An Epigenetic Clock to Measure Biological Age in Mice
Researchers have constructed a mouse version of the DNA methylation biomarkers of aging currently under development for humans. This will hopefully enable rapid assessment of potential rejuvenation therapies in mice, speeding up progress in the field and lowering costs. There is a fair amount of work to be in order to prove out such a biomarker, however, and that starts with running it against mice subject to the numerous interventions known to modestly slow aging in mammals, including senescent cell clearance. Expanding their initial selection of methods is the next step for this research team.
Lots of factors can contribute to how fast an organism ages: diet, genetics and environmental interventions can all influence lifespan. But in order to understand how each factor influences aging - and which ones may help slow its progression - researchers need an accurate biomarker, a clock that distinguishes between chronological and biological age. A traditional clock can measure the passage of chronological time and chronological age, but a so-called epigenetic clock can measure biological age. Epigenetic clocks already exist to reflect the pace of aging in humans, but in order to measure and test the effects of interventions in the lab, investigators have developed an age-predicting clock designed for studies in mice. The new clock accurately predicts mouse biological age and the effects of genetic and dietary factors, giving the scientific community a new tool to better understand aging and test new interventions.
To develop their "clock," researchers took blood samples from 141 mice and, from among two million sites, pinpointed 90 sites from across the methylome that can predict biological age. (The methylome refers to all of the sites in the genome where chemical changes known as methylation take place, changing how and when DNA information is read). The team then tested the effects of interventions that are known to increase lifespan and delay aging, including calorie restriction and gene knockouts. They also used the clock to measure the biological ages of induced pluripotent stem cells (iPSCs), which resemble younger blood.
The research team hopes that their technique will be useful for researchers who are studying new aging interventions in the lab. Currently, it can take years and hundreds of thousands of dollars to study mice over their lifespans and determine the effectiveness of a single intervention. Although it is no small feat to sequence the entire methylome, the new clock could allow for studies to be carried out much faster and on a larger scale. "Our hope is that researchers will be able to use this biomarker for aging to find new interventions that can extend lifespan, examine conditions that support rejuvenation and study the biology of aging and lifespan control."
Link: https://www.eurekalert.org/pub_releases/2017-04/bawh-ba040517.php
Using any one bio marker to quantify aging seems misguided and counter productive to me. In the unlikely event one bio marker becomes widely accepted, focus will be shifted to therapies that enhance that one bio marker, at the expense of other necessary therapies.
Yes, I agree. For evaluating a specific damage-repairing therapy a specific biomarker will be the better choice and you need a profile instead of a single marker if you want to decide what therapy suits you best. Epigenetics may provide that, too.
One good thing I see coming out of this work on epigenetics is that it provides us with some very valueable tools - cheap epigenetic profiling, computer assisted tools and the experience to analyze it, etc. Add to the mix that the next generation of supercomputers can calculate protein folding and how big genetic databases are analyzed statistically today.
All this taken together I estimate we will get a computer assisted complete map of human metabolism and complete documentation of the human genome within a decade or two. Together with the tools necessary to simulate it and test new drugs this way.
Hi !
The question that lingers about this biomarker is, ......
what to do about it (?). Will they do 'something' about it (to...like..stop aging)? All this biomarker found data, and 'no acting' on it. It's not enough
to make a biomarker, it's about doing something to stop that aging' (biomarker-caused) process - from that biomarker information we have.
The old saying is : 'Stop talking, about walking...start walking/start to walk the ''talk'' ' Back that (info) up by doing something about that (info)...
DNA methylation (the programmed side of aging) is important and
as was shown with epigenetic drifting and transcription fidelity loss;
the global DNA methylation levels in CpG-poor islands is a determinant
of human specie max lifespan. Recent studies on reversal of DNA methylation loss have been,
sadly, not what I expected and muddied the whole thing. One study
of DNA methylation reversal in mice led to an extension of the mice lifespan
by 30%, which is impressive yet not that impressive (akin to CR in mice).
Same thing for another study in which their was mitochondrial respiration reversal
in a 97-year old donor's fibroblast line to back to a fetal-like state by feeding glycine which restores mitochondrial respiration
(same as iPSCs reprogramming, which also reverses epigenetic DNA aging and increases global DNA methylation levels back to fetal levels).
The mitochondrial respiration defect was reversed in the oldest-donor (97-years) fibroblast line.
This is about what you get with DNA methyl donors, acting the same way, such as vitamin b12, Folate/folic
acid, glycine and SAM (S-adenosyl-methionine). All of them activate DNAMTs (DNA-Methyl-Transferases..)
that add/incorporate methyls to the DNA (and in fact, studies have shown that when DNAMTs
are inhibited or KOed, the mice suffer accelerated aging like progeria/accelerated demethylation in DNA
and subtelomeric DNA (sub-telomeres/centromeres, demethylated telomeres are weak, short and unstable/become
uncapped/accelerate senescence), by a loss of total methyl levels (for example loss of 5-methylcytosine,
mice that are dying/old have lost nearly their entire 5-methylcytosine levels). And, in general, there
is drop of telomeres length - with a drop of DNA methylation levels; meaning that oxidative stress is accelerating
global demethylation in chromosomal sub-telomeric DNA and chromosomal telomeric DNA; and thus, accelerating
telomere lenght shortening/increasing the number of short telomeres.
I think now I am back again, more, on the side of damage as larger cause of healthy aging (not to say DNA methylation
loss as no say, it does but perhaps not as strong as hoped (thus, making DNA reprogramming or DNA methylation
tinkering not as great as hoped).
I still hold that the major (long/lenghty) healthy (not sudden pathological) aging element is damage, consequential damage,
that reduce cell cycle capacity. And one of the major damages of that is the 'aging pigment', accumulating in the lysosomes
such as Lipofuscin. Lipofuscin has been shown time and again as one huge reasons why we age. Not AGEs, not protein carbonyls,
not prostane. The fact that immortally replicative cells don't accumulate lipofuscin is more reason it is
a major Cause of aging, not just correlation. Some studies have shown very mixed things...accumulation of AGEs, accumulation
of carbonyls, prostanes and so forth - yet not with MLSP/Longevity...thus there are 'certain' damages that are consequential
to 'healthy aging' and 'certain' damages that are consequential for 'pathological aging'. But we lump them all in one category:
'Damage'...of course that's where studies falter and you don't get a consensus in the results between the studies; we have to Nuance them.
But with aging pigments, you do, because they are the direct blockers of the proteasome (clogging it), the proteasome at large
is our junk disposal system (when cells are dailily exposed to oxidative insults and damage accumulated in them each day),
if it's gone - it's good bye. Immortal cells like cancer cells never acccumulate lipofuscin, how not so surpising, same for Werner SV40
virus-infected fibroblasts that are immortalized; no lipofuscin either. Same thing with C.elegans who are long-lived mutants,
their intestinal lipofuscin content accumulation is greatly retarded. Demonstrating a slowing of aging pigment accumulation with
extreme longevity. Daily Oxidative stress from 'Regular respiration' is what causes this lipofuscin (in fact it was shown
that when fibroblast were put on low ambient O2 levels (hypoxia), they have low mitochondrial ROS H2O2 emissions
- and thus lower lipofuscin levels. That's why breating air kills us each day from regular ROS metabolism),
That's also why I put my money's worth on LysoSENS therapy as the single most one that could actualy make LEV
possible (the only true one). Clearing lysosomes would make a dramatic effect. Although, certain studies have ssaid that lipofuscin
increased lysosome/endosome membrane stability (where it seems to be detrimental but the cell evolved with it - to make it 'less
detrimental' and even 'positive' (sort of like Senescent cells who help in skin healing... they are bad but our cells adapted
to them - and use them in some 'positive' way when they show up - despite the obvious inflammatory nature of them and that they
must be disposed of.). My take is that the smallest and most - frozen - amount of lipofuscin would allow immortality/LEV.
Not that damage/junk alone of course, but it would have a dramatic impact - much more than anything Selse ENS offers. But it would have to
be in the Entire Body, all organs...or else it will fail :
There was a study that showed lipofuscin reduction or removal in a aquatic animal (lobster) and it happened when
they did eye stalk removal, meaning the body compensated for the loss of vision/eye on one side by reducing lipofuscin
levels, specifically in that area. AS weird as it is, it did not make the lobster live that longer, it did nothing
on its lifespan. Demonstrating that - consequential - lipofuscin is what it's about. I.e. in the organs.
Liver, heart, brain, lung, kidney, stomach, intestine, squeletal muscle, etc;
those ones are that greatly affect lifespan, not in the eyes (you can live to 120 as blind). Just like the mutant C.elegans that lived much
longer by reduced intestinal lipofuscin accrual. Lipofuscin is caused by one the major problems : mitochondrial membrane lipoperoxidation,
peroxidization of polyunsaturated fatty acids in the inner membranes fragile phospholipids. These fatty acids destruction catalyze Huge
chains of peroxidation (MDA, TBARS, and so forth), that create the 'aging' problem. In fact, studies have shown that there is an increase
in longevity the more saturated the fatty acids become (PI peroxidizability index), that is the swaping of DHA/EPA for less unsaturated
fatty acids. IN humans, we have tons of DHA/EPA in our brains (it's what keeps alive because DHA/EPA polyunsaturates increase membrane
fluidity/more 'watery', while saturated fatty ones decrease it and increase membrane viscosity. The speed/kinetic of membrane equals
to speed of the metabolism and enzymatic reactions. Of course, having a 'Fluid' membrane is much faster than a 'thick/fatty' slow viscous membrane.
That's why the brain uses DHA/EPA for powerful 'thinking IQ' capacity, it requires membrane speed - the downside is that these fluid
fatty acids are 'perodizable' by their chain length and atom configuation/they create peroxides that are extremely damaging to mitochondria and
mitochondrial DNA - thus affect the ATP constance over time; cells become energy starved much quicker if they ahve internal peroxidation.
This process is greatly accerelated in high ambient O2 such as is the case with humans as sea level (20% O2 oxygen levels, what you breathe
right now if at sea level. If were breating at high mountain levels or underwater anoxia/hypoxia, it would drop to 5% or less O2; this
would kill us but ROS metabolism would be reduced and membrane peroxidation also greatly reduced - thus lifespan would increase dramatically
(this is seen in anoxic tolerant animals like Nake Mole Rats (35 years) or Bowhead whales (211 years) or GreenSharks (500 years) or Icelandic Quahogs (507 years).
All of them have strong capacity for reduced oxygen need. Some studies showed taht they have increase antioxidation levels to 'prep' them
for resurfacing to oxygen levels (meaning the moment the O2 levels go back up the enzymes are 'ready' for the ROS burst which is immediately
nullifed/quenched). Us humans couldn't do that because our cells rely on 20% O2 or so, although ultra-high-mountain-living peoples have developped anoxia-tolerance
and can live in lower O2 levels at extreme altitude in huge mountains (like Everest/Himalayas' Tibetans).
One study showed a 'trend' in mammals where liver PI was correlated to MLSP if anti-oxidative enzymes are Equal, Demonstrating that Lipofuscin (which is compose mostly of the breakdown
of oxidized membrane phospholipids or aldehydes MDA), is causal to the MLSP of animals.
My take is that the Redox is most crucial elements deciding of Lipofuscin (since GSH is the most major IMM lipid peroxidation quencher) and consequential-damage from peroxidizing IMM membranes which
create massive cataclysmic peroxidation 'chains' that destroy our mitochondrias (each day as we breathe) and then our nuclear chromosomes are affected/genomic dysfunction ensues.
It was shown that ultra long-lived quahogs (500 years old) have reduced polyunsaturates, but also, have higher redox capacity - over a very long time (maintenance).
There mV was -100mV cell redox or more mV down from the shortest lived quahogs (which became rapidly +mV (oxidized) and accelerated aging). Not only
that, there mantle lipofuscin content is absolute nill and very sloowwly accrued...over the centuries vs short-lived quahogs who accrue a lot quickly. Showing that indeed the age pigment is major
causal contributor to lifespan (not just a mere correlation or after residue, this gunkclogging of the proteasome/lysosomes is fatal over long term). What I fear is that most of the SENS therapies end up a rejuvenation for health treatment rather than a longevity
extension, even if it targets lysosomal lipofuscin levels - it could be just - not enough. It needs be Systemic and Entire body, and Entire cells.
It's a Huge Ordeal and I'm not sure nanorobots or even, magnetic-nanobacterias', will be capable of 'magically 'dusting off' all the age pigement crap - in All - cells.
Still we have to start somewhere, I just think LEV is impossible will the 6 other therapies, except maybe LysoSENS, DNA methylation improvement is sadly
not gonna be enough (if all we can do is a 30% lifespan extesion in mice by DNA methylation improvement, forget about LEV on DNA methylation therapy; and forget about for all other therapies *these damagse are much more inconsequential to regular maximal specie lifespan but rather health/pathological-state lifespan*, except lysosomal one)... jus my'2 cent.