News of Another Potential Family of Senolytic Drugs for Clearance of Senescent Cells in Aging
Effective clearance of senescent cells in humans is arguably the form of SENS-style rejuvenation treatment based on repair of cell and tissue damage that is closest to practical implementation. A therapy capable of safely clearing even half of the senescent cells present in all tissues should prove very beneficial - and it is something that can be applied multiple times, as needed, repeatedly turning back this contribution to degenerative aging. As is always the case in these matters, however, only a few research groups are actively working on the problem, and funding is a desert in comparison to other areas of far less interesting research. This is why the research materials I'll point out here, news of a new potential class of senescent cell clearing drugs, still in the early stages of investigation, is worthy of attention rather than being buried by a score of similar announcements. In populous and comparatively well-funded fields such as the treatment of heart disease or arthritis there are far too many potential new drugs under study at an early stage in laboratories and noted in research papers to remark upon each of them. Few of these promising starts in cell cultures will ever get much further than that; there are many possible reasons why good results in cells don't translate to good results in animals. Similarly many of the promising results in animal studies fail on the next stage beyond that. So temper your enthusiasm.
Cells become senescent in response to damage, toxic environments, or as an alternative to self-destruction when they reach the end of their replicative life span. Some are destroyed by the immune system, but enough remain and linger that many tissues are made up of a sizable proportion of senescent cells by late life. These cells behave badly, secreting compounds that alter surrounding cellular activities, spur chronic inflammation, and degrade the extracellular matrix that is fundamental to tissue properties such as elasticity or load-bearing strength. Even partial and uneven clearance of senescent cells has been demonstrated in animal studies to provide lasting benefits to health following a single treatment. Better and more comprehensive clearance should produce greater benefits. That, of course, requires the development of improved methods of clearance.
The research materials quoted below can be taken as a representative sample of the sort of work that should be taking place in many more laboratories, an exploration in search of ever more effective ways to eliminate senescent cells from the body. Inevitably there will be dead ends, surprises, and much more failure than success. That is always the way in research. The way to make progress is to take many chances, invest in many diverse approaches to increase the overall odds of at least one useful result. Perhaps the most useful outcome here is that these results provide another solid demonstration that senescent cell clearance produces meaningful health benefits in aging mice. It is worth remembering that SENS rejuvenation research advocates have been calling for investment in this approach to the treatment of aging for more than a decade now, providing detailed research and development plans along with that advocacy, and were initially mocked for it in many quarters. Only in the last couple of years has the research community directed even a modicum of funding towards senescent cell clearance. There are lessons to be learned here, and one of them is that we could be closer to the defeat of aging than we are today had more people listened back then.
The first broad spectrum drug that can potently kill senescent cells in culture
Researchers are reporting the discovery of the first broad spectrum drug that can potently kill senescent (or aging) cells in culture and effectively clear the cells in animals by specifically targeting a pathway that is critical for the survival of senescent cells. Because senescent cells are believed to play a role in the late effects of radiation on normal tissues and certain age-related diseases, this study has broad implications for future therapies targeting the common biological mechanism that contributes to late tissue injury caused by radiation and aging. Cellular senescence, the loss of cells' ability to divide, normally functions as a tumor suppressive mechanism; however, senescent cells become "toxic" as they accumulate after exposure to radiation and with age. This is because they cause stem cell aging that reduces the ability of tissue regeneration and repair and drive chronic inflammation and oxidative stress. Since chronic inflammation and oxidative stress are thought to be the root cause of some late effects of radiation and many age-related diseases, including radiation-induced long-term bone marrow injury and age-related osteoarthritis and atherosclerosis, eliminating senescent cells has the potential to mitigate radiation-induced late tissue injury and treat many age-related diseases.In the current study, ABT-263, a molecule initially developed as an anti-cancer therapy, was given orally to either normally aged mice or irradiated mice to induce premature aging of the hematopoietic system, the organs and tissues involved in production of blood. ABT-263 effectively depleted senescent cells, including senescent "stem cells" of the bone marrow and muscle. Depletion of the senescent cells appeared to reduce premature aging of the bone marrow caused by irradiation, and even rejuvenated the function of stem cells in normally aged mice. "Our results demonstrate that clearance of senescent cells by a pharmacological agent is beneficial in part by rejuvenating aged tissue stem cells. Because a decline in tissue stem cell function is associated with exposure to radiation and aging, we believe clearing senescent cells and rejuvenation of tissue stem cells could have a major impact on mitigation of radiation injury and treatment of diseases of aging. ABT-263 was originally developed as an anti-cancer agent. It has toxic side effects that make it inappropriate for development as an agent for diseases of aging. We are investigating next-generation small-molecule drugs that are optimized to clear senescent cells without drug-induced toxicity."
Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice
Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a 'senolytic' pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug.We show that ABT263 selectively kills SCs in culture in a cell type- and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.
Hopefully we hear more about this after today. I'm happy about this news, but like you suggested, it's tempered. Also, has anyone heard anything about the senolytics found by Scripps earlier in the year? I haven't seen much since.
I wonder how long any of these senescent cell clearing methods are from an in human trial?
@Ham our Major Mouse Testing Program has Senolytics aka Dasatinib(Sprycel) & Quercetin as part of it's first phase candidates. We have also added ABT263 aka Navitoclax to our candidate list so we can test for lifespan on this too.
We will be launching the project site soon I will keep you posted and we are consulting SENS too.
Our immediate aim is to test Dasatinib(Sprycel) & Quercetin ala Scripps and Alk-5 inhibition ala Conboys.
Steve, that sounds great. Best of luck with that. Hoping for great results.
I am hoping the tests are set up right based on Michael's suggestions (thank you for that Michael) and we can get meaningful and useful data to share with other researchers including SENS.
@Steve H: Is there a rough estimate of the cost of the project? Will you go for it in one single fundraising campaign or will you repeat it every year during the lifespan of the mice?
I hope it will be successful.
If senolytics work in humans, I wonder how much of an effect they alone would have? It seems like these might be the first type of treatment available.
Information on the various approaches in the pipeline can be found at the U.S. Patent Office's web page for advance search for patent applications -
http://appft.uspto.gov/netahtml/PTO/search-adv.html
- and typing "abst/senescent" in the "Query" box.
If I weren't in my 20's and strapped for cash, I'd consider trying some of these - unless I have reason to believe that I may have a significant burden of cells presenting with SASP already. At what age is senescence thought to become a significant contributor to aging damage?
Hi !
I'm not sure how much biorejuvenation (no matter how powerful) can do more on senescent cell clearance if studies
show it is a uncoupled secondary 'old age frailty/insult/diseases', from regular 1st cause of aging. Meaning they are two different things,
so aging jus continues regularly; those secondary effects just will make you ill and diseased and die prematurely before your time of some disease (before the regular 1st intrinsic aging limit).
Senescent cell clearance seems is secondary health/pathology/degenerative aging effect, not a regular '1st intrinsic cause of aging' effect. Hence it will help slow progression, not reverse, pathologies and do nothing on regular aging.
''Organisms in which cells fail to undergo senescence **do not live longer**; rather, they die prematurely of cancer (Rodier et al., 2007).''
''The [senolytic] drug then initiates the natural process that leads to cell death by puncturing the membranes of those cells alone. They treated some mice over the course of their lifetimes and found a “quite dramatic delay” in the development of cataracts and age-related changes to muscle and fat, Dr. van Deursen said. In some mice, the compound was administered in old age. Clearance of senescent cells in those mice **did not reverse the decline that had already occurred; however, it did prevent further deterioration**.''
''It should also be noted that clearance of senescent cells **did not extend lifespan**, which Baker et al. claim is due to their mice dying primarily of heart disease which is not affected by the treatment.''
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Clearly, senescent cells can be found **in vivo **without telomere shortening** (Melk et al., 2003). Since cells taken from old donors do not endure less CPDs, one hypothesis is that **senescent cells in vivo are not widely caused by shortening telomeres but instead by various stressors and insults**. Exemplifying, studies in centenarians have raised doubts on whether telomere shortening occurs in vivo and whether senescence-associated genes in vitro are also differentially expressed in vivo (Mondello et al., 1999).
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So, senescent cell clearance, by telomere length proof disconnect, show they are secondary effect of inflammation; rather than a driver of first intrinsic aging (telomere DNA bp shortening/loss). This means anymore studies on senolytics will reach to the conclusion they are a health effect on
their diseases, but will do jack on intrinsic aging/maximum lifespan. Therefore will remain health therapeutics.
But if a strong senolytic, à la red wine grape Quercetin (slightly dubious) or Dasatinib or other... makes us live to 122 years MLSP healthy with little disease, I'm all for it though, the more ways we can live healthy long the better our chance to we increase our life potential and live longer healthier lives ! So great news !
Yeah, I wasnt thinking senescent cell removal would lead to rejuvenation per se, but more along the lines of slowing or removing some of the damage, and allowing you to be in better health, for longer. Certainly not a singular magic bullet.
@CANanonymity Senescent cells
From the 2015 Mayo study into Quercetin/Dastanib:
"In animal models, the compound improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan," said Laura Miedernhofer, co-lead author of the research. "Remarkably, in some cases, these drugs did so with only a single course treatment." Source: http://www.ibtimes.co.uk/anti-aging-drugs-senolytics-could-significantly-slow-aging-increase-life-expectancy-1491430
If you look at the study it does improve various aging biomarkers including cardiovascular function. As Reason and SENS have said many times, the effect on lifespan using a single SENS approach are not going to be huge, it is through combining them we will see big results.
We will soon have Quercetin/Dastanib in lifespan testing and repeat the research. We can test for improved biomarkers as well as overall lifespan at this point and confirm or refute it extends lifespan. I suspect it improves healthspan and should as a result increase lifespan too, however data is king so we will find out!
Having tissues filled with SASP is obviously not good so let us see what we shall see.
I agree that clearence of senescent cells will be amongst the first forms of true anti-aging, along with clearance of extra-cellular junk (arterial plaque, amyloid etc). Hopefully we see these treatments emerge within the next decade, i think it could be possible that these treatments alone would lead to people reliably breaking the 100 year mark.
@Steve
Hi Steve ! Thanks for that, I wish you great luck on your project ! Even if it doesn't do anything on maximum lifespan, I will still take it and it will be better than nothing. I just have this sinking feeling,
I am puzzled, I am guessing senolytics by clearig senescent cells derepress genes like PGC-1 and ATP ase/synthase that are critical for mitochondrial respiration and ATP energy production. Like the study you listed with cardiovascular, osteoporosis frailty and increased the mice exercise endurance
(PGC-1 alpha/beta behind this), yet other study shows they did not increase lifespan and did nothing on their heart defects. Again, this shows, if not Too ill with disease senolytics seem capable of something but there seems to be a pathology threshold where if you are really advanced in your illnesses senolytics will do very little. There is lots of confusion on the wording used to describe the effect, healthspan increase is understandable, it means an increase in Average lifespan by an improvement of health which allows the animal to get closer to its Maximum Lifespan natural limit imposed on its specie. These studies sometimes say ''lifespan extension'' without specifying if an Average lifespan (Healthspan improvement/extension) or an actual increase of the specie Maximum Lifespan (intrinsic aging by chromosome Telomeric DNA/methylation loss). These vagueness or slight omission think no one will notice, but people do, It's more honest to not make people overhyped and then reveal the sad truth/destroying their hopes/expectations. The fact that that it was found In Vivo that telomeres loss was dissassociated from senescent cell accumulation clearly means they are an end effect of pathological aging of elderly age disposition to illnesses, little to do with the regular primary 1st driver of Intrinsic Aging in normal healthy and disease free people who age and die like anyone; but by their constant great health, they get Closer to the human specie Maximum Lifespan potential limit (122 years). Senolytics, in theory, would do that, it is sure they will improve healthspan, thus Average Lifespan extension to the Maximum Lifespan limit possible, but won't make humans start living longer than this Maximum no matter how healthy for regular primary 1st intrinsic Aging continues its course (up to 122) and senescent cells have no say in this (uncoupled from telomeres loss in chromosome DNA).
This is a death blow to senescent cell clearance doing anything on 1st Intrinsic Aging/MLSP :
'' the fact that cells taken from old donors do not endure less CPDs [by senescent cells rise] ''
Senescent cell accumulation does not hinder Continuous Population Doublings, and this Population Doublings count is an accurate method for biological measuring, there is a good correlation between total cell Population Doublings and actual human lifespan (about one Population Doubling per year to Maximum Hayflick limit, Replicative senescence; ironically senescence accumulation is not causing this in the first place as seen from senescent cell telomeres disassociation)
ps: just wanted to add and nuance, some animals such as C.elegans live 10-fold lifespan after lipid gene therapy tha t modulates their lipid towards lipid peroxidation resisantace via reduced insaturation and double-bond index, yet these very mutants are very much nearly 'half-dead', meaning their health quality suffers and they development is dramatically reduced (so much so they are like in a torpor state where their quality of life is gone (nearly dead but not yet) as their metabolism goes down to nearly 0, plus they show developmental defects and are in 'fragile state' all along (, like their pumping rate is dismal (as if they are on 'life support', it's ironic some of these mutations in humans happen too, like human Marfan syndrome where you see dramatic reduction in polyunsaturates in their phospholopids just like the mutant C.elegans) yet these people die earlier from compromised health, it is not compatible with our metabolism and functions (we need our polyunsaturates for membrane fluidity and signaling). So in a sense, lifespan can be Uncoupled from healthspan (as some animals live longer - when they're half-sick (irony) because they extend the period of morbidity to an extreme by slowing metabolism so much so it doesn't work with the organism's normal development; yet at the same time they accumulate Less damage over such a long period of time that they outlive the regular controls who they are forced into a compressed morbidity window that happens much more rapidly in time) it is paradoxal.
It's almost 3 things, Average Lifespan, Maximum Lifepan and Healthspan; all related, all different and can be uncoupled (except Maximum from Average, you need average to get possibility to reach maximum limit). I have a feeling healthspan is extremely more important in long-lived animals as they are in decades, years time not days like in short-lived species; and the compression of morbidity will allow us much more to reach maximum human lifespan; I have doubts that chronic long-lasting sickness mutation (as in C.elegans mutants) can make us go above maximum human lifespan; it just doesn't work (for we are talking Years and years of low (but strong enough) inflammation accumulation that leaves one in a 'diseased/ill-but not dead yet' state but soon will be dead if it continues for another 25 or so years. In humans,these changes are much more abated and slow in progressoin (except in extreme advanced diseases state where in changes in a few months or weeks))). For humans, the order :
1. Healthspan (is quite important in humans to make 2. longer)
2. Average Lifespan (is needed to reach 3., but as shown doesn't necessarily need 1. in certain mutant specie)
3. Maximum Lifespan (is where things get interesting and have yet to read paper on human that talk about that)
It's not surprising that there was no increase in lifespan since only a percentage of a subset of senescent cells was eliminated.
@Florin Clapa
Hi Florin,
Apparently senescent cells only make a small percentage of total cells, thus seem to be mild in actual effect (the thing, even if they are a small percentage they have a large impact inflammation wise so removing them does help tremendously to halt inflammatory/degenerative pathologies) but for Regular 1st intrinsic aging, it seems is not an impact that is considerable or meaningful (wether % sub senescent cells or total 100%, as seen from in vivo telomere disconnection).
'' Interestingly, despite only clearing **30 percent** of the senescent cells, improvement in age-related phenotypes is profound.Thus, interventions that reduce the burden of senescent cells could ameliorate **age-related disabilities and chronic diseases** as a group (Tchkonia et al., 2013; Kirkland & Tchkonia, 2014).''
Only 30%, I would say, it's still 30%, quite a good percenate out of 100, a third...meaning 30% did -Only that...
Let's say it did clear 100 percent, that's 3 times the effect (it may not bea multiple but may be an exponential effect, but highly doubtful, if 30 percent gives this health effect optimization result for diseased ones, it won't be magic at 100% clearance (for healthy people I mean) - because some healthy 'geneticallygifted' people surely already have ultra low senescent cell numbers and they are the ones who will make it to MLSP, so how is senescence clearance all that applicable to them; not that much). Centenarians studies' on senescent cells are vague and seem to say they don't have any/very little of these senescent cells (obviously to reach 100 you need to not have senescent cells and SASP won't help either getting there);
but these centenarians still die anyways. 'On Clock' before 122.
Plus there is the replication end problem (telomerase and polymerase triy to fill in that telomeric DNA void with strand elongation during imperfect DNA replication), during each division telomeres lose telomeric DNA because of this problem. AdultStem cells are Not immune to that either, meaning they Too lose telomeric DNA and age, they have more difficulty differentiating, dvide, regenerate/self-repopulate and keeing their pools quiescent (there can be stem cell depletion). The point I'm trying to make is that the 'course of things' continues (Intrinsic Aging : Telomere shortening, Demethylation, 5-methylCytosine loss, telomeric DNA 'matter' loss from the chromosomes, mtDNA Deletion, Lipofuscin and other residues junk).
'' "Earlier we discovered that senescent cells accumulate in tissues with aging and that removal of these cells delays age-related functional decline in these tissues," says Jan van Deursen, Ph.D., a Mayo Clinic molecular biologist and senior author of the study. "The key advance of the current study is that the **progenitor [adult stem] cell populations are most sensitive for senescence, thereby interfering with the innate capacity of the tissue to counteract degeneration**."
''Mayo Clinic researchers have shown that adult progenitor or stem cells -- important for repair and regeneration of skeletal muscle and maintenance of healthy fat tissue -- are subject to cellular senescence, and that clearance of these cells limits age-related deterioration of these tissues''
The tissue can't regenerate because the stem cells are being hindered by senescent cells secretion of inflammatory cytokines and factors. Yet, these Adult stem cells (unlike primordial fetal-like immortal germ cells, like in the testicules who use telomerase non-stop) have a ''Time-Age' Clock'' count like other cell, and telomerase can't save them, one day the stem cells' telomeres are ultra-low and they can't regenerate the tissue anymore (Hayflick limit/replicative senescence). What happens then, aging continues is course as the telomeres drop down. Lipofuscin, aggregates, ceroid and AGEs accumulate until it doesn't 'work' anymore, the ECM is completely gone, the organs are involuted beyond salvage from the passage of time (brain pruning by 25% at healthy 100 years old, or up to 50% if with Alzheimer's), etc.
@CANanonymity: Up to 20% senescent cells in aged baboon skin:
https://www.fightaging.org/archives/2008/06/why-do-we-accumulate-senescent-cells-anyway.php
And here is a reference to a paper with some human skin senescent cell numbers for comparison, though of course it isn't open access:
https://www.fightaging.org/archives/2015/08/senescent-cell-presence-in-skin-correlates-with-skin-aging.php
@Reason
Hi Reason !
I feel it's a correlative vicious circle rather than a cause/causative. Senescent stem cells demonstrate whole body inflammation, they are the 'result', they are not the primary Driver/Cause, as such 'they appear' with age, contribute to the viscious inflammatory circle (DNA damage response), they just accelerate the whole process with pathologies appearing and people think they are the reason we age; they are not, they are a Correlative end-result 'residue' marker of inflammatory aging rather than The Cause of intrinsic aging.
''Irreparable telomeric DNA damage and persistent DDR signalling as a shared causative mechanism of cellular senescence and ageing.''
..shared causative mechanism is the important word, it's not correlative, but Causative; a very big difference.
DDR DNA damage response is a sign that the system is trying act on this inflammation damage to mitigate it; but it only fuels a vicious circle of senescent cells who secrete More inflammatory substance, activating DDR, and so forth...
''In these mice, termed INK-ATTAC [62] a promoter element drives the expression of caspase 8 fused to the FK-506 binding protein. The fusion protein dimerizes after the administration of a drug, designated AP20187 thereby activating caspase 8 which induces apoptosis. In this model cells expressing p16INK4a are eliminated. Such cells are considered as senescent, but more rigorous proof still has to come.
When INK-ATTAC mice were crossed with a progeroid mouse expressing constitutively a hypomorphic form of the BubR1 checkpoint protein (BubR1H/H) it resulted in premature aging and death mostly by heart failure. The drug-treated BubR1H/H-INK-ATTAC mice were protected from most age-related pathologies exhibited by the original mouse strain,
however they did not show a significant increase of their life span. They did not suffer from cataract, sarcopenia or loss of subcutaneous fat''
Very much a health optimization effect rather than a slowing of intrinsic aging.If they removed p16INK4a and the mice did not even live longer, you have to wonder how much of an impact it does have in Regular aging; it does have some; but it seems it is more a correlative than a causative marker (for cell replication it looks definitely a causative marker because cells without p16/p53/p21 become immortal cancerous and evade Hayflick limit end replication; as such p16 like TNF is a tumor inhibitor and oxidative stress marker).
As for baboon and humans who accumulate p16 positive senescent cells in skin ECM, this is again more a correlate rather than a 1st driver (they contribute but not in a Major 1st way), AGEs are the ones who are far more Causative to skin ECM crosslinking/destruction/aging for studies show that increasing advanced glycation end products and crosslinks make p16 positive cells go through the roof. Thus, glycation/glycoxidation damage is a causation that creates this 2nd p16 senescent state in skin ECM. Plus these INK-ATTAC mice have p16 removed and don't even live longer making p16 moot and more a correlation, than causation of aging. Inflammatory/Pathological aging should be the classification for p16, Intrinsic aging, no; correlation, yes; causation, no.
'' Irreparable telomeric DNA damage and persistent DDR signalling as a shared causative mechanism of cellular senescence and ageing.''
Cellular senescence is a secondary effect,
Ageing is a secondary effect and the Cause of these secondary effects:
Irreparable telomeric DNA damage and persistent DDR activation.
'' Unifying model explaining the role of telomeres in replicative, DNA damage-induced and oncogene-induced senescence both at cellular and organismal levels. DNA damage at telomeres cannot be repaired, independently from the source that generated it, both endogenously (i.e. telomere shortening, replication stress) or exogenously (i.e. X-rays). Irreparable telomeres are, therefore, associated not only with replicative cellular senescence but also with oncogene-induced and DNA damage-induced cellular senescence. These events prevent cancer onset on the one side, but on the other side, cause impairment of regenerative capacity during ageing both in proliferating and non-proliferating tissues at organismal.''
1. *Telomere shortening* -> *Irreparable Telomeric DNA damage* -> Replicative Senescence -> Ageing in proliferating tissues.
2. Oncogene Activation (Replicative Stress) -> *Irreparable Telomeric DNA damage* -> Oncogene-induced senescence -> Block Cancer.
3. *Random DD DNA Damage* -> *Irreparable Telomeric DNA damage* -> DD-induced cellular senescence
-> Ageing in non-proliferating tissues.
Telomere shortening is a Different thing from Random DNA damage, one contributes in proliferative tissues the other in non-proliferative tissues; yet both contribute. Thus, it is cancer blocking mechanism and a regenerative limit counter (by stem cell telomere loss and inability to regenerate tissues).
So,
Intrinsic Aging is *Caused By : Telomere shortening, Demethylation, 5-methylCytosine loss, irreversible/ irreparable telomeric DNA damage/loss from the chromosomes, mtDNA Deletion, Lipofuscin, AGEs and other residues junk and excessive DDR.
That goes to show how powerful telomeres, DNA and chromosomes telomeric DNA dictate intrinsic aging for they are the Source, 1st True Cause of intrinsic aging, it now makes more sense why telomerase gives immortality in certain species, stem cells and cancer cells. We knew it all along, DNA was obviously the code that was damaged and the Cause, chromosome telomeres/telomeric DNA were the missing link, we just couldn't seperate correlation from causation. I'm happy that telomeres are the cause and we were right all along
1. http://www.sciencedirect.com/science/article/pii/S0959437X14000628
Removing of the senescent cells in process of their accumulation can cause tissues rejuvenation because removal of any cells stimulates dividing of stem cells to keep tissue homeostasis. However, the aging clock will fast in this case, which will lead to a decrease in lifespan. Life will be healthy, but short (See "The Lag of the Proliferative Aging Clock Underlies the Lifespan-Extending Effect of Calorie Restriction". Curr Aging Sci, 2015, 8: 220-226.)
@CANanonymity in my view the signalling environment plays a key role in aging, this includes negative factors produced by SASP, rising TGF-beta from AGE and from secretions from the brain etc, decline of hormones etc...
It seems clear that removing senescent cells that escape the natural death cycle should be removed as they do significant damage to that signalling environment. Sure Senescence is a secondary effect but the SASP it produces feeds back into creating an increasingly poor signalling environment. Therefore removing senescent cells that refuse to die is important.
If you want to keep telomeres in stem cells in good condition then you need to remove the source of that signal loss. TGF-beta and the other factors that inhibit stem cell function are a result of damage/waste accumulation leading to decline of this signalling environment.
So Remove the source of that damage and the body will continue to work. We know this as the conboys have demonstrated the importance of signalling environment many times as have others and when the signalling environment is normalized stem cell function normalizes as do tissue repair routines.
As the Conboys have suggested in their recent review "a systemic problem" removal of senescent cells combined with calibration of the signalling environment could lead to systemic rejuvenation. SENS proposes similar outcome but via addressing the root cause of that signalling decline rather than attempting to compensate for it and juggle various factors in an attempt to keep things ticking over.
Repair the root damage and clear the junk out the body cannot and the rest should fall into place.
@.A.Trubitsyn
Hi .A.Trubitsyn !
Thanks for that ! You are very right, one more reason to make sure we stop damage accumulation to our telomeric DNA for it is causal, rather than correlative, to our death and intrinsic aging. SENS therapies blocking damaging causes will help (especially glucosepane crosslink breaking, AGEs and lipofuscin removal, these will give telomeres some slack). As for continuous tissue rejuvenation by stem cells when senescent cells, senescent stem cells, or any impedeing cell, are removed that allows organ tissue homeostasis, we must not forget these are Adult stem cells, not fetal primordial like ones, they are not immortal and are too bound by telomere loss counting limit; they could not just keep on differentiating and self-regenerate their pools/niche constantly, for telomere attrition by replicative senescence makes them mortal. Plus, as you mention, constant self-differentiation/dividing depletes the niche and must stay in quiescence to avoid depletion.
"Attenuating inflammatory chemokines and cytokines, including those produced at high levels by senescent cells (SASP), and ablating senescent cells (for example, via the use of their cell-surface markers) are expected to enhance tissue maintenance and regeneration, as well as diminish the risk of the age-related flare of cancers. In this regard, excellent mouse models reporting senescence in vivo and enabling selective ablation of p16high cells in live animals have been recently described*"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637204/
*http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730395/
*http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629/
This makes perfect sense to me that if we reduce SASP we boost tissue maintenance and regeneration which is a good thing. The best way in my view to do this is go to the source of the underlying damage instead of attempting to compensate for it.
Data is king so we will test this in our mouse program.
Oh and senescent cells of course take up "biological room" that could otherwise be occupied by healthy cells so again this is bad news.
I am not too concerned about stem cell depletion which has been mentioned above either as the technology to replace them is for many cell types available now and we are only improving the scale and quality of what cell types we can create (blood cells into neurons very recently for example).
It is also perfectly plausible to periodically remove failing stem cells and replace them and again this is something we are becoming better at too.
To bring it back to the OP: Senescent cells are not a primary aging cause in my view but they are a secondary one that feeds back and accelerates loss of signalling environment.
@Steve
Steve, sorry for being the Canadian jerk : > .I'm not trying to rain down on your parade (is it the correct expression?) seriously no ill meant towards your research program. I hope you and the scientists discover great things ! I'm totally with you blocking SASP will help tremendously.
It's true that if you remove the cause/source of 1st intrinsic (primary base level) aging, you basically cure death and allow immortality. For my part, I feel SASP and senescent cell clearance is a health effect - that ties in to some degree in intrinsic aging, how much is hard to say. There is also the fact that (adult) stem cells can't save us (not talking about immortal ones in gonads), they are mortal and are bound by telomeric DNA repeats/irreparable telomeric DNA damage by replicative senescence also called 'replicative end problem', end problem' indeed, telomerase/polymerase can't save them for they don't appropriate themselves of telomerase like gonadal stem cell do to stay immortal. The reason being it's a evolutionary trade-off between limited cell rejuvenation/proliferation by a Control DNA replicative senescence damage count mechanism (mortality) vs uncontrolled proliferation and cancer/mutational error load/tumor formation increasing possibility (oncogenic immortality). And, we all know that the most proliferative immortal stem cells harbor cancer like qualities, like using stem cell factors Oct, Nanog, Sox who contribute to stem cell immortality and cancerous cells highjack them and become stem cell like themselves to become immortal. It's very fine crafted balance between Just Enough damage, Not too much not too little to Allow senescence and avoid tumor transformation immortality.
''Organisms in which cells fail to undergo senescence do not live longer; rather, they die prematurely from cancer (Rodier et al., 2007).''
I still see the signalling environment and decline of said environment the primary driver of aging with the bloodstream as the medium which spreads that dysfunction. Accumulated waste and damage contribute to this signal decline to the point it overcomes the system. If we fix that damage we buy a lot more time. We can replace stem cells periodically, the technology to do this is coming along nicely.
PS: you are not raining on anyone's parade bud this is a conversation about something we all care about. The MMTP is setting out to prove or disprove such things so either way we learn something useful.
@Steve
ok cool then : ) can't wait to hear from your MMTP result.
"Removing of the senescent cells in process of their accumulation can cause tissues rejuvenation because removal of any cells stimulates dividing of stem cells to keep tissue homeostasis. However, the aging clock will fast in this case, which will lead to a decrease in lifespan. Life will be healthy, but short (See "The Lag of the Proliferative Aging Clock Underlies the Lifespan-Extending Effect of Calorie Restriction". Curr Aging Sci, 2015, 8: 220-226.)"
Is anyone able to expand on this?
@Ham @.A.Trubitsyn
Hi Ham !
I read his abstract, he is professional researcher.
''This clock governs the rate of the aging process via programmed, proliferativedependent and stepwise bioenergetics decline.''
My 2cent take... on the fact that saying removal of senescent cells could make rejuvenation is simply by the fact that stem cells are not impeded anymore, they can differentiate more, and the subset of senescent stem cells affects other non-senescent stem cells; so of course, removing them will allow stem cells new vigor for tissue regeneration/replacement by self-differentiating faster to replace damaged tissue by senescent cells.
But as he says, it will accelerate aging for the fact that stem cells may become depleted by the proliferative clock accelerating, thus tissues will run out of stem cell at some point and will degenerate too; only much faster since stem cells will deplete and their proliferative 'timer' will be on 'accelerated'. I have a feeling this is linked to overproliferation and not enough quiescence which destabilizes the self-regeneration vs self-cell differentiation balance. So a healthy but short life. I could be totally out in the field though :D
The Lag of the Proliferative Aging Clock Underlies the Lifespan-Extending Effect of Calorie Restriction.
1. http://www.ncbi.nlm.nih.gov/pubmed/26428550
@.A.Trubitsyn
.A.Trubitsyn, congrats on your paper ! It is very interesting and thought provoking !
''This clock governs the rate of the aging process via programmed, proliferativedependent and stepwise bioenergetics decline.''
Just my opinion : )...
I have a feeling this ties in neatly with telomeres and telomeric DNA, yeah had to bring them up, nearly everything revolves around them when talking aging, telomeres control are co-responsible during replication and cell division/proliferation/cycle. Telomerase is needed during that process to slow replicative end problem of telomere shortening per cell cycle. Cell size, mass, bioenergetics and epigenetic programmation (telomere gene silencing/signal of genes depending on methylation/repeat content) are also in line with telomeres control. Telomeres are all behind these steps. Telomeres (for they contain the very Genetic DNA material that acts to drive the aging process) are also the Program. Damages accrual to Telomeric DNA repeats due to multiple imperfections of cell biology are the main driver.
Calorie Restriction CR, as in your paper, delays some of these defects by slowing cell division/cycling/ replication, which keeps the cell in a undividing state and a small 'cell size' (cell size growth determines cell lifespan) thus needing less construction matter and unallowing the damage (aging) to accumulate if divisions continue. Yet, you can't stop cell division, as you say, it can have consequences where cell become growth arrested and die. Immortal cells are continuously dividing.Their trick: they don't accumulate the damages; SENS will remove (telomeric DNA damage, lipofuscin, AGEs).
Ok, thanks. Yeah I wasn't questioning what he said, just wanted a bit easier of a breakdown of it. So basically senescent cell removal could be a bit of a double edged sword? Shorter, but healthier life?
@Ham
Exactly, paradoxal. I'm only speculating really, but it really seems there is an evolutionary trade-off going on, senescent cells seem a integral part of the package deal 'balance', they have a role (mostly oncogene inhibition by 'senescence' accelerating organismal termination to avoid cancerous transformation). It's been all balanced by evolution's pressure on our human genes and DNA, it crafted that balance - With senescence in mind.
So of course us tinkering with our genes and trying to outwit evolution by removing senescent cells can yield unforeseen results, like a healthy short life by fine stem cell balance loss as said by .A. Trubitsyn. Plus, organisms whose cells do not undergo senescence do not live longer, they die of cancer.
If you attenuate tgf beta which reduces expression of tert then stem cells will be able to divide at more youthful rates. Combined with senescent cell removal it would not be an issue. The conboys talk about this in their last review.if you remove the source of damage the signalling environment improves allowing cells to replace list ones at a normal rate, if tert and telomerase activity are normalized then tissue repair would occur normally.
Sens needs a number of things applied at once to provide robust lifespan increases.
"To achieve a healthy and unlimited life it is necessary to reprogram gene expression so that cell bioenergetics levels either remain at a previous level after cell division, which will stop aging, or else grow, which will result in organism rejuvenation."
Yes this is what I am saying, repair the reason for the decline of signalling environment and the system will maintain itself. The Conboy papers are vindication of this and SENS repair strategy is the logical and robust way to do that.
So I suspect we are all talking about the same thing here!
CANanonymity, the stem cell clock that you're referring to is probably the so-called Hayflick Limit, but it's actually not been proven to exist in vivo for any cells other than senescent cells, AFAIK.
CANanonymity, we won't know whether lifespan can be significantly extended by eliminating senescent cells until close to 100% of SCs are eliminated. And it could turn out that lifespan won't be significantly extended until most or all of the SENS therapies are applied at the same time. Remember that even if cancer was completely cured, human lifespan would only increase by a few years, but that doesn't mean we can ignore curing cancer.
Determining whether SCs are caused by extrinsic or intrinsic aging is not that helpful, since whatever caused them (i.e., mutations caused by extrinsic cosmic rays or intrinsic free radicals from mitochondria) can't be avoided.
@Steve @Florin
Yes, definitely, improving signalling environment loss will allow rejuvenation. But signalling environment is tied to the gene network, which is tied to the nuclear chromosomes, yes, those pesky telomeres, our clock counters. It's where I'm puzzled as to how those adult stem cells escape aging replicative senescence. I feel they don't escape it, perhaps stem cell reprogrammation (as in iPSC reprogrammation) occuring in vivo somehow, but most studies point towards Adult stem cells Aging too themselves so at a certain point stem cell attrition ; I'm willing to bet it's via replicative senescence end problem', how much telomerase do these Adult stem cells use for themselves ? None ? How do they solve this telomere attrition problem from imperfect replication ? Immortal ones appropriate telomerase others who die seem not to, for reasons of senescence control of mutagenic cancerous transformation. I don't know how much good it is to reduce TGF and telomerase, kind of like biting the hand that feeds you, double edge sword. Reducing TGF and telomerase can reduce cancerous transformation, but what about stem cell telomerase link ?
@Florin
Some studies show that iPSC have their telomere reset after stem cell factors Nanog, Oct, Sox use when reprogrammed. What does this mean , is these stem cell are bound by telomere maintenance. Most likely by replication end problem' too, it is a Part of the telomere paradox and mechanism. If cancer cells and primordial fetal like germ cells avoid end problem ,it is most likely a problem too for adult stem cells or any other cell. Chromosome are part of the cells' make up in their nucleus, so too telomeres at chromosome termini.
Ps: for everyone, don't take anything I say for cash $.. Just speculating from limited knowledge : ]
@Florin
Florin, it's also my point and why, I have certain doubt SC removal will Extend Maximum lifespan, most likely it will reduce inflammatory pathology and increase Healthspan, Average lifespan too to some point; but not intrinsic aging, the one that allows to reach and Surpass Maximum Lifespan.
And, yes you are right, it does mean we should not concentrate on curing cancer. It's a tricky thing, this cancer/telomere/inflammation/senescence/stem cell axis inter connection. We have to be careful to not burn ourselves, but it's better to try than regret not having to.
As they say,'' if you can't take the heat, get out of the kitchen'' So let's burn ourselves trying.
@Florin
we 'should' concentrate on curing cancer, typo, I apologize.
Yeah, the lifespan vs expectancy thing is interesting. I wonder about the expectancy increase as far as senescent cells go, but I wouldn't expect that to push people past 122 alone. Maybe it'll help more people see 100 with regularity (which is certainly an accomplishment), but not entirely what everyone is looking for with the maximum lifespan. We'll see.
CANanonymity, if stem cell aging will turn out to be a big problem (and even if it won't in case WILT is necessary), stem cells could be rejuvenated in vitro and reintroduced into their niches after the aged stem cells are killed off.
@Ham
It has been the sort of concensus in biogerontology that there was no way humans could go above 122 MLSP, we tried and it failed, so we must now focus on health and average lifespan instead. It's a normal acceptation, but SENS Could change that, I so Hope that. Till then, I await Any paper that talks about human MLSP Future with enthousiam (as the one like Trubitsyn, because it touches intrinsic aging). Some SENS therapies have capability to make us live longer than MLSP, or at least I hope. Curing disease, very important, Curing death, Also important.
@Florin
It could work, I think we are getting there but there are obstacles and I'm not sure stem cell replacement will make us live beyong MLSP until it is fully harnessed in mice, to make them live the age of Naked Mole Rat, until then it seems it has the Rapamycin CR calorie restriction like effect, so don't hold your breath (for now, SENS could change that, but it's going to take massssive stem cell renewal it seems, and slight 'tune up' at the doc for stem cell replacement seems is not it yet). Hopefully, we can repeat this transplatation on and on and somehow delay infinitely; but it seems a 'catch up' game, where one day or another, we lose to it and replacement can't overcome speed of aging. A transplant each month, year or so, could do it, but in mice it give calorie restriction effect result like 20-30%. This is mostly average lifespan territory by health and average lifspan extension, not maximum intrinsic aging.
'' The recent study, published in Stem Cells TM, demonstrates that infusions of mesenchymal stromal cells (MSC) can impact aging and longevity. ''
''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). Overall, these results suggest that transplantation of BMSCs derived from young animals extends life span.''
''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. Transplantation of AMMSCs and ADMSCs improved cognitive and physical functions of naturally aging rats, extending life span by 23.4% and 31.3%, respectively.''
1. http://www.nature.com/articles/srep00067
2. http://stemcellstm.alphamedpress.org/content/early/2015/08/26/sctm.2015-0011.abstract
CANanonymity, only getting rid of SCs and rejuvenating stem cells won't allow most people to reach 110 and beyond. To reach those ages, ALL age-related diseases (which is equivalent to SENS' seven categories of damage) need to be eliminated.
A number of the SENS damages need to be addressed before we get radical life extension. Our group will get data on SCs and lifespan increases soon, we will move into stem cell work after this again to demonstrate effect on lifespan. We are also testing stem cell in-vitro rejuvenation and lifespan increase.
However to beat that 122 we will need a number of the 7 deadly SENS to happen at once. We are interested in tested combinations in phase 2 eg, SCs cell removal + Alk= 5 inhibition. We could also try SC removal + stem cell transplant/replacement and see if there is a synergy greater than them both alone.
I concur with Florin about needing a number of things to be done though, otherwise you fix one thing something else gets you. Glucosephane is my biggest concern so let us hope something can be done about it.
Steve,
Wasn't there some recent progress with glucosepane? I could of sworn I read something on it, but the source is escaping me right now.
Ham there was indeed yes. They can now make it in the lab thanks to SENS funding and work at Yale IIRC.