Aubrey de Grey Summarizes Rejuvenation Research at the MIT Technology Review
In this piece at the MIT Technology Review, Aubrey de Grey of the SENS Research Foundation summarizes the strategy of rejuvenation research based on periodic repair of the cell and tissue damage that causes aging. This is a philosophy of development that has proven its utility over the past fifteen years, and especially recently with the growing data on senolytic therapies that remove senescent cells. Clearance of senescent cells was specifically called out by de Grey in his position paper in 2002, and he and his allies have advocated for it and supported it with research funding where possible since then. SENS, the Strategies for Engineered Negligible Senescence, is an assembly of all that is known of the root causes of aging, coupled with potential means to reverse or bypass them. If all portions of SENS were supported to the same degree as other lines of research into aging, then rejuvenation could be a near future reality.
There is a little history here regarding the venue. The editor of the MIT Technology Review was, back in the day, quite opposed to SENS and spent some effort attempting to find researchers willing to tear it down in public. This led to the SENS Challenge in which a prize was offered to people for success in proving SENS wrong. That came to the expected result, as SENS back then was, as it is now, based on a very large body of research and data, yet a decade ago the culture of science and the popular culture was inclined to dismiss out of hand anyone who talked rationally about treating aging as a medical condition. SENS was correct back then, and it is correct today; the only difference is that a great deal of work has taken place in the intervening years to persuade the scientific community and the world at large that, yes, building therapies to address aging is plausible, practical, and possible. The culture of aging research and the public perception of this research is now very different.
Since the dawn of medicine, aging has been doctors' foremost challenge. Three unsuccessful approaches to conquering it have failed: treating components of age-related ill health as curable diseases, extrapolating from differences between species in the rate of aging, and emulating the life extension that famine elicits in short-lived species. SENS Research Foundation is spearheading the fourth age of anti-aging research: the repair of age-related damage, that is, rejuvenation biotechnology. The Strategies for Engineered Negligible Senescence (SENS) approach was first proposed in 2002; we seek methods to convert a population experiencing a non-negligible level of senescence into one experiencing a negligible level.
To see how the goal of negligible senescence could be "engineered," it is useful to consider a situation in which human ingenuity and perseverance has already achieved an analogous result. Motor vehicles experience a process of wear-and-tear essentially similar to organismal aging; the paint flakes, windowpanes chip, rust infiltrates the pipework, and so forth. Nonetheless, as vintage car owners will attest, it is entirely possible to keep one functional for an essentially indefinite period. Critically, this is achieved not by preventing the wear but by repairing the damage that does occur at a rate sufficient to ensure that the function of the machine is never irretrievably compromised.
Aging can be characterized as a three-stage process. In the first stage, metabolic processes essential to life produce toxins. Secondly, a small amount of the damage caused by these toxins cannot be removed by the body's endogenous repair systems, and consequently accumulates over time. In the third stage, the accumulation of damage drives age-related pathology. This model - metabolism causes damage causes pathology - allows us to clarify the requirements for successful intervention in aging. Unlike the dynamic processes of metabolism and pathology, accumulated damage represents a relatively stationary target. That is to say, it may not be clear whether a given type of damage is pathological (on balance), but its absence from healthy twenty-year-olds indicates that it is not required for healthy life. Conversely it is clear that the total ensemble of types of damage in a fifty-year-old is pathological.
Accepting the implications of this model leads us to the SENS approach; by identifying and repairing all of the damage accumulated during aging, we can restore the body to a youthful state. Consequently, its dynamic metabolic processes will revert to their own norms, and the risk of mortality will be no higher than in any other equivalently "youthful" individual - whether they have actually lived for twenty years or 120. Furthermore - so long as our inventory of damage classes is sufficiently comprehensive - we can repeat this effort on a regular basis, and thus remain indefinitely below the threshold of pathology.
SENS is a hugely radical departure from prior themes of biomedical gerontology, involving the bona fide reversal of aging rather than its mere retardation. By virtue of a painstaking process of mutual education between the fields of biogerontology and regenerative medicine, it has now risen to the status of an acknowledged viable option for the eventual medical control of aging and its credibility will continue to rise as the underlying technology of regenerative medicine progresses.
Link: https://www.technologyreview.com/s/609576/undoing-aging-with-molecular-and-cellular-damage-repair/
Good to see more and more Aubrey de Grey in the public! Hovewer, I believe he have to not only say how SENS is good but show the amazing results from a lab, which is no problem now.
"There is a little history here regarding the venue. The editor of the MIT Technology Review was, back in the day, quite opposed to SENS and spent some effort attempting to find researchers willing to tear it down in public."
Yes and Jason Pontin still continues to oppose SENS. Look at the pathetic slap fight he engaged in last year on Facebook where he literally started name calling Aubrey and tagged him in his post. Then he clammed up and refused to discuss the science behind his objection when challenged. Hilarious!
Still good to see Aubrey getting some deserved attention in MIT.
One thing I've never understood about the opponents of SENS is that even if there is some damage out there that science is just nowhere near removing, and we are all going to die pretty much on schedule because of it, SENS damage repair is still the most cost effective research approach to healthier lives.
How opponents go from assuming that indefinite lifespans are impossible to basically implying that little or no funding should be spent on repairing the damage underlying aging is a bit of a mystery to me.
@Jim, I very much agree with your comment. Society is so irrational, it is quite frustrating. Very naive people, such as Jason Pontin as Steve H mentions drives me crazy.
I saw this article a few days ago and was happy to see Aubrey getting closer to the mainstream news. I hope to soon see his name and senolytic therapies on the front pages of daily newspapers. It is well past due, IMO.
Hi there, just a 2 cent,
I believe it's a combination of things as to why it may be a mystery to some. I think it is great that AdG is going forward and kind of minding his own, but a part of me sort of empathizes with the why certain people still say no and don't believe in it/him (SENS/AdG), or just 'rejuvenation' altogether. It's because it's a bitl ike cryonics, it suffers from 'unkwown' effect or that 'creepy' effect of trying to play with the natural order (we live/we die). Most people don't know what it is (or care to). We fear what we don't know (a natural human response). We fear what tries to 'change things' (in general) or change the 'order' of things/status quo. SENS is definately a small revolition in the making (in a small jar so far, hopefully an ocean later). But for many it's no different than metformin, rapamycin or any other anti-aging method vying for a small parcel of their attention (and money and time). A bit like Cosmetic business for women, but in the anti-aging section (like anti-aging creams for beautfiul faces in women, I smile when I see this (and sigh/laugh slightly at the futility); at least they are trying but I think why just a cream christ...why not something that literally reverses aging and your face will get young again. I might be overly optimistic, but I really believe rejuvenation is the only solution that will work (enough) so far; because everyhting else (other methods so far) is just slowing aging slightly, live a semblant of better health/life quality and then you die (so not much difference))). It really makes me 'happy' (not) thinking a bout it. I think what we need is more Proof is in the Pudding from AdG and SENS....but it's not there yet, as such people still think it is 'fringe' and can also think he/the endeavor is 'full of it'/snake oil - Even if papers and Research disprove otherwise - it does not matter. People don't care. They will care Only when a mouse is rejuvenated and
so AdG has no answer but making 'talks' (which is a good thing/advocacy/getting funds...I'm not saying otherwise he made so much good but being the One who spearheaded this whole thing and got people talking about it in the first place...but now...we are a bit like at a long Kickstarter/indigo campaign....years after it started, the backers (investors/donors) WANT to see something concrete they expect it from you (they invested inyour 'product'); the senolytics proof therapy is a start but it took so long. And from the results in these online crowd funding campaign you realize something; if it goes on and on and on with Nothing to show - it's doomed. As such, you have to Back your Words with Concrete Tangible stuff or else people will abandon ship. I'm not talking about 'glucosepane has been finally recreated' to be studied to find a crosslink breaker or we made senescent cells be 'cleared' as junk....that's Nothing.
What we need is a mouse that is DEaging or some Physical results on that body/animal. But nothing so far, so we are swimming in the 'unknown' (and unknown campaigns on Kickstarter fail miserably); we need results and there has been enough FUNDs going towards this; why are people are going to be More willing to Send MORE funds, it's not working. It's also a chicken and egg thing. From one side we need FUNDS to make it happen Faster than NEver, but from the other side is it taking too long (TIME is money); people die each day..etc. Now the counterargument might be : Well, if it does Cure most everything it will be worth the wait. True. IT's just people are giving up' and sort of like 'nah...it's bs, snake oil, I've thrown all my money in this money pit and what comes out of it...'promises and 'advancement's - Vapor Air aka Nothing (except AdG making More 'talks/conferences' saying 'it will happen'...no so far, that's not the case and it MIGHT it might not, it seems too much of a Large Project that requires too much funds,resources, people and too much time. In kickstarter campaings it's called 'you will fail' because you underestimated the Needs that will be incured to accomplished such a Astromnomic Goal as such you ''OVERshooted' (you ''Aimed for the Moon'' but you realize you will only get to the earth stratosphere and then fall back down because it is humongous in requirements/ needs))))'. We have to remeber that cancer/CVD/diseaess and other have poured TRILLIONS of dollars and gotten knowhere (albeit the methods were wrong, where rejuvenation works or least should because it works on the cause of aging (damage/junk cumul))). Still, it does not change the fact that huge amounts of money have been thrown and we are still at square 1. As such people are sort of 'not buying it' that throwing money at rejuvenation is 'wise', until they have ANTTHING tanhible to show/Prove their words/Preach what they say by example (study example showing a mouse rejuvenated somehow and not 'a little' but a lot, otherwise peple will be like...this no different than Rapamycin, Senolytics (red wine quercetin) and sh*t...like that so yeah Unconvinced and Unworthy/worthless/'pie in the sky' dream-lie or snakeoil altogethere (it is not inherently charlatanistic, it is seeks good but it has only 'words' to show so far, that'S the problem; while rapamycin/metformin EXIST for real, and shown to help (such as in diabetes type II, father taking metformin and controls blood glucose/HbA1) and as such why gerontolgist Back that over SENS and other 'mirage' rejuvenation or worse, 'cryonics', this is very Ethical stuff you get into when you touch on cryonics, and rejuvenation too; becaus they could allow eternal life possible as such people don't like 'Change' of things; they jkust like 'give me a full health' and I die at 99 years old; I'll be happy to kick the bucket...sigh).
Just a 2 cent.
I have spent a couple of hours reading the links to old 2005-2006 articles, here at FA! and outside. A very interesting reading indeed.
This year the goal were only exceeded with $ 1497. Thats scary! Have people as CANonymity writes lost hopes?
@Gekki: I think it is the case that much of the fundraising in our community this year has been invisible. A lot has been raised, but look to the startups and the funds as to where it has gone. Because of the SEC these groups tend to be less open and frequent about communicating the results of their fundraising.
We still need to fund the non-profits and their work. A balance must be found, and we should take the current fundraising signs as a signal that much more needs to be done to expand the community and reach new supporters. It is a challenge.
I think people are still turned off by any talk of immortality or 1000 year lifespans, not that Aubrey ever uses such terms anymore. But then you don't want him to sound just like the rest to the healthspanners, which is basically a done deal now and not very ambitious.
In a nutshell the problem is that you need to demonstrate results to get the big funding, but you need the big funding to get the results. Otherwise you have to convince some billionaire based on hints that this can be done. We need someone like Elon Musk to literally drive this to some sort of implementation, even if that is only a partial rejuvenation. Think Calico but with a rocket under their arse. As things stand I think we are in the situation where something on the cards now might exceed expectations, like senolytics or stem cell therapy, or maybe in vivo cellular reprogramming or telomerase therapy.
Otherwise it is just slow attrition, chipping away at scientific consensus and public opinion until the weight of all arguments breaks the dam. But for that I suspect we'll need more results.
Well, Michael Greve came just in time, the same year that Aubrey's own funds were exhausted. He can't expend the amount Calico is expending in its projects, but it allows SENS research to continue at its pace.
Jim Mellon's future actions are a big question mark. Will we see some donations of him to SRF or only investment in (SENS-related and SENS-unrelated) biomedical companies?
As for the year end fundraiser, I don't know what happens. Maybe the number of supporters is reaching a ceiling? It doesn't seem so when accounting for Youtube viewers or Facebook likes. Or maybe they don't have money? I myself am in the latter situation, but I don't assume it's so common. Maybe it's as Reason says, people are investing instead of donating.
I think that if something doesn't exceed expectations quite drastically and quite soon, the debate will drag on for decades. Even on this blog life expectancy gains for senolytics are estimated at 5 years, which is more or less what you can already get by tinkering with metabolism - even with one single intervention (see bisphosphonates). I can't see why another one of these small improvements would shift things into a higher gear. Big paradigm shifts require big results to say the least.
@Barbara: While your prediction can be true, there is a big difference between senolytics and bisphosponates. The former are in trials or proposed for trials for many diseases, from lung fibrosis to osteoartritis to adjuvant therapy against adverse effects of chemotherapy. So they are a big bussiness opportunity, even when not targeted against aging. I would not be surprised for glucosepane breakers to become a similar case: against blood hypertension, as skin cosmetic treatment, etc.
@Antonio: For all intents and purposes I can't see the difference between a drug that adds 5 years of extra life by reducing all-cause mortality and a drug that adds 5 years of extra life by curing (or better, ameliorating) one, two, or seven age-related diseases.
The argument on this platform is that senolytics are "different" because they repair damage rather than push metabolism into sidestepping it, but if the end result is exactly the same, where is the practical advantage of the first method over the second?
If senolytics or glucosepane breakers or any other of the engineering-based interventions advocated by SENS and the Hallmarks don't generate an absolute WOW of an improvement, Aubrey will be giving these talks until he looks like Methuselah himself.
@Barbara: "Even on this blog life expectancy gains for senolytics are estimated at 5 years"
Hmm, if this is the expected increase in extending life outside of additional rejuv treatments, does anyone have an educated guess when the next one or two treatments (2nd or 2nd/3rd lowest hanging fruit) could come on-line and the estimated additional life extension.
I know these are very rough guesses but getting just an additional 5 years here or there is not too exciting (better than nothing, I suppose). I was thinking/hoping each rejuv treatment could yield at least 10 additional years. I realize that other components of the 7 causes of aging keeps getting more dysfunctional until it gets repaired or we may incur sickness (or gone) in the interim. And, yes, some of these repairs probable work in conjunction more effectively with others of the 7 rejuv repairs (synergy?)
Hopefully, there is a lot of work going on behind the scenes and we will be seeing increases in advancement each year with each of the 7 rejuv repairs. Thankfully, Reason in helpful in keeping us abreast of some (most) of the advancements.
Barbara:
I think we must distinguish between why senolytics are different for us and why they are different for pharma companies:
1) For us, they are different because, when joined by the other six SENS treatments, we will reach LEV.
2) For pharma, they are different because they can be trialed and sold for many specific diseases, instead of a fuzzy 5-year survival increase for all-cause mortality. The former is big bussiness, the latter requires at least a political reform in the FDA and even in that case it would be less salable to the average customer.
So, because 2), senolytics will be developed fast and become a big leap forward in the race for LEV, even if the companies selling them know nothing about LEV or SENS. And, once developed, they will be a very strong argument for the validity of SENS. For people like Pontin or Estep, it would be very difficult to continue discrediting SENS or AdG. It would also change the opinion of more and more gerontologists about SENS, and that will change the grant landscape, at least a bit.
Yeah, a 5 years increase is a 5 years increase, but people will see it differently, because the possibilities are different.
PS: I have relooked the 7 therapies and just made a wild guess like that (guessing is bad I know, just conjecture and extrapolation for the fun of it (just a 2 cent))) (TLDR: it's long)
-RepleniSENS: I believe this one will improve healthspan and thus somewhat, lifespan; average lifespan. The point is that you would replace the organs with new organoids/stem cells made from the adult cells of the own person. It has potential but hurdles. They wish to make the cells be embryonic-stem-cell like from adult cells; and then go on to repair/differentiate into whatever organ cell. By reprogramming to embryonic state their are reversing epigenetic clock and telomeres must have risen. From studies that did stem cell reprogramming to rebuid tissue, it was an improvement of healthspan of about 20%; which would translate at 20 years in humans; but since it is a mouse you can half it (effects are stronger in mice and weaker/non-existent in humans); so about 10 years healthspan extension (average lifespan). I think that RepleniSENS can achieve that (about 10 years), maybe more if there are many more types of cells that are targeted; it will depend on the body 'reach'. Replacing old organs to 'juvenile-like enough' organs is one of the most powerful approach because it circumvents so many problems. But we haev to build these 'young' organoids (from our own old adult cells through reprogramming)).
1.Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model
https://www.nature.com/articles/ncomms1611
2.In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming
http://www.cell.com/fulltext/S0092-8674(16)31664-6
-OncoSENS: This one is very intriguing and freaky at the same time; because we don't know the implication of WILT approach that they wish to do. WILT(Whole Body Interdiction of Lenghtening of Teloemres (by Telomerase)) is very interesting, it makes much sense. Most cells (somatic ones/post-mitotic ones) have very little telomerase activity or barely/none. As such, it would be not so dramatic, except for one problem; certain cells do make us of Telomerase (besides the cancer cells) and that's the immune cells. As such, it is a gamble to Cut Telomerase Entirely in the body when certain stem cells depend on it (though they do they say this therapy is just once a blue moon as such teh stem cell pool is not affected enough to show loss of tissue renewal; like a very 'occasional' (once in 10 years) thing, it would be not dramatic - but it still does not solve the fact that certain immune cells use telomerase -and They Are Responsable for Detecting/Killing Cancer (NK cells, T-cells, macrophages, WBC...). As such, WILT could increase the possibility of mutations because immune system will be weaken by WILT and, though cancers will not highjack Telomerase) they will abuse ALT (alternate telomere lenghtening) in order to survive (they will adapt - and OUTWIT - WILT). Telomerase is very present in many cancers that's true and as such a heavy blow to them; but not Winning the War; just one battle. I greatly hope that we can sort 'Finish them off' with heave WILT blow and then use some other technique to stop them from 'converting' to ALT as an escape route last ditch survival effort gainst elimination. Safe that say, that the burden will easily be halved but there will be 20-33% whom will use other tactics to beat that therapy. Just like when you kill bacteria with kitchen germkilling product - it kills 99.9%, there is still 0.1% left and it can 'grown' to a 100% again (albeit it will take an immense effort but cancer cells are know for that/survival at all cost and by any 'cheat' possible). There won't be any lifespan extension from this therapy, except 'healthspan' extension (if it works as planned); by removing cancer ..and living your 'regular' healthy life (cancer-free up to 122).
-MitoSENS: This one too is very special and we don't know how much it will really impact. From my wild guess, it will be more therapeutic than lifespan extending. It will be akin to MELAS improvement or Progeria improvement; mitopathy mutation solving. IT should improve ATP production and improve Complex I, III, IV respriation/ETC in the mitochondria; thus more efficient, ATP maintenance. Does this change the problem of 'replicative senescence' or epigenetic clock becoming 'old', it does not. It is mitochondria specific thing. And will surely improve many mitochondrial defects and mutations. It will improve healthspan, and also lifespan; possibly a bit above maximum lifespan because your health would be kept much longer and replicative senescence would be slowed/along with telomere attrition. If you look at something like mitochondrial targeted antioxidants like CATALASE or Ubiquinol; they improve ETC and Complex function; thus better mitochondrial respiration/ATP. And they increase lifespan in mice by around 20% (again), half it for human result (10 years). The synergistic effects of the 7 therapies will not be 7x7x7x7x7...it will be much more 7x2..or something because there are MAny Redundant pathways and as such the 'effects' of each additional therapy is 'halved or quartered' since it works on the Same pathways or uses 'connecting ones'. They don't 'add up or multiply' in power; they just do their job through similar pathways that another therapy uses (in part). This is a limitation of the body ('rate/passage-liming').
3.Ubiquinol-10 Supplementation Activates Mitochondria Functions to Decelerate Senescence in Senescence-Accelerated Mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025630/
4.Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1
https://www.ncbi.nlm.nih.gov/pubmed/28209927
-ApoptoSENS: They aim to stimulate the immune system to target dysfunctional cells for degradation by proteasome or litteraly engulfed by macrophages/T-cells/NK cells. This is in contradiction to the first therapy (WILT) because you need telomerase for immune activity; as such it conflict (the two therapies should not be done at the same time or else conflict with each other on some points). A weak immune system by WILT will make a catastrophic problem where APoptoSESN will not be able to profit from immunity (because it's gone). While removing senescent cells will definately Improve Healthspan - average lifespand and a bit Maximum lifespan (the replicative senscence will be stalled 'slightly' by this because you're health is kept in order by removing inflammation (that accelerates aging) from SASP senescent cells when aging). It will not stop replicative senescence only delay it, the course will continue and telomeres will shorten (and WILT will accelerate that). This therapy I would wager about 20 years healthspan extension at the best scenario otherwise it would be 5 years or less (10 year avg) in human.
This estimation is based on p16-ink removal in mice giving about 20% lifespan extension.
5-Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
https://www.nature.com/articles/nature16932
AmyloSENS : This one could have dramaTIC effect, or not. Most likely not, but it's not sure. Because it targets the JUNK, yes so it is Good Thing. Amyloids are protein aggregates and Protein Aggregates have extrmely detrimental effect on lifespan; in fact, slowing this would have largest impact on health and lifespan. humans start to have 'clumps' and other junk proteins/unfolded very Early and it continues on for life and contributes to the 'burden' in the lysosome (lysosomal mass) and other junk. Plus, people with alzheimer's/parkinson/hutchison/dementia/dengerescence/and other mental problem would greatly benefit - a sharp mind and a sharp WiTs = more chances of a long life and slower attrition of brain size (brain pruning with age; centenarians keep a 'younger-like' brain and 'bigger' one (less involution/less greymatter and whitematter loss over the decades)). And, also, NRG = MLSP, brain Neuregulin levels equals maximum lifespan in mammals; keep your brain active and amyloid-free is more NRG activity/longer. Also, more BDNF (brain-derived neutrophic factor/brain neurogenesis/synaptogenesis/keeping your memory and no mem 'holes' by Beta-amyloids protein clumping/aggreation of aging that makes your brain a a swiss cheese full of holes filled with junk amyloid plaque). Also, Transthyrethin in the heart in the supercentenarians - this therapy would have certain impact there and would improve our chances of beating Maximum 122 because we ermove the element that keep supercentenarians from 'not dying' : heart brown pigment transthyretin. I would guess about 20-30 years improvement. So 25 avg.
-LysoSENS : the big kahuna...this one could change everything and I alwaus believed in it more than all others. LysoSENS has the power to remove the junk also and especially, the lysosomal one (LIPOFUSCIN, the AGE PIGMENT that kills us slowly)/autophagy/proteasome function, would this translate as extreme lifespan elongation I am not sure but it would have a strong impact for sure and I am even cautious because cells' lysosomes have become 'adapted' to this lipofuscin and lifposcin itself stabilized lysosomal membrane; so it's like...ok, we want to remove it but will it be consequential because it BAD but 'helpful' too...a paradox. I think it should not be eradicated because it could unbalance the finite balance in 'aged' lysosomes (that have had lipofuscin since birth dumped there and staying there). Still, one study showed that lipofuscin Reduced in a lobster after eye stalk removal which meant the body was compensating for eyestalk removal and there may have sort of 'rejuvenated' the lobster. We have to remeber that cancer cells do not accumulate lipofuscin (and are immortal (no Hayflick/immortalized), in part, because of that) and lipofuscin cumul is correlative of Replicative Senescence and thus, of telomere length also. I would say that this specific one could allow 50 year lifespan extra, about half human life (in best scenario and in a 'surpise' scenario could offer centuries lifespan or near infinite; but you would need to fix the rest; it would not do this alone as a single therapy).
Total : [10 + 10 + 10 + 25 + 50] / 2 (because you have halved it since redundant pathways thus weaker 'combined' effect than one therapy alone) =
52.5 YEARS (approx.)
Extra in health-span/average lifespan and this would 'overlap' on the maximum lifespan; it would increase it but not by 55 years that is if SENS therapies are started at 110 years; you must start at the age of 40-60, no more. And this is in the BEST scenario and with 100% response in the patients. If not you have to 'divide' the number even further. If that last LysoSENS therapy is not as powerful as hoped we can bring it down to about 10 years.
As such, the recaculation would be:
[10 + 10 + 10 + 25 + 10] / 2 =
32.5 YEARS.
And at worse, if it is a 'third' the effect (not half) it would be
[10 + 10 + 10 + 25 + 50] / 3 =
35 YEARS.
Best case.
or worse case
[10 + 10 + 10 + 25 + 10] / 3 =
21.5 YEARS.
Conclusion we have a range of 20-50 years or an average of 35 years in second-best scenario.
Of course, all of this is nice, it sure it NOT LEV. LEV has a possibility to escape death and though AdG will say do the 7 therapy and you get an extra 35 y avg...it is implied/supposed/presumed/assumed/'hoped' that...once you would Do it Again in 35 y you would go 'back' to your 35 BIOLOGICAL year earlier while gaving aged 35 years chronological in real time. And ad evitam eternam 'repeating it' to repair the damages. I think that is where we may hit a stumbling block and the 7 therapies don'T seem to addres certain porblem of aging (epugenetic clock, demethylation, replicative senescence, eand so forth; and thus, why LEV would fail and SENS would be a Very Strong Therapeutic effect but not giving you LEV either. Again this is just conjecture).
Just a 2 cent.
It may well be that there won't be a wow moment when we are seen to have beaten aging, but it will happen all the same. Main stream media may still be painting rejuvenation as a fantasy, whilst missing that old people are more like what middle aged people used to be, still playing tennis, and working at 80, and not getting heart disease or cancer at nearly the rates they used to. And Hollywood stars will be looking young, not in a fake way like now, but genuinely with glucosepane breakers and senolytics targeted to the skin, and sports people are still competitive till 50 with stem cell infusions in their knees, etc. And even we won't be sure we've reached LEV even though the new treatments are still appearing, not all effective, but just enough are, until finally we realise we've made it!
That's my vision for how it will happen, anyways.
@Antonio
Why is the assumption that senolytics "will be developed fast"
Before a company like Unity doses their first patient, assuming they are done all their in-vitro pharmacology and animal models with an optimized candidate, they still need to go through and finish all their analytical assays in multiple species, dosing formulation development, PK studies, ADME studies, Cytochrome P450 studies, hERG / purkinje fiber studies, safety pharmacology studies, dose ranging studies, 14 day repeat dose tox studies, 3 month repeat dose tox studies, genetic tox studies, and even some minor CARC work.
Beyond this blog, senolytics carry no special status in the world of drug development and regulators
They need to get in line and prove their value versus everything else
And, no, drug development never has it's WOW moments for anything beyond the immediate gratification or short term success
Viagra - Wow
CAR-T result in end stage patient - Wow
Most everything else - zzzzzzzzzzzzzzzz
DrugDev: Of course, 'fast' means 'faster than average drugs' not 'faster as never seen in medicine'. Almost every month there appears a new paper that shows that senescent cells cause X disease or that eliminating senescent cells help to treat X disease in preclinical studies. That means more companies investing in senolytics. And that means a faster development than usual, because there are more shooters aiming at the target.
To be clear, it's not like the average pharma manager saying "Wow, senolytics are awesome! We have to develop them!" but more like the number of pharma managers saying "Mmm, I think we should try to develop a senolytic" to be above the average for new kinds of drugs, due to their wide applicability.
Antonio wrote: "I think we must distinguish between why senolytics are different for us and why they are different for pharma companies:"
@DrugDev U.S.: I think he where thinking that it will be developed faster than if it were to be based on not for profit.
@Antonio: You wrote: 2), senolytics will be developed fast and become a big leap forward in the race for LEV, even if the companies selling them know nothing about LEV or SENS.
Then I came to think that since its not in all interests to extend life as much as possible I think we should keep quiet and not write to much about our intentions. That might awake the opposition and we loses time.
Gekki, I don't think big pharma really cares or even knows what we say. The same for the general public. Life extensionists are a very small niche community. Almost all people don't know we exist, what LEV is or what cryonics is.
Where should we place the funding emphasis in life extension research? I think to begin with, we should emphasize crosslink A.G.E.. breakers. The reason for this, is that this research would, if successful, provide a WOW moment for the SENS program, because it would be so noticeable, young skin, no wrinkles, everyone throughout the World would say WOW, that's impressive. And think of all the other problems it would help address, like stiff muscles, aching joints, arthritis and lower back pain, blood vessel stiffness and many other CVD symptoms, kidney disease (nephropathy).
@CANanonymity, Antonio: The only strategy we can attach a pretty much definite number to is WILT, because we know that by eliminating all cancer we would gain approximately 4 years of extra life. I don't think that gains can be extrapolated from animal studies, firstly because they don't translate well to humans, and secondly because the SENS damage categories impact different systems - some of which specific to us - and do so to different degrees.
Again, we know that our risk of dying doubles roughly every 8 years, so if senescent cell clearing were to reduce the incidence or mortality rate of all main age-related diseases by 50% we would live 8 years longer; if it reduced it by 75% we would gain roughly 16 years and so on.
It doesn't look like any of the SENS strategies in isolation will have an effect on all mortality causes though, so even if senolytics cut cardiovascular diseases, respiratory diseases, diabetes, and cancer in half, we would still live 8 years longer minus the years lost to the killers that this therapy is unlikely to do much about - if at all - like Alzheimer's.
My point is that unless it turns out that senolytics can reduce mortality rates in the elderly by over 50%, it is highly unlikely that anyone will wake up to anything anytime soon. As DrugDev pointed out: "beyond this blog, senolytics carry no special status in the world of drug development and regulators", so expecting the tide to change with the first trials is extremely optimistic.
In fact, no single intervention - SENS-based or otherwise - is likely to produce results that would be even noticeable outside of a carefully designed epidemiological study. Perhaps the spark for a true revolution could be ignited if someone decided to test a combination of different therapies at once hoping for a large effect, but realistically: who would have the ability and motivation to do so considering that people/efforts in this field are stopped by patents and moved by profits?
For multiple reasons I agree with Biotechy that cross link breaking should be the primary focus of current longevity research. I doubt that will happen though because other areas of research provide more patentable molecule solutions.
Barbara:
I agree that the effect on lifespan of the partial application of SENS can't be predicted. My comment was only a reply to your 5 years vs 5 years comment. It didn't mean that I agree with the 5 year prediction. The SRF guys always say that the 7 categories are interrelated and probably you will need to address 6 or 7 of then to see a change in lifespan. OTOH, even without SENS, we are seeing a rather predictable rate of life extension in the last century or two. So I really don't know what LE will senolytics bring.
OTOH, the effect on particular diseases, like osteoarthritis, is a different story. As I said, this will differentiate senolytics from bisphosphonates.
@Barbara
Hi Barbara ! I agree with you that in general we can't really use mice studies as proof or extrapolate much from them; but they are still an estimate. In general, studies in mice, flies or other animals have yielded (in general) bigger impact because of their lifespans : they are not optimized (like us humans) for extreme longevity (we have more genetic repair and longevity genes and host of other things that allows us to live so long; from our body mass humans should live about 25 years no more; but we are the exception to the rule in mammalia; just like naked mole rats who should live 2 years no more (like mice) but go on living 35 years), as such these short-lived 'handicapped' animals gain the most when they are used the research animal. And, in general, so far most studies that have seen results in mice have seen little to no results in human; it has rarely, if ever, been the inverse. I.e. where a study result will be Much More powerful in Humans than in mice. And that's because we are already optimized (by evolution pressure on our longevity genes)). As such, we don't benefit, mice or flies or C.Elegans do...they are short-lived. It's also why I divided my extrapolation by 2 or 3; and I was generous, I could divide it by 4 or 5 or more...because of gene/pathways redundancy in the therapies and because we are humans are Already live long; while mice don't as such one more reason to Divide the extrapolation estimation even further..until we pretty much have No lifespan extension whatsoever. I can understand that we could say that certain therapies can affect us more strongly than in a mice, and that's true but, in general, mice are 'sort of' 'alright' as a model they are not best that is sure but they give a 'sort of idea'. And when their results are replicated in house flies or C.Elegans it means something; that short-lived gain Gains, we don't. Our closest animal cousins, are the apes (and also studies done on dogs, pigs, or other large mammals that live long-enough) and studies in them have been very 'mix bag' and conflictual/ambiguous...so it does not look good. If we can't even make a rhesus macaque live much longer on CR (calorie restriction) or other therapy like SENS, it is why I would feel that you need to Divide the extrapolation even more because if Apes don't live much longer by the SENS therapy; then Our chances, as humans, are nearly nill (since we share so much in common with them, biology wise))). All the extrapolations I made are very 'out there' and we don'T know, but so far; as you said yourself, it has to be WOW and it does not look like that. It will help healthspan for sure but on the question on lifespan elongation that is where we are in the unknown; in theory it should help but the results have More Chances of being Weaker, than Greater. Thus, more Not Wow, than wow. The way I see it, it is possible that all 7 therapies will be much more therapeutic and will improve our health to Allow us to reach our Maximum Lifespan; and that is where the buck stops. It will not (or not by much) increase the Maximal lifespan, the maximal lifespan is in correlation with telomere length and replicative senescen (Which the therapies don't address), as such the 'limit' is still there, it will just be 'post-pont' slightly above the 122 limit; I wager 20-25 years (half the 52 I predicted), and allow humans - the most genetically gifted - to reach 150 (if they start SENS Very Young at 40 years old or so)). Above 150, Very Very Very doubtful - hayflick limit (replicative senescene telomere dependent. And it is why I believe replacing organs to 'young organoids' - your whole body/Entirely - is only solution to this problem)).
Just quoting you (quote me no problem! :)
''Again, we know that our risk of dying doubles roughly every 8 years, so if senescent cell clearing were to reduce the incidence or mortality rate of all main age-related diseases by 50% we would live 8 years longer; if it reduced it by 75% we would gain roughly 16 years and so on. ''
Exactly, but it has a 'limit' of it; even after 100% removal (which would be analogical to a babybody), it does not stop the continuing of aging. Senescent cells contribute to inflammation (by secreting SASP (senescence associated secretory phenotype)) which creates accelerated damage and 'diseases' of age. But, IF, they are removed as in the study I pointed (p16-ink4a mouse study) they gain approx. 20% lifespan extension because a large amoutn of these senescent cells are removed - which is exactly what itaims to do - will this cut mortaliy by 50% or even 75%, if extrapolating (I know not the best but just as an example) we would gain roughly 10 years in lifespan - no more. Which mortality is reduced by 50% we get 8 years extra, then it would be about 60% reduction in mortality and no more (over an entire human lifespan)), that would be the Limit of the Effect of this therapy of senolytic/senescene cell removal.
To reach 100% mortality reduction it would take much more than that. Mortality is going to happen in the 80-120 brackets and keep on rising. The mortality % will rise again (because, as said, intrinsic limits do not allow you to keep 'reducing' mortality % infinitely)). And the Effect of SENS as you age, will be lesser and lesser; so it is why you must do it in the early part of life, not late because or irreversible damage/junk accumulated in old age.
The cells we have have limits and no much can circumvent that. Only total replacement of yourself can (which organoids/cells that are embryonic like). Rejuvenation is just that, it is going back to the 'young' self when you had less damage/junk/younger epigenetic clock/away from replicative senescene cell limit).
So, in a sense, we are saying the same thing; it will take a Wow effect to get that 35-50 year lifespan extension by 7 therapy-combo and as you said, if other senolytics can't even make that, why would other SENS therapy give much beyond 4 or 8 years extension. That's a reality we have to face. Still, as many have said, what Else is there, nothing; it's the best there is so far so we must keep on hoping it turns to be better but then we realize why many people think it is not going to work (as well as planned, such as LEV which may overshoooted WaY above and may not happen altogether (I sincerely hope not but from the study results so far it does not support LEV or any WOW effect. But, we have to remember we are Tackling the BiGGEST thing EVER - aging, it 's monumental nearly Undefeatable, it's why we are losing to it rather than winning (after having thrown trillions of dollars in curing diseases and got nowhere. Must keep hoping nothing else to do (we die anyway so why not try our best, if we get 15 years extra, we get that; it was not in vain))))).
Just a 2 cent.
Well humans suffer more from things like lipofuscin and glucosepane because of the length of our lives, so clearance here would likely be a game changer for human life extension but probably wouldnt do anything for mice. Also, although both humans and mice suffer from cellular senescence, mice suffer more because of replicative and oxidative stress, whereas we probably don't suffer from such a large contribution from these two causes of cellular senescence but more from cells slowing because of shortening telomeres. So stem cells or telomerase might well do more for us than mice. Will be interesting to see once human therapies start in earnest.
Hi Mark !
Thanks for that ! Just a 2 cent,
It is intriguing ... I hope it does turn out better. I am also wondering the impact of removal of lipofuscin and glucosepane/AGEs and other crosslinks. Different studies that have shown lifespan extension were accompanied by either no change in lipofuscin or almost always a reduction of it or a slowed accrual. Likewise for glucosepane. It's the extent of the effect that I am curious. I really believe in LysoSENS and GlycoSENS because they will tackle lipofuscin (lysosome mostly) and glucosepane (skin/cartilage ECM), respectively. A study had researched to effect of lipofuscin on aging, when it was inserted in the proteasome/lysosome areas it clogged the proteo-lyso systems and accelerated aging, demonstrating the completely need of our proteasome/lysosomes because they degrade so much unfolded/damage junk, and I wager that through cell cycling some lipofuscin is diluted or at least 'spread/dumped in' to daughter cells since it is undegradable (though LysoSENS will have an answer (hopefully) in the form of a bacterial enzyme that degrades lipofuscin (akin to Sudan Black dye that can degrade lipofuscin or 'bleach it' if you will). As for glucosepane, hopefully a glucosepane breaker will finally be found but after reading (SENS' Michael scientist's) very deep comments (a year ago or so here), it is Very hard to deci^her this one (getting the enzymes or the MMPs (matrix metalloproteinases) to just 'Reach' the molecular environment in the ECM is very very hard (they can't 'get to it'); and why 'cutting/breaking glucosepane out' is near impossible, this crosslinked mess is untanglable without 'hacking/slicing away' in the ECM (and damaging it) and why still no glucosepane breaker yet.
Immortal cancer cells whom keep on replicating near-infinitely don'T accumulate lipofuscin, and lipofuscin was shown to accelerate/restart senescence when back-inserted in the proteasome/lysosomes. While glucosepane has been shown to correlate to maximal lifespan, in mammals (if I remember correctly mice accumulate about 40 times faster pentosidine, CML and other AGEs; along with glucosepane crosslinking than humans; and thus live, 40 times shorter.
AGEs = MLSP as a correlation, not necessarily a Pure Causation, but a definite Contribution for sure (especially, health wise (diabetes complication from accelerated AGEs and HbA1c accumulation; and diabetes itself shows accelerated senescence (faster telomere attrition also), accelerated 'Aging' and accelerated Epigenetic Aging))). The four largest accelerated aging are diabetes, cancer, hypertension and progeria (HGPS, Werner Syndrome and Down Syndrome/Trisomy 21). They may be Direct forms or Indirect forms of aging, but they still show accelerated aging, especially accelerated Epigenetic aging (all of them, as visibly 'older' DNA methyl clock (they demthylate it faster) and for example, HGPS progeria (Hutchison-Gilford Progeria Syndrome) lose 500 bps, vs 50 bps (50 nucleotide base pairs (0.05 Kb/y/telomere) in telomeric DNA, if normal health/'normal telomere shortening speed'), in telomere size each year. That'S a 10 time faster telomere loss in the most drastic progeria (these HGPS progeria people live about 15 years, it correlates to how long a normal human can live in Maximum in the human specie (122 years, 12-15 x 10 = roughly 122-150 years))). Thus, they age 10 times faster.
I too hope that stem cells/embryonic stem cells could somehow circumvent replicative senescent in humans; wel'll have to see, from the results of Mrs. Liz Parrish (Bio Viva CEO whom did herself (as the patient 0) using her own telomerase hTERT therapy) she gained about 1 kb telomere lenght (or a 1000 bps, which is roughly 10-20 years lifespan extension) but we don't know how much this impacted the damages she already incurred (did she keep everything or it reduced, and it was a True Rejuvenation; or just telomere elongation, period and no changes to damage/junk markers). And one study, done in exercise in humans, showed that exercise activates telomerase in certain tissues/cells and we gain from that hormone boost (exercise increases hormone and activates estrogen-dependent estrogenic-receptors that are 'telomerase' activating, it is one of the reasons why women live longer, because they activate estrogenic receptors in the brain and body which themselves - activate telomerase; men have a conversion, they produce testosterone (in higher quantity) and other androgens, it is converted by aromatase enzyme to Estrogen - and then, goest to activate estrogenic receptors in men/thus get telomerase too. Testosterone itself can activate telomerase, but it is the estrogenic receptors that activate telomerase mainly and confer extended replicative lifespan thourgh telomerase enzyme recruitment. In that study, they showed that exercise, through activating telomerase by oestrogenic receptors, actually endedup increasing the people's telomere length by about 300 bps. (300 basepairs)). As such, a third of Mrs. Parrish's results. It means there is a intrinsic limit to telomerase itself (rate-limiting) and that if exercise results in about 300 bps telomere length it yields to about 5 years lifespan extension (the bulk of our lifespan is about 12-16 Kb, but we age for about 5kb (5000 bps/100 years)). But, truthfully, exercise has never made any human go over 122 years or not much above that (it would have been recorded in history); this discredits telomerase has a possibility to revert aging but to slow it/post-pone it a bit. Telomer dependent senescent is more important as you age, and get in the 100-120 bracket. One woman of 115 years old had 2-3kbs left in the leukocytes, it means she was the end of the road for telomere were so low that the signal for 'entry into replicative senescence/geroconversion by mTOR to replicative senescence' was much too stong (this p21/p16/p53/BEta-Gal signal is present at the 2-5 kb telomere region (so far that's been the case in regular somatic cells although if that signal would be 'stabilized' with Shelterin proteins (like POT or TRF1 TRF2 Ku67) then the telomeres could remain Capped insteaf of becoming Uncapped and unstable (short demethylated telomeres/centromeres and sub-telomeres))), cancers evade mortality by 'hanging' at the 2kb size and never going under that)). IT means that she was entering 'immunosenescence' and elderly people oftenly die of immune problems because immunity is gone (pneumonia or other virus/immune diseases) as shown by her very short telomere in her leukocytes. The study said, she was at 'The limit' of human specie lifespan and why she could not continue much further.
Let's hope for the best. Just a 2 cent.
I personally don't think the public will care much if Senolytics, glucosepane removal, or removal of some forms of lipofuscin get into the clinic and start showing safety and effectiveness and are predicted to extent lifespan by 5, 10, or 15 years. It is just to far off in the future for most people to think about. Much the same way that people smoke or get fat, but do no more than vaguely worry about it because the consequences are off in the far future.
I do think that if any of these therapies, or a combination of them, make people in clinical trials look physically younger, through having younger looking skin, that will garner intense public interest and awareness.
@Jim: I actually believe the opposite: there are plenty of surgical and non-surgical cosmetic procedures that can shave 5, 10, 15 or even more years off people's faces already. And there are also plenty of baby boomers who are now of the age at which people start to seriously contemplate their own mortality.
These individuals may not be swayed by a *guaranteed* 5 years life extension from senolytics, since they've been forever sold stories about how aspirin / antioxydants / melatonin / HGH / DHEA / etc.etc.etc. can do the same. Moreover, five years out of an average lifespan of 80-85 really looks likes a margin of error. Ten or fifteen years on the other hand....
CANanonymity: In your last comment above you referred to a 115 year old lady that she only had 23kb's of telomere cap left and very near to immunosenescence. As you say, elderly people often die due to immunosenescence after getting a virus/infectious disease. Well, it apparently turns out that Centenarians sometimes/often, have a remodeled immune system based on a kind of hybrid NK-like T cell type that protects them from infections at very elderly ages (Joshua Michel, 2016, Functionally diverse NK-like T cells are effectors and predictors of successful aging. Could this be a immune system change/remodelling that could somehow be a useful therapy for life extension in immuno-deficient people?
PS: Remarkably, the Centenarians with the remodeled immune system have better physical abilities and cognitive preservation and abilities than those who do not have the remodeling.
@Biotechy
Hi Biotechy ! Thanks for that ! Just a 2 cent.
That is a very good point you bring, I definitely believe it is a beneficial compensation for extended lifespan - since in those extreme age (100-120 brackets), the body is just so weakened and frail; as such the immune system is not what it once was; it can't protect from invaders as strongly as a 20-year old's immune system can. We also have to remember that Centenarians are 'aged' and sure may be 'functional health' to 'live on' there last days - it does mean they are Biologically young/Epigenetically as young as a 20 years old; they have accumulated large amounts of transthyretin and other junks of age; as such, they lived 'around it' and survived this problem to go on to reach 120 where the replicative senescence hits them like a ton of brick (immunosenscence) or die from age pigments (heart transthryretin).
Strong NK killing power means easier capability to remove 'new poppin' cancerous cells and pathogens/virus and other nefarious bacterias. Especially, in the colomn/intestines where much immunity resides (along with the blood ABC, and bone marrow CD8 cells/T-cells/NK cell production and thymus 'activation' of hte immune cells) So keeping Strong bones (no osteoporsis) BMD (bone mineral density) makes for more immature CD8+ memory cells that go on to be activated in thymus (that by a 100 years old is pretty pruned/skrunken (thymic involution))). The immunse system has so much 'reach' in our body and why it is crucial for extreme longevity - without it we succomb to cancer, pathogens and other problems. And not only that it is responsible for other secondart, tertiary tasks that relate to other pathways, and as such affects the Senescence pathways; including replicative senescence, and especially Oncogenic senescence (cancer))).
I am not surprised about the bit of improved cognitive preservation and fitness
Better Amyloid removal and macrophages or NK/T cells that ingulf virulentce, better Brain function (because protein aggregate/amyloid plaque freed), more autophagy/mitophagy/lysophagy and Macrophagy/'phaging' (macrophages) 0 all the immune system's doing.
Less oxidative damage, less Tumor Suppressors of immune (p53, p16, TNF-a) meaning less inflammation, less tumors, less cancer - longer life, healthier, sharper mind. The immune system gives us these tools, and can inflammatory (IL-6, TNF-a, P16, p21...) or Anti-inflamattory (IL-10, SOD, CAT, Telomerase...), all of them have a purpose; inflammatory - to destroy cancers; anti-inflammtory - to not destroy - You. It all fits.
Just a 2 cent.
PS: This remodelling concurs with mitochondrial remodelling in Centenarians; Centeraisn (LLIs Long Lived Individuals) have Hypermitofusion happening in their mitochondrias to support enough ATP production and relieve the dysfunctional mitos (fissionated) that hang around alone and damage the others; so a reordering/remodelling of the mitonetwork (in a 'large fused network of bad mitos - that work together and it still 'works'') for cell survival/energy ATP maintenance.
Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032796/
PS: typo ''it does not* mean they are Biologically young/Epigenetically as young as a 20 years old''