The original sin : gastrulation

Fact 1. P16Ink4a causes senescence in aging cells
Hypothesis1a : p16ink4a  causes senescence because aging cells are more frailty, have more DNA damage and more stress as a result of methylation changes a.k.a. epigenetic clock
Hypothesis 1b: p16ink4a causes senescence because itself is more upregulated as a result of age related hypomethylation
Hypotheis 1c: p16 ink4a causes senescence as it senses the epigenetic clock

Fact2 hTERT expression inhibits p16ink4a   
also here
Hypothesis 2: this is a way for stem cells to avoid age related senescence

Fact3a in some epithelial cell cultures p16ink4a causes premature senescence, these cultures lack cell-cell adhesion
Fact3b in some epithelial telomere immortalized cells there is accelerated epigenetic aging  
Hypothesis 3: lack of cell-cell adhesion accelerates epigenetic aging

Fact4: There is a growing body of evidence that suggests induction of epithelial cell migration is associated with upregulation of p16expression

Hypothesis 4a: epithelial cell migration accelerates epigenetic clock
Hypothesis 4b: gastrulation accelerates epigenetic clock
Hypothesis 4c: the epigenetic clock  synchronizes cells  in embryogenesis in triploblastic animals
Hypothesis 4d: the epigentic clock continues to tick after adult state is reached and results in epigenetic damage to the cells, causing cancer or mass senescence. Both fatal.

Fact5a: Diploblastic animals do not gastrulate
Fact5b: Diploblastic animals have all kinds of lifespans and sexual reproductive strategies
Fact5c: Triploblastic animals are more committed to strict lifespans and  strict sexual reproduction
Hypothesis 5a: Gastrulation had enormous evolutionary advantages, see Cambrian explosion, but it also brought about strict lifespan regulation as a pleiotropic effect of more complex embryogenesis
Hypotheis 5b: Animals evolved "cheap hacks" to trick the epigenetic clock, for example Fact2

Understand aging - in the cell culture

okay this will be messy. I seem to understand several things...

• Limits on cellular growth
• some cultures are limited by p16ink4a, some are not
• cells in  culture age faster than in vivo
• some cultures might age faster than others
• p16Ink4a might be the true gatekeeper of aging cells

In cell culture cells divide until they adhere to media (contact inhibition)
Then they need to be passaged (dish changed, contacts cut) to start dividing again.
With repeated passage, human cells in culture reach senescence after about 50-60 doublings, This is the Hayflick limit, caused by telomere erosion.
Around year 2000 it was widely researched what happens when telomeres are restored by expressing human telomerase in the cells (hTERT).
In some cultures a new, extended cell doubling limit was reached and to overcome this the p16/rb pathway had to be disrupted

Both Rb/p16^INK4a inactivation and telomerase activity are required to immortalize human epithelial cells

http://www.nature.com/nature/journal/v396/n6706/abs/396084a0.html

 But in other cultures this limit was not present, Telomerase alone was enough to immortalize cells

Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions
https://www.researchgate.net/profile/Jerry_Shay/publication/12101866_Putative_telomere-independent_mechanisms_of_replicative_aging_reflect_inadequate_growth_conditions/links/0c9605293d097c4714000000.pdf

However cells immortalized by hTert only showed premalignant growth (accelerated growth,no contact inhibition) in some cultures

Prolonged Culture of Telomerase-Immortalized Human Fibroblasts Leads to a Premalignant Phenotype

http://cancerres.aacrjournals.org/content/63/21/7147.full#ref-29

"Growth of three independent mass cultures was uniform for ∼150 PDLs after telomerase infection, followed by a progressive acceleration of growth in two of three cultures. Expression of p16^INK4A was significantly elevated in the immortalized cells but gradually disappeared during the accelerated growth phase. This alteration correlated with loss of the contact inhibition response and conferred the cells with sensitivity to H-Ras-induced transformation"

However other research found no such effects

http://s3.amazonaws.com/academia.edu.documents/42760130/Morales_C.P._et_al._Absence_of_cancer-as20160217-3135-ewf9bc.pdf?AWSAccessKeyId=AKIAJ56TQJRTWSMTNPEA&Expires=1474663740&Signature=zysMp%2F%2FpvbcbABlRRw9i9U1qIdE%3D&response-content-disposition=inline%3B%20filename%3DAbsence_of_cancer-associated_changes_in.pdf

P16 is clearly associated with aging

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961602/

p16INK4A Influences the Aging Phenotype in the Living Skin Equivalent

 http://onlinelibrary.wiley.com/doi/10.1002/stem.1908/full

Age-Specific Functional Epigenetic Changes in p21 and p16 in Injury-Activated Satellite Cells

This research is the key to understand aging

Epigenetic clock analyses of cellular senescence and ageing

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=7383&pubmed-linkout=1

hTERT immortalized cells age 10 years epigenetically in just a few months!

This might be the key. In some cell cultures cells age more rapidly so they become constrained by the p16Ink4a. p16ink4a is normally silenced by DNA methylation but as age associated hypomethylation progresses , p16 expression increases thus limiting cell division. Later as hypomethylation progresses and genetic instability grows, some cells overcome p16 limitation and become precancerous.

In other cultures cells do not age in an accelerated fashion, so they can freely proliferate when telomere erosion is not a limiting factor anymore.

There must be some factors in different cell cultures that facilitate slower or faster cellular aging!

Mice are also interesting. Mice have much longer telomeres than humans, but live much shorter lifespans.

Mouse cells in some culture also stop dividing waaay before reaching the telomere limit.

http://www.biolchem.ucla.edu/labs/Tim_Lane/login/StemCell_pdf%20files/Wright.pdf

Telomere dynamics in cancer progression and prevention:

fundamental differences in human

and mouse telomere biology

But in other experiments mouse cells can divide indefinitely

Loo, D.T., Fuquay, J.I., Rawson, C.L. & Barnes, D.W. Extended culture of mouse
embryo cells without senescence: inhibition by serum.
Science
236
, 200–202(1987)


My conclusions:
telomeres are the red herring of aging. Telomeres serve as means to prevent differentiated cells to divide too much, to control tissue mass and  prevent accumulation of mutations.
The tissue stem cells express telomerase in a limited way so that they can escape the Hayflick limit. If it wasnt this way we would run out of blood cells and intestinal epithelial cells pretty soon as these cells have a high turnover.
But what really counts is the epigenetic clock. It makes stem cells age, so they lose plasticity and regenerative capacity. p16 becomes more and more expressed with aging cells (epigenetic pattern is inherited by differentiated cells from their parent stem cells) causing senescence and tissue erosion.
In cell culture this process can be mimicked with different speeds of biological aging depending on culture media. Lot more research is needed on culture media. Trial and error is not enough. The cellular environment is very important!

Update:
This is the last research I could find on p16/TERT interplay.

Methylation of the p16^INK4a promoter region in telomerase immortalized human keratinocytes co-cultured with feeder cells

http://www.nature.com/onc/journal/v25/n56/abs/1209729a.html

In the absence of feeder cells, cultures of human epithelial cells accumulate p16 protein in a passage-dependent manner. This increase in p16 expression eventually leads to growth arrest by telomere-independent mechanisms. There is a growing body of evidence that suggests induction of epithelial cell migration is associated with upregulation of p16 expression (Jung et al., 2001; Natarajan et al., 2003; Svensson et al., 2003; Nilsson et al., 2004; Darbro et al., 2005). 

Epithelial cell migration happens during embryogenesis. During embryogenesis and young age, the epigenetic clock (developmental program) ticks much faster. Thus certain cell cultures (plastic with serum) mimick embryonic environment and makes the cells age faster. The cell culture with feeder cells - on the other hand - mimicks adult tissue environment thus the epigenetic clock ticks slower.
See Figure 6 for the logarithmic nature of the epigenetic clock
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015143/pdf/gb-2013-14-10-r115.pdf
Methylation levels change a lot near birth, much less in adulthood if we apply the embryonic methylation shift in later age, we got a lot more aging in calendar years.

 

Oxidation - maybe the ultimate agent in aging

Oxidation causes damage to cellular organelles, proteins, DNA nucleotids. However these all can be repaired by the cell, because there are templates.
There is one thing that's hard to repair - the methylation state of the DNA. Because the methylation state of the cell only resets early in embryogenesis and from then on its a one way process.
There are enzymes that can actively remove methyl group from cystein through oxidation.
Maybe the process works in an active manner too?

The Emerging Nexus of Active DNA Demethylation and Mitochondrial Oxidative Metabolism in Post-Mitotic Neurons

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284726/#B17-ijms-15-22604

Mechanism and Function of Oxidative Reversal of DNA and RNA Methylation

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786441/#R12

Genome-wide Analysis Reveals

TET- and TDG-Dependent

5-Methylcytosine Oxidation Dynamics

http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.702.7534&rep=rep1&type=pdf

Charting oxidized methylcytosines at base resolution

http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.702.5833&rep=rep1&type=pdf

Nutrition, circadian cycles

Good review on nutrition vs aging
http://europepmc.org/articles/pmc4547605

Circadian clocks, feeding time, and metabolic homeostasis

http://journal.frontiersin.org/article/10.3389/fphar.2015.00112/full

Age related changes in bone caused by shift in stem cell differentiation?

First paper, expression profile, DNA methylation changes in mesenchynal osteo progenitor cells
http://www.ncbi.nlm.nih.gov/pubmed/25827254
Many differences between aged and young? Is there a casual relationship between methylation and expression? Couldnt find it out from the abstract.

Second paper claims that epigenetics (my favourite Polycomb repressor group2) influences the balance in differentiation into osteoblast or adipocyte, suggesting this is the reason for age related bone loss and age related obesity. However here PRC2 catalytic subunit EZH2 is upregulated by age - previously PRC2 targets got methylated by aging. This is controversial at first sight. Need to get the paper.
http://onlinelibrary.wiley.com/doi/10.1002/stem.2400/abstract

Do adult stem cells form by lineage commitment or from normal differentiated cells?

As adult stem cells are different from differentiated cells only in transcription profile, maybe they just form form differentiated cells if there is a need for them?
There is some evidence in this thesis that differentiated cells can de differentiate into the originating stem cell state, however transformation into different cell type is unusual. This is kind of expected if DNA methylation indeed determines cell type, but stemness is only determined by gene expression which is much more plastic.
 

Epigenetic modifications of aging have weak direct link on the expression profile

 Steve Horvath reported he had found no universal transcription profile signature of aging.
However there is clearly and aging phenotype of cells. I mean functional decline of the cell. (think of immunosenescene for starters)
Maybe this is caused by transcriptional noise resulting from hypomethylation of repetitive elements (and others)?

Study
Longitudinal epigenetic and gene expression profiles analyzed by three-component analysis reveal down-regulation of genes involved in protein translation in human aging

Fibroblast samples from same person after 10+ years analysed for expression, DNA methylation and certain histone modifications. Shockingly very weak correlation between upregulated sequences and methylation or histone modification.
Expression profile changes match phenotype changes of aging (metalloproteins upregulated , collagen downregulated).

Previous entry concluded stem cells differ not in DNA methylation but in transcription profiles
Maybe its the plasticity and potency of stem cells that is affected by the epigenetic clock by methylating PRC targets. What we see in expression profiles of fibroblasts is the profile of fully differentiated cells, probably different from stem cell profiles.