Fight Aging!

Hi there ! That's a great study, telomere are currently in biogerontology limbo, it seems.

Though telomeres are not the most accurate aging biomarker in general (because senescence can be triggered via
a spontaneous stress-induced pathway vs replicative senescence lifespan pathway that can be oxidative stress/or
no activated (p53/p21, p53/p16). I think we should reassess its worth because most of these studies verify
telomeres alone; they do not give a full portrait by comparing epigenetic clock of DNA methylation levels/DNA methylomes
(in CpG islands) with telomeres - but also with(in) subtelomere/subtelomeric regions. Also, some of these studies
use very small timeframes of people, they do not compare over a full lifespan from birth to death. It's pointless to just verify
telomere dynamics in a 5 year range of say 65 to 70 years old. We know that they can change drastically from one decade to the next.
As such, these studies are focusing 'too small' and only see the 'small' erroneous picture; they need to see the whole picture
(measure in full life from birth to a 100/over the decades, even each 2, 3 or 5 years would be more precise; but for the entire lifespan).
Getting measures at a fix-point in life is almost always poor and can be *invalid*, because you don't compare it - to the previous decades
or following ones. Aging is 'muting' unfolding process/thing/program, you must always verify it - in time/over time (as it changes over timespan).
Not a set point in time and call this a 'aging' study. I almost always discard studies that verify one group of age and makes a claim, and that's it.
Not comparing it to other age groups over time. There is such a thing as 'aging history/registry' (which is how many years you have aged already
and how does that impact where you are now, studies that do not take in that information give a half-ass*d story and have no point; because
they don't factor in the 'aging history' of the person (the aging dynamics that led to the age of that person; that person could have aged fast or slow
during the previous years - you must factor that in).

''The centenarian DNA had a lower DNA methylation content and a reduced correlation in the methylation status
of neighboring cytosine--phosphate--guanine (CpGs) throughout the genome in comparison with the more homogeneously
methylated newborn DNA. The more hypomethylated CpGs observed in the centenarian DNA compared with the neonate
covered all genomic compartments, such as promoters, exonic, intronic, and intergenic regions. For regulatory regions,
the most hypomethylated sequences in the centenarian DNA were present mainly at CpG-poor promoters and in tissue-specific genes,
whereas a greater level of DNA methylation was observed in CpG island promoters. We extended the study to a larger cohort
of newborn and nonagenarian samples using a 450,000 CpG-site DNA methylation microarray that reinforced the observation of
more hypomethylated DNA sequences in the advanced age group''

5-methylcytosine loss and reduced global methylation/DNA demethylation in two extreme set points (birth, and very late near death) is proven in
this study; showing us that DNA methylation loss happens over aging.

'' We identified 65 gene promoters enriched for CpG sites at which methylation levels are associated with
leukocyte telomere length, and 36 gene promoters enriched for CpG sites at which methylation levels are
associated with telomere length in DNA from EBV-transformed cell-lines. We observed significant enrichment
of positively associated methylated CpG sites in subtelomeric loci (within 4 Mb of the telomere) (P < 0.01),
and also at loci in imprinted regions (P < 0.001). ''

''Among 44-45 year-old men, we have identified multiple gene promoters enriched for sites at which
methylation levels are associated with telomere length in human blood DNA. Furthermore, these associated loci
are significantly overrepresented in subtelomeric and imprinted genomic regions.''

''However, four of the gene promoters that we found to be associated with telomere length also contained sites that belong to a set of 353 'age-predictor' CpGs30:
those at the CYP2E1, DIRAS3, FAM50B and SGCE loci.
****This may indicate that part of the epigenetic 'signature' of chronological age is related to telomere length shortening.****''

''It is well-known that there is wide inter-individual variation for the risk of age-related disease in people of the same chronological age.
***Loci at which methylation levels are associated with both chronological age and telomere length may thus be of particular
relevance to the investigation of factors that influence successful ageing.***

''
We discovered that a significant proportion of the sites associated with telomere length are located in
***subtelomeric regions***, and that for the majority of these,
*******increased methylation levels are associated with longer telomeres******.
This finding supports previous evidence from animal and in vitro work that
***heterochromatin is lost in subtelomeric regions as telomeres shorten40***.
Age-related global hypomethylation of subtelomeric regions has been observed in both
healthy Japanese individuals and those with Parkinson's disease and sarcoidosis41,42,43,

although the same group also report hypermethylation of subtelomeres in short telomeres in blood DNA from Alzheimer's disease patients44.
The authors postulate that this latter observation may result from the selective
loss of cells with short, hypomethylated telomeres from the blood of Alzheimer's patients
''

Overall, there is far more hypomethylation in subtelomeres with aging, than there is hypermethylation. Some cancerous cells have hypermethylated
subtelomeres (this is needed for their immortalization).

''If confirmed,
******our finding that shorter telomeres are associated with decreased methylation levels of
multiple cytosine sites located within 4 Mb of telomeres suggests a possible
causal explanation for the relationship between shorter LTL and age-related diseases:
as telomeres shorten, the resulting epigenetic changes in subtelomeric regions may
alter the expression of disease-related genes.
Such a mechanism was first postulated after the discovery of the 'telomere position effect' (TPE)
in eukaryotic cells, in which the expression of transgenes located close to telomeres is repressed in a telomere length-dependent manner*******''

''Our results suggest that the relationship between telomere length and both LINE-1 and subtelomeric methylation is dependent upon telomere biology gene function.''

''Our results are consistent with distinct mechanisms being responsible for
maintaining telomere length in blood and early passage EBV-transformed cells,
with activation of the ALT pathway in transformed cells overriding DNA methylation states
of genes that are associated with telomere length and telomerase activity in blood cells.
Some of the CpG sites identified in our study as being associated with telomere length in
cell-line DNA may provide further insights into the immortalisation process''

This means there is a strong link between epigenetic clock (DNA methylation) and telomeres, subtelomeres to be more precise - and Intrinsic Aging. They work both
independently and dependently in the chromosomes. As such telomeres are not such a bad correlative damage marker, if you know how to look more precisely
and deeply (chronological age, verification over time (over the decades in full life), subtelomeres, CpG, DNA methylation all factored in to Telomere Length).
The more factors are factored in the big picture/the better the correlative power, the more telomeres/subtelomeres become very telling of aging and
better markers despite all the 'telomeres are useless'; In the right context and with enough factors they are decent. The sole fact that they shorten
is an indication something is going on (damage accrual oxidatively stress telomeres) and that we are indeed aging. And the same goes for ALT cancer cells who override DNA methylation state and keep
on increasing telomere length over time by ALT telomere fusions/recombination - and, by immortalization, become replicatively immortal.
Lending more credence to chromosomes (sub)telomeres, in various tissues (not just leukocytes) being a strong indicator of Epigenetic aging (by correlating to DNA methylome).
I will conceed, though, to this study in this news that telomere and health is not always correlative (having a disease and telomeres are not affected much, though this can be because of study limitations (like small sample pool or not researching 'over time' or disease progression, but in just a fixed point of disease);

but (Sub)Telomere and Intrinsic Aging (Epigenetic Clock) is, definitely, correlative.

What remains to be more seen, is if telomeres are useable for chronological aging; so far, that is not the case as individuals of the same chronological ages - can have the different telomere sizes (meaning one is biologically/physically aging faster than another - in the same alloted amount of real chronological timespan, showing us that telomeres are a true 'biological aging' marker rather than chronological).

PS:

I found a incredible study that shows that
epigenetic aging, via (sub)telomeres and CpG locis, is causal
to intrinsic aging. Calorie Restriction in this study
affects DNA methylation in both ways, by hypermethylating
and hypomethylating DNA promotor/exon regions.
Calorie Restriction has been shown to increase Mouse Lifespan
and Maximum Lifespan by damage reduction/accrual slowing.
As such, itself would lend creedence to the idea that subtelomeres/epigenetic
aging would determine one's life by way of DNA epigenetic clock methylomes :

'' For example, hypermethylated promoters were associated with pathways such as neuroactive ligand-receptor interaction,
cancer, diabetes, and nitrogen metabolic process (arginine and proline metabolism, alanine, aspartate, and glutamate metabolism).
In contrast, hypomethylated promoters were highly associated
with cytokine-cytokine receptor interaction and chemokine singling pathways,
which are involved in the inflammation response''

'' Recent studies show that demethylation of these elements over time may contribute to human
senescence and degenerative diseases. For instance, a cohort study of healthy elderly subjects
showed that methylation in LINE-1 and Alu decreases over time (Bollati et al., 2009). Also,
reduced methylation of repetitive elements might contribute to a higher risk of developing and
dying from cancer (Zhu et al., 2011). These findings are consistent with our data showing
five repetitive elements in old and OCR rats that were hypomethylated compared with young rats
(Fig. 2B). Thus, the aberrant methylation of repetitive sequences
may contribute to genomic instability during aging, and it is thought
that short-term CR could not prevent the demethylation process.""

''...although genomewide hypomethylation occurs with aging...''

'' In addition, hypermethylation of CpG islands in cancer-associated genes
was observed in 45 different normal prostate tissues (Kwabi-Addo et al., 2007).''

What does all of this means ? It means that as the organism ages,
diease genes are activated and their regions Hypermethylated,
while regions that control 'healthy aging/regular lifespan' become
Hypomethylated (the promoter CpG repeat regions). These demethylating
regions are 'inflammation response'. Meaning, as the system ages, it
has difficulty in creating an inflammation response, in other words,
it becomes blind to inflammation - because it cannot 'respond to it',
by creating the appropriate action (inflammation (response)).
That they found the hypomethylated region concerned cytokines is quite
surprising when you think inflammation itself causes diseases;
it seems the 'Real' intrinsic aging problem, is when the system is just 'not responding'
to insult (by creating the 'inflammation' response - which would Resolve the insult,
the inflammation would be the Response and the ensuing DNA damage repair the Resolve).
But, here there is no more 'response' as such no more 'repair'. So it is totally
'unknown' that there is 'a problem' going on, it just lingers and damage keeps on piling
and there is no Resolve to it (by Repairing it since there was no Recognition/Inflammation Response to it);
and so you intrinsically age.
I was curious and surprised, and not so, that Glutathione metabolism featured in the hypermethylated DNA region with age. Makes sense though,
it is compensation by the Redox to try to maintain itself in front of disease activation by hypermethylation
of disease genes with age.

''Thus, hypomethylation of repetitive elements may reflect the degenerative phenotype of aged cells or tissues.''
And this single line demonstrates without a doubt that hypomethylation (Telomere loss/demethylated short telomeres)
is correlative of intrinsic aging :

''Methylation in the promoter and intron regions decreased with age and was ameliorated in OCR [Old on Calorie Restriction] rats (Fig. 2C)''

Showing that CR increased methylation in these demethylating regions precisely which control intrinsic aging (as aging humans have reduction of methylation
in exactly these regions). These regions of 'inflammation response' creation (and thus DDR DNA Repair Response) are the ones who control aging.

Cancer and diabetes are just 'Degenerative' genes activation by hypermethylation outside the promoter and intro regions (that control intrinsic aging).

''Our signal pathway analysis of hypermethylated promoters in old rats showed a significant association with degenerative diseases such as cancer and diabetes;
****the hypomethylated promoters were related to inflammation [response]****''

''In contrast, hypomethylated promoters were highly associated with cytokine-cytokine receptor interaction
and chemokine singling pathways, which are involved in the inflammation response.''

If you don't die of diabetes, Alzh or cancer, meaning you don't have hypermethylation of said hyperregions well you're down to the 'hypomethylated' regions (aka you're left with the intrinsic aging process to normal regular 'healthy' death 'from old age'):

Hypomethylating regions with age (intrinsic aging/inflammation response) genes targets are:
Endocytosis (makes sense, not being capable of molecule transport from Cytosol, and if all parts included the Cytoplasm, would be problematic with age)
Cytokine-cytokine receptor interaction (cytokines and chemokines are at the heart of (anti)inflammation/response, also this shows that Cytosol environment is extremely important, more so than mitochondria almost because it 'bathes in' all cell compartments bathing in it)
Chemokine signaling pathway
beta-Alanine metabolism

Short-term calorie restriction ameliorates genomewide, age-related alterations in DNA methylation

1. http://onlinelibrary.wiley.com/doi/10.1111/acel.12513/full

"Thus their average length in any particular tissue, in our species at least, where other factors are less important, is a function of how often cells divide and how often the stem cells supporting that tissue deliver replacement cells with long telomeres"

Meaning, if it was possible to rejuvenate the stem cell population including reconstructing division rate of the population, there was no reason to worry about telomere shortening at all.

Yep we want somatic cells to die only the stem cells and keeping the niche populated and youthful is important. Telomere loss is a downstream effect and fixing the upstream damage will replace loses.