$36,000
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A Demonstration in which Cellular Senescence is Reversed

In principle any cell state can be reprogrammed into another cell state - it is a matter of figuring out the machinery involved, which remains no small task even now in this age of revolutionary progress in the tools of biotechnology. Some cell state changes are more plausible and easily discovered since they correspond, nearly or exactly, to transitions that already take place in at least some circumstances and species. So skin cells can be turned into the induced pluripotent stem cells that are near identical to embryonic stem cells, and which can then differentiate into another cell type, such as a neuron. Alternatively those skin cells can be converted directly to entirely different cell types without going through the pluripotent stage, via forms of transdifferentiation.

Senescent cells are those that have entered a state of growth arrest in response to damage, a toxic environment, or hitting the replication limit that exists for all somatic cells. Senescent cells do not replicate, and they either remain in this state indefinitely, in a tiny minority of cases, or self-destruct, in the vast majority of cases. They never return to replication. But when we say that the state of cellular senescence is irreversible, we mean that it is observed to be irreversible in the normal run of things in our tissues, just as skin cells don't randomly turn into induced pluripotent stem cells in the normal run of things in our tissues. Once researchers can start tinkering with cell programming and the controlling levers of cell state, however, all the rules are there to be broken. Senescent cells can be made to replicate once more, given the right modification.

The presence of growing numbers of lingering senescent cells is one of the root causes of aging. In recent years there has been an explosion of interest in developing therapies to prevent the contribution of cellular senescence to aging - and to turn it back to generate rejuvenation in the old. This is enormously gratifying to advocacy groups such as the SENS Research Foundation and Methuselah Foundation, and advocates such as Aubrey de Grey, who have been trying to create this surge of investment and progress since just after the turn of the century. The primary therapeutic approach to senescent cells is to selectively destroy them. It is simple, it absolutely gets rid of all the problems, whether known or yet to be cataloged, and it is shown to extend life and reverse measures of aging in mice.

Should we be interested in reversal of senescence as an approach, however? Senescent cells are generally senescent for a reason, and that reason either involves their age and amount of replication, or it involves internal damage that can be harmful to the surrounding tissues. That includes cells with DNA damage that causes them to be potentially cancerous. The relationship of cell damage to outcomes such as cancer is a numbers game: simply re-enabling replication in all senescent cells will probably raise the risk of issues down the line. However, the harms done by senescent cells due to the characteristics of their state are also significant. These cells cause harm through their signaling profile, a mix of secreted molecules that generate chronic inflammation, fibrosis, and all sorts of other woes in surrounding tissue. Turning off senescence and enabling replication in senescent cells should be a considerable improvement over leaving them as they are, provided that it does in fact prevent their damaging signaling. This is true, at least, in the short term, but I think it a poor second best to their destruction over the long term. These are not high-quality cells; on average they will bear a burden of damage and dysfunction that is distinct from whether or not they are senescent. Cancer is definitely one of the concerns.

Old human cells rejuvenated in breakthrough discovery on ageing

A new way to rejuvenate old cells in the laboratory, making them not only look younger, but start to behave more like young cells, has been discovered. A team has discovered a new way to rejuvenate inactive senescent cells. Within hours of treatment the older cells started to divide, and had longer telomeres - the 'caps' on the chromosomes which shorten as we age. This discovery builds on earlier findings showed that a class of genes called splicing factors are progressively switched off as we age. The team found that splicing factors can be switched back on with chemicals called resveratrol analogues. The chemicals caused splicing factors, which are progressively switched off as we age to be switched back on, making senescent cells not only look physically younger, but start to behave more like young cells and start dividing.

The discovery has the potential to lead to therapies which could help people age better, without experiencing some of the degenerative effects of getting old. Most people by the age of 85 have experienced some kind of chronic illness, and as people get older they are more prone to stroke, heart disease, and cancer. "This is a first step in trying to make people live normal lifespans, but with health for their entire life. Our data suggests that using chemicals to switch back on the major class of genes that are switched off as we age might provide a means to restore function to old cells. When I saw some of the cells in the culture dish rejuvenating I couldn't believe it. These old cells were looking like young cells. It was like magic. I repeated the experiments several times and in each case the cells rejuvenated. I am very excited by the implications and potential for this research."

As we age, our tissues accumulate senescent cells which are alive but do not grow or function as they should. These old cells lose the ability to correctly regulate the output of their genes. This is one reason why tissues and organs become susceptible to disease as we age. When activated, genes make a message that gives the instructions for the cell to behave in a certain way. Most genes can make more than one message, which determines how the cell acts. Splicing factors are crucial in ensuring that genes can perform their full range of functions. One gene can send out several messages to the body to perform a function - such as the decision whether or not to grow new blood vessels - and the splicing factors make the decision about which message to make. As people age, the splicing factors tend to work less efficiently or not at all, restricting the ability of cells to respond to challenges in their environment. Senescent cells, which can be found in most organs from older people, also have fewer splicing factors.

"This demonstrates that when you treat old cells with molecules that restore the levels of the splicing factors, the cells regain some features of youth. They are able to grow, and their telomeres are now longer, as they are in young cells. Far more research is needed now to establish the true potential for these sort of approaches to address the degenerative effects of ageing."

Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

Messenger RNA (mRNA) processing has been implicated as a key determinant of lifespan. Splicing factor expression is dysregulated in the peripheral blood of aging humans, where they are the major functional gene ontology class whose transcript patterns alter with advancing age and in senescent primary human cells of multiple lineages. Splicing factor expression is also an early determinant of longevity in mouse and man, and in both species these changes are likely to be functional, since they are associated with alterations in splice site usage for many genes. Recent data suggests that modification of the levels of SFA-1, a core component of the spliceosome, influences lifespan in C. elegans through interaction with TORC1 machinery.

The splicing process is regulated on two levels. Firstly, constitutive splicing is carried out by the core spliceosome, which recognises splice donor and acceptor sites that define introns and exons. However, fine control of splice site usage is orchestrated by a complex interplay between splicing regulator proteins such as the Serine Arginine (SR) class of splicing activators and the heterogeneous ribonucleoprotein (hnRNP) class of splicing repressors. Other aspects of information transfer from DNA to protein, such as RNA export and mRNA stability are also influenced by splicing factors. Intriguingly, in addition to their splicing roles, many splicing factors have non-canonical additional functions regulating processes relevant to ageing. For example, hnRNPK, hnRNPD and hnRNPA1 have been shown to have roles in telomere maintenance and hnRNPA2/B1 is involved in maintenance of stem cell populations.

Splicing factor expression is known to be dysregulated in senescent cells of multiple lineages and it is now well established that the accumulation of senescent cells is a direct cause of multiple aspects of both ageing and age-related disease in mammals. These observations suggest that an interrelationship may exist between well characterised mechanisms of ageing, such as cellular senescence, and the RNA splicing machinery where the mechanistic relationship to ageing remains largely correlational.

In contrast to the situation with core spliceosomal proteins such as SFA-1, perturbation of a single splicing regulator by standard molecular techniques such as knockdown or overexpression is unlikely to be informative for assessment of effects on ageing and cell senescence, since ageing is characterised by co-ordinate dysregulation of large modules of splicing factors. Thus experimental tools capable of co-ordinately modulating the expression of multiple components simultaneously are required to address the potential effects of the dysregulation of large numbers of splicing factors that we note during the ageing process. Small molecules such as resveratrol have been reported to influence splicing regulatory factor expression. Unfortunately, resveratrol has multiple biological effects, and thus a 'clean' assessment of the effects of moderation of splicing factor levels on cell physiology cannot be achieved using this compound alone.

We have overcome this limitation through development of a novel library of resveratrol-related compounds (resveralogues) which are all capable of either directly or indirectly influencing the expression of multiple splicing factors of both SRSF and HNRNP subtypes. Treatment of senescent human fibroblasts from different developmental lineages with any of these novel molecules shifts expression patterns of multiple splicing factors to those characteristic of much younger cells. This change occurs regardless of cell cycle traverse and is associated with a marked decrease in key biochemical and molecular biomarkers of senescence without any significant alteration in levels of apoptosis. Elevated splicing factor expression is also associated with elongation of telomeres, and in growth permissive conditions, these previously senescent populations show significant increases in growth fraction and in absolute cell number, indicating cell cycle re-entry.

Comments

This has always been my problem with the idea of extending telomeres and the like for rejuvenation. I've thought that telomere shortening, being a managed process, is part of autophagy, where the body rids itself of damaged and otherwise dysfunctional cells.

Posted by: Abelard Lindsey at November 7th, 2017 8:23 PM

Hi Reason,

I've been a five times a week lurker on FightAging! for more than a decade and this is my very first post I'm ashamed to admit. FightAging! is pretty much the second site I check in the morning (after BBC News). Apart from occasionally donating to SENS (though I've just become a monthly patron) & crowdfunding projects, I've been rather passive, however that's been changing this year as I've joined LongeCity and am actively trying to get members in the Toronto area to meet up so that we can organise and contribute more to this noble cause. This posting is another small step in that direction...

So I just want to say thank you for all of your hard work - you've been a real inspiration! :-)

Now the reason (no pun intended) for breaking my silence has nothing to do with the post above, rather, I wanted to point out an interesting 4 part video discussion on anti-ageing from the investment site Mauldin Economics. It appears to be an invitation only event if you subscribe to Patrick Cox's Tech Digest, but here is the link to part 1:
http://www.mauldineconomics.com/riding-the-gray-tsunami/event/comp1456

Oddly enough, each part is only going to be available for 24 hours, so this link might not work after 9am Eastern Time Wednesday. The discussion itself is a bit wishy-washy, talking about Metformin et al, but still of interest as it is coming from an investment/societial perspective and showing how our movement is starting to spread.

Of more interest to readers of FightAging! will be parts 3 & 4, which will involve Aubrey de Grey and Jim Mellon repectively. (part 2 will be some guy from the Cleveland clinic talking about lifestyle & what supplements you can take now) I will post the links once they are emailed to me over the next three days.

PS - if there's anyone in the Toronto area who'd like to meet up (I've already had one fantastic discussion with a local FightAging! reader/LongeCity member) check me out on LongeCity under the moniker Chris Pollyana or in the Canada section.
@CANanonymity & Mark Borbely - do you ever get to Toronto?

Posted by: Chris Pollyana at November 7th, 2017 11:25 PM

This is the work of Richard Faragher, I see he was off debating Aubrey yesterday convincing everyone that Healthspan is the only worthy goal for funding and not increased healthy lifespans. Interesting experiment all the same, but I am interested in getting rid of senescent cells not papering over the problem in the name of healthspan, it simply isn't good enough.

Posted by: Steve Hill at November 8th, 2017 2:58 AM

I am not convinced that reversal of cell senescence is occurring in this instance. They use replicative senescent cells which likely still have non-senescent or near-senescent cells present. I doubt they will see the same result if they used chemotherapy or irradiation-induced senescence to ensure all cells are senescent. Much more convincing research is required.

Posted by: E.Kelly at November 8th, 2017 5:02 AM

Steve,

I haven't seen the debate, or a transcript yet, but I imagine it was probably as pleasant as always. This is all I saw about it in general on another site:

"Professor Richard Faragher of the University of Brighton, will today argue for more research into the degenerative effects of ageing in a debate into whether science should be used to extend people's lifespans"

What exactly is his issue? Does he think these things that effect healthspan won't make the average person live longer than they normally would (life expectancy)? Or does he have a problem with talking about pushing past the known lifespan or 120? I can't help but think that if you were otherwise healthy in your 70s and 80s with this increased healthspan idea, that you're probably going to outlive your life expectancy, especially with intervention. Perhaps he feels healthspan would provide more funding than more "radical" ideas?

Posted by: Ham at November 8th, 2017 5:03 AM

You see, in the eyes of people like Richard, the tradeoff between increased cancer risk from restoring senescent cells and the short-term gain of removing senescent cell SASP by returning them to work is acceptable. Because it will let people live until a ripe old age in health then die suddenly. Rounding the curve is the goal of Healthspan and it is being presented as the only goal. And there is every change one can improve healthspan and not increase lifespan as modern medicine already shows. Business as usual is the way of such people.

Posted by: Steve Hill at November 8th, 2017 5:22 AM

"At a time when our capacity to translate new knowledge about the mechanisms of ageing into medicines and lifestyle advice is limited only by a chronic shortage of funds, older people are ill-served by self-indulgent science fiction. They need practical action to restore their health and they need it yesterday," he said.

Says it all really. Such ideas will drain the coffers dry playing with Resveratrol and related compounds like Pterostilbene to perhaps round the curve a bit and other more ambitious things will languish. This is why private enterprise and community crowdsourcing are the solution here and allow us to bypass such entrenched ideas.

Posted by: Steve Hill at November 8th, 2017 5:25 AM

It just seems like striving for mediocrity and squandering of funds... but everyone has to justify their work, and I guess it's easier to get people to invest in more "safe" sounding ideas? Is "rounding the curve" really the only goal, or is that just a much easier sell for funding? And again, I guess there's a difference if everyone is going to see 100 in good health instead of 80 in poor health.

Posted by: Ham at November 8th, 2017 6:01 AM

First time I'm hearing Aubrey was in a debate yesterday.
Nothing of the like was in the SENS events calendar.
Didn't even know he was in Europe, he was supposed to be in Brazil last week.
Anyway, I hope he had a better luck with the crowd than the last debate he took a part in a some months back.

Posted by: Anonymoose at November 8th, 2017 6:33 AM

@E.Kelly: A good point.

Posted by: Reason at November 8th, 2017 6:52 AM

An increase for the "after the debate".
Could be better could be worse. Still there is a hard bias we're facing here so not the worst outcome we can get by far.

Posted by: Anonymoose at November 8th, 2017 7:04 AM

To reiterate what I've said last time - if the debate is focused on "science making humans immortal" the answer currently will always be NO from the general public.

If I was Aubrey I'd make them lower the bar to a more realistic "make humans live longer" and then we can have a non loaded debate.

Posted by: Anonymoose at November 8th, 2017 7:11 AM

Yes, the public does not like the implication of immortality and will often consider this augmentation and against nature. This is absolutely the wrong platform to debate such matters. It would be better to debate Healthy Longevity Vs just Healthspan and then people will see which is the poor second choice.

This is how we can effectively communicate the goals and potential of rejuvenation biotechnology and avoid playing into the traps and pitfalls associated with radical life extension. Debating people like this the deck is loaded as it is so better to engage them on a level footing so they cannot dismiss wanting to live longer and healthier as "self-indulgent science fiction".

That said, I firmly believe that the future of the field lies in private enterprise and grassroots activism and fundraising over expecting the establishment to do much about aging. The establishment is dominated by people like Richard who lack vision. Best to simply bypass such entrenchment and get the work funded by other means.

Posted by: Steve Hill at November 8th, 2017 7:30 AM

Without basic research being conducted by people like Faragher at academic institutions there would not be the foundations of scientific research that leads to private enterprises. They cannot simply be dismissed.

Posted by: E.Kelly at November 8th, 2017 7:48 AM

@E.Kelly: I think one still has to make the attempt to distinguish between useful and not so useful research programs, otherwise you end up with structures like the NIA, which spends a lot and achieves little.

Posted by: Reason at November 8th, 2017 8:00 AM

@E.Kelly no one is suggesting his work is to be dismissed only that entrenched views about healthspan over all else can and should be. I have a great deal of respect for his actual research so let's not mistake what I am saying here ok.

Posted by: Steve Hill at November 8th, 2017 8:36 AM

E. Kelly said: "From the debate yesterday (may need to translate from Spanish). Votes at the end may be of interest...http://www.gciencia.com/ciencia/inmortal-humano-regueifas/"

That's actually Portuguese. The translation of the result is:

Question: "Should science help people to live forever?"

Before the debate:
- YES: 24%.
- NO: 64%.
- DON'T KNOW: 12%.

After the debate:
- YES: 33 %
- NO: 61%.
- DON'T KNOW: 7%.

Posted by: Antonio at November 8th, 2017 8:58 AM

Well those results are depressing, but its not surprising at all. Why is that even being debated? With a title like that, I feel like we're being set up to fail. Talking about living forever to the general public doesn't seem to press the right buttons at all. Not to mention, you know, forever is a long time and we're only living ~80 years currently. I feel like talking about getting to 100 or more ambitiously, 120 in good health would get a bit more support... even if there are more ambitions goals after that.

Posted by: Ham at November 8th, 2017 9:16 AM

Yes, the title is purely and simply a trap. I would not even debate such a topic because it is not about that at all its Healthspan vs increased healthy lifespan. Different entirely from fantasy stuff like "living forever" and "immortality". No wonder Aubrey lost if this is the title of the debate.

Posted by: Steve Hill at November 8th, 2017 9:21 AM

I think the issue is credibility in the eyes of the public, who don't know much (if anything) about the science. They are being told (truthfully) that scientists can improve healthspan a great deal, and lifespan a little, in mammals - basically CR without eating less, and that this will soon be possible to translate to humans. This is an easy sale.

But we suspect (with good reason) that much more is possible, and by investing now we might bring seriously extended lifespans within the reach of those alive today. However we are yet to prove this. Even senolytics appears (in mice atleast) to mainly be a healthspan effect.

I am not sure it is in Aubrey's best interests to debate with healthspanners. It might be better just to state that we've as good as solved healthspan issue already, and it's worth investing in more ambitious goals such as preventing any death from aging.

Posted by: Mark at November 8th, 2017 9:24 AM

Don't forget that greatly increased healthspan and modestly increased lifespan ALONE will revolutionise the medical and care industries. What we are interested in (true rejuvenation) is science-fiction to most people.

Posted by: Mark at November 8th, 2017 9:28 AM

Mark,

All that shifting the conversation to the idea of preventing any deaths from aging is going to do is lead the general public to ask the same original questions over and over again about the pensions, population, and the evil dictators. There's a fine balance somewhere. Perhaps they should talk about extending your healthy expectancy a bit? After all, there's about 49 years difference between our expectancy and our known maximum lifespan.

Posted by: Ham at November 8th, 2017 9:35 AM

It's not as bad as you make it out to be as I said before.
A 10% increase in acceptance from an hour long debate or so is pretty good.

Posted by: Anonymoose at November 8th, 2017 10:00 AM

@Chris Pollyana: I used to live in Niagara :) So yes, I've been to Toronto many times.

For now I'm in Calgary and don't get home much.

Posted by: Mark Borbely at November 8th, 2017 10:21 AM

@ Steve : I fully agree. Although we might not want to completely stop trying to get some mainstream scientists onboard, by and large it's clear that we have to take back control of where anti-ageing research is going ourselves, as a private community. And so far, I'd say we've been proven right. We've got both scientific achievements to show and a growing public support.

Posted by: Spede at November 8th, 2017 1:07 PM

A lot of stuff to digest here...

We have the science of cell programming, a debate on where we should point our resources, another debate on healthspan vs lifespan, and then we have the cold, hard truth.

I'll give my point form 2 cents and then I'll bloviate on and on with my inane babble as to why this is overall a good thing

-Any knowledge of cell-reprogramming is a good thing.

-Was this the best use of resources? Probably not, but I'll argue that it was part of a necessary to move consensus in our direction.

-The outcome of this demonstration is more important than the scientists position on LE.

-We are WAY ahead of the curve, and we are slowly chipping away at public consensus.

OK, now for me to defend my assertions. Go get a coffee. Its tasty and good for you.

So, we had a life-spanner do some cell reprogramming and discovered we can turn senescent cells from the Dark Side. Kudos! No issues here. One of my biggest fears (And this is echoed in the scientific part of our community) is that we can do all these wonderful things in mice, yet when it comes to humans, we fail miserably. Remember the small number of drugs and treatments that make it through clinical trials? That keeps me up at night. What if our adventures in small molecules for killing senescent cells turns out to be toxic? Or just fizzles, or more likely can't be used in humans because it interferes with wound healing or whatever. Suppose this method or one based on it becomes the way we HAVE to deal with them. It's better to have this knowledge, than NOT to have this knowledge. It can also lead into ways we can re-program cells to do other things we may need them to do. Programming cells is going to be a MAJOR path we can use to do all kinds of things, like up-regulating NAD+, or reducing mutations. Its just a useful tool, and better tools mean more capabilities... ALWAYS. Anyway... not a waste of time. We may need it. Example... Gorilla glass sat in the archives of Corning for decades before it became useful. Now look at it. Same thing applies here.

This science also proved that rejuvenation is INHERENT in even damaged and harmful cells. It just needed to be re-directed and re-educated to become a productive member of your bodily society. A life-spanner just showed on the micro level that we can take highly damaged cells and return them to "Health"? Ok, maybe that's too strong a word... "Functionality"? ok. I'll go with that. We have restored a cell from sickness to health. Its proof of concept that this kind of thing is doable. Its another nail in the coffin of those who say we can't do anything about aging (I'm looking at you Len Hayflick, I love you man, but c'mon you gotta give credit where its due). This is the kind of science that eventually turns the scientists from the "It can't be done" to "Its just a matter of time and resources". This is a win.

It doesn't matter what Richard Faragher thinks is worthwhile or not. The science is going to bear out Aubrey's assertion that to be healthy and to even HAVE a health span, we have to repair and return cells to a level of homeostasis or we will fail at even achieving a descent healthspan. . This is biology 101. And why a distinguished, capable scientist like Faragher is even trying to argue the other side is science fiction compared to what Aubrey proposes. We know what it takes to make a body healthy, and its a youthful phenotype. He just proved a basic tenet of SENS. Thanks Richard Faragher! You just put another notch on our wall!

Last point, I've been looking into Life extension for 18 years now. I can say without a shadow of a doubt that 2017 was a banner year for us. I'll let Reason do the grand tally as he does every year in Dec, but for brevity's sake, we have had some fantastic movement both with the science (Thank you Belmonte!) and the greater perception of why LE is a good thing (Thank you Aubrey!). We KNOW what this technology will do for our species. And we are making progress towards moving public perception in our direction. 10% for an hour long debate is MASSIVE. Especially with this topic. Remember, we are changing a fundamental tenet of what it means to be human. We die. Every human story ends badly. We have built our whole society to be structured around that. Every moment of our lives is based on it. People HATE change, and even a change as positive as this, is going to be met with resistance. PLUS, these options at this time are PURELY pie in the sky. None of it is real or tangible. That's going to change. I believe Aubrey is correct saying that this is going to be common knowledge everywhere in a couple of years as animal studies are going to make every Gerontologist come out on our side and say "This is possible, its a matter of when not if". I'd like to see this quiz taken again after they see footage of an aged mouse before and after senolytics. Not just snapshots... but a mouse LIVING again. Running around it cage, mating, eating, grooming itself.

And right now I'll quote Patrick Cox "When Mick Jagger goes to Japan for treatment and returns a year later looking and feeling 30 again, people will take notice. That's going to happen". He's right. And boy oh boy, I've spent YEARS working in technical sales, and trust me when I say, seeing is believing.

So boys and girls at LEAF... lets show em :)

Posted by: Mark Borbely at November 8th, 2017 1:38 PM

Life extension is going to be a step by step process up a long and winding staircase. Research can and should jump ahead a few steps, but as a practical matter, we all have to try to use the best available health span technology year to year for our own personal survival, and that may include using resveratrol, curcumin, pterastilabine, Nictotinimide riboside or what ever, while the advanced life extension research goes on.

Posted by: Biotechy at November 8th, 2017 1:43 PM

Skimmed it. Nothing worthwhile in the debate, don't waste your time.
The against group weaponized altruism against our side. A good use of psychology.
Regression toward the mean is a powerful mechanism.

Posted by: Anonymoose at November 8th, 2017 3:07 PM

Anonymoose,

Agreed. Farragher's smugness and trying to claim moral superiority and proclaiming everyone on the opposite side of the argument selfish was fairly off putting. But that's still where the consensus seems to be, despite a 9pct change in the vote. The nonsense speculation about how you would feel about all your relationships after 7000 years was kind of an eye roll for me too. But maybe that's just me.

Posted by: Ham at November 8th, 2017 3:33 PM

@Mark "This science also proved that rejuvenation is INHERENT in even damaged and harmful cells. It just needed to be re-directed and re-educated to become a productive member of your bodily society. A life-spanner just showed on the micro level that we can take highly damaged cells and return them to "Health"? Ok, maybe that's too strong a word... "Functionality"? ok."

They call it rejuvenation, but those cells aren't turning any younger, not even healthier, they only recovered the capacity to reproduce. Very different things.

I agree that every bit of knowledge or technique can be useful some day, the problem is *when* is exactly that day. I'd prefer it to be before I die, at least for biogerontology knowledge.

Posted by: Antonio at November 8th, 2017 4:56 PM

Now, commenting on the debate:

30 years for senolytics to reach market?? Does really Dr. Faragher think that??

Next, the usual naturalistic fallacy like "OMG, if we were immortal, we would be very different beings. Currently human lives have a beggining and an end, that's how things are now, so that is how things must always be. If not, life would have no meaning. QED." Total nonsense. Simply an irrational fear of change.

Of course, the usual overpopulation BS... believing that birth control can be avoided by avoiding life extension.

And the disequality BS... Some children in Africa don't have clean water, so 100,000 people per day must die of aging. And, of course they must die at current lifespans of 80-90 years, not lifespans in XIX century, because, you know, how things are today is how things must be. Naturalistic fallacy? Oh yeah.

"We are finite, so we must die." More nonsense...

Posted by: Antonio at November 8th, 2017 6:00 PM

I think the debate would have being better with only de Grey and Faragher. The bioethicist doesn't know enough biology and medicine, and the genetist does know gerontology but not much about SENS, only things like genetic manipulation in mice and worms to extend lifespan and the like (he even falls in the Thitonus error at some point in the debate).

Posted by: Antonio at November 8th, 2017 6:45 PM

Antonio,

And that's exactly my problem with some of these 'bioethicists'. Well, in addition to coming up with absurd and contrived scenarios about the loss of meaning and importance on all the relationships formed over the course of a 7000 year life, or moaning about having to work longer. I don't know how so many people value input like this. I'll be damned if my life is going to be affected in a negative way due to the recommendations or absurd concerns of some of these ethicists.

Posted by: Ham at November 8th, 2017 7:04 PM

"30 years for senolytics to reach market??"

Ok, that is almost certainly a very bold statement. Antonio, could you give a time stamp of when that was said?

I get the feeling that this statement was said as a counter argument to Aubrey pointing out that senolytics will enter human clinical trials within the next 6 months and could be available in 5-10 years. Maybe there will be unforeseen problems with senolytics, but there isn't actually any evidence for there being problems yet.

I saw one bit where Prof Faragher said that when people read the internet all they see is a bunch of immortalists, which then hurts public perception and hence funding for basic gerontology research. Is this fair? On the other hand I don't think Aubrey and SENS have to worry to much about over promising, as in areas like glucosepane or mitochondrial gene therapy research, if they can raise any money to get funding from near zero to something, that is a win for them. I think unfortunately there is a bit of a real conflict where increasing funding for research on actual interventions may end up shrinking the basic size of the research funding pie a bit.

Posted by: Jim at November 9th, 2017 2:17 AM

He has no clue about what people see when they read the internet and he just comes across as rude and disrespectful if he sums up the entire community as "a bunch of immortalists". LEAF has raised over $250k for basic research so that proves him wrong for a kick off. The whole thing is a farce anyway.

Posted by: Steve Hill at November 9th, 2017 3:50 AM

Eight category of damage confirmed? The loss of the ability to splice RNA correctly.

https://youtu.be/EkSExBrOEuo?t=1h4m15s

Anyone with more than my layperson's knowledge care to comment on this?

Posted by: Jim at November 9th, 2017 4:20 AM

The "you're scaring off the normies" argument is quickly becoming a classic. I've heard it from 3 unrelated researchers this year.

Posted by: Anonymoose at November 9th, 2017 4:23 AM

@ Antonio

I've read the paper thoroughly now, and in agreement with what E. Kelly said above the treatment DID NOT REVERSE SENESCENCE. You can see from Fig 6b that 15% of the cell retained some proliferative capacity, as measured by the Ki67 protein. And after treatment 15% of the cells were no longer SA-galactoside positive, Fig 6c. Coincidence? Almost certainly not. The author admits as much in the discussion section: 'Interpretation of data are also made more complicated by the observation that even a population of senescent cells derived from a single 'young'culture is actually fairly heterogeneous, consisting of deeply senescent, newly senescent and pre-senescent cells.'

So what is happening here is that the treatment is restoring proliferative capacity in cells that have lost that ability because the signaling from nearby senescent cells.

The work is not a waste of time however, because it showed that mechanism by which these resveratrol analogues work is by altering splicing factors back to a more youthful pattern of expression, and that this led to telomere lengthening. Interesting, but it's not reversing cellular senescence.

Posted by: Mark at November 9th, 2017 4:30 AM

@Jim

About senolytics: https://www.youtube.com/watch?v=EkSExBrOEuo&feature=youtu.be&t=1415

About a 8th damage category, we had a discussion some days ago: https://www.fightaging.org/archives/2017/08/cellular-senescence-as-a-cause-of-aging-from-wishful-thinking-to-case-closed/#comments

I think sources of funding are very different for Faragher and SRF. AFAIK, Faragher doesn't do crowdfunding nor receive funding from high net worth individuals. So I don't see any real conflict there. I think he is mostly affraid of bad reputation for gerontology due to Aubrey's predictions, and that reputation leading to lack of government funding for mainstream researchers. Of course, I think that fear is unwarranted, because, even if you dissagree with SENS, it's undeniable that thanks to SENS we have obtained practical and useful results and tools, like senolytics, therapies for LHON, etc. Even if you dissagree with SENS as the correct theory of aging, it's clear for everybody that the SRF guys aren't snake oil sellers, they are obtaining real and useful results, some of them very big results, like senolytics.

Posted by: Antonio at November 9th, 2017 4:58 AM

@antonio How exactly has SENS contributed to the identification of known senolytics?

Posted by: E.kelly at November 9th, 2017 5:04 AM

E.kelly: SRF has funded Judith Campisi's research for some years.

Posted by: Antonio at November 9th, 2017 5:09 AM

Here is a truly exciting new discovery on cell rejuvenation of senescent cells. Just posted on ScienceDaily "Old human cells rejuvenated in breakthrough discovery on aging." Professor Lorna Harries, a molecular biologist at Exeter, has rejuvenated splicing factors in senescent cells so they so these old cells become young again with longer telomeres, and begin dividing again. Everyone here who has read and commented on the main article should read this new study.

Posted by: Biotechy at November 9th, 2017 7:49 AM

@E.kelly Not only has SRF funded Judy Campisi's lab for many years but also Oisin is the direct evolution of SENS based research.

Beyond that, they have numerous publications of which they are either the primary researchers or have funded directly. If you would like to see a sample of their contribution look at the cited literature at the bottom of this page:

https://www.leafscience.org/sens-3/

Posted by: Steve Hill at November 9th, 2017 8:51 AM

Florin: As I pointed out above, UNITY Biotechnology is in part a creation of Campisi's lab.

Posted by: Antonio at November 9th, 2017 2:22 PM

Yeah, but the SRF/SENS didn't fund any of the senescent cell research that led to Unity.

Posted by: Florin Clapa at November 9th, 2017 5:53 PM

@Florin - you seem to have an axe to grind about the SRF and senescent cells. Why not just say what you mean and state your argument rather than trying to imply it by stating facts but not a conclusion?

Posted by: Jim at November 10th, 2017 4:16 AM

@Jim / @Antonio

The "30 years to market for senolytics" was an analogy he was drawing to the Nolvadex / Tamoxifen research back in the 1970's

Originally developed as an anti-estrogen for second or third line use as an adjuvant therapy in breast cancer, it did not get a formal "prevention of breast cancer" claim for decades after the fact

I think he is suggesting that any senolytics drug program will need to go a similar path, developed for niche indications first, well before they get ever get a formal "anti-aging" claim decades from now

Posted by: Ira S. Pastor at November 10th, 2017 8:47 AM

Actually, Jim, I'm trying to get Antonio to say what he means. It seems to me that he is implying that the SRF somehow had a significant role in funding senescent cell research (beyond Oisin and what Kevin Perrott is doing at Campisi's lab) which is not the case. It has also been implied in the past on this blog and without evidence that SENS or Aubrey had some sort of role in bringing about the published senolytics breakthroughs. So, yeah, I suppose I do have an axe to grind—against historical revisionism.

Posted by: Florin Clapa at November 10th, 2017 11:21 AM

Florin, what I said initially was simply that SRF has been an important actor in creating the current senolytics revolution. It's you who asked specifically what role did SRF had in currently known senolytics and later also in the 25% LE paper. But I never said that they had that specific roles. Also, I don't consider currently known senolytics to be terribly good. Probably none of them will enter a trial finally.

SRF had a role in pioneering senolytics research at Campisi's lab, and thus a role on creating UNITY; also in bringing more mainstream attention to senescent cells and senolytics, and finally in creating Oisin, whose approach I consider the most promising (but they don't have a "currently known senolytic" yet).

Posted by: Antonio at November 10th, 2017 12:04 PM

@Ira I also think that senolytics will first reach the market for a specific condition, not aging, but hey, reaching the market for a specific condition is also reaching the market, anyway.

Posted by: Antonio at November 10th, 2017 12:10 PM

I mean, Dr. de Grey admits himself that SENS doesn't play a large role in senolytics: https://www.reddit.com/r/IsItBullshit/comments/6vt3dy/isitbullshit_aubrey_de_grey_antiaging_ideas/dm4jn8g/

"As for senescent (and other death-resistant) cells, our work similarly complements others; in this case we are exploring genetic and immunological approaches, in contrast to Unity which is focused on small molecules." They focus on work that isn't funded: at this point, as far as I know, senolytics is fairly well-funded and wouldn't need SENS support. The two current senescent cell related projects they have are such:
http://www.sens.org/research/extramural/controlling-senescent-cell-effects
http://www.sens.org/research/extramural/clearing-space-for-immunity
Which lines up with the focus on immune system and genetic approaches. They also participated in funding Antoxerene, however, which from the looks of it is focused on drugs against amyloids and senescent cells.

Posted by: Miranda at November 10th, 2017 12:26 PM

Yes, that's what I think you said, but I'd like to see some evidence for your claims. I've seen no evidence that the SRF "has been an important actor in creating the current senolytics revolution" nor had any role in creating Unity as you've claimed.

Posted by: Florin Clapa at November 10th, 2017 12:53 PM

@Miranda

"Dr. de Grey admits himself that SENS doesn't play a large role in senolytics"

He don't say that. He only says that they do a complementary approach to other researchers (genetic and immunotherapy approaches instead of small molecule approaches). Also, he refers to what they do now, not what they did in the past.

"They focus on work that isn't funded"

Yeah, totally true.

"at this point, as far as I know, senolytics is fairly well-funded and wouldn't need SENS support."

Yes, but that doesn't mean that funding were that way before.

Posted by: Antonio at November 10th, 2017 1:36 PM

Florin: About the role in UNITY, I already posted the link before. About the former, I can't point out to a single breakthroug paper, it's more the whole of the papers they did along the years and the advocacy at conferences, etc.

Posted by: Antonio at November 10th, 2017 1:38 PM

Genetic research seems to be more than holding its own in the biotech field of longevity science. Take, for example, EDIT, a small firm out of Mass. that is doing some gene editing work to genetically cure diseases. I might mention, the stock is up over 6% today.

Posted by: Biotechy at November 10th, 2017 2:57 PM

Hi there !

This study is incredible (it is reaffirming that aging is not Uncurable, or least it might be Uncurable but Postponed long enough to matter/like postponing for multiple times the current lifespan), I hope this pans out : I think the problem with this is Repetition,
or false hope by saying 'cells can be rejuvenated and we reversed senescence in them', but we omit the detail that it is 'temporary' and not Continuous reversal (aka Permanently Repeatable). You can Apply This, and ReApply it, and ReApply it again...but it is 'finite/teporary relief-MakeBelief'; you still come to a replicative senescence Again at some point.
That is what I found out with certain studies that increased NAD+ levels which slowed telomere erosion and allowed more PDs (since it kept redox in homeostasis/more unoxidized thiols thus better telomeric DNA protection); thus retarded entry into replicative senescence (aka postponing Hayflick). I hope this is not just post-poning Hayflick; but from reading paper, it is - resveratrol analogues reversing senescece through reduce protein errors (independent of SIR nuclear activation, I doubt it, SIR is there somewhere, they say there is 'transcription' activation of SIR). When has wine resveratrol or the analogues they made been able to make a human live about MLSP of 120 or so. Resveratrol, quercetin, senolytics and other senescence reversal elements don'T stop the replicative senescence from coming, one day or another as the cell replication continue. Telomeres can because they are the guardians of cell replication. SENS has no answer for that (stem cell replacement, not sure), they want to stop telomerase to block cancer highjacking of the enzyme. Yet Bioviva Mrs.Parrish increased her telomeres via hTERT activation, she might not have reverted the damages but she did renew the potential for longevity and cell replications - thus lifepsna extension. NAD activators work the same, such as niacinamide/NAM, they extend lifespan because they reduce mitochondrial ROS production by 8-fold from 30 to 80 PDs in fibroblasts; this in turn affect telomere erosion/shortening rate.
As was said, HGPS have 500 base pair loss per population doublings in telomeric DNA - they live 15 years. Healthy humans, living up to 122, lose 50 base pair per PD in same telomere DNA. A 10 fold faster loss and nearly 10 fold lifespan diff. When HGPS fibroblast are cultured with NAD/NAM, they have replicative lifespan extension and start to look like 'normal' fibroblasts - they have massive reduction in ROS production and redox stabilizing. What is the answer to that 'Limited repeatability', it seems only continuous/repeated Complete cell replacement can answer to that and outwit the repetition limit. IT seems too hard to keep a dead beat horse to keep on living (that is why I feel the rusted car analogy works - but only for aw hile, it is not because you keep on repairing parts that it will work forever (because of 'intrinsic limits' on these old pars). Total Replacement with fresh young tissue/cell (near 100%) changes that; since you become 'another' person altogether - as if you Replaced yourself to your Young self. It's the old catch up/mop up game again that wins 'with time/uses us...like slow-death by a trillion micro-sized needle stings)

Just my 2 cents.

PS: @Chris Pollyana

Hi Chris ! Thank you for that; I do/did, but Toronto is not a door's away for me [(near 300 miles); I'm far east and northward]. Thank you sincerely again.

Posted by: CANanonymity at November 10th, 2017 6:38 PM

Antonio, the page you linked to doesn't contain evidence that the SRF had any role in the creation of Unity, and again, there's no evidence that the MF, SRF, SENS, or Aubrey played any significant role in creating, not advocating for or participating in (which are entirely different things), the senolytics revolution.

Posted by: Florin Clapa at November 10th, 2017 8:08 PM

Hi CANanonymity! As I said above I don't think the regenerated cells were actually senescent. So I think this is more of a case of just rescuing cells whose proliferative capacity has been limited by the presence of the SASP. I agree, I think we'll need to cycle more cells eventually, maybe even things like neurons. That way most damage will be dealt with, and enzymes and antibodies developed by SENS will do the rest. Also cellular reprogramming might do the job. Remember we don't need to repair everything perfectly, like Aubrey says they are aiming for 30 years life extension. After that tech will be much more advanced, it's not inconceiveable things like nanobots will completely defeat aging.

Posted by: Mark at November 11th, 2017 3:45 AM

Dear all,

My attention has been drawn to the large number of comments concerning our article on this site. I have read the comment thread with interest. As I have said before I dislike commenting on internet fora but I feel I may have something to contribute to these discussions. So did my colleague who alerted me but apparently the response of the site administrators to his comments was to suspend his IP. Perhaps it is a technical matter, perhaps not.

Firstly, thank you for your interest in our work. As some of you will know I posted the paper here in advance of our press release and debate because I thought it might prove of interest to this community. I will also like to acknowledge those commentators who kindly assisted me with the provision of references and gave their ethical lens on ageing research in advance of the "regueifa". I intend to publish the material if possible and will acknowledge appropriately, as I promised.

1: OUR PAPER
Of the various comments concerning my smug demeanour and lack of vision I take no account. However I am irritated by "Mark" who has apparently read LaTorre et al (2017) BMC Cell Biology 18:31 "thoroughly" and asserts the view that resveralogue treatment did not reverse senescence but that instead "the treatment is restoring proliferative capacity in cells that have lost that ability because (sic) the signalling from nearby senescent cells." This is specifically with respect to Figure 6.

Frankly, after working on senescence for nearly 30 years do you seriously think I (or any of the other four senior staff named on the paper) would make the rookie mistake of discounting that possibility? It was the first thing we thought of. At the same time we discounted senolytic effects from the compounds, not I might add, without considerable sadness ;-)

"Marks" reasoning is fallacious because Figure 6 shows the results of a set of experiments conducted under conditions of serum starvation. In normal human fibroblast cultures, if the serum concentration is reduced below 0.5% then proliferation competent cells exit the cell cycle and enter quiescence. No cell proliferation can be seen from the cell number Figure (6a, hopefully I don't have to explain the concept of an error bar as well?). The drop in the fraction of SA beta gal positive cells occurs in a population of fibroblasts that are non-proliferating. That's the whole point of that experiment!

Regarding the question of release from paracrine senescence a.k.a. "cells that have lost that ability because (sic) the signalling from nearby senescent cells". Leaving aside the fact that this is irrelevant in Figure 6, we considered that possibility as well. This is why we are using a panel of resveralogues. Figure 2 shows the mesoscale heat map of canonical SASP components in cultures treated with the different reseralogues. Resveratrol does affect the SASP. However as a general statement the resveralogues either don't alter it or in some cases actually increase SASP components. That's why we are using a panel of molecules (oh, and to rule out the involvement of SIRT1).

The Ki67 reactive fraction in the populations studied almost certainly represents a G2 arrested senescent population (e.g. Kill & Shall (1990) Senescent human diploid fibroblasts are able to support DNA synthesis and to express markers associated with proliferation. J Cell Sci. 97:473-8). A final spike in Ki67 reactivity is frequently observed in serially passaged normal human cell populations with moderate rates of the loss of the growth fraction as they senesce (e.g. compare Thomas et al (1997) Different kinetics of senescence in human fibroblasts and peritoneal mesothelial cells. Exp Cell Res. 236:355-8 with Kalashnik et al (2000) A cell kinetic analysis of human umbilical vein endothelial cells. Mech Ageing Dev. 120:23-32). Given the sensitivity of the detection system I wouldn't like to rule out the possibility of a small baseline false positive fraction but overwhelming these are G2 arrested senescent cells.

Thus Figures 2 and 3 demonstrate exit from senescence of a subpopulation of cells in G0S. The point that primary human cell populations are complex mixtures and that senescence itself is a mixture of substates does not represent an "admission" in "Mark"'s terms of anything other than the cytokinetics of normal human fibroblast populations. I would recommend anyone interested in senescence acquaint themselves with the classic literature of the 1970s-1990s concerning the composition of normal cell cultures some of which I contributed. Pontén J, Stein WD, Shall S.(1983) A quantitative analysis of the aging of human glial cells in culture. J Cell Physiol. 117:342-52 is a good read. Of course, leaving all this aside, the 'thorough' reader should still at least attempt to come up with some explanation for extension of telomeres post resveralogue treatment in what are obligate hTERT null cell populations.

E.Kelly makes a valid point but the reason we chose to use replicative senescence was because it is physiologically reflective of normal cell turnover during life. Obviously radiation induced senescence will reflect an individual who has received radiotherapy but does not exclusively induce senescence by telomeric attrition (e.g. Gorbunova et al (2002) Expression of human telomerase (hTERT) does not prevent stress-induced senescence in normal human fibroblasts but protects the cells from stress-induced apoptosis and necrosis. J Biol Chem. 277(41):38540-9).

2. ETHICS
Please let me make my own position clear. I have no wish for an extended lifespan and couldn't care less if the work we are doing extends maximum lifespan or not. This is not "I don't think". This is "I don't CARE". Big difference in attitude to some.

If it is significantly extended (e.g. by +30 years) then the arguments I made in the debate come into play. They are novel-ish within the field of ageing but are simply an extension of those pre-existing in ethical discussions around other areas of medicine and rights based ethical systems. The arguments come into play when people start invoking "their rights" or saying things like "everyone is free to do x or not to do x". The latter comment typically indicates that the only rights the actor really cares about are their own (i.e. they are, or are akin to, libertarian transhumanists)
I think it is important to clarify that the 'normies' (among whom I count myself) are not "frightened" by internet "personas" demanding indefinite lifespans. Rather we are repulsed by them. Our beliefs are honestly and strongly held, not a debaters trick to win over the "sheeple".

One only has to look at the "Three Laws of Transhumanism" (https://www.huffingtonpost.com/zoltan-istvan/the-three-laws-of-transhu_b_5853596.html) to see vile, reprehensible selfishness in effect. People demanding indefinably extended life often exhibit this lack of "third person ethical concern" which deeply upsets the majority of people including me (for explanation of term see Partridge et al 2009 Ethical concerns… Am J. Bioethics, 9: 68-76). There are sound evolutionary reasons for this. People following Istvan's three laws will stab you in the back without a second thought. "Normies" aka decent people don't trust them and won't help them with anything. That is why support for gerontology is solid (80-90%) but support for extended lifespans never gets much above 40% (Donner et al 2016 Great Desire for Extended Life and Health amongst the American Public Frontiers in Genetics- thanks guys for pointing me to it!)

3. FUNDING, SENOLYTICS AND SENS
Thanks also to LEAF for raising $250k. A genuinely great effort but it pays only for 2.5 AFAR new investigator awards in ageing. The arguments about the difference non-state actors and the majority of high net worth individuals are making to the field seem to be being conducted without any actual numbers. This is unhelpful.
The NIAs budget is roughly $2 billion and has been $1 billon since 2005. Not nearly enough of this goes on fundamental ageing mechanisms but it still dwarfs the amounts put into the field from other funders. AFAR for example, with great effort and little helped by the lunatic fringe manages to raise enough each year to disburse about $5 million annually whilst staying fiscally prudent. It has done things like this since the 1980s. Thus, the 'heavy lifting' on the science of ageing is borne, year in, year out, by Government funders both in the US and here. The NIA budget is about 500 times that of SENS or AFAR. Maintaining that SENS has played a major role in moving the field forward since the foundation started is perhaps accidentally disingenuous, to put it mildly. The Glenn Foundation have played a larger role for many years and the views of Mark Collins on the utility of promoting the field through promising extended lifespans are sufficiently well known not to require me to comment further. That being said we do need visionary people to start founding companies now. But please be aware of the failure rate. Most ventures fail. I wish Orien and Unity and all the others success and great profits but we need about another 200-300 start ups to increase our chances of a drug. Remember drugs cost $2.5 billion and take an average of 10 years. They can take a LOT longer. It's a brutal numbers game.

Lastly, the idea that SENS has made any large scale conceptual shifts in the field is rather trying. For example the idea that senescent cells have deleterious effects and that they should be therapeutic targets is old, significantly predating any utterances by Aubrey on the subject or his entry into the field. (e.g. Faragher & Shall (1997) Gerontology and drug development: The challenge of the senescent cell. Drug Discovery Today 2:64-71; West et al (1989) Replicative senescence of human skin fibroblasts correlates with a loss of regulation and overexpression of collagenase activity. Exp Cell Res. 184(1):138-47. This latter was an inspirational paper for many of us, but it has its antecedents. Thanks to those on the thread who have tried to combat 'revisionist history'. Perhaps it's simply a lack of context?

People sometimes ask me "why don't you like SENS?" my reply, on behalf of many older scientists is "I'm sick of seeing its devotees claim Aubrey had MY ideas and then accuse me of failing to credit him". Tiresome, quite tiresome. But I suppose it can't be helped, even by Aubrey. Few of us were there in the 1980s and what isn't shouted about remains in silence.

All best wishes
Richard Faragher

Posted by: Richard Faragher at November 11th, 2017 1:17 PM

I will reply only the ethical issues raised by Mr. Faragher.

It's rather astonishing that he is "repulsed" by we immortalists and consider us "reprehensibly selfish" considering that he wants to kill us all in a short time (not more than 80-90 years) by stopping all life extension research (as he defended in the debate) while we immortalists don't want to kill him and think he is free to live for how long as he wish, whether it's 90 years, 500 years or whathever amount can be achieved in this universe.

I simply can't imagine what kind of twisted logic can lead to that conclusion.

Then he builds a strawman by pointing out the "three laws of transhumanism" of Zoltan Itsvan and quickly attacks it as "vile and reprehensibly selfish", obviating the possibility that not all transhumanists (let alone immortalists) follow them or even know them (I myself is the first time I read them) and creating a false dichotomy: you can (a) be a decent person and care about others or you can (b) be an immortalist and ruthless killer. There is no more possibilities, according to him. Again, that is rather astonishing considering that he thinks he is in (a) but at the same time he wants to kill us all when we reach 90 or so.

Posted by: Antonio at November 11th, 2017 1:59 PM

Only a short note about funding:

It's not quite smart to measure the impact of research by how much money it used. If one could simply throw a lot of money at problems and surely obtain solutions...

Posted by: Antonio at November 11th, 2017 2:10 PM

I think everyone will agree with Mr. Faragher that more start-ups are needed in the anti-ageing space (can't comment about the number needed, though).

As far as drug development go, we can hope that the currently huge cost will decrease overtime thanks to ever-improving machine learning. Which in turn could could lower the barrier to entry for upcoming start-ups (and boost the revenues of major pharma companies, no wonder they're all actively hiring and forging deals with AI firms).

Posted by: Spede at November 11th, 2017 3:33 PM

Dear Antonio,

Thank you for your note. Perhaps you have also forgotten a couple of matters.

1. I am Professor Faragher, or at a minimum, Doctor when we correspond on professional matters. Unless of course you intend to insult me. Since you have been told this before you will forgive me if I assume that is your aim.

I confess I would value your comments more if you had the courtesy, or just the courage, to post your real second name. Just who and what are you, behind the poorly written text and second rate evasions noted by others here? Come out, if you dare, or do we have to draw our own conclusions about why 'Antonio' won't? A 'man' who dares to be immortal should at least have the guts to show his face. Since you hope to dance on my grave what have you to fear in the vast span of time ahead? Or don't immortalists believe that 'cowards die every day and brave men only once?'

2. Since you cannot imagine the ethical framework of the majority of the human race perhaps I could recommend "Being good: A very short introduction to ethics" by Simon Blackburn . It's nice and short and should allow you to get to grips with some of the articles I have posted. It is written for the absolute beginner in the area and assumes no prior knowledge.

3. It would appear that you don't read things closely either, nor do you have a good memory. Here's a little quiz. Which person on this thread bitched about, my F1000 article on this site (incidentally drawing my attention to it) by posting '2-0 for Aubrey, even if he and SENS aren't mentioned in the article'- (a) the Queen of Sheba (b) Antonio no name. Hint (b) and feel free to explain why SENS deserves the credit for anything in there, except perhaps my RSI? Interested parties may wish to consult 'Fight Aging' for the 9th August.

4. On the same thread, the appropriate end to a polite discussion is not 'WTF'- your final response to a carefully written and (I trust) unexceptional explanation of contracting ethical human frameworks . Perhaps if words fail you to that extent additional English language practice would prove beneficial? I am happy to recommend some books if asked.

5. Please rest assured that your views as an 'immortalist' Will be properly represented in my submission to a suitable journal. Your responses have proved illuminating and informative and I
am confident will do so to the wider bioethics community.

6. I agree that it is 'not quite smart' to equate scale of funding with results. But it's pretty stupid to assume every dollar you spend matters five hundred times more than a long established agency with funding sections staffed by the very scientists who's work you keep citing. Perhaps illiteracy and innumeracy are functionally related? Not my field.

7. I note that it has proven acceptable to close threads here with quotes from HL Mencken.
I refer you to them- especially the one about not engaging in a duel of wits with an unarmed opponent.

Richard Faragher

Posted by: Richard Faragher at November 11th, 2017 5:41 PM

Richard, the stats from the Donner et al paper indicate that up to 80% want extended lifespans (28% want 120 years, 9% want 150 years, 42% want unlimited years), not 40% as you've claimed.

Posted by: Florin Clapa at November 11th, 2017 5:41 PM

Play nice, people. I think it now well established that Richard Faragher doesn't build upon the same axioms as most of us here. It isn't a constructive use of time to do more than outline the opposing views; neither side is going to convince the other, and we're all well aware of what those views are.

The world will follow those who build successfully, and to the extent we're doing anything here, it's recruiting additional support for the builders of rejuvenation therapies. Everything else is just color along the way, and not all that important.

Posted by: Reason at November 11th, 2017 7:27 PM

Hi, interesting. (I am uninformed anonymous stranger online).

I'm a nobody (in terms of science) and anonymous (from my username using this word for privacy from crazies online), just my 2 cents.

I think things have been changing like such (sorry english is not my language);
we see it everywhere, it may not be the 'best'; but I guess it is the change that is happening.
Individualism and Collectivism in opposition; or tagging along in parallel. Altruism
or Individualism. Selfishness Individualism or Selflessness Altruism. Toxic individualism.
Toxic Altruism. Our societies are becoming individualistic in nature, we don't say hello
to strangers on the street, we mind our business in our iphones and it is 'evolution' if you will
because internet has allowed communication opening/widening/exchange; this is a good thing but also a bad thing (individualism
is lost - everyobdy knows you and if you want that, that is great you can plug yourself either online *facebook twitter or outside and make friends;
if you don't want that, it's a problem; individualism and being solitary helps there; not necessarily selfish egotistical).
Sometimes we can't help everybody, we wish to and we think for almost
everybody. Also we have to live our lives and nobody else lives in ours; as selfish as it sounds at the end of the day nobody left but you in your body.
It is akin to the captain in a sinking boat analogy (far fetched a bit), he does not to be traitorous
and let the boat sink; he wishes to save the crew too (altruistic/human quality); he
is leader and must do so - but what about him, he will drown with the boat when everybody
is off of it. He`'s not selfish egotistical, he really wishes to protect the crew and save them
from drowning - he puts them first before him, but the boat is sinking anyway. He drowns. That is problem, he
could have a moment just to get off the boat and save his life; a fraction of seconds, he could have that chance
to life too,just like these people he saved from drowning. We can't put all people in the same basket/generalize
and feel that peple who wish to live long lives (like 150 years or more, in good health) would all be selfish morons
who are heartless, insensitive, traitorous and just bad altogether for society (but life is a competition, everyone competes everyday). I think when someone says that
wish Everyone to live infinitely, it is like giving the gift of eternal life to people; Everyone gets it. It is a selfless act but people
can see it inversely, as a selfish act - because humans always aged and die....it is natural response and do not wish to change this old
concept because it messes up the ethical balance too much. I think we have to be ready for new changes and many people are willing
to try something new - selfishness will have to creep in - it's not good but it will happen. We only need to look at animals in the animal
kindgom to see cooperation, competition, collectivism and individualism play out. It is going to happen, it could be a sort of 'altruistic individualism'
it sounds very wrong but it could be possible.
It's true that when Only you is immortal, then selfishness it is because only care about your own life not of the others. But life is not easy, it really is survival of the fittest; ethics
make us good humans but we die, that is a problem too. Other's do not see it a problem and wish to let go. In my case, I suffered from atherosclerosis and I'm young, so it's like - no, I don't like death nor wish suffering on anyone; nor wish to die of my disease; curing the disease; curing death more important as ludicrous it sounds.
With that said, I fully understand why someone who 'leave' their friends to protect their life - their immortal life. it is selfish.
It's true that future is more cold than we thought but I think we can make it warmer and offer people the health they wanted, and if they so wish to live long lives - of maybe not immortal life but you know 3 centurioes or something; it would be a new change and perhaps something good could come out of it, even it sounds ethically tottally wrong. I will respect people who believe curing death is wrong and death (infinite end)
has a meaning in this world; it is an ethical meaning not a biological one. I'm just saying let's give this is a shot (in the dark) and see what happens. Many of us are young and wish to 'start young' to live Very old/long life and
if possible (lucky) who knows break the 122. It might be day dreaming but it is something we can do to 'keep on dreaming' in color. Sorry for typos.

Just my 2 cents.

Posted by: CANanonymity at November 12th, 2017 12:00 AM

Here's my take on the funding thing. The public funding situation can't significantly change until you yell at the top of your voice that you have a way to cure a specific disease. The problem is that even if you tried to do that, other voices are going to drown you out. The only way out of this that I can see is to advocate for the creation of a DARPA-like agency tasked with funding medical research which has a good theoretical chance of preventing or curing disease and to prioritize that research by taking into account which diseases debilitate and kill the most people. The need for this kind of agency is obvious: despite decades and trillions spent on research, the medical research community has mostly failed to prevent or cure any disease.

Posted by: Florin Clapa at November 12th, 2017 12:27 AM

Dear Dr. Faragher,

(I omitted the "dear" before because, honestly, it's difficult to call "dear" to someone that wants me to die in a few decades. I will try to be polite as Reason asked and will use it.)

I'm also a doctor, but I could not care less whether people call me doctor or not, and I usually don't use the title to address other doctors, mostly because I'm a Spanish speaker and it's rarely used in Spanish, even in academic contexts, and usually I forget that in English it's more used. I will use it from now on. Sorry if that was insulting to you, I didn't intend that.

My full name is private data and it doesn't change whether my arguments are correct or not. It's not a matter of cowardice or courage. I simply value my privacy, and there is absolutly no need to reveal it, as there is no need to reveal my address, my phone number or what I ate yesterday for dinner. I'm not a gerontologist nor a researcher in any field related to medicine or biology, if that is what you want to know by asking my name.

"Since you hope to dance on my grave"

I will not take this as an insult, even when I already said in my previous comment that for me (and in general the other immortalists) you are free to live 90 years, 500 years or the amount you want and can.

Recommending an introductory book to a field is not really useful as a reply for a very specific question about a matter in that field.

I already explained in the previous thread, where we discussed in October for some time, what SENS exactly is and what its originality is. As for its importance or worth, I think that it's the only current plan that has a high probability to significantly increase current lifespans. As for why I think that, it would be too long to explain, basically it would amount to rewritting "Ending Aging". Anyway, its worthness or worthlessness will probably become evident for all in a couple of decades, if current trends in funding are maintained (both for SRF itself and for SENS-related startups).

As for the '2-0 for Aubrey', yes, I still think that. He said that senescent cells are a root cause of aging and that there is no real distinction between 'aging itself' and 'age-related diseases'. And thus he was right in both topics, so 2-0 for him against the people that said the opposite, even if he or SENS is not mentioned in the article. And it didn't mean that I counted you in the "people that said the opposite". I sincerely don't know your previous position on those topics. That expresion was not a "de Grey vs Faragher" result and never intended to be.

The "WTF" was totally intentional. It was not polite but it was a reaction to the much much much much more unpolite statement that all people must die at a fixed age instead of trying to live as much as they can, the biggest genocide in world history and proposed as an ethical obligation. Thus the WTF (and it really falls very short of what should be said, but I tried to be polite).

"Please rest assured that your views as an 'immortalist' Will be properly represented in my submission to a suitable journal"

I hope you submit my real views, not Zoltan Istvan's views or what you think immortalists views are. Anyway, I don't think anything said in such a journal can change life extension research in any way. It will follow its pace whathever is said there.

The rest is not worth answering.

Greetings.

Posted by: Antonio at November 12th, 2017 1:32 AM

@Florin Clapa

I expect nothing from governments. They will probably arrive only when almost all is said and done, save for stem cells research and other gerontology fields that have a clear indication for diseases outside aging. Things like glucosepane and allotopic expression of mitochondrial genes will be done first by philantropy and then by private investors.

Posted by: Antonio at November 12th, 2017 1:37 AM

So what exactly is the line that Professor Faragher has on length of life here? I can't see it being 90 or 100, as people hit those numbers with a degree of regularity now. Is it when it comes to pushing much past the theoretical limit of 122? While I think it's somewhat silly to want to put a limit on life, I feel the same when it comes to speaking about living to 150, 175, 1000 or 'forever' now also. I'm just curious on the specifics, as the average life expectancy is different than maximum life span.

Posted by: Chris at November 12th, 2017 8:23 AM

Would any of the 76 commenters posted so far think of taking a resveratrol pill?
Doesn't sound like it.
For the record, resveratrol was equal to its analogues in Sirtuin1 activation which was a primary but not sole factor in RNA splicing, and resveratrol lengthened telomeres (which is a marker but not governor of aging via its antioxidant properties).

Posted by: Bill Sardi at November 12th, 2017 11:27 AM

@Bill Sardi: Size of effect matters. We know what resveratrol does in humans, which is to say nothing big enough or reliable enough to care about. You are far better off exercising or eating less. Or, more to the point, putting effort into getting proven senolytics into the marketplace.

Posted by: Reason at November 12th, 2017 11:33 AM

Actually, government is funding ALL of the SENS strands. And yes, that includes even LysoSENS, MitoSENS, GlycoSENS (maybe), and WILT (ALT-related). While SRF funding is still essential to fill in the gaps, government spends a lot more on SENS than the SRF, even though it is a tiny fraction of the other non-SENS stuff it funds.

LysoSENS
https://projectreporter.nih.gov/project_info_description.cfm?aid=8181189

MitoSENS
https://projectreporter.nih.gov/reporter_searchresults.cfm?redir=sh&sl=12ECCF0B488BCEDF7598B8961CAA4A01A2FFCEB861BF&icde=35606688&hsid=20583145&shQID=0
https://clinicaltrials.gov/ct2/show/study/NCT01267422
https://projectreporter.nih.gov/project_info_description.cfm?aid=9084594

GlycoSENS
http://gtr.rcuk.ac.uk/project/11840F21-0B28-416F-BE6A-123E371FB2C3

WILT (ALT-related)
https://projectreporter.nih.gov/project_info_description.cfm?aid=8897311
https://projectreporter.nih.gov/project_info_description.cfm?aid=9154553
https://projectreporter.nih.gov/project_info_description.cfm?aid=9178183
https://projectreporter.nih.gov/project_info_description.cfm?aid=9069444
https://projectreporter.nih.gov/project_info_description.cfm?aid=9031082
https://projectreporter.nih.gov/project_info_description.cfm?aid=8928060
https://projectreporter.nih.gov/project_info_description.cfm?aid=8913070
https://projectreporter.nih.gov/project_info_description.cfm?aid=8985668
https://projectreporter.nih.gov/project_info_description.cfm?aid=9174657
https://projectreporter.nih.gov/project_info_description.cfm?aid=9102981
https://projectreporter.nih.gov/project_info_description.cfm?aid=9097525
https://projectreporter.nih.gov/project_info_description.cfm?aid=8960088
https://projectreporter.nih.gov/project_info_description.cfm?aid=9037618

Posted by: Florin Clapa at November 12th, 2017 12:07 PM

Thank you Dr Farragher for responding here. I must admit I do find the splicing factor link to telomeres fascinating and would love to see this mechanism elucidated. I would also like to see you show beyond doubt that you actually are rescuing senescent cells; there is obviously a fuzzy line in this naturally aged cell line between senescence and quiescence and despite your argument that a resveratrol like molecule does not inhibit the SASP, or even makes it worse in some aspects, and yet still shows some positive effects, does not prove what you claim.

I find your attitude to Antonio to be condescending and rude. Directing someone to improve their english, especially when they are not a native english speaker is bad enough, but then also to suggest they read a beginners guide to ethics is plain ridiculous. Any child knows that aging to death is horrible and wrong, anything else is just solipsism.

Posted by: Mark at November 12th, 2017 2:35 PM

Regarding SENS, Antonio mention this before, but it won't hurt to emphasize it again. The best thing about SENS is that it's (still) the only framework theoretically capable of eliminating all of the conditions and diseases associated with aging using current and foreseeable biomedical technology. The key conceptual insight of SENS is that repairing damage would be more productive than tinkering with metabolism to slow down damage creation or adapt to that damage. These are some of the reasons why we are impressed by SENS and don't care that much about most of the other kinds of proposed gerontological interventions like rapamycin and metformin.

https://www.fightaging.org/archives/2017/08/cellular-senescence-as-a-cause-of-aging-from-wishful-thinking-to-case-closed/#comment-29057

Posted by: Florin Clapa at November 12th, 2017 2:43 PM

The selfishness argument makes no sense. It implies that there is some sort of societal benefit to normal lifespans that would outweigh any benefit provided to individuals by unlimited lifespans. I haven't heard of any likely scenario under which such a societal benefit would occur. And if we're honest with ourselves, it seems that almost everyone prefers to be extremely selfish, despite their pretensions, on both a personal and societal level. Even if the desire for unlimited lifespans was a form of selfishness, it would be no different than any other, so why single it out? Will those that pretend not to want an extended lifespan, kill themselves for the greater good? Is it better to have the appearance of selfishness or to be an actual hypocrite?

Posted by: Florin Clapa at November 12th, 2017 4:27 PM

If speculative scenarios are discounted and all things are kept equal, to prefer a society with normal lifespans rather than one with extended lifespans is equivalent to preferring to increase the total amount of death and therefore suffering that must be endured by the members of that society. This preference is something far worse than selfishness. Some would call it evil.

Posted by: Florin Clapa at November 12th, 2017 6:10 PM

@Florin Clapa

I don't know why it's so difficult to remember: SENS IS BASED ON PREVIOUS RESEARCH. Thus, I don't claim that SRF is the only one that researches X or Y, or the first one that researched Z. Again, SENS originality (apart from maybe WILT) is the creation of a comprehensive and near-term plan to defeat aging, rejuvenating people. Also, another difference between SENS and other research is its focus on engineering (searching for cures) instead of science (searching for knowledge). For example, there is a big difference between synthesizing glucosepane for the first time and using it to develop antiglucosepane antibodies, and this research you linked above:

http://gtr.rcuk.ac.uk/project/11840F21-0B28-416F-BE6A-123E371FB2C3

"In our study we will quantify and locate levels of important sugar-mediated cross-links in tendons from individuals of different ages and link this to how the collagen structures perform mechanically and renew themselves within the tendon tissue. In addition, we will investigate ligament and bone tissue to determine whether a similar pattern and level of age related crosslinking is present suggesting commonality in ageing of different skeletal tissues."

Posted by: Antonio at November 13th, 2017 2:31 AM

That engineering focus and the guidebook of a clear and specific plan to defeat aging is why I think that SRF and related companies will cure aging before government, which lacks them, even if it has lots of money.

Posted by: Antonio at November 13th, 2017 2:38 AM

After reading the latter comments by Florin, I must apologize, he clearly knows what SENS is. Anyway, the rest of my comment still applies, I don't claim that SENS researchers are the only ones studying X or Y, but the only ones that have a real possibility of fixing X or Y.

Posted by: Antonio at November 13th, 2017 2:44 AM

Yes, Antonio, I agree with all of that, but where I disagreed was when you mentioned that you "expect nothing from governments," and I tried to point out that your expectation is at least somewhat misplaced.

Posted by: Florin Clapa at November 13th, 2017 11:55 AM

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