CpG Site Density in the Genome Predicts Species Maximum Life Span

Researchers investigating epigenetic modifications and their relationship to aging have found that the density of CpG sites, where DNA methylation occurs in order to modify the pace of production of specific proteins, correlates with maximum species life span. This is an interesting finding, but, as for the epigenetic clock used to assess aging in individuals, it will likely require the work of many research groups and many years to build a firm understanding as to why this correlation exists.

Ageing involves the decline of diverse biological functions and the dynamics of this process limit species maximum lifespan. Longevity of individuals is strongly linked to specific alleles in genetic model organisms. Ageing is also associated with several epigenetic changes involving DNA methylation (DNAm). DNAm of cytosine-phosphate-guanosine (CpG) sites, involves a covalent modification to cytosine to form 5-methylcytosine. This modification to DNA has the potential to regulate gene expression, including of genes critical for longevity, without altering the underlying sequence.

The observation that DNAm at promoter CpG sites can accumulate or decline predictably with age, over and above the more random process of epigenetic drift, has enabled the development of "clock like" biomarkers for age. Individual human age, for example, can be predicted with great accuracy in a range of tissues by an epigenetic clock. Similar epigenetic clocks have been created in a range of mammal and bird species.

Maximum lifespans differ greatly among species, even among fairly closely-related species. In vertebrates, species such as the pygmy goby (Eviota sigillata) live for only eight weeks, while the Greenland shark (Somniosus microcephalus) may live for more than 400 years. In mammals, the forest shrew (Myosorex varius) has one of the shortest reported lifespans at 2.1 years, whereas some bowhead whales (Balaena mysticeta) have been reported to be older than 200 years. Despite profound importance, lifespan is poorly characterised for most wild animals because it is difficult to estimate.

Maximum lifespan is believed to be under genetic control, but so far, no gene variants can account for differences in lifespan among species. Because ageing is characterised by changes in gene expression caused by DNAm, another potential controller of lifespan is genomic changes that accommodate DNAm's effects on regulation of gene expression. Specifically, clusters of high density CpG sites, also known as CpG islands, are highly conserved within promoter sequences and well known for regulating gene expression. CpG sites are also prone to mutation and their function in regulating gene expression may make them prime targets for evolutionary pressures to vary lifespans.

Here, we extend observations of the correlation between promoter CpG density and lifespan in mammals to produce a predictive model for lifespan in all vertebrates. We use reference genomes of animals with known lifespans to identify promoters that can be predictive of lifespan. We combined data from major databases including NCBI Genomes, the Eukaryotic Promoter Database (EPD), Animal Ageing and Longevity Database (AnAge) and TimeTree to build a predictive model that estimates lifespan. Our results show CpG density in selected promoters is highly predictive of lifespan across vertebrates. To our knowledge this is the first study which has built a genetic predictive model to estimate the lifespan of vertebrate species from genetic markers.

Link: https://doi.org/10.1038/s41598-019-54447-w

Comments

Hi there! Just a 2 cents. This a great study, best Christmas present whole year.

''This is an interesting finding, but, as for the epigenetic clock used to assess aging in individuals, it will likely require the work of many research groups and many years to build a firm understanding as to why this correlation exists''

Nonesuch, I understand the questioning Reason, but the answer is there already, no need to build many research groups, instead we must Attack it and fix it, just like your website, fightaging. We have to be more 'dire' about aging, it can't be passive anymore. Aging/death is very dire. A call to action rather than information/research for research(ing)/more infos and less 'action' on it. (just like your call to donate to make therapies come sooner). 99% studies are informative/passive research for researching and giving 'potential therapeutic leads'...but many offer nothing of such and are, indeed, Just informational and more 'research purposes'. There is a large body of data to work with now...enough biolitterature. Enough researching and we must start doing/fixing it/aging/curing phase (thankfull AdG/SENS were always about that, rejuvenation is a call to action (to fight aging) instead of passive info researching (''we see that we age...'' (indeed...so what? (are you going to do about it? we all die anyway, start acting on it)). Sometimes, I feel, the people don't realize it that they are aging, all the while this happens/they research; basically, they mortality salience is not strong yet (when you experience near death event/health degrades, mortality salience rises in you or you think it is your time/don't care) and they probably think there is not much we can do about it - except, research about it, some more.

This study is really great and of the Researching ones, it is in best ones (by comparing many long-lived animals to us, they are proofs of longevity (proof is in the pudding, long-lived animals are our best proof, it doesn't mean we can translate it but we 'get it' and we can improve ourselves following their model(esque) 'non'-aging)) because it demonstrates that we are inherently limited (by evolution on epiprogram) in longevity. It is what I said in previous message, if we can't bypass epigenome, it will be hard to overcome our human MLSP maximum lifespan potential.

''why this correlation exists''.

Because, the epigenome (at large) régulâtes genes (gene silencing and activation, gene expression/repression), genes are the major cause of why we age, those of inflammation are activated cause havoc and damages (mainly the not-so-friendly 2-faced oncogenes); it is not just damages 'byproduct' of regular metabolism but are Caused by epiregulation/gene unsilencing. The main driver in the mitos, because of the minute process of Oxygenation - it - causing ROS. ROS destroys everything in us, at it rises in emission with age,& in the long run, ROS are far more damaging than 'beneficial' (hormesis by slight ROS boost priming detox and autophagy). They contribute to the cascade of all 'end product macromolcular' damages down the line. ANd with age, they amplify and makes Faster damages, which ages and changes the epiclock/advancing quicker. Faster Epigene Activation, faster dysfunction, faster deregulation, faster loss of homeostasis, faster inflammation arrival, faster senescence entry, rising total cumul 'burden' of damages/residue junks - taking toll, etc.

''Because ageing is characterised by changes in gene expression caused by DNAm'',
This.

''In vertebrates, species such as the pygmy goby (Eviota sigillata) live for only eight weeks, while the Greenland shark (Somniosus microcephalus) may live for more than 400 years. In mammals, the forest shrew (Myosorex varius) has one of the shortest reported lifespans at 2.1 years, whereas some bowhead whales (Balaena mysticeta) have been reported to be older than 200 years.''

Yes, and there is a nearly linear correlation between loss of epigenome and their lifespan. Meaning a 2 year old forest shrew is losing over a 100x times more DNA content than the gröenland shark living 400. It thus lives about 2 years.

''Maximum lifespan is believed to be under genetic control''...it is more than believed... It Is.

They say this, tentatively and responsibly, because studies in the past said ''genetic/genes have 'no say' on your avg/max lifespan...it's all in your diet/exercice/environment/your life choices...Nope, I believe, genes are still very much behind all that (studies that overall, all along, genes were Always behind it all, like a silent doer); the external factors mold the internal factors; but genes are still the 'makers' of it, the outside stimuli are just that, stimulus to mold you differently, but internaly, Something made that change happen/be affected to these stimuli. How so? Well, we Clearly see epigenetic changes when switching environment/food/etc...so Something happening.

''Our results show CpG density in selected promoters is highly predictive of lifespan across vertebrates.''
Indeed, nuclear/mitos DNA, is the key to the aging riddle. DNA nucleotide CpG-rich/poor islands with age change/are lost or gained, the ones that matter to aging, are lost. Thus, why a 2 year old forest shrew loses it 100 times faster than a 4-century living shark in cold waters. Same thing with people with progeria, dogs, or mouse, all them have different loss of telomeric DNA content and all them different lifespans longevity (because short telomers/loss of telomeric DNA and global DNA demethylation/loss of 5metC/CpGs = DDR = replicative senescence/hayflick).

Just a 2 cents.

Posted by: CANanonymity at December 24th, 2019 1:23 PM

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