batches of 40+ Black 6 mice and bulk test interventions that include some things SENS may find interesting. As much as I dislike using mice we really have no choice but to start with mice then move to rabbits or dogs before humans, the thing we can do is speed that up a bit so we are using 18 month old mice. We have Alexandra Stolzing, Arlan Richardson and Jean-Marc Lemaitre all ready to begin work for the project. We just need to work out what should be a testing priority to achieve something useful that potentially SENS can also use.
Telomere restoration does show good results and at least partial reversal of the aged phenotype and a switch to a more youthful pattern of gene expression. The problem with it is that it is is still not addressing the damage that is occurring upstream eg, stem cell decline via rising TGF-beta etc... So shoring up the telomeres is only going to buy some more time in theory but the damage will still keep piling up and compromise the situation eventually.
Some labs are using their funds to try to find which genes might participate in super-longevity, by comparing the DNA of centenarians and super-centenarians with controls.
Are they doing the same with mtDNA?
Personally I feel searching for "longevity" genes is of limited value. We do have varying genes of course and some are indeed associated with longevity but we all share the same mechanics, a repair strategy sidesteps the complexity of metabolism and tinkering with genes and treats the source of the dysfunction. This makes sense as a system cleared of crosslinks, Lipofuscin and so on would be able to function and maintain homeostasis.
I feel this is a far more valid approach until we can 100% map and work out the complex interactions of genes (possibly with robust AI) Mitochondria are linked to telomeres via the P-53/PCG-1a axis and mito count correlates with the level of telomere dysfunction as some studies have shown (eg, Rando), so it makes sense that if you fix the underlying damage you fix both things. Things like AGE should be the priority along with otehr accumulated junk the body cannot remove.
@Steve - To use the SENS Foundations approach to making mtDNA damage redundant, you'd probably have to do whole organism genetic engineering in a mouse, or at least do it comprehensively in the muscles, neurons, and other long lived high metabolic areas.
I see a lot of breathless reporting about CRISPR, but is this actually possible at this point?
And it it possible to put in a piece of DNA as big as that encompassing all 13 mitochondrial protein coding genes?
@Jim CRISPR just became a lot more accurate but as I said on Longecity whilst it is great that accuracy and safety are a lot better now we still do not know what to edit. That kind of understanding IMO is the work of decades, this is why SENS makes more sense to me.
http://www.sciencedaily.com/releases/2015/11/151118155446.htm
Still it could be a part of the SENS toolkit though Michael might elaborate further on how it could be used. I think it is a very powerful tool though the question is can we use it to effectively edit someone who is already aged? Maybe Michael may pop up to comment....
@Steve H
Hi Steve! Thanks for that! I feel I am not qualified for that plus I live outside US. I'm just an observer and visitor to fightaging. Ok, well, I'm a (big) commenter too lol ; ). It's you the expert : D. I await your results.
@CANanonymity not me I dont work with CRISPR just part of the mass mouse testing project.
@CanAnonymity - those copy and paste walls of text are unreadable, and are only tangentially related to Reason's posts. Assuming you are not spam trolling can you cut th length down and increase the content. Or provide a tl;dr summary paragraph at the top?
@Jim
Hi Jim, that's your opinion. I apologize for the length but there is nothing copy paste in the text, everything I compose it. still it takes a f...very long time to write it and get the sh*t together to (try) to make a deeper point and make you think (not simply copy paste, that's easy, I also apologize for my grammar errors, english is not mother toungue so I will cut down and not break ears). As per your suggestions, I will try to cut the length down and give a brief summary at the top, if the comment is very longer than usual and not make it like you think that I would troll with spam messages. I have no problem with people who want to judge my writing style like you do here. So no biggie, I know my message was seriously long, but I tackled many connex points to the point of this message that have very valid reasoning (at least I think..you might not think that like me); that's how we improve our overall understanding. Sorry, if it seems I derailed the subject to you and was not writing valuable input to it. So no hurt feelings.
K' ?
@CANanonymity- Although I do appreciate your input as I believe everyone else does too, it would be nice if you could shorten your comments. I usually only read maybe 20% of your comments if they are lengthy.
You seem quite knowledgeable (certainly smarter than me), but I end up getting lost and uninterested if comments get too long. I admit I love people's comments along with Reason's commentary of the forthcoming attached article that Reason is presenting.
But in my opinion, keeping it brief is more effective in bringing across your ideas and thoughts.
@Robert Church
Hi Robert ! Thanks for that ! I will keep it in mind and will cut down as best as I can, sometimes it's just I feel it's hard to explain a point really shortly and I just hope the readers will stick in to read through it; so it may take me more talking to get there (on top of not being my mother toungue, so it's double effort), but I would understand if it's too long, people will stop reading as it gets boring or confusing science rambling written in poor English grammar, makes for crap reading. And trust me, you are as much knowledgeable as I am (and smart too) : ).
I too usually don't read CANanonymity comments. They are too long and usually don't have much on-topic content.
@Antonio
Huh ?
Ok then, do me a favor spare yourself from writing about me, don't read them, I will skip your non-comments too and ignore you and whatever you say, Ok ? Don't address me, I won't to you either.
We agree to disagree. Come on. Florin/Robert told me change certain things, I am trying to do that.
So to anyone who hates my comments for their length and zero content, please do no write about them or response to them; make me a favor, ignore me I will be glad.
@CANanonymity: I'm sorry if I have upset you, but that was not my intention. I also didn't said that I will never read your comments, or that I don't read any of your comments, only that I don't read most of them, and I explained why. I said that to show that Jim is not the only one that has problems with your comments. I did read what you said to Jim, that you will try to make them shorter and more to the point, and I think that's good.
Best whishes.
@CANanonymity
I am perfectly fine with your long comments but then again I usually spend 2-3 hours a day reading studies and doing research on aging. It's like anything else if you want to get something out of it you have to put in the time.
@Antonio
Antonio, none'' taken.. I accept your apology. Thank you, best wishes to you too. : )
@Santi
Hi Santi ! Thank you for that, because I don't want to burden or disturb anyone, I am reducing them.