A Conservative Scientific View of Cellular Senescence and Aging

The evidence for cellular senescence to increase with age, and in doing so act as a root cause of aging, is extensive and compelling. It starts with decades of indirect evidence, increasing the research community understanding of how senescent cells behave and what the results of that behavior are at the small scale, and has led up to recent animal trials of senolytic treatments that selectively destroy senescent cells, demonstrated to produce extended life and reversal of specific, measurable aspects of aging. It is, however, still the case that from a very conservative scientific view, in which outright, direct proof of every aspect of a theory is desired, there are sizable gaps in the understanding of cellular senescence in aging. That will not stop the development of senolytic rejuvenation therapies, which can proceed on the practical basis of following the path that works, which is to say targeted removal of senescent cells, but it does make it possible to write papers on the sort noted here, in which those gaps are explored.

The present consensus view of senescence cells is that there are numerous distinct types of such cell, their senescent state caused either by stress, toxins, or reaching the Hayflick limit on cellular replication. All these classes of senescent cell behave in similar ways, and most destroy themselves quite quickly after becoming senescent, or are destroyed by the immune system. A few linger, however, and churn out a mix of signals that disrupt regenerative processes, spur inflammation, scramble important extracellular matrix structures, and alter the behavior of nearby cells for the worse. A small number of senescent cells, even just 1% by number in a tissue, can significantly damage organ function.

Nonetheless, a fair amount of this picture is not completely stitched together and beyond reasonable doubt, if the point of view is to be one of absolute proof, demanded end to end. There are self-contained studies showing benefits attained through clearing senescent cells, and of course the life span study from last year, but also question marks over how cellular senescence is assessed, what the common markers for senescence actually signify, and the degree to which senescence increases in various tissues over time. This is usual for any developing field of research. As a topic, like much of practical aging research, cellular senescence was poorly funded, near ignored for decades. Now that proofs have emerged of its importance, more researchers are interested and the funding is available to double back and fill in all the places that would benefit from more rigorous assessment. Again, that really doesn't make much difference to the development of the first generation of rejuvenation therapies based on destruction of senescent cells; that is forging ahead as an exercise in engineering rather than science. Filling in the gaps in understanding will probably help to improve the quality of the second generation of such therapies, however.

Stress, cell senescence and organismal ageing

Because cells are the fundamental building blocks of humans and animals, it is clear that cellular changes contribute to the ageing process. A major open question, however, is the nature of those changes and how exactly they contribute to degeneration and disease in old age. In 1961, it was discovered that human cells can only divide a finite number of times in culture. The limited proliferative ability of human cells in vitro, known as replicative senescence (RS), has since become a major focus of research in biogerontology. In addition to RS, a number of factors can accelerate and/or trigger cell senescence, including various forms of stress like oxidative stress.

For a long time it was debated whether the discovery of cellular senescence had any physiological relevance or was merely an artefact of cells grown in relatively artificial culture conditions. It was proposed that senescence may represent ageing, however, recent data has revealed that this view is too simplistic, since senescence has been shown to play multiple important physiological roles, such as: tumour suppression, tissue repair and wound healing, embryonic development, and age-related degeneration. In addition, senescent cells have been detected in the context of many different age-related diseases, including atherosclerosis, lung disease, diabetes, and many others.

Given the multitude of functions of senescent cells, which can be of a positive or negative nature depending on the context, it has been argued that there may be different types of senescence rather than a universal phenotype. For instance, senescence during embryonic development occurs transiently, since senescent cells are rapidly removed by the immune system after executing their role, and is not associated with the activation of a DNA damage response (DDR). In contrast, during ageing, senescent cells are thought to be persistent, induced by random molecular damage and associated with the activation of a DDR. Recent work has demonstrated that senescent cells are able to attract (potentially via the secretion of chemokines) different immune cells. It is possible that persistence of senescent cells in tissues during ageing and age-related diseases is a consequence of the inability of the immune system to clear senescent cells - in view of the well reported decline of the immune system with age - however this has not yet been experimentally tested.

Do senescent cells accumulate with age? One of the main challenges to the study of senescence in vivo has been the absence of a universal marker that can unequivocally identify senescent cells. The most widely-used marker is the presence of senescence-associated β-galactosidase (SA-β-gal) activity. Both in vitro and in vivo, the percentage of cells positive for SA β-gal increases with, respectively, population doublings and age. However, there are major limitations to the use of this marker, since SA-β-Gal staining can also be detected in immortalized cells and quiescent cells. Also, it has been suggested that a major limitation of using SA β-gal staining in vivo is a false-positive signal from macrophages and other pro-inflammatory cells. In addition, since it requires fresh tissues, its detection is not straightforward technically and has more than often generated conflicting results.

Given the challenge of identifying a specific marker able to identify senescent cells, most researchers currently rely on a multiple marker approach. Indeed, several markers have been identified which are closely associated with cellular senescence, including absence of proliferation markers, changes in heterochromatin, telomere-associated DNA damage, expression of cyclin-dependent kinase inhibitors p21, p16, and senescence-associated distension of satellites (SADS). In a variety of mouse tissues, it is clear that most of these markers increase with age; however, given the fact that most of these markers are not exclusive for senescent cells, the exact frequency of senescent cells in older tissues is still unknown. Furthermore, given the limited availability of tissues, little is known about the accumulation of senescent cells with age in healthy humans.

Interestingly, many senescence markers have also been found in post-mitotic tissues such as neurons, adipocytes, and osteocytes, which goes against the dogma that senescence is restricted to proliferating cells. It is possible that with ageing, senescence-inducing pathways (which play roles in tumour suppression and during development) can be inadvertently switched on during ageing of post-mitotic cells. However, given that the primary characteristic of senescence is a permanent cell-cycle arrest, the consequences of the activation of these pathways in post-mitotic cells are still not understood.

While there is little evidence to suggest that cells running out of divisions are a major factor in ageing, it is possible that stress and various insults are contributors to senescence in vivo. Even a small fraction of senescent cells in organs may impair tissue renewal and homeostasis, decrease organ function, and contribute to the ageing phenotype, as shown by the studies genetically ablating senescent cells. While our knowledge about senescence in vivo has increased exponentially in the last decade, this is mostly through work using laboratory mice, which have known limitations. As such, one major challenge in the field is to determine levels of senescent cells in human tissues and whether they contribute to ageing and/or pathologies in humans. Furthermore, given the diverse functions of senescent cells in processes such as repair, wound healing, cancer, development and ageing, we still need to better characterize senescence in vivo in these different contexts. Finally, we still know very little about in vivo rates of occurrence and turnover of senescent cells. Therefore, in spite of recent advances in our understanding of senescence, many questions remain and these will be timely and important areas of research for years to come.

Comments

Hi ! Interesting study, Just my 2 cents,

''...While there is little evidence to suggest that cells running out of divisions are a major factor in ageing...''

I would disagree to that. Cells running out of division Are a contributor to Late Ageing, the fact that fibroblast cells accumulate Lipofuscin over the divisions and telomere shorteninng means that intrinsic aging is continuing its course, this applies in longlived post mitotic cells like neurons (whom you are born with and still have some ofthem from that time). Telomere are the counters of these divisions, they shrink as a 'mechanism' (evolved) to counter cancer formation (when life extends and cancer possibility increases), and put a clock 'end' to the organism when the telomeres activate inflammatory genes and get the DDR/telomeric signals at low kb (hypermethylation of p53 and others), p53 is increased because cancer formation can increase (to counter it) when the telomere become unstable and mutations form (genome dysfunction), this is signal to enter senescence (oncolytic senescence). So when we think of rapidly dividing cell tissues, these can be replaced and senescence has more or less impact - because of turnover - but in slow dividing non-dividing cell tissues that's different.

Cells that age are a very bad sign for us, especially the undividing ones. If there is little replacement of these cells (by stem cells) it means slow attrition of the organ over time. It could even be possible they are just not replaced altogether and we have to make do with some of the cells we had at birth. That is the part of 'intrinsic aging', one where we rely on these long-lived cells (like neurons) and when they die, we slowly are aging - and all these cells show telomere shrinking - one day senescence onset would happen. They forget the problem of telomere shrinking and how it is tied to cell division/replication/end problem.

''While there is little evidence to suggest that cells running out of divisions are a major factor in ageing, it is possible that stress and various insults are contributors to senescence in vivo''

Of course they are, oxidative stress causing DNA damage/an insult, this in turn accelerates telomere shortening in vivo. Just check in vivo fibroblast of progeria patients,

Progeria is accelerated form of aging caused by impossibility to form correct chromosome configuration by Lamin/A/Histone loss problem. Yet, other study showed that humans who do not have Progeria - Experience progeria daily (without knowing it) Just Slower : in healthy humans, Lamin/Histones go through the same process as progeria (chromosome become dysfunction, so does Lamin and so does we see Histone loss/decompaction) but over a much longer period of time (full life), while a progeria person, it happens in 15 years from birth).

So no there is Evidence that cells running out of divisions are bad luck and soon, death for the entire animal if this becomes a massive senescence - just like progeria.
Progeric Werner Syndrome fibroblast make only 20 PDs yet when near-immortal they make 275 PDs,
people with Werner Syndrome never reach a 100 years old : they have progeria just like HGPS.
Only a less form of it and have less damage accumulation, but still faster than healthy people.
HGPS: 500 bp/y loss in telomeres
Werner : 150 bp/y or so
Healthy : 50bp/y loss

So don't ask yourself why people with HGPS progeria live 15 years, Werner ones live 30-60 and healthy ones reach 90-122. Cell replication end problem/Telomere tandem is an Strong contributor to Intrinsic aging - because Both of them regulate the 'Genetic/Signal' component of aging (gene activation/silencing/telomere feedbacksignal, depending on telomere size, activating genes in subtelomere regions/DNA methylation working with that (methyl count in DNA methylome and Telomere/Subtelomere/Centromere methyl count (hypermethylated telomeres are long, demethylated ones are short/uncapped/unstable).
A woman whom was 115 years old had telomeres down to 2 to 3 kb in her immune cells .... ask yourself how long can it go if the telomeres keep on shrinking - cell cycle arrest and geroconversion to Senescence will happen when that telomere is just rock bottom (remember the telomere is 'counting' mechanism made to put a 'limit' on human lifespan - to 'limit' cancer formation spread/bad gene transfer in the species/compromise the specie survival by these deleterious mutation transfer to offspring that cause cancer from genomic dysfunction later on in life :
Replicative Senescence, the last barrier that we have know answer for (except slowing the metabolism down (increasing the time to completeing one division to slow metabolism, and/or increasing telomerase which has been sadly unable to make mice live all that much longer because telomerase cannot stop (enough) the 'end replication problem'). Just my 2 cent.

Posted by: CANanonymity at July 13th, 2017 3:40 AM

We do have an answer for it.
Replacing the stem cell pools - strenuous procedure if it has to be whole body but it might be made easy with the right kind of automation.
Of course the outcome depends on the quality of the procedure.
Using current stem cell therapies - it won't be extremely efficient.
When you culture cells now from an adult - you get cells which are already damaged and in the middle of their replicative lifespan, the procedure of extraction puts stress on the cells, the culture puts more stress on the cells, putting them back in the body is even more stress, they lack the right signals, the right environment to proliferate and so on.

Using future synthetic biological means and therapeutic cloning techniques and the right ways of transplanting the cells - the outcome should be much better.

The devil is in the details.
The problem as I see it is purely a technological one, rather than a theoretical one.

Posted by: Anonymoose at July 13th, 2017 4:06 AM

I'm not sure what to think of the ever recurring them of telomere shortening. As I understand it, stem cells replace dividng cells continuosly with new cells that have long telomeres. So the shortening of telomeres is due to the stem cells decreasing ability to replace those cells - but that is a problem that theoretically can be coped with independent of telomeres. The stem cells ability to replace new cells with long telomeres must be maintained by understanding the exact mechansims of the stem cell cycle. The ultimate goal must be to renew the stem cell cycle in vivo - not by transplantation. This cannot be impossible, but the damage of the stem cells and the micorenvironment of those cells must be repaired and restored.

Posted by: K. at July 13th, 2017 4:40 AM

Agree CANanonymity, replicative senescence is a hurdle we have to jump if we are to reach LEV. I also think it does affect humans in normal aging, you don't need to shorten telomeres all the way to start getting deleterious effects on tissues.

Short term solution is to slow down replication without compromising tissues that need to proliferate quickly (intermittent rapamycin treatment).

Middle term treatment is to deliver telomerase to as many cells as possible (probably with AAV treatment) - I think the mouse data from Blasco is very promising using this method (remember she only did it once, it would be a regular, say once per 10 years treatment in humans).

Long term treatment - as Anonymouse says, completely refresh and renew all stem cell crypts with stem cells with long telomeres.

Posted by: Mark at July 13th, 2017 5:09 AM

This is a very good paper.

The reconstitution of those cellular "gaps", resulting from the popular cellular removal approach, is going to be a critical part of the equation, and an underappreciated hurdle

As negative as the local SASP cellular niche may be, it is not operating in a vacuum, but is simultaneously performing other tissue level functions, providing potential protection against negative / disease tissue level patterning dynamics.

Recent findings such as the "senescence-stem lock model" highlight that you cannot just expect everything to revert and stay normal.

Much more work is required.

Posted by: Peotr Kazen at July 13th, 2017 6:35 AM

@K
"The ultimate goal must be to renew the stem cell cycle in vivo - not by transplantation. This cannot be impossible"

You can renew the cycle by activating Yamanaka factors intermittently like Belmonte did in his study. But those are still your lipofuscin loaded, DNA damaged and who knows what else broken down stem cells.

The ultimate goal is to get pristine stem cells back in the system and have them replace your old stem cell populations completely and currently the only viable method we can imagine for achieving that is synthetic biology - we're far away from synthesizing a full human genome and the protein structure of a cell, but at least we're on the path towards it - it's not inconceivable that it could be done in our lifetimes.

Posted by: Anonymoose at July 13th, 2017 7:40 AM

Whole human genome synthesising is in it's starting R&D area. See this initiative:

http://engineeringbiologycenter.org

If it becomes possible to donate, I will donate to this project.

Posted by: Norse at July 13th, 2017 8:26 AM

@Anonymoose

Hi Anonymoose ! It's true that replacing stem cells could be a way to circumvent the problem.
In rats, there was a study that extended their lifespan by AMMSCs implant from mid age (both their healthspan and their lifespan, although It doesn't say if they went over MLSP (maximum lifespan potential) of rat specie, I doubt that though or if yes (they might have specified it), most likely not all that much)).

1. https://www.fightaging.org/archives/2015/08/regular-stem-cell-transplants-extend-life-in-normal-rats/#comments

The study,
2. http://onlinelibrary.wiley.com/doi/10.5966/sctm.2015-0011/abstract;jsessionid=DA0DD23E331ED2B88775916885C06E61.f03t01

''Human amniotic membrane-derived mesenchymal stem cells (AMMSCs) or adipose tissue-derived mesenchymal stem cells (ADMSCs) (1 × 106 cells per rat) were intravenously transplanted to 10-month-old male F344 rats once a month throughout their lives''

''With this in mind, we recently retrieved MSCs from extra-fetal tissues in the equine species [4]. For the first time, we compared the proliferative and differentiative potential of amniotic membrane-derived MSCs (AMCs) with bone marrow derived MSCs (BM-MSCs). together with their possible application in the treatment of horse tendon injuries [5], [6]. We next demonstrated the potential immunomodulatory properties of AMCs and their conditioned medium (AMC-CM) in vitro, and proved the efficacy of AMC-CM in the treatment of spontaneous horse tendon and ligament injuries in vivo [7]. Data obtained in this study demonstrated the crucial role of soluble factors in inhibiting peripheral blood mononucleated cell proliferation in vitro and in improving healing in vivo. Taken together, the AMCs features described so far by our group suggest this cell type as the most suitable for regenerative medicine approaches [5] and its derived conditioned media (CM) as a novel, cell-free therapeutic product in regenerative medicine.''

This means that the most 'pristine' 'young' 'featal' Stem cells are Already being used (AMMSCs) - if they can'T even make a mice/rat live all that much longer (ok, albeit this stydy started at 10 months old so that would be a middle age human), and were continuously transplanted; I fear that stem cell replcatement/renewal is alomst like a 'mop/catch up' game that we (seem) to lose at. Perhaps, More Types (?) of Stem Cells would improve this, but I have doubts for this is the Best of The Best type (?) stem cell (supposedly, with no damage 'young/embryonic like' in amniotic fluid, and with tall telomeres (of course)) - why then is it not enough to make mice become immortal or something...it seems that's not enough, Pristine 'youth/ebryonic' stem cell replacement seems like a part'-solution but not enough for LEV.

I had difficulty finding a study that did stem cell injection for the Entire Lifespan of the healthy wild-type mice from birth to death (there are basically none), to see how much of an impact it has when started at birth instead of doing this in 'aged old mice'. It's obvious the effect would be stronger if started much younger - but how much; I doubt it would go over 50% lifespan extesion because other types of cell reprogramming and lifespan extesion started from the 'young' age mice made not that much difference : always 20-40% ballpark wethere started young or old age.

Here is another study in mice, but there these were bone mesenchymal Stem Cells (Bone marrow rich source) and they also started the injecting 'late' at 18-24 months in 'old mice' rather than young ones :

Transplantation of mesenchymal stem cells from young donors delays aging in mice
3. https://www.nature.com/articles/srep00067

''BMSCs transplantation affects the longevity of recipient mice

Without further treatment, we noticed that most of the mice transplanted with young BMSCs had a significantly longer life span than other groups of mice (Figure 4A). The mean life span of control mice was 765 days (Figure 4B). However, the mean life span for mice that received young BMSCs transplants was 890 days (vs. control group, p = 0.009). The increase of life span is probably unrelated to radiation, since the mean life span of mice transplanted with old BMSCs was 789 days (vs. young BMSCs transplants, p = 0.002) (Figure 4B). In addition, there was no significant difference between control animals and mice transplanted with old BMSCs (p = 0.846). ''

''These observations suggest that transplanted old BMSCs are relatively unable to populate, replicate or differentiate into osteoblasts within bones of aged recipients.''

''For BMSCs transplantation study, we used female Balb/C mice (female, 18-24 month old)''

And another one, but this is in a progeric mouse model thus is mostly pointless for it just slows down the aging to healthy 'normal aging' speed rathern than accelerated 'progeric aging' speed.

3. http://www.collective-evolution.com/2014/03/03/stem-cells-could-extend-human-life-by-over-200-years/

4. dujs.dartmouth.edu/2013/01/stem-cells-the-solution-to-live-more-than-100-years/#.WWeGK-n_pph

The study (pertaining to 3. and 4.):

Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272577/

All of these data lead to be believe that it seems stem cell therapy cannot overcome the replicative problem but definately improve health and 'age 'healthily/well'; and as a bonus get a lifespan extension (in mice/rats, in humans that would be less, for mice and humans are not the same, and result translation is always weaker in humans beacuse they are already optimized for extreme lifespan, thus the longevity effects are weaker/or nill. This leaves only 'health' effect improvement - but the MLSP still would stand (122 years Maximum)) and thus LEV would be difficult (if not impossible?) to reach.

Posted by: CANanonymity at July 13th, 2017 10:41 AM

@K.

Hi K. !

''The stem cells ability to replace new cells with long telomeres must be maintained by understanding the exact mechansims of the stem cell cycle. The ultimate goal must be to renew the stem cell cycle in vivo - not by transplantation. This cannot be impossible, but the damage of the stem cells and the micorenvironment of those cells must be repaired and restored.''

Exactly, from the studies so far, transplantation seems not enough to twarth replicative problem of (late) aging. And that'also because stem cells Themselves age by replicative senescence too (for they are devoid of Sufficient telomerase, except gonadal stem cells and immune stem cells where the telomerase levels are high enough to stop telomere loss completely - not in other stem cells whom have less telomerase for themselves or not as efficient, and Do lose telomeres despite having some telomerase).

Stem cell cycle - depending on stem cell telomere, thus again once more, telomerase. Wethere stem cell or regular cell, they are bound by senescence (both, the only ones whom evade that are the gonadal/primordial germ cell and certain immune ones - because they have sufficient telomerase to counter the telomere loss and are, thus, technically immortal (they can have as many replication rounds they want the telomere genetic 'counting' mechanism never goes down (for cell cycle arrest to happen)).

Stem cells 'age' too, so it'S a problem, and using pristine embryonic/fetal/young ones (with no lipofusicn or nearly none, no damage and tall telomeres) it makes no difference (from the studies so far).

In essence that's the 'essence' of it, it's as if evolution made sure we can't outwit that one.
It also made sure our stem cells were dying too (except specific ones). Just a 2 cent.

Posted by: CANanonymity at July 13th, 2017 11:33 AM

Hi Mark ! Great response,

''Short term solution is to slow down replication without compromising tissues that need to proliferate quickly (intermittent rapamycin treatment).

Middle term treatment is to deliver telomerase to as many cells as possible (probably with AAV treatment) - I think the mouse data from Blasco is very promising using this method (remember she only did it once, it would be a regular, say once per 10 years treatment in humans).

Long term treatment - as Anonymouse says, completely refresh and renew all stem cell crypts with stem cells with long telomeres.''

I think it has potential but truthfully all of these hit the same stumbling block wall we talk about, replication problem.

The short term solution of rapamycin is akin to CR (for rapamycin works the same pathway as CR, for they both affect mTOR (mechanistic target of Rapamycin), obviously rapamycin-targeted mTOR being the element here responsable for this CR effect since it alters senescence (mTOR is needed for geroconversion to senescence after cell cycle arrest)). Rapamycin studies have been mixed bag and extend lifespan lkie CR, which is rough 20-50% lifespan extension but MLSP is barely increased (maximum lifespan). Rapamycin truly acts on 'replicative senescence' for alters the component that alters senescence entry : mTOR and thus, telomere rate of shortening and increases the replicative lifespan potential of cells. For as we talked before, we are just slowing the '1-round to completion' time of cell replication (which manifests as slowed metabolism).

Middle treatment has potential for sure, telomerase could boost lifespan (it does so in mice), I still wonder how much of an effect in humans; BioViva self-telomerased Mrs.Parrish did it but no follow-up yet besides a study saying her telomeres are longer. But then you can compare other studies like astragalus/TA-65/cycloastregenol that activates telomerase - same for certain herbs that telomerase activating capacity (Ginkgo biloba/Ginseng/and so forth); do you see any study of a mice on these living extremely long ?...clearly, telomerase is not enough to twarth replicative senescence. It counters it but it's not sufficient enough to maintain telomere in a Positive No-loss Size, not a Negative loss each cycle round. I fear that telomerase (like BioViva did) will improve lifespan strongly but still enough for LEV either.
As some have said, telomeres might be increased, but some damage might still be lingering too and the epigenetic signature might still be different (because of previous permanent irreversible damage that had accumulated and is still there after telomere elongation).

As for long term treatment, it seem stem cell therapy - too- is not enough for telomere maintenance and end replication problem solution.

I knew that we would have more 'fun' problems down the road....sigh.. but if SENS can make us reach 122 and that's it that's all, then it will be still worth it for I rather live to 122 than die at 92 or 62...

Posted by: CANanonymity at July 13th, 2017 11:48 AM

@CANanonymity
Again - this is a technological problem.
They weren't replacing the stem cell pool - they were adding to it.
Stem cell replacement won't work unless the original stem cell pool is systemically eliminated and replaced. That's why it's called replacement.

The way I see things, it isn't a lack of stem cells that leads to decline, although that might play a SMALL (yes small, otherwise senescence would've been much more of a problem and easily detectable in old age in humans) part of the problem - the real problem is the ones you have are producing damaged cells. As long as they are a part of your system you will not escape disease and death.

The quality of cells isolated or the result of expansion of the cell cultures used and so on in all of the experiments done so far, believe me, that is quite an issue in itself.

Even if they get embryonic stem cells with the technology we have currently they get a small amount - then they go through many more divisions than the cells do in the same span of time in a live organism to get enough cells for transplantation - who knows what the real biological age of the cells they transplant ends up as being. It's not embryonic age - that's for sure.

Then there's the problem of HOW the cells are transplanted. To be honest most stem cell procedures we do nowadays even the approved ones are not much better than surgery in the 17th century - imagine if we stopped developing that part of medical science 400 years ago.

The only thing we know so far is this - putting cells you've stressed beyond reason in a syringe and spraying them inside a mouse doesn't make the mouse immortal - WELL COLOR ME SURPRISED! I would've never thought it would go that way! /sarcasm

We're just starting on our long journey of developing stem cell therapies. This is the reality removed from hype - significant longer lifespans awaits us at the end, whenever we reach it. I'm not going to guess when that is.

Posted by: Anonymoose at July 13th, 2017 1:06 PM

@Anonymosse and CANanonymity

The important questions for me are:

What (kind of damage) is it exactly that makes stem cell function decline with age? I suspect it is a combination of first damage in the stem cells as such, including lipofuscion load, telomere erosion and (possibly, but not with certainty) mutations in the DNA and second damage in the stem cell niche, including altered niche metabolism. All of that must be reversed at the same time in order to restore stem cell functioning in vivo - something that cannot be done today. The epigenetic remodeling by Yamanaka factors is surely not enough alone, but it can help when combined with true damage reversal. I reject the notion that transplantation in any case should be our ultimate goal. If stem cells need prevention of telomere shortening, then the amount necessary must be exactly established and then targeted to those cells. If gonadal stem cells can keep their telomeres constant, it should be doable for every other stem cell as well. I know cancer is a problem, but (I personally) would try to get rid of cancer indepedently of stalling telomere lenthening.

Posted by: K. at July 13th, 2017 1:13 PM

I don't think we can write off stem cell transplants as a bust based in the work done so far. As Anonymoose says, it has all been too crude.

I also think telomeres can be extended very effectively to keep things going for quite some time. Yes Bioviva have hardly done a great service to this treamtment with their half arsed approach, but i think we will see better (AAV genetic delivery) efforts in the coming few years (small molecule activators are far too weak telomerase activators IMO) .

We don't know how much junk in cells is impermeable- I.e. can't be cleaned up by a cell restored to youthful health by long telomeres. It may well be that we can comfortably beat the 122 years old limit before lipofuscin etc, does us in. More than enough time for SENS to come to the rescue.

Posted by: Mark at July 13th, 2017 3:12 PM

Since the immune system is so easily compromised in the elderly and those who have had frequent bouts of infection, disease, etc., I think it is an early area for research and development of rejuvenation therapies. We know the telomeres of leucocytes often become shortened faster than normal with infections, and are in need of telomerase activation to lengthen them. The gene ADA allele G does this normally to those lucky enough to have it in their genome, and in the future, perhaps it could be implanted by CRISPR technology to improve the length and function of leucocytes. This is just one way geneticists might begin to solve the problem of a compromised immune system.

Posted by: Biotechy at July 16th, 2017 12:42 PM

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