Lower Epigenetic Measures of Age Observed in the Children of Long-Lived Individuals
Researchers here demonstrate that a biomarker of aging presently under development shows a lower measure of age in the children of long-lived individuals. A number of research groups are involved in trying to create a standard measure of biological age based on patterns of DNA methylation, a type of epigenetic modification that regulates the production of specific proteins from their genetic blueprints. Cells react to circumstances, and one of those circumstances is the accumulation of molecular damage that causes aging. These forms of damage are the same in all of us, and so we should expect to find patterns in the epigenetic changes that accompany aging: some are individual, a matter of circumstances and environment, but others are shared and reflect the level of age-related cell and tissue damage suffered over the years.
Ageing researchers and the general public have long been intrigued by centenarians. We find it useful to further distinguish centenarians from semi-supercentenarians (i.e. subjects that reach the age of 105 years, 105+) and supercentenarians (subjects that reach the age of 110 years, 110+) because subjects in these latter categories are extremely rare. As of January 1, 2015, in the 60,795,612 living individuals in Italy, 100+ are 19,095, 105+ are 872, and 110+, which constitute an even smaller subgroup, are 27, according to the data base from the Italian National Institute of Statistics. On the whole, 105+ and 110+ subjects have to be considered very rare cohorts of particular interest for the study of both the ageing phenotype and the healthy ageing determinants. This means that 105+ and 110+ are most informative for ageing research, even if it is not yet known whether 105+ reach the last decades of their life according to a molecular trajectory which progresses at a normal rate of change or whether the attainment of this remarkable age results from a slower molecular ageing rate.Relatively few studies have looked at epigenetic determinants of extreme longevity in humans. Here we test whether families with extreme longevity are epigenetically distinct from controls according to an epigenetic biomarker of ageing which is known as "epigenetic clock". We analyze the DNA methylation levels of peripheral blood mononuclear cells (PBMCs) from Italian families constituted of 82 semi-supercentenarians (mean age: 105.6), 63 semi-supercentenarians' offspring (mean age: 71.8), and 47 age-matched controls (mean age: 69.8). We demonstrate that the offspring of semi-supercentenarians have a lower epigenetic age than age-matched controls (age difference of 5.1 years) and that centenarians are younger (8.6 years) than expected based on their chronological age. Future studies will be needed to replicate these findings in different populations and to extend them to other tissues. Overall, our results suggest that epigenetic processes might play a role in extreme longevity and healthy human ageing.
Link: http://www.impactaging.com/papers/v7/n12/full/100861.html
"Inflammaging" may be responsible for some epigenetic drift, e.g., -
"Eyes turn into skin: How inflammation can change the fate of cells"
http://medicalxpress.com/news/2015-12-eyes-skin-inflammation-fate-cells.html
Hi all !
Summary : DNA methylation is linked to telomere methylation level which is determined by their repeats.
This is a great study that reinforces the causality of telomeric repeats in intrinsic aging. Chromosomes are all about genes and epigenetics, chromosome caps (telomeres) are the age counters for they contain the DNA repeats; and as shown damage to telomeric DNA is irreversible. The main contributor is Replicative Senescence by telomere end-problem per population doubling (and the others are Oncogene-induced, and Random DNA damage), we can cover those last two but the first one is a big puzzle, telomerase therapy couldn't halt it totally. Telomeres that become demythelated become unstable and defective (check Redox Methylation, S-Adenosyl-Methionine:S-AdenosylHomocysteine ratio/trans-sulfuration pathway (with methylating controlers like folate, B12 that alter DNMTases (Dna Methyltransferases that assure CpG island methylation in telomeres/telomeric DNA), and especially GSH:GSSG ratio by increasing GSSG that dictates telomere attrition from oxidative stress caused by oxidized intra/extra cellular glutathione).
In this study here, the centenarians, and their offspring, have higher DNA methylation; higher methylation equals higher telomeres, more stable genome and more methylated CpG islands (Cytosine/Guanine DNA nucleotides in chromosomes). More telomeres from base start (birth) means more telomeres at the end (death), kind of like starting with that extra chunk helps a lot much later in life (so if people told you you like look 'old' for your age,not so good sign, if people told you you look teennager babyface 20 or something (and you are double that age) than you are on your way to centenarian possibility), centenarians were often 'young looking' (baby skin face with no wrinkles ever, super late bloomer/late puberty) during their 30s-40s, they even smoked, ate sick amounts of junkfood, did no exercise, drank booze (lot) and did tons of deadly crap for the rest of general pop. and stillll, lived to a 100 with little disease whatsoever (lucky genetic, nothing else explains this dilemma, they had them high telomeres very young and kept them like that longer over the decades, some of their bad ways 'primed' them and their genes to 'overcompensate' (stress resistance/ hormesis) and so they could do those nasty things plus still not die from them; whereas this would be oxidative stress overkill for non-gene gifted general people who even doing all the good things (eat well, exercise, mental stimulation, no smoke, no drink) will die before 100 because inherited genes dictate (at over 75%) the final outcome in high age.
This study above makes me think of another study (below link) that verified telomere lengths with a great detail and helped to really see what is going inside of us in terms of telomere dynamics over time. It correlates greatly to what is going on with DNA methylation pattern and reaffirms the utter role of DNA methylation pattern, by DNA damage accrual, in sub-telomeres, centromeres, telomere repeats and every other. The main finding is that
humans born with high telomeres, will live longer, we knew that, but that to 'survive' longer in old age you need higher previous RTL (relative telomere length), so you need that extra slack shield so that later on you are still 'high enough';
the most incredible finding though is that humans with base Higher RTL Telomeres age Faster over a period of time (10 years in study) that 'already old ones' who have shorter telomeres at base RTL; meaning those who had smaller telomeres (and thus Reduced DNA Methylation) were aging 'Slower' during the follow up 10 years; at first this doesn't make any sense; but when you think it through, it could mean that someone 'young-like' with tall telomeres is more 'affected' by oxidative stress than a 'biologically' older person with 'already' short telomeres (not really choronological age, as seen in the study, only biological age truly mattered (by RLT)). I have a feeling this overcompensation by the aging body, slowed metabolism (capable of 'taking it') and a capacity to accumulate senescent cells (it's why sometimes mature old cells can sometimes tolerate insults better than young cells (they are 'primed for inflammation and live it', when in fact they die much quicker after a while from 'near-death', young cell can repair themselves better but they can face fragility like old cell, and hyperoxidative challenges may overstress them and seriously compromise them from unadaptation (new thing for them, not for old cells who are better adapated to chronic inflammation)). So that is why I feel as the body senesces with short telomeres it 'gives a last ditch effort' before death, trying to 'slow down' telomere attrition in the shortest telomeres (at this late point in life, they are everywhere, so senescence is getting really big, apoptosis is next thing).
If we extrapolate this to a human centenarian, it means (just my unfounded beleif), that
when we age, if we remain 'young-like' our body will age Faster in a short period of time (from oxidative stress chunking out our telomeres by larger chunks over that period) - But we will Still have more Telomeres length when we reach to the same chronological age of another person who has shorter telomeres.
I sincerely hope this study is So wrong, and hat young-looking people, have Taller Telomeres AND their telomeres are shortening slower Too; apparently and paradoxially, from this study, it's not the case. If it's right it means that when we reach a 100 years old, we Could Die the very next day if 'we look a very young looking Centenarian', our telomeres who lose massive chunks in the compressed spaces of a days or weeks (makes senses when centenarians die abruptly like that, one week they are are 'OK', next week they are dead; of course, short telomeres everywhere in the chromosomes and wide genome are the Major reason, but so is losing lots of telomeric DNA in a short amount of time). My theory is that centenarians, have more telomeric DNA, more DNA Methylation, More gene code to 'work with' from birth, they may lose a bitmore around early-mid-life but it abates and they have more to work with, nearing death. In the study, they are 75 years old, not centenarians, so perhaps it Does Not apply to centenarians because some of those 75 years old died; still they study says they had Shorter telomeres, which means they were 'post-poning' their death as much as possible - with their shorter telomeres (from less loss of telomere at base RTL) and then they died at 75 or so.
Influences on the reduction of relative telomere length over 10 years in the population-based Bruneck Study: introduction of a well-controlled high-throughput assay
1. http://ije.oxfordjournals.org/content/38/6/1725.full
ps: I don't entirely buy this because other studies showed clearly that - at all time points in life - centenarians had higher telomeres and their telomereic loss was lower than the reduced population (meaning they had less inflammation inside them, thus less oxidative stress, thus less telomere attrition speed/rate), this study could simply 'an artefact' where it may show some 'vague flux' in some people, they may age a bit faster than others, Even If they had higher telomeres (perhaps their ways or genetics made them lose more, 'slight aging acceleration phase' in 'some people'..perhaps they were stressed out ??) But it does not fit with the centenarian model, whom Most Likely had Tall Telomeres, from birth and up to death (like one study recently, who verified the telomere length of leukocytes of a 115-year old woman super centenarians, they were very low at 4-5 kb height, which means she used up her Whole Telomeres over all that time; Thus she had Reduced Telomere Attrition per year - spread over 115 years. And we have to remember that centenarians have higher Redox glutathione, and when antioxidants/glutathione are increased telomere attrition speed rate drops a lot. Why ? Because Redox controls Telomerase activity/access to telomeres during cell cycle (reduction in GSH:GSSG ratio can make a 80% drop in telomerase, accelerating Replicative Senescence end problem of telomeric base pair nucleotide loss) So This means, two things, this study is not applicable that much for longer lived people; and that to live to a 100, you unconditionally need slow telomere loss - and - Tall telomeres from the start; makes much more sens. So, please scratch that study as valid for many peopulation, but not for all and not really for centenarians. Remember this study here of this news showed that DNA methylation is Higher in Centenarians and their offspring, and methylation is unconditionnaly linked to Telomere Length; we can suppose that they had taller telomeres and very low oxidative stress (antioxidant Redox); thus reduced telomeric attrition rate.