Fight Aging!

Hi all,

I believe in my opinion
this immunosenescence seems to fall in the intrinsic aging, but is rather more about pathological aging.
White blood cells, Leukocytes PBML, lymphocytes, monocytes, neutrophils, NK cells, T-cell, macrophages of the immune system are often activated in pathological states with contributing inflammatory cytokines (TNF-alpha, Interleukin-6), because of the inflammatory immune response. This inflammation elevation brings about senescence; the inducible kind.

Cells that are culture face senescence in two major ways, replicative senescence (intrinsic aging in healthy state) and inducible senescence (pathological aging in unhealthy state).
Replicative senescence is limited by passaging/passage count/population doublings count (because telomeres are lost due to end-replication problem; telomerase is mostly absent from somatic cells and only gonad stem cells use it, that means telomere loss is a DDR (dna damage response) signal that triggers 'passaging limit' senescence).
Inducible senescence is different, it is an extreme oxidative challenge (by inflammation) that triggers cell arrest (in the cell cycle) and entry into senescence. The major different between the two is that replicative senescence is dependent on cell cycle inhibitors (CDK)/oncongene inhibitors (tumor supressors) death protein p53 signal that activates p21 protein and retinoblastoma protein, pRb. This is a sequential pathway. Cell cycle inhibition in senescence leads to growth arrest. This replicative senescence is triggered by DDR from telomere signal due to telomeric repeat loss. Maximum passages and population doublings of the cell makes the cell enter replicative senescence despite it having not gone through any inducible 'oxidative challenges' during its passages.

Inducible senescence/pathological senescence is different because it recruits a different pathway. It yield the same effect but the triggering mechanism is different. While replicative senescence is telomere-dependent;
inducible senescence is oncogene-dependent. During passages, Ras oncogene activates p53 pathway when there is extreme oxidative challenge due to overinflammation (pathology/disease), p53 then switches mechanism to p16 activation (rather than p21), p16 creates entry into pathological inducible senescence - despite no loss in telomeres and can happen in young/high telomeres cells.

This means it is a different mechanism from telomere loss-based replicative senescence from maximal cell culture passaging; and thus is in accord with pathological inflammation second aging/non-intrinsic. Senescence is still Senescence; it can happen during cell passage (inducible/pathological inflammation) or at the end of cell culturing when cell DNA is lost from telomere chromosome activating telomere-replicative senescence. Strategies currently are aimed at reducing (auto) immune diseases. The immune system is two-faced, it helps to ward off cancers and tumors but by recruiting tumor inhibition proteins (p53 and TNF) and activating Ras/Arf oncogenes; it is also part of the equation in aging when these proteins accelerate replicative or inducible senescence; and reinforces the notion that the body fights tumors, and while damaging them/killing them, also damages telomeres from excessive ROS production to kill tumors (tumors strive with enough ROS but at extreme amounts of ROS, die too) but highly damaging to the rest of cells; which contributes to intrinsic aging. But what is clear is that senescence is purely gene controlled and ROS or not, damages or not, gene signals are the cause of entry into senescence and cell cycle arrest. ROS, inflammation and damages are 'signals' too, if these signals are blocked or emulated, such as cell DDR checkpoint (when they are in fact absent); then senescence is completely turned on or off depending; meaning genetic signals trigger/orchestrate this whole state. This gives credence to the fact that if we can't stop all endless types of damages with biorejuvenation limitation, manipulating these signals could twarth senescence; but even then, telomere DNA loss by end-replication problem is irreversible. Righ now it is unfeasible, as cells encounter two stages M1 and M2 crisis (M1 is replicative senescence from excessive telomere loss, overcoming M1 allows a little bit of passaging and M2 is second barrier, where it is impossible to be overcomed, otherwise rare forms escape this limitation by immortalization/cancerous transformation using hTERT or ALT chromosome-recombination (M2 is at about 2Kb in shortest telomere size, M1 is at 3-6Kb, average 5Kb (5000 bp base pairs)). At that M2 point only tumors form and somatic cells with no telomerase cannot escape because the DDR signal from low telomere is so strong; the fac that the entire telomere is nearly gone means replicative senescence is the last final thing. Removing damages help to maitain telomeres high and postposne replicative senescence so long as it is above M1.
Continuous stem cell renewal and culturing and injection could in theory circumvent this problem, which is what SENS proproses as a solution. But, stem cell injection in mice showed that replicative senescence cannot be overcomed by stem cell injection, it is like a very very slow moving train, nothing can stop it but it still 'marches' on to it final destination, we only slow it down a bit further during its very slow course.

For now it is about curing inducble pathological 'inflammaging' kind of rapid 'in passage' senescence, using senolytics that will improve health and give average life boost (but will not do anything on replicative finality, because lifetime-telomere damage attrition DDR signal-replicative senescence continues its merry course over the decades).

It seems increasingly evident that there can be no rejuvenation without first handling immune senescence.

There is no such thing as intrinsic aging or pathological aging.

@Antonio: I think he means primary versus secondary aging. The boundaries are blurry, especially for the immune system. Do we count immune exhaustion due to chronic pathogen exposure as primary or secondary aging if it differs because of your lifestyle and availability of medical technology?

@Antonio

Hi Antonio ! Thanks for that, can you explain more what there is then ?

If you are saying there is only 'aging', it is an error and misunderstanding (I believe, just my 2 cents :).
What is aging really ? Damage accrual ? Senescence ?
You have to understand that cell culturing really shows what aging is because we are composed of cells and yes some die quicker than others, but some are long lived and we have good correlation - and causation - means ofshowing that aging is really a process inside of us and that there is more than one form of it, it is still 'aging' in the large sense - but not happening the same way, Antonio. Thus, something else is going on and as such, we can infer a ''sort of'' different form of aging - even if the bases are the same; the result and triggereing mechanisms are - not the same.

The fact we can show that ''Sudden Inducible Senescence'' (pathological) is different that replicative senescence (intrinsic) shows that aging can have variations and that the pathways can be altered in different ways to yield a 'different' kind/form of aging. Like for example, the fact we see that p53 activates - only - p21 during replicative senescence - and not p16; means it is a Specific type of aging (intrinsic one). While in pathological state (due to oxidative inflammatory/overload burst), Ras is only activated in that state, Ras commands p53, p53 is also activated but its downstream effector is not the same - it recruits p16 - no p21. p16 commands the cell to enter senescence - despite there being no DDR signal from telomeres (meaning the telomeres are High, and Senescence Happens Anyway (this was proven in young donor cells with high telomeres who after extreme oxidative challenge entered a premature senescence despite having tall telomeres). Thanks to Ras oncogene, we can understand this is a mechanistic/evolutionnary inducible 'premature' senescence 'in the immediate' (during the cells passaging (it may not even be that old and has a lot more cell cycles left) to prevent from tumor formation). So really, this shows, the cell can die during its lifetime, from excess oxidative stress/inflammation (inducible/pathological senescence), or it can stay very 'low in inflammation', but it dies one day too (replicative senescence from telomeric attrition from telomere DNA damage DDR signal). Cells that evade these two types of aging are immortal and always transformed into cancers by using strategies to overcome end-of-life barriers (telomerase hTERT mutation highjack and Alternate recombination telomere lenghtening without telomerase). Somatic cells can't do that, they are programmed by telomere signals to die after replicative senescence.

What do you mean by "sudden inducible senescence" and "replicative senescence"?

@Reason

Hi Reason !
'' Do we count immune exhaustion due to chronic pathogen exposure as primary or secondary aging if it differs because of your lifestyle and availability of medical technology? ''

Good question, I believe this falls definitely More into secondary aging (it's not so much 'secondary' but rather 'in-life' aging or 'mid-passage crisis' 'premature' aging by oxidative challenge; so when we say secondary form of aging, we really mean something that happens 'in between' the regular lifespan of the cell; like some 'tacked-on' challenge that kills the cell mid-life point. 'Intrinsic aging (Replicative)' would be analogic to going to point A to Z, while Sudden Premature/INducible secondaryy aging (Inflammation/Oncogene) would be like stopping at the letter D, for 'dead'...meaning you don't reach letter Z because oxidative challenge at D killed it; if there was no oxidative challenge; cell goes all the way to Z - and at letter Z, die; also. Not from the same thing that happened at letter D (induscible senescence) but from replicative senescence end-of-life finality at letter Z.).

Immune exhustion due to chronic pathogenload exposure is more inducible secondary aging because it is an oxidative inflammatory challenge (immune system activation of cytokine TNF, INF-gamma, p53); rather than telomere-dependent problem. As such, it is of 'viral pathological nature', and as such pathological aging or inducible premature senescence - not having to do do with telomere-replicative senescence.

For in imune challenges leukocytes telomeres drop a bit because they are affected, but it is not 'main' reason, but rather oncogenic reason of Ras/Arf pathway sensing inflammation and activaing 'premature senescence' though the precise p53 -> p16 activation (while replicative senescence requires p21 (it just happens in that sequence order, p21 is an effector of telomere signal, p16 is not, it is an effector of p53 by oncogene Ras), p21 Ko abrogates senescence and creates immortalization once p16 and p53 are Ko too).

Like you say, it is very blurred fine line, but it is still a line we can detect that creates a different outcome by different means. (Inducible

@Antonio

Sudden Inducible Senescence : Sudden because it happens 'mid-life' like a mid-life crisis happens. It is a 'sudden' oxidative burst that creates this entry into premature senescence. Inducible because it can be 'made' to happen, it can be 'induced' by inflammation oxative challenge, again - during - the lifespan (mid-point of life).

Replicative Senescence : Cells are in constant 'Cell Cycle' growth, during this cell cycle, DNA replication is happening but it faces a problem of not being able to keep their telomeric DNA repeats because of imperfect replication during DNA strands creation (end-replication problem); as such, the cell lose a bit of 'telomeres' on the chromosomes each times it does a cell cycle (or a population doubling). It is also called Leonard ''Hayflick limit''. Replicative Senescence happens only at the end of the cell culture (after it has been serially passaged for many passages; for example, human skin fibroblasts have a a population doublings capacity of about 60 PDs (60 population doublings, or 60 cell ''cycles''), it ties in a to about 1.5 PD per year of life. Which means each year, the cell made a little more than 1 cycle. When the fibroblast cell reaches about 60 PDs, it slows down and enters a phase of ''growth arrest''; it does not continue proliferating because during all those 60 PDs telomeres were lost each round of cell cycle (each year), and as such the DDR signal (DNA Damage Response Checkpoint) became strong as the telomeres shortened. DDR by short telomeres makes the cell become ''growth arrested'' and as such change morphology in senescent state (large, flat, with high S-Beta-Galactosidase staining). p53 tumor inhibitor responds to DDR and activates p21, which makes cell senescent. This final 'end-of-life' state is called Replicative Senescence. Cells that overcome this state transform into immortal cancerous cells.

@CANanonymity:

"Sudden Inducible Senescence : Sudden because it happens 'mid-life' like a mid-life crisis happens. It is a 'sudden' oxidative burst that creates this entry into premature senescence."

Do you have any proof that happens suddenly? AFAIK, oxidative stress in mitochondria is allways present, a consequence of the normal operation of metabolism.

And, anyway, aging is much more than oxidative stress.

"Cells are in constant 'Cell Cycle' growth, during this cell cycle, DNA replication is happening but it faces a problem of not being able to keep their telomeric DNA repeats because of imperfect replication during DNA strands creation (end-replication problem)"

Two things:

- Cell senescence is not same as aging. Senescence is a state of cells in which the cell reproductive cycle is arrested. Aging is a state/process of whole organisms (humans, for example). The simplest definition of aging is the increase in mortality rates with time.

- In the body (instead of the lab), senescence mostly happens because there is some damage to the cell (DNA damage, abnormal epigenetic changes, ...), or as a response to a wound in their tissue or other processes in fat tissue, NOT BECAUSE they reach the Hayflick limit. In the body, most cells become senescent before reaching the Hayflick limit.

@Antonio

''Aging is a state/process of whole organisms (humans, for example). The simplest definition of aging is the increase in mortality rates with time.''

Aging must be 'something' : D...it can't be thin air, what creates this mortality rate increase then ?
Frailty ? Tissue damages ? What is the cause(s) ?
Please understand that studies studying Hutchison-Gilford Progeria (people with accelerated aging who die as teenagers (around 13 years old lifespan) with the biological body of a 90 year old) show exactly what I'm telling you; they show that senescence is greatly accelerated in these people. This is the exact same thing happening in diabetes (accelerated aging) or midler progeric syndromes such as Werner progeria or more severe progeria that resemble Hutchison-Gilford; is Atypic Werner syndrome (who can die as teenagers). All these accelerated aging forms show 'accelerated' replicative senescence and even inducible senescence when they have complication collateral diseases - on top of their major disease aging syndrome. Meaning a Werner syndrome fibroblast is defective in important antoxidant enzymes such as SOD and can't go to the same doubling levels as a normal person's fibroblast (who has functioning SOD. For example, skin fibroblasts are weaker and have more rapide replicative senescence than Oral mucosa fibroblast in the gums (these fibroblasts keep a 'juvenile' profile (that is why there is never fibrosis/macrogranular scarring in your gums, it heals itself extremely rapidly upon wounding; unlike skin fibroblasts which make for adult skin scarring) and remain young; when replicative senescence hits the skin fibroblast; at that late point the oral fibroblast elevate SOD-3 (Extra-cellular Super Oxide Dismustase which scavenges superoxides (the major ROS that is transformed, by SOD, into H2O2 (hydrogen peroxide, which is quenched by Catalase) and -OH (hydroxyl radical, quenched by Alpha-tocopherol and Ascorbate; GSH scavenges them all too)) which protects them from further telomere loss and allows much more population doublings/post-poning their replicative senescence).

''
"Sudden Inducible Senescence : Sudden because it happens 'mid-life' like a mid-life crisis happens. It is a 'sudden' oxidative burst that creates this entry into premature senescence."
Do you have any proof that happens suddenly? AFAIK, oxidative stress in mitochondria is allways present, a consequence of the normal operation of metabolism. ''

Any state of advanced disease is marked by an increase in inflammation and oxidative burst - that is different than ongoing oxidative stress in mitochondria. It's something added On Top of the regular aging. You are right to say oxidative stress happens in mitochondria; but this is just 'base stuff' it happens all the time, just like we breathe and contributes - also - to speed of onset of replicative senescence. How so ? Well, fibroblast that are cultured at 20% oxygen vs 5% oxygen never go as far as those culture in low O2; meaning there is less ROS production under low oxygen; as such mitochondrias produce less ROS under low O2; low O2 reduces the speed of telomeric loss and mitochondrial DNA deletions, allowing for replicative senescence to happen later in the cell passaging. Mitochondrial membranes peroxidation from superoxide anions ROS release at Complex I is transformed into H2O2, which after Fenton reaction (iron catalyzed) it creates Hydroxyl Radicals (the most reactive ROS) who themselves travel all the way to the membranes and steal a hydrogen atom from Polyunsaturates; beginning the 'initiation' phase of lipid peroxidation (which will lead to hydroperoxide LOOH formation (from DHA peroxidation) and then formation of 4-HNE and Acrolein, MDA, and other lipid eroxidation products which continue on to attack mitochondrial DNA in vincinity). This is why hydrophilic antioxidants such GSH are extremely important because they neutralize hydroxyl radicals, the main starters of this lipid peroxidation chain event. But the main starter still remain mitochondrial production of superoxide anion; which SOD is the first line of protection against (hence oral fibroblast use SOD-3 for they extended protection).

''In the body (instead of the lab), senescence mostly happens because there is some damage to the cell (DNA damage, abnormal epigenetic changes, ...), or as a response to a wound in their tissue or other processes in fat tissue, NOT BECAUSE they reach the Hayflick limit. In the body, most cells become senescent before reaching the Hayflick limit.''

Yes exactly. Senescence happens...as like in wound tissue repair...and it's true many cells do become senescent before that. Cell replacement by stem cell has its limit though.
I think I will have to 'agree to disagree' : ) on the causality of hayflick limit; when you say senescence does not happen because of the hayflick limit since cell become senescent before reaching it...you have to wonder then,,of what exactly do we age then ? If our cells - die - and are replaced ? What exactly keeps us alive other than continuous renewal - but especiall why is it that we age then ? If our cells continue to replace themselves...why do we age then ?....
and the answer to that is Replicative Senescence.

Why, ...When studies measured the leukocytes telomere length of a young child vs an old person...we see a big difference...the old person has short telomeres and this - triggers - in the whole genome - death - replicative senescence death. So yes, certain cells Reach The End sadly, the one that is Telomere-caused. Caused by activation of
p53 -> p21 -> irreversible arrest.
You are losing telomeres as a 'normal aging' mechanism in somatic cells as they continue to divide. Replacement of cells (by stem cells) hits a limit by this mechanism.

This happens Also in Stem cells (who are not immortal such as in gonads and can't use Telomerase to save themselves ,as such are Bound by Replicative Senescence - too) as such cannot Continuously Replace and Repair Tissues`; their Telomeres shorten - too and one day; telomeres are short Everywhere in nearly the entire body (the organ tissue replacement is not maintained anymore). That - is - the Replicative Senescence and causes death at the end of lifespan.

@CANanonymity:

"Aging must be 'something' : D...it can't be thin air, what creates this mortality rate increase then ? Frailty ? Tissue damages ? What is the cause(s) ?"

Huh? Where on earth do I said that aging is nothing or thin air? I clearly said what aging IS. Another thing is what aging is CAUSED by. What I said is the mainstream and more general definition of aging. See for example the first chapter of this book: http://www.longecity.org/forum/page/index2.html/_/feature/book

"Please understand that studies studying Hutchison-Gilford Progeria (people with accelerated aging who die as teenagers (around 13 years old lifespan) with the biological body of a 90 year old) show exactly what I'm telling you; they show that senescence is greatly accelerated in these people."

HGP is not accelerated aging. It has some features that superficially resemble aging, but many features of aging aren't present on HGP and their causes are totally different.

"This is the exact same thing happening in diabetes (accelerated aging)"

Nope, for the same reasons above.

"All these accelerated aging forms show 'accelerated' replicative senescence"

HGP causes a form of DNA damage. That damage causes cellular senescence. BUT it's not the same DNA damage than in real aging, and cellular senescence is not the only cause of aging. See for example: https://www.fightaging.org/archives/2015/01/comparing-senescent-cells-and-cells-from-progeria-patients.php

And a more comprehensive explanation by Michael Rae: http://sens.org/research/research-blog/accelerated-aging-inspiration-beyond-equivocation

"Any state of advanced disease is marked by an increase in inflammation and oxidative burst"

Nope. There are many disesases that don't involve an increase in inflammation or oxidative burst.

"You are right to say oxidative stress happens in mitochondria; but this is just 'base stuff' it happens all the time, just like we breathe and contributes - also - to speed of onset of replicative senescence. How so ? Well, fibroblast that are cultured at 20% oxygen vs 5% oxygen never go as far as those culture in low O2; meaning there is less ROS production under low oxygen; as such mitochondrias produce less ROS under low O2; low O2 reduces the speed of telomeric loss and mitochondrial DNA deletions, allowing for replicative senescence to happen later in the cell passaging. Mitochondrial membranes peroxidation from superoxide anions ROS release at Complex I is transformed into H2O2, which after Fenton reaction (iron catalyzed) it creates Hydroxyl Radicals (the most reactive ROS) who themselves travel all the way to the membranes and steal a hydrogen atom from Polyunsaturates; beginning the 'initiation' phase of lipid peroxidation (which will lead to hydroperoxide LOOH formation (from DHA peroxidation) and then formation of 4-HNE and Acrolein, MDA, and other lipid eroxidation products which continue on to attack mitochondrial DNA in vincinity). This is why hydrophilic antioxidants such GSH are extremely important because they neutralize hydroxyl radicals, the main starters of this lipid peroxidation chain event. But the main starter still remain mitochondrial production of superoxide anion; which SOD is the first line of protection against (hence oral fibroblast use SOD-3 for they extended protection)."

This wall of text doesn't provide what I asked for: a proof that there is a sudden increase in oxidative stress some time in middle-age.

''In the body (instead of the lab), senescence mostly happens because there is some damage to the cell (DNA damage, abnormal epigenetic changes, ...), or as a response to a wound in their tissue or other processes in fat tissue, NOT BECAUSE they reach the Hayflick limit. In the body, most cells become senescent before reaching the Hayflick limit.''

"Yes exactly. Senescence happens...as like in wound tissue repair...and it's true many cells do become senescent before that. Cell replacement by stem cell has its limit though. I think I will have to 'agree to disagree' : ) on the causality of hayflick limit; when you say senescence does not happen because of the hayflick limit since cell become senescent before reaching it...you have to wonder then,,of what exactly do we age then ? If our cells - die - and are replaced ? What exactly keeps us alive other than continuous renewal - but especiall why is it that we age then ? If our cells continue to replace themselves...why do we age then ?.... and the answer to that is Replicative Senescence."

Huh? What all of this paragraph has to do with the Hayflick limit? You clearly said in your previous comment that the Hayflick limit causes senescence in humans cells. I replied that it only does that in the lab, not in the human body. Researchers use the shortening of telomeres to artificially cause senescence in culture. Now you reply that, since something must cause senescence, it must be Hayflick limit. Again: huh? It's a clear non sequitur. And I already stated the causes of cellular senescence in my previous comment. And again you seem to mix cellular senescence and human aging, two very different things, for example in this part: "when you say senescence does not happen because of the hayflick limit since cell become senescent before reaching it...you have to wonder then,,of what exactly do we age then ?"

"Why, ...When studies measured the leukocytes telomere length of a young child vs an old person...we see a big difference...the old person has short telomeres and this - triggers - in the whole genome - death - replicative senescence death."

Cells from old people cultured in the lab and forced to replicate reach the Hayflick limit after more or less the same number of divisions than cells from young people. Also, mice have telomeres five times longer than human telomeres, but they live much much less than humans.

As for the causes of human aging, there are many theories. The mainstream opinion is that age is caused by cellular and molecular damage that is a byproduct of metabolism. What forms of damage are more important varies from researcher to researcher, but I'm not aware of none of them that thinks that aging is caused only by cellular senescence. I personally belong to the camp that thinks that the relevant damages are the seven categories of SENS.

HGP is not accelerated aging. It has some features that superficially resemble aging, but many features of aging aren't present on HGP and their causes are totally different.

Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome
1. http://www.nature.com/nature/journal/v472/n7342/abs/nature09879.html

Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes.
2.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1682068/

Whether Progeria, Down syndrome, Werner, Trisomy 21, is another special type of aging doesn't matter that much (they show they are different but) because it works
around the similar mechanism, replicative senescence and also inducible senescence from the diseases they may acquire along their hastened aging.
It is a mix-mach of both but an especially clear showing of replicative senescence.
For example, Werner syndrome progeria skin fibroblasts have a population doublings capacity
of about 30 or so PDs. Healthy people have a populationg doublings capacity of 60 PDs.
This means onset of replicative senescence is two-folds quicker in Werner syndrome. And of course,
these people die younger than healthy people. Even if Werner fibroblast had the same replicative capacity they - do not - have the same telomere rate loss per pd, explaining accelerated aging.
That - is - accelerated 'form' of aging/premature aging.
Wether it is that different from us doesn't matter all that much, ours is still based on
some of the same shared mechanism one as theirs. Replicative senescence happens in our cells and inducible senescence
happens too when we are tested by chronic inflammation in disease progression.

'' This wall of text doesn't provide what I asked for: a proof that there is a sudden increase in oxidative stress some time in middle-age. ''

My mistake, I did not mean to say that there is a 'sudden increase of oxidative stress' during mid-life rather that during inflammation there is sudden increase of oxidative stress (oftenly at least) such
as in certain disease states. These can happen early, mid or late in life. I used mid as 'average point', meaning it is generally around mid-life that diseases start to show up and that the impact of aging is becoming apparent;
as disease can show up rapidly around mid-point. They can show in early, mid or late as said; but they are more apparent in mid-life because by 40 years old, certain disease appear quicker (as you age) because your aging body can't ward them off anymore.

''Researchers use the shortening of telomeres to artificially cause senescence in culture.''

You're right, it happens quickly in lab, but in our body it's happening over the long term.
It does not really matter if it's artificial...the end result is the same, only slower in our bodies.

''Cells from old people cultured in the lab and forced to replicate reach the Hayflick limit after more or less the same number of divisions than cells from young people.
Also, mice have telomeres five times longer than human telomeres,
but they live much much less than humans.''

Mice are not the best model in translatability for results in human.
Telomere loss is not needed for senescence (as said earlier that Oncogene pathway can
create senescence with no telomere loss, short or long doesn't matter it happens anyways via Ras oncogene activation p53 and p16(INK4a) ,
but the one that terminates long-lived healthy humans is Replicative Senescence-based, and it activates another protein (p21).

''Our results also indicate that the p16(INK4a) signaling pathway may play a key role in the early stages of senescence in CECs while the p53/p21(WAF1/CIP1) signaling pathway may exert its principle effect in the late stages of senescence in CECs''

Inducible senescence (oxidative challenge with no immediate telomere loss) = p53 -> p16(INK4a)
Replicative senescence (late emptied telomere problem from 'long-term' telomere loss) = p53 -> p21

Molecular evidence of senescence in corneal endothelial cells of senescence-accelerated mice.
3. http://www.ncbi.nlm.nih.gov/pubmed/19381346

''Cells from old people cultured in the lab and forced to replicate reach the Hayflick limit after more or less the same number of divisions than cells from young people. ''

Yes true. But how can you explain telomere loss then (that is the end-replication problem), when leukocytes from Down Syndrome show a twice faster rate of telomere loss, this means
they may not reach replicative lifespan regular end point but they are aging twice faster too. Once their telomere reach twice-faster the telomere M1 low point, then Replicative Senescence is activated.

Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes.
4.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1682068/

Telomere length and replicative aging in human vascular tissues.
5.http://www.ncbi.nlm.nih.gov/pubmed/7479963

@Antonio

In regular healthy aging, in fibroblasts, from initial telomere length, we lose :
0.01 MPD (mean population doubling) per bp (base pair) or in other words
1 MPD per 100 bp (0.1 Kbp). That translates to roughly correlation of :
(m = -15 base pairs per yr; r = -0.43; P = 0.02). -15 bp per year, when you realize that telomeres are about
11,000 bp (11 Kbp), at adolescence they drop from 11,000 bp down to 9,000 bp, than in adulthood (around 20years old), some drop down to 6,000 bp, but some are still higher than others, it is an accumulation of shorter telomeres among taller ones. In centenarians, this can continue down to even 3,000-5,000 bp.
This very slow loss of bp shows that the body is at extreme apex of protection and even then, telomere-based growth arrest happens one day or another. Adults have about 3,000 bp slack before 'replicative-telomere-based' death. That death is Telomere M1 growth-arrest crisis point, and is around 6,000 bp and M2 second growth-arrest crisis point is at 2,000 bp; below 2,000 bp cells die, if 2,000 bp is maintained, cancer transformation and immortalization happens.

Other studies showed extreme telomere loss from 100-500 bp per cell cycle, but as the telomere loss is reduced by decreasing telomere loss rate; it becomes clear that DNA damage is being totally repaired and removed; as such, humans in general don't have much DNA damage (it's why we live long) and it also makes a case Against damage removal; meaning damage removeal strategy is good but clearly we have many damages but they do not have Such an impact on telomere loss as we believe...The Major contributor is the End-Replication problem - much more than 'random DNA damages' along the way. For this study shows we lose very little in our fibroblast, so we can realize that we keep our bodies quite healthy in reality (which allows us to live 100 years), and as such renders the whole 'lets stop damages' strategy more moot. I'm not saying we should not stop damages, it's just I have to question the extent they participate in aging (not as much, it seems. Perhaps, in inducible senescence they are important/disease state; but not as much in regular intrinsic aging. For regular intrinsic aging - it fully optimized to have as little damage as possible. Thus, how much more can we optimize it or how Relevant is it, if it won't do anything to solve a Riddle (end-replication problem/telomere loss)).

From the study, it clearly shows that donor age and initial telomere length as an effect on MPD (the mean population doublings left); and that donor age TRF length drops as time goes. Meaning older people have shorter telomeres and this means not so much 'replicative' life left ahead.

Telomere length predicts replicative capacity of human fibroblasts.
6. http://www.ncbi.nlm.nih.gov/pubmed/1438199