Senolytic Therapies to Clear Senescent Cells will Transform the Field of Medicine for Age-Related Conditions

A new paper published yesterday is perhaps the fourth in a recent series of similar commentaries and reviews from a variety of research groups involved in the study of senescent cells. Each declares in its own way that senolytic therapies, approaches capable of selectively destroying senescent cells in old tissues, are a development of great importance in aging research. Senolytics have the near-future potential to produce sweeping change and improvement in the treatment of age-related conditions. The degree to which removal of senescent cells is better than the vast majority of present day medicine is hard to overstate. Accumulation of senescent cells is one of the root causes of aging, and removing these cells is a form of rejuvenation, capable of partially turning back the progression of most of the common age-related medical conditions.

Senescent cells well illustrate the SENS view of aging as an accumulation of unrepaired damage, generated as a side-effect of the normal operation of metabolism. Senescent cells are generated in large numbers in our tissues, day in and day out, but near all are destroyed, either by their own programmed cell death mechanisms or by the immune system. A tiny, tiny fraction of these cells evade this fate, however, and linger. Senescent cells generate a range of signals - the senescence-associated secretory phenotype, SASP - that corrode nearby tissue structures, change surrounding cell behavior, and generate an inflammatory response in the immune system. This is all beneficial in the short term and in small numbers, and senescent cells play a temporary role in steering embryonic development, or in regeneration of wounds, or in suppression of potentially cancerous cells. The problem arises in the long term, as growing numbers of lingering senescent cells continually run their program of inflammation and corrosion.

In recent years, studies have definitively linked senescent cells to age-related fibrosis, a major cause of organ dysfunction, to the progression of inflammatory conditions such as osteoarthritis and atherosclerosis, to the failing function of lungs, and to a range of other measures of age-related decline. Removing senescent cells from old mice has been shown to partially reverse the progression of many of these conditions. Since the mechanisms of cellular senescence are very similar in mice and humans, the hope is that the benefits of senolytics in old people will be significant. Since human studies have commenced in a variety of venues, we will find out in the next few years just how transformative this new approach to the treatment of aging might be.

Researchers review the clinical potential of senolytic drugs on aging

Researchers are moving closer to realizing the clinical potential of drugs that have previously been shown to support healthy aging in animals. In a review article aging experts say that, if proven to be effective and safe in humans, these drugs could be "transformative" by preventing or delaying chronic conditions as a group instead of one at a time. The drugs being tested are called senolytic agents, because they target senescent cells. These are cells that have stopped dividing and secrete toxic chemicals that damage adjacent cells. Accumulation of senescent cells, which increases with age, is associated with chronic conditions, including diabetes, cardiovascular disease, most cancers, dementia, arthritis, osteoporosis, and frailty.

In a recent study researchers confirmed that the first senolytic drugs to be discovered effectively clear senescent cells while leaving normal cells unaffected. The study also describes a new screening platform for finding additional senolytic drugs that will more optimally target senescent cells. The platform, together with additional human cell assays, identified and confirmed a new category of senolytic drugs, which are called HSP90 inhibitors. The platform will help researchers quickly identify additional drugs that target aging processes, which he says will be useful as they move closer to clinical intervention. "We've moved rapidly in the last few years, and it's increasingly looking like senolytic drugs, including the recently discovered HSP90 inhibitors, are having an impact on a huge range of diseases. We will need to continue to test whether there are more optimal drugs or drug combinations to broaden the range of senescent cell types targeted."

As senolytic drugs and drug combinations are discovered, researchers then will need to test them in clinical trials. The review article, "The Clinical Potential of Senolytic Drugs," acknowledges the unique challenges of these trials in the field of aging, including the difficulty of testing long-term end points, such as life span and health span - the healthy, productive years of life. Outcomes such as effects on median or maximum lifespan cannot be tested feasibly in humans. That's why researchers are using new clinical trial paradigms, which include testing the effects of senolytic drugs on co-morbidity, accelerated aging like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age-related loss of physiological resilience, and frailty. The authors also call out a need for additional geriatricians with research training to lead future clinical trials.

The Clinical Potential of Senolytic Drugs

Chronological aging is the leading predictor of the major chronic diseases that account for the bulk of morbidity, mortality, and health costs worldwide. Furthermore, age-related chronic diseases, geriatric syndromes, and disabilities tend to cluster within individuals, leading to multimorbidity. These observations support the concept that fundamental aging processes not only cause aging phenotypes, but also predispose to chronic diseases and the geriatric syndromes. Thus, it has been predicted that therapeutically targeting these processes can delay, prevent, or alleviate age-related chronic diseases and disabilities as a group, instead of one at a time-the "geroscience hypothesis."

The biological processes that underlie aging phenotypes and are active at the nidus of most chronic diseases include chronic, low-grade, "sterile" (absence of known pathogens) inflammation; macromolecular and organelle dysfunction (e.g., changes in DNA, such as telomere erosion, unrepaired damage, mutations, polyploidy, proteins - e.g., aggregation, misfolding, autophagy - carbohydrates, lipids, or mitochondria); stem and progenitor cell dysfunction; and accumulation of senescent cells. These four processes are linked; that is, in general, interventions that target one process also attenuate the others. For example, DNA damage causes increased senescent cell burden and mitochondrial and stem or progenitor cell dysfunction. Conversely, reducing senescent cell burden can lead to less inflammation, less macromolecular dysregulation, and enhanced function of stem and progenitor cells.

To remove senescent cells pharmacologically from wild type animals, "senolytic" agents, including small molecules, peptides, and antibodies, are being developed. Since the article describing the first senolytic agents was published in 2015, progress in identifying additional senolytic agents and their effects has been rapid. In that first article, a hypothesis-driven senolytic agent discovery paradigm was implemented. Senescent cells are resistant to apoptosis, despite the SASP factors they release, which should trigger apoptosis. Indeed, pro-apoptotic pathways are up-regulated in senescent cells, yet these cells resist apoptosis. The hypothesis was therefore tested that senescent cells depend on pro-survival pathways to defend against their own pro-apoptotic signaling.

Using bioinformatic approaches based on the ribonucleic acid (RNA) and protein expression profiles of senescent cells, five senescent-cell anti-apoptotic pathways (SCAPs) were identified. That SCAPs are required for senescent cell viability was verified in RNA interference studies, in which levels of key proteins in these pathways were reduced. Through this approach, survival proteins were identified as the Achilles' heel of senescent cells. Knocking down expression of these proteins causes death of senescent but not nonsenescent cells. The SCAPs discovered so far have been used to identify putative senolytic targets.

The first senolytic agents discovered using this hypothesis-driven approach were dasatinib and quercetin. Ten months later, the third senolytic drug, navitoclax, a BCL-2 pro-survival pathway inhibitor, was reported. Since then, a growing number of senolytics have been reported. Yet more senolytics are in development, and additional potential SCAPs are being identified. The SCAPs required for senescent cell resistance to apoptosis vary according to cell type. The Achilles' heels, for example, of senescent human primary adipose progenitors differ from those of a senescent human endothelial cell strain, indicating that agents targeting a single SCAP may not eliminate all types of senescent cells. The senolytics that have been tested across a wide range of senescent cell types have all exhibited a degree of cell type specificity. For example, navitoclax is senolytic in a cell culture-acclimated human umbilical vein endothelial cell strain but is not effective against senescent primary human fat cell progenitors.

Senolytics do not have to be continuously present to exert their effect. Brief disruption of pro-survival pathways is adequate to kill senescent cells. Thus, senolytics can be effective when administered intermittently. For example, dasatinib and quercetin have an elimination half-life of a few hours, yet a single short course alleviates effects of radiation-induced senescent cell creation in vivo for at least 7 months. The frequency of senolytic treatment will depend on rates of senescent cell re-accumulation, which probably varies according to conditions that induce cellular senescence. Advantages of intermittent administration include less opportunity to develop side effects, the feasibility of administering senolytic drugs during periods of relatively good health, and less risk of off-target effects caused by continuous exposure to drugs. Another advantage of senolytics is that cell division-dependent drug resistance is unlikely to occur, because senescent cells do not divide and therefore cannot acquire advantageous mutations, unlike the situation in treating cancers or infectious agents.

The introduction of effective senolytics or other agents that target fundamental aging processes into clinical practice could be transformative. These drugs may be critical to increasing healthspan and delaying, preventing, or alleviating the multiple chronic diseases that account for the bulk of morbidity, mortality, and health costs in developed and developing societies. They could also delay or treat the geriatric syndromes, including sarcopenia, frailty, immobility, and cognitive impairment, as well as age-related loss of physiological resilience, in a way not imaginable until recently. These agents could transform geriatric medicine from being a discipline focused mainly on tertiary or quaternary prevention into one with important primary preventive options centered on a solid science foundation equivalent to, or even better than, that of other medical specialties.

Senolytics might prevent or delay chronic diseases as a group, instead of one at a time in presymptomatic or at-risk individuals. Furthermore, if what can be achieved in preclinical aging animal models can be achieved in humans, it may be feasible to alleviate dysfunction even in frail individuals with multiple comorbidities, a group that until recently was felt to be beyond the point of treatment other than palliative and supportive measures. Although considerable care must be taken, particularly until clinical trials are completed and the potential adverse effects of senolytic drugs are understood fully, it is conceivable that the rapidly emerging repertoire of senolytic agents might transform medicine as we know it.

Comments

We are seeing again the four stages of acceptance of J.B.S. Haldane.

Posted by: Antonio at September 5th, 2017 5:56 PM

Well... look at that...barely a month the lobbying has already begun!

Expect to see more and more of this. Its just ramping up now. The medical community, scientists, and likely some PR firms will be moving to massage public opinion in the move to make aging a disease in the eyes of the FDA.

Truth, this is happening faster than I thought it would. Very happy to see this.

Posted by: Mark Borbely at September 5th, 2017 7:16 PM

@Mark Borbely: Things go fast once the tipping point is reached. Took a long time to get here, however. It is also very possible that, absent suitable advocacy, people won't join the dots between one form of damage repair working well, and all the other forms of potential damage repair that are not yet there.

Posted by: Reason at September 5th, 2017 8:46 PM

Yea, I am very excited, too. I hope we will soon see this in the mainstream news.

I just hope that we will soon see the treatments for the next 2 or 3 the causes of aging shortly thereafter, I.E, within 10 years (if not sooner).

Posted by: Robert at September 5th, 2017 8:54 PM

Lotsa hope and enthusiasm here. Do we have any data? Hints? Anecdotes at least?
I am getting concerned that we haven't heard anything solid yet in humans.

Posted by: Chris Zell at September 5th, 2017 10:08 PM

Why not have a two-pronged research approach that also researches the idea that we can somehow transform senescent cells into young cells. Why should we give up on these senescent cells?? Maybe that is the impossible dream, and maybe it isn't.

Posted by: Biotechy at September 6th, 2017 1:03 AM

Biotechy, that sounds much more difficult (and costly and lenghty) and dangerous (welcome, cancer) than simply killing them, something that we already can do.

Posted by: Antonio at September 6th, 2017 1:25 AM

I still find it hard to believe how quickly senescent cell research has gone from backwater to active field and the clinic. Remember that only 6 years ago the team at the Mayo clinic were denied further public funding for their research, which was only continued with a grant from the private Glenn Foundation. And they were only able to carry out their initial research due to a grant from the private Elison Medical Foundation:

http://www.nytimes.com/2011/11/22/science/research-on-senescent-cells-is-denied-nih-grant.html?mcubz=3

"Two reviewers gave the proposal a perfect score, but the third said he thought senescent cells were too rare to do much damage - a conjecture that the Mayo team's new experiment has proved incorrect. Yet the third reviewer's mark renders Dr. van Deursen's new proposal ineligible for government research financing, unless the National Cancer Institute's council steps in to reverse the peer review group's decision."

Posted by: Jim at September 6th, 2017 2:02 AM

This might have been posted here already many times, but I found a list of the many diseases that have been linked to cellular senescence : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412760/#S2title

I want so badly for these treatments to become available in the next couple of years. I'm suffering badly from prostate enlargement, like millions of other middle-aged men, and it appears that BPH is just one of countless age related health problems that might be cured by senolytics. My 84 year old mother suffers greatly from osteoarthritis. These drugs have the potential to transform millions of lives, and yet this is one of the very few sites online that is dedicated to highlighting and lobbying for these kind of treatments.

Posted by: G Turner at September 6th, 2017 5:49 AM

"Yet the third reviewer's mark renders Dr. van Deursen's new proposal ineligible for government research financing, unless the National Cancer Institute's council steps in to reverse the peer review group's decision."

Isn't this kind of a big deal? What do you think the odds are that the National Cancer Institute's council actually steps in here?

Posted by: Ham at September 6th, 2017 11:52 AM

Ham: that was in 2011.

Posted by: Antonio at September 6th, 2017 12:21 PM

Right you are. I noticed everything else in the article, sans the date :(

Posted by: Ham at September 6th, 2017 12:51 PM

I would hope that the NCI would jump on the bandwagon when we can prove that senolytics prevent cancer.

Patient advocacy groups are fantastic allies.

Posted by: Mark Borbely at September 6th, 2017 1:41 PM

Has this community (or the broader aging community) done any outreach to patient advocacy groups? In one sense those groups are part of the problem because they are usually organized around individual diseases and (I assume) specifically advocate for progress only on their specific disease. Thus, in a sense they help perpetuate 2 core problems: the silo approach to research individual diseases, and the emphasis on cure rather than prevention.

If we could flip several of the big ones and get them to pool their resources and advocacy into the mode of thought of preventing/reversing aging as the best bang-for-the-effort bet to make, that would be a huge win.

Posted by: Karl Pfleger at September 6th, 2017 3:12 PM

Does anyone here think senolytic therapies can solve this problem?

Facial Aging is More Than Skin Deep
https://www.urmc.rochester.edu/news/story/2800/facial-aging-is-more-than-skin-deep.aspx

Patterns of Change in Facial Skeletal Aging
http://jamanetwork.com/journals/jamafacialplasticsurgery/article-abstract/2646779

This is my area of concern. I am 61, and I don't have diabetes, cardiovascular disease, cancer, dementia, arthritis, osteoporosis, or frailty, nor a strong risk towards any of those conditions.

Posted by: NY2LA at September 6th, 2017 6:21 PM

@Karl Pfleger: that is a question for some of the SENS Research Foundation and Methuselah Foundation folk who've been around for a while.

I know that I haven't managed it in any meaningful way; the obvious ones were either (a) very focused on their particular single disease (Michael J Fox Foundation), (b) more involved in politics than research (AARP), (c) too large to pay any attention to our community at the time a connection was tried (Wellcome Trust), or (d) already involved, but bought in to non-SENS views of aging (Alliance for Aging Research).

Posted by: Reason at September 6th, 2017 9:54 PM

@NY2LA - It seems skin aging is the result of many things, but that senolytic therapies might help. It might be a very little, it might be a lot. There was an article here last year : https://www.fightaging.org/archives/2016/04/senescent-cell-clearance-and-a-focus-on-delaying-skin-aging/

The original study that the article was addressing : https://www.ncbi.nlm.nih.gov/pubmed/27031122

It would indeed be a shame if senolytics give 60 year olds the health and fitness of 30 year olds and yet remain on the outside largely looking their chronological age. However, there is a company called Replicel which is hoping to bring to market a stem cell skin rejuvenation treatment : http://replicel.com/product-pipeline/rcs-01-skin-rejuvenation/

Posted by: G Turner at September 7th, 2017 5:01 AM

@ Reason : "non-SENS views of aging"
Ha ! I love it. How non-SENSical of them !

@ G Turner : Yes that'd be a shame, but at the very least senolytics (and other treatments) would buy these people enough time to fix the more cosmetic issues. So, still a good reason to support the SENS approach right now even if their concerns aren't directly addressed yet.

Posted by: Spede at September 7th, 2017 7:04 AM

@G Turner,

I always thought there would be a cosmetic surgery, 2.0 very soon. Best thing about this, is it actually repairs the damage, not cover it up as current cosmetic surgery does now. Hopefully, this company will be successful and soon we will have it available, 10 years?

Posted by: jRobert at September 7th, 2017 11:44 AM

Does anyone have a comprehensive list of the beneficial effects of senolytics? I heard Ned David saying he had a list of 22 indications that were improved via clearance.

If Senolytics can help with AD... well then.. we have a HELL of a bargaining chip. No treatment or cure, and a not nearly enough money to take care of the tsunami of patients coming down the line.

That would be the first advocacy I would look for if Senolytics can help.

Posted by: Mark Borbely at September 7th, 2017 1:30 PM

@G Turner, @Spede, and @jRobert. Thank you. But please bear in mind, my post points out that addressing only skin aging for facial cosmetic purposes is probably going to be limited. It's going to be necessary to address the underlining changes in facial bone morphology, because the bone structure is necessary to hold the skin in place. I suspect ReplicCel's RCS-01 may only help facial skin look "good for your age". Faces will still look their age unless the underlining bone structure can be addressed.

The loss of subcutaneous fat pads in the face is also an issue, and now all we have is fillers. It is a case where loss of fat leads to looking older, because the face looks more hollow!

Posted by: NY2LA at September 7th, 2017 3:53 PM

@NY2LA, I have heard that when they do Facial Feminization, they contour parts of the face/head, via trimming the bone structure. Sounds painful, but it has been done many times.

Posted by: Robert at September 7th, 2017 4:08 PM

@NY2LA: you can get facial implants and fat grafting already. What looks off on nipped and tucked celebrities is the waxy skin...

Posted by: Barbara T. at September 7th, 2017 4:38 PM

@Barbara T. I know about facial implants and fat grafting. I am trying to play devil's advocate on this forum. As far as I am concerned, nothing should be called "anti-aging" unless it makes people look younger.

Posted by: NY2La at September 7th, 2017 9:04 PM

Otherwise, the whole concept of age-related conditions and aging being the same process breaks down. It would just mean repairing damage consists of better medical treatments, but is not anti-aging.

Posted by: NY2LA at September 7th, 2017 9:14 PM

@NY2LA

Hi NY2LA ! Just my 2 cents,

I think, it's because it depends on what damage, where, etc. Certain damages are more consequential than others, hence have greater impact where they are inhibited. The concept that age-related conditions and aging being the same process, is (just my opinion) not really true. They are definately linked/interlinked, but, at the same time, seperate. Co-dependent and co-independent. The mere fact that you can die immediately determines that health is independent from aging (as we know it/call it). Immediate death can be dysfunction in a single organ and shut down in others after (complications). This is a health 'threshold', if you maintain your health - you could live 120 (if gifted of genetic jackpot). You, still, die at 120-130 or so. That is intrinsic aging and it continues its course everyday whether you are 'healthy' or not. This is manifested as Junk crap accumulation in the proteasome/lysosome/autophagosome and also chromosomal laxing with aging; this is just the tip of the iceberg (below the water lots more iceberg : AGEs, crosslink, amyloids, transthyretin, 8-oxodG, carbonyls, pH acidifying in cell while become alkalin in lysosome (vesicles can't degrade anymore), redox failure (you are becoming oxidized thiols), telomeres getting short and 'weak/uncapped' (especially in immune cells whom depend on telomerase, like leukocyte T-cell/NK-cell (thymus getting small), people whom are 115 have tiny leukocytes telomeres = immunosenescence, once immune system gone - death (cancer, entry of pathogen/infection/many elders die of infections)). So I could sum this as so many damages and it is why, the skin may be rejuvenated a bit (like increasing FGF-11 activity and improving ECM/collagen/HA production, thus reducing fibroblast senescence but their is still the other damages), still reversal of skin aging is very good start and skin, itself, is a good barometer of overal aging (collagen depth (measure as sub-surface scattering)) can tell us the biological age of someone, in my mind near to as a DNA methylation marker because skin is an intregral part of our body (it is an organ) and it shows the effects happening Inside (there is good correlation between skin plumpness (collagen/HA/decan/scaffolds ECM) and your bioage. Collagen injection (which gives that wax effect) is actually a reversal of bioaging because studies showed that the ECM was capable of retarding biological aging if it was reconstructed. One of the largest element is collagen in it and long-chain hyaluronic acid. But to answer more about the 'skeletal' problem of having a bigger face with age and it looking hollow, as was suggested, bone trimming may be a solution but (just I) would never do it (do Dangerous, same thing with sugical operations, risks outweigh benefits (I'm amazed people whom go Under the bistouri on and on , don't realize (or feign/ignore) the great risk of dying on the table while surgery (they don'T care they would perish on table make no diff), may a times people's body decided to stop as the surgery was way to exhauting and created a 'hyper' stress responses (kind of like toxic shock or organ rejection for the body, heart can stop dead)), many people did it and were Lucky with no damage. It is Something to think about - it is better to look Young and be alive, and look 'old' morphologically than try to get skull fixed (to look younger) and potential death. It is a personal choice and assuming the risks.

PS: I think senoylitics have power (quercetin and dasantib combo), sorry typos It's getting late, to be truthful, as seen mice studies, I believe senescence therapy will be stronger but nowhere near we hope; it will be a complement to the other 6 or so ones. I feel that the senescent cells have a great say on health and capacity of stem cell renewal - not so much on intrinsic aging that determines that your maximum possible (as human) is 120 years or so. If you are healthy and not getting much senescent cells, there is great possibiliy to reach 120, disease free. But, there, it stops. I am betting very strong morbid compression and in athe space of a year or a few months, the redox becomes totally whack and we assist a 'Flash' of oxidation (a major one as seen in C.Elegans whom have these pre-determined intense'FLashes' of damage in life (this is most likely linkeed to Epigenetic failure (DNA methylome) not possible to rebound Againg and Again, going in tandem with methyl loss in telomeres) and if you have them quicker it is), where you enter death. Quercetin and other senolytic allow a possibility to live long (you can find them in certain herbs and wine etc), they improve health and as said can greatly reduce amyloid formation (they disentangle amyloids), and also reduce the inflammation cause by AZ or Parkinson or even general dementia/degenrescence of brain. They increase blood TAC/FRAP/ORAC and improve plasma membrane redox system capacity. But to say taht senolytics 'stop aging/reverse it', is too much and far fetched; that is why I hold certain holding, reduction of p16 senescent cells in mice grreatly reduce their inflammation they live longer (average lifespan and improve maximal a bit); but Nothing miraculous. SENS therapy of reducing senescent cells (we have small % only otherwise it is catastrophic), small impact on Maximal liefspan in humans - big impact on Health.

Health different - seperate- from Intrinsci Aging (determines you live to 120 as human specie max).
Just a 2 cent.

Posted by: CANanonymity at September 8th, 2017 1:15 AM

@CANanonymity "Health different - seperate- from Intrinsci Aging (determines you live to 120 as human specie max)."

Health is not separate from aging.
The current usage of the term in a healthcare context is incorrect - the way you would use healthy now it means different things at different ages - obviously that cannot be correct, you're either healthy or not.

You shouldn't be able to define a person incapable of climbing a fly of stairs - healthy, even if he's 105. As example.

This is why building a database of biological markers of health is important. We need to disconnect health from the current "you don't have a chronic disease? then you're healthy" sophistry.

Posted by: Anonymoose at September 9th, 2017 9:45 AM

Its going to take some time to change the public's opinion on aging. Not only is this change necessary to assist the FDA in classifying aging as a disease.. but to get the public ready to pay the big bucks that these drugs deserve.

The money will allow the nascent industry to hire tens or even hundreds of thousands of scientists to do the R&D necessary.

The money flowing towards this should be looked at in a positive light. In the West we have untold amounts of capital searching for a yield. And we have several millions of young adults with scientific and technical degrees who are not utilizing their training or their full intellectual potential, to the benefit of mankind.

Senolytics and other promising areas of biotech, can absorb large amounts of scientists and large amounts of capital.

To show the challenge look at how many governments are under pressure to cut prescription drug prices. (yet cutting the funding will then shrink the industry, and thus slow their research and development efforts).

Posted by: aa3 at September 10th, 2017 1:30 AM

@Anonymoose

Hi Anonymoose ! Thanks for that. If we use the example of the C.Elegans (not that we should use this as the be all end all but still an applicable model (somewhat)) where there C.Elegans lived longer when their health was compromised (age-1 mg44 C.Elegans have a 10-fold lifespan elongation they are very Slow growth (and infertile) and low pumping (thus, weak), they live 250 days while the 'healthy' wild-types live a big total of 15-20 days (but healthier)); we have to rethink this whole thing. You are right, health is a part of our aging (I am not refuting at all, it is Linked to it, you need, humans it is far more apparent that health is critical to longevity (than in a C.Elegans whom can actually 'survive it' half-dead). IT goes a bit to our previous discussion about 'frailty' vs 'reproduction' vs longevity vs nutrients (mTOR...IGF) vs growth vs metabolism vs damage accrual etc...

''You shouldn't be able to define a person incapable of climbing a fly of stairs - healthy, even if he's 105. As example''

I second that truly. But, still, is this not certain irony - I am sure you need to keep healthy for many decades in order to Reach 100 years old; but, it seems, that like C.Elegans age-1 mg44 -we too 'can tough it' and can tought a sh*t-load of stuff (we have to remeber three main types of Centenarians : Escapers (never get any disease), Delayers (delays disease) and Survivors (gets disease and survives through it despite so)). If you saw the list of ills that they had, many Had Something at some point (though I do concede that IN General they did not have many diseases and were pretty disease-free (either delaying, escaping or surviving them if they had any); while, the rest of the populations get stricken with many diseases and it Does kill them. So it is hard to quantify the level of damage (as a centenarian Survivor of diseases) vs the impact of the lifespan; to be able to say Health is absolutely the Same as Intrinsic Aging. I'll concede to you, I might be scratching the bottom when there is none; but I am realisizing that so many elders are not healthy as said - and still live on anyways. As if, they are forces of nature (or like AdG analogy a very rusted car but it still hanging on (instead of going kaput like the other 'younger dying cars' (younger elders))).

You are right to say if we keep sick it is just incompatible and you need health (at least decent enough/about that threshold where organs fail) - but damage accumulates in them from intrinsic aging (time passing by). Aynways, I'm getting lost but I still feel they are connected but have their peculiarities, are dependent of each other but Health itself will not make you live to 250; only, if we meant 'Biorejuvenation' where you body was rejuvenated to a younger form of you/yourself (meaning removal of lysosome matter (lipofuscin), telomere change, mitochondrial fixing, removal of oxidative lesions, and so on and so on).
I would say that yes Health is the same as Instrinsic Aging. I kind of liken it to the proteasome, it's a necessite mechanism for you life but it is the ultimate decider of why stop living at 120-130. It is component and important, but only biological instrinc aging reversal would allow you above that maximum lifespan; health would just follow along because it is a necessite for general organ function.

@aa3

Hi aa3 ! True, I think we are still far (sadly, I wish it was otherwise I think we are too early (darn...for us whom are a few decades old). IT is just so snail-crawling slow pace, it's staggering. All this stuff should have been done eons ago, we're so late. But never say it's too late (and never say never (they say)), that'S optimism but let's not be blinded. I agree that senolytics have power to attract many investors and diver the moneys, kcik start this whole thing. But, I feel we have been talking about it a lot - lots of press and now, it's known....what next...the money is not coming and people not convinced (don't care and fatalist/think is bs, it seems doomed for the get-go when your team is nano0small). Rich individuals, yes, but they are a few. We need more tangible (i know that costs a lot) but like a rejuvenated mouse and then rejuvenated dog or ape - later, human. But, we should accelerate this whole thing, too long; bee talking about it for 15 years. snail pace death. We need rabbit pace. 2 cents.

Posted by: CANanonymity at September 10th, 2017 4:10 AM

PPS: typo. ''but it is the ultimate decider of why stop living at 120-130''; I meant it is not.
Health is very vague and is very much dependent of the same pathways (senescence, apoptosis, etc); You could die right away as your health decline but you still have a that 'gauge' (replicative guage for replicative cell counts) in you that says if you did not die you could continue on living (up to around 120 and then, clocks out).

Posted by: CANanonymity at September 10th, 2017 4:17 AM

There's more money coming in now than ever before. Maybe not directly to SENS but to the field nonetheless. There's tons of people involved in senolytics now, and there's a consistent amount of articles about them. That said, if we need a majority of the public to be on board for the FDA and other regulatory bodies to change their stance, then we're going to be in a world of trouble. Especially in the US, in my opinion. I feel like the general public has no idea about any of this, and is probably more hostile to it than not. However useless it may be, at least the TAME trial might be nudging the FDA in the right direction. It's not like more and more scientists aren't calling for more preventative measures for disease and targeting the root cause (aging) than ever before. Who knows?

Posted by: Ham at September 10th, 2017 7:11 AM

@CANanonymity
Intrinsic aging absolutely is reflected in health.
Or would be once we have some real measurements of health to use.
We cannot say what intrinsic aging is if we don't build true measures of health.

Telomeres were considered a measure of "aging" before but it doesn't take more than a cursory glance at laboratory murine breeds telomere lengths for anyone to see they are neither a big factor in longevity, nor quality of life, or even give any significant protection from disease.

The same could be said about any "accumulated damage" - just like ROS most of them seem to be a part of hormesis and activate compensatory and defensive mechanisms. So figuring out what is casual and what is correlative is hard or impossible currently.

As for senescent cells - removing them has led to certain interesting discoveries, fibrosis which has been considered "intrinsic" aging until now because it is a classical type of accumulated damage is not only halted but it seems also reversed in some cases when senescent related p21 gene is blocked. Not only are senescent cells removed but significant ECM remodeling takes place.

Posted by: Anonymoose at September 10th, 2017 10:03 AM

Has been investigated areas where people are living longer over 100 and blood work has been done on them to see any difference from any other people like in Sardinia Italy?

Posted by: ben droblas at March 28th, 2019 4:20 PM

@ben droblas
So far there was no significant genetic difference found(apart missing the major defects). It might boil down to pure luck, active lifestyle, forced calorie restriction and selection bias.

After all, siblings can can look. A few years young and older of their true age.

On the other hand it seems senolytics can bring wide benefits for various groups and cohorts.

The information that Gary shares about the ongoing OISIN study suggest that the benefits might be at least as good as a moderate calorie restriction.

And the answers are already in the pipeline. There might be a few setbacks, disappointments and busts after overly optimistic hype, but ultimately, senolytics will work for humans. The question is are we talking about 3 or 15 years for human results. 3 years, for example, means my parents could benefit from the first wave. 15 years would mean they most likely will not make it. And if it is 20, suddenly I will be needing them desperately.

Posted by: Cuberat at March 28th, 2019 5:35 PM

Interested in knowing more about how it will help type one diabetic's

Posted by: Sonia Flores at November 9th, 2019 8:34 PM

I hope this treatment can help me. 14 years ago I had colon cancer surgery at Scripps Green Hospital, La Jolla, followed with 6 month of oral chemotherapy (Xeloda), 2 week on, one week off. The initial daily dosage was very high, and on the 8th day my hands and souls of my feet were extremely sensitive, prompting the Doctors to stop the chemo. 2 weeks later, I was back on chemo at a lower dosage allowing me to complete the 6 months. Being cancer free for 14 years, I feel very fortunate to have the excellent health care Doctors at Scripps Clinic, La Jolla, CA.
Starting in 2019 I was experiencing lack of feeling in souls of feet.
Is there anyway I can be accepted in one of the trail treatment groups?
After reading this article I have added Quercetin to my daily supplements.

Posted by: Clifford Ellerby at October 5th, 2020 12:10 PM
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