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SENS after de Grey

A recent article on Aubrey de Grey, in which he is presented more in the mode of amiable fellow next door than the mode of instigator of the SENS rejuvenation research movement, reminded me that planned obsolescence is very much an anticipated goal for de Grey. He has for a while now seen a "retreat into glorious obscurity" ahead, perhaps wisely given the way movements tend to grow into unruly children, disrespectful of their founders. We'll see whether it actually comes to pass or not, given that a diet of interesting success is always a challenge to set to one side, but it is also true that going on two decades is a long time to be working what is essentially the same demanding, even consuming job. Still, look at folk like George Church and Craig Venter; there is no shortage of opportunity for third acts in this life. Note that the short article linked here is published by the Financial Times, and so you'll probably have to employ the usual stratagems to bypass their paywall; Google is your friend in this, at least.

Aubrey de Grey: scientist who says humans can live for 1,000 years

Fifteen years ago, de Grey was lead author of a paper in the Annals of the New York Academy of Sciences which claimed the "indefinite postponement of aging . . . may be within sight". Since then, he says, his position among gerontologists - the scientists of ageing and its related ills - has changed from sidelined dilettante to one of the discipline's most influential and public voices. While his science may now be more widely accepted, his pronouncements of impending immortality remain unpopular among his peers. Their squeamishness is unsupported by the evidence, he says. It belies an intellectual dishonesty that has at its heart a deeply emotional - and increasingly erroneous - attachment to the inevitability of death, according to de Grey.

In some ways de Grey's tumbledown mountain retreat seems a fitting castle for this self-appointed "spiritual leader of what I regard as the world's most important mission". To most eyes, the sprawling four-bedroom property falls on the wrong side of the line dividing shabby kitsch-and-chic from basic decrepitude. "The most expensive thing I had owned before this was a laptop. I don't like too much modernity and artifice, I like to be surrounded by mellow things." De Grey's asceticism amounts to more than a disregard for modern interiors and a voluminous beard. While many visionaries come to Silicon Valley to make a fortune, de Grey gave one away. In 2011, his mother - "the formative influence" of his life; his father left before he was born - died. De Grey, her only child, inherited her £10.5m fortune from two Chelsea houses she bought in 1953 and 1963 for a total, he estimates, of £30,000. De Grey took roughly £2.1m for himself, most of which, after inheritance tax, he spent on his home. The remainder, £8.4m, he donated to SENS. When his fiancée arrives he hopes, in time, to "retreat into glorious obscurity" with her, pulling back from a busy speaking schedule that takes him around the world to publicise his work.

It is in the nature of revolutions to bury those who led the first charge. The wages of wild success are indeed obscurity, and fighting that truth seems futile; a matter of standing against the tide. If you start a movement to change the world, and people can still easily pick you out from the crowd of change-makers and supporters fifty years later, then I'd say you didn't do so well. The point of the exercise is to create a sweeping wave of leaders, viewpoints, and endeavors that up-ends the present inadequate system to produce radical improvements. The point of the exercise is to make yourself irrelevant as rapidly as possible, in other words. Human nature being what it is, no matter how hard it was to convince the first few people, and no matter how much work was needed in the early days, the talking heads of the world will later agree that it was obvious in hindsight, anyone could have done it, and weren't those people in the second wave of activities, ten years in, far more important anyway? Validation in this scenario is something that you have to accomplish for yourself, which is worth thinking about while considering one's own efforts and future. Do the work because it is important to your eyes, and because you want to, not for any other reason.

It is true that there is a great deal left to accomplish in order to achieve the technical goal of robust mouse rejuvenation, through prototype implementations of therapies that repair the seven classes of cell and tissue damage that cause aging. The first such therapy, senescent cell clearance, seems a sure thing now, given the state of funding and the field. But the others? Still in the labs, some quite a way from realization. Still, SENS has won, the movement came into being. It is bigger than any one group of people, even now, while a sizable fraction of the necessary laboratory work remains coordinated by the SENS Research Foundation. The goals of SENS will survive the retirement or exodus of any given handful of people, and there are a number of alternative SENS-like formulations out there now, backed by their own advocates and researchers, such as the Hallmarks of Aging. The high-level concept of treating aging by reverting its distinct causes is now spread far enough not to fail. The next twenty years will be a matter of various viewpoints and implementations competing on the only metric that matters, which is the ability to produce rejuvenation in patients.

The battles of tomorrow will be fought over advancing the most plausible approaches more rapidly to the front of the queue, and obtaining the broadest possible funding and adoption by research groups. Later, the battles will be fought over ways to drive existing therapies into low-cost mass production, bypassing the existing regulatory system in favor of something simpler that will save vastly more lives, enabling widespread deployment of rejuvenation therapies both within and beyond the wealthier parts of the world as rapidly as possible. The very first seeds of that future are in progress today, but first things first. The construction of a new industry of rejuvenation biotechnology, from start to finish, is something that will span more than one career - though of course the hope is that it will not span more than a single lifetime, no matter how long it takes. Those who finish will be vastly more numerous, and an entirely different set of people, from those who start. That is the way of things.

Comments

I don't think it's time for him to bow down just yet. That is his choice to make of course but there's more than enough work left to be done before life extension can truly be called an active movement.

Posted by: Anonymoose at February 10th, 2017 8:06 PM

Hi,

I fell off my chair when I read that he inherited millions of dollars (I'm sorry for the loss of his mother) ... I lost my mother too
(in 2004) ...but some people are just Lucky$$, I did not receive a penny on my mother's death or later (my family was poorer) some people are born in a rich family and can then inherit it from dead rich parent, to then go on and make huge endeavors (creating SENS). Which is itself is a good thing, if reserved to Lucky ones. He knows he's full of Luck. But his endeavors repay themselves because he wants to help everybody heal and cure death so he's giving back his fortune (8M, although he did keep a not so shabby 2M dollars from Mom's money, which I'm sure his Mother wanted him to have, being her only child).

That's life for you.

I stumbled on a paper that completely dismantles SENS as optimistic sci-fi. Read it and weep. I hope it isn't so but every argument the author brings forth is credible and a real problem, AdG answered it but it does not change the fact that some of these points seem very plausible 'real' problems. His main point is that repetitive rejuvenation by damage repair is futile because of 'patchup work' (patch damage) catch-up mop-up failing game rather than curing the, source, of these damages from happening in the first place. I only mitoSENS (mitochondrial mutations) and oncoSENS (nuclear epimutations) as 'at the source', the rest (glycoSENS, lysoSENS, repleniSENS, apoptoSENS, amyloSENS) are patch-up work (damage repair/junk removal).

The Impracticality of Biomedical Rejuvenation Therapies: Translational and Pharmalogical Barriers.
1- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142774

Posted by: CANanonymity at February 10th, 2017 10:21 PM

Senescent cell removal always looked like one of the easier forms of damage to deal with, given the body tries to remove the cells anyway, and because the cancer research community has been developing specific cell targeting technologies for decades already.

I don't know if any other type of damage will be as straightforward to deal with. Some of the objections by William Bains to SENS stress that we just don't yet know the technological problems that we face in implementing SENS.

Fifthteen years ago the path to dealing with Alzheimers seemed pretty straightforward, just generate some antibodies to amyloid beta clumps and inject them. 15 years later there are zero effective antibodies against amyloid beta. 15 years from now we may have solutions to this, or we may have discovered further technological problems.

Posted by: Jim at February 10th, 2017 10:25 PM

I've personally talked with Kyriazis before he's a good man and a proponent of life extension, but he also has some strange ideas (look for his papers on evolution it's an amusing read) and often falls victim to oversimplified thinking in general like is often the case for medical professionals trained a good 40+ years ago.

Some of his critiques quite honestly make little to no sense. Just from taking a quick look at that paper I can see an implication that removing all lipofuscin by chemical means is possible and quoted as a negative ... I'd be happy to hear him give an example of any medicine that can remove any substance from a live organism - a similar concern has been voiced for senescent cell removal and it makes even less sense in that case.

Jim, I can't say I follow Alzheimer's research too closely, but if I'm not mistaken there has been success with amyloid beta antibodies in human trials recently and it does seem to SLOW the progression of AD. Whether AD is caused by just abeta is a better question and if we hadn't started work on abeta antibodies we wouldn't have had this insight that there might be more to it than just the amyloids.

Posted by: Anonymoose at February 11th, 2017 12:47 AM

Sometimes I'm affraid of the possibility that SENS is overthrown by a similar but less efficient strategy, like the Hallmarks. It has happened in other fields. Linus Torwalds is mucho more known than Richard Stallman, and worse, most people that use Linux don't care why it was created (as a free alternative to Unix) and use it as a non-free system. So in this case, Stallman success was only partial (or even a failure). Another case of "successful failure" is the Arab Spring. They overthrown military dictatorships only to fall to religious dictatorships, never reaching democracy.

So we must fight against the possibility that a more inefficient, slower, less ambitious version of SENS replaces the original in the decades ahead.

Posted by: Antonio at February 11th, 2017 3:22 AM

Jim:

Interesting reading. Well, maybe he was right about Alzheimer's, but he was clearly wrong about MitoSENS. He puts it (in 2008) as if we didn't even know where to start, and now, 9 years later, we have allotopically expressed 3 of the 13 genes, one of them being in phase III trials.

Posted by: Antonio at February 11th, 2017 3:54 AM

Wise words from Reason y Antonio.

One thing I like with the SENS approach is its boldness. Detecting a middle way which could seriously address ageing, and going all in - just like AUbrey did with his inherited fortune as he put it where his mouth was.

This is where the community plays a role, acting as a vigilante against a "corruption" of the original SENS goals.

Posted by: Spede at February 11th, 2017 4:13 AM

"Sometimes I'm affraid of the possibility that SENS is overthrown by a similar but less efficient strategy, like the Hallmarks."

How is Hallmarks less useful? It incorporates all the SENS damage (bar crosslinks) and gives detailed evidence based explanations as to why these aging processes occur? I dont see them as competing just different ways to illustrate aging.

Re the article, yes no one person is or should be so key that their leavng a movement ends it. Whilst I hope Aubrey will remain with us till the final hurdle ultimately he has already set things in motion.

Posted by: Steve Hill at February 11th, 2017 5:17 AM

Steve:

The Hallmarks advocates say their 9 categories of damage are the root causes of ageing. The SENS advocates say there are only 7 categories of root causes. So, if the former ones are wrong, and some of the 9 categories are really secondary causes, and we pursue them, we are wasting money and time in their research.

Say, for example, that telomere shortening is really secondary damage and it will be fixed by the repair of the 7 SENS categories. We could waste a couple of decades and billions of dollars on telomere enlargement research, like previously was done with sirtuins.

Posted by: Antonio at February 11th, 2017 7:15 AM

Indeed, there is this paragraph in the Hallmarks paper:

"There are multiple lines of evidence suggesting that aging is
accompanied by epigenetic changes and that epigenetic perturbations can provoke progeroid syndromes in model organisms. Furthermore, SIRT6 exemplifies an epigenetically relevant enzyme whose loss of function reduces longevity and whose gain of function extends longevity in mice (Kanfi et al., 2012; Mostoslavsky et al., 2006). Collectively, these works suggest that understanding and manipulating the epigenome holds
promise for improving age-related pathologies and extending healthy lifespan."

But it doesn't stop there. One of the 9 hallmarks research is calorie restriction research! (called "deregulated nutrient sensing"). And we all know the poor outcomes of the CR monkey experiments and all the other evidence of how CR effect on life extension depends on "natural" lifespan.

Posted by: Antonio at February 11th, 2017 7:30 AM

I certainly hope Aubrey doesn't disappear just yet.

Posted by: Nicola at February 11th, 2017 7:37 AM

Antonio I dont think you are quite understanding deregulated nutrient sensing if you simplify it as just being CR, it isnt the case at all and in context it makes sense. It isnt a primary Hallmark anyway.

Telomeres are a sub set of genomic instability and the research to support them is good. However recent publication by SALK and Blasco shows that telomeres are reset when epigenetic changes are reversed. It does not change that they are still a hallmark of aging, just confirms they are closely linked to the others.

I am however not prepared to debate the merits of Hallmarks and why it incporporates SENS quite nicely within it. Needless to say I am concerned with your comments above where you suggest fighting other approaches. This is bordeline dogma in my view and borders on almost religious ardoration. Science isnt like that and we should follow the data where it leads and be prepared to rethink things based on new data.

Posted by: Steve Hill at February 11th, 2017 7:52 AM

"The Hallmarks advocates say their 9 categories of damage are the root causes of ageing. The SENS advocates say there are only 7 categories of root causes."

Are you interested in science or religion here? SENS advocates and hallmarks advocates, are you really making a division between people with the same common goals but who are looking at aging through a slightly (and its only slightly) different lens?

This kind of blind faith is not science and it is not helpful.

Posted by: Steve Hill at February 11th, 2017 7:56 AM

It's certainly not dogma! I'm an atheist and a matematician, indeed.

Since the Hallmarks approach is centered on damage repair, it's certainly better than previous gerontology, based on trying to slow aging. OTOH, it's also true that your life can depend on which damage repair approach is chosen by the research community.

Given the evidence I have read about, it seems to me that Hallmarks is not the better approach, and even it can make me not be in time for LEV.

Of course, this space is too small to discuss Hallmarks vs SENS in enough detail to be able to choose one.

Posted by: Antonio at February 11th, 2017 8:00 AM

"Are you interested in science or religion here? SENS advocates and hallmarks advocates, are you really making a division between people with the same common goals but who are looking at aging through a slightly (and its only slightly) different lens? This kind of blind faith is not science and it is not helpful."

You are the only one talking of faith here. I only discussed about the Hallmarks paper and what evidence is in favour or against it. Against that, you started talking about me, putting me as a religious fanatic without ever knowing me and ridiculling what I said putting it as faith instead of discussing what I really said, like the part were the authors seem to advocate for more research on sirtuins and sirtuin-like compounds, and the hallmark that is CR in disguise.

Posted by: Antonio at February 11th, 2017 8:07 AM

I know you are a matematician but your words seemed borderline dogma to my eye. I see an almost blind faith from a significant number of people who follow SENS and that worries me when they are closed to all other ideas despite emerging evidence to support them. We cannot afford to be dogmatic in science.

Yes Hallmarks is a repair approach, they explain the nutrient sensing pathway and its far more than simply CR. I would be happy to dive into that in depth but unfortunatley I dont have the time now and as you say, this isnt the ideal place for such things.

Epigenetic changes we know thanks to SALK and Blasco this year are important and when you reset epigenetic changes we see increased lifespan and cells restored to younger function. Almost certainly a pathway worth pursuing.

However, the point is we do not know the best approach but we are learning at a rapid pace. The mark of a good scientist is someone who evaluates and changes their approach based on new evidence. There is no doubt SENS has merit as does Hallmarks and in biology there is rarely a single way to achieve the same results.

That said I support SENS and others working on similar approaches such as Hallmarks because I think this is a group effort.

Posted by: Steve Hill at February 11th, 2017 8:07 AM

"I see an almost blind faith from a significant number of people who follow SENS and that worries me when they are closed to all other ideas despite emerging evidence to support them. We cannot afford to be dogmatic in science."

Since you insist on talking on a personal basis, writing statements about me and my thoughts that you can't know about, since we only talked a little by mail and a little in forums and here, I will stop replying to you.

Posted by: Antonio at February 11th, 2017 8:18 AM

That is a good idea as I am sure we both have better things to do.

Posted by: Steve Hill at February 11th, 2017 8:22 AM

Why does this area of life extension / anti-aging always degenerate to these types of arguments? I've never met oncologists, or neurologists, or endocrinologists, etc. that fight like this so early in the game - usually they work hard, raise money, get a product to market, and then fight in the marketing pits. THIS is the real answer to that constant whining question of why no one believes much in this space - it has set itself up to self-destruct in the eyes of the public

Posted by: unreasonable at February 11th, 2017 9:46 AM

Because some people (including some researchers) have put themselves in camps, the "damage camp" and the "program camp" and refuse to budge or consider anything else despite what the data shows. That is dogma not science and that is what holds us back.

Posted by: Steve Hill at February 11th, 2017 9:53 AM

I think when he says lipofuscin removal could be deleterious he means that the body is a self-adapting system carefully balanced, thus tinkering the balance can lead to reverse (new/unforeseen) problems in the long run. Because, he says, lipofuscin plays a positive role in the homestasis (lipofuscin improves lysosome sturdyness/integrity), a bit like ROS as negative damaging free radical species but also as positive signalating elements (mild ROS signalate hormetic activation of redox elements such as NRF2 nuclear translocation; basically an oxidative stress survival signal); or like senescent cells that, despite negative, have positive function in skin tissue healing :

The body is this 'adapted' to its 'damages', and thus its damages are 'part' of the finite homestasic balance. What happens when you mess with the balance ? You can create (new/unforeseen) problems rather than 'obvious' solutions, as in the simplistic straightforward 'cure damage = cure aging', it seems it's not as straightforward or simple as that. Because the body is a self-adapting system carefully honed to its current state/age...that's where evolution comes in and it's hard to outdo evolution's million years work of adaptation in our evolved body's biology.

Posted by: CANanonymity at February 11th, 2017 9:57 AM

@unreasonable: Because the funding situation is unfortunate, I suspect. It is harder in this field to raise money for even areas with very good pedigrees. Senescent cell clearance is a great example: a very large amount of evidence, but it took immense effort and eventually philanthropy to get the funds to undertake an animal study. So lower levels of funding, much more stratification of those groups with the ability to raise and those who do not, which means much more infighting in public as a strategy to open doors to funding, especially given that those with the ability to raise are largely not producing meaningful results, and even today are largely not doing anything to work towards treating aging at all.

Posted by: Reason at February 11th, 2017 10:03 AM

@Reason like Calico for example? They have big funds but so far do not seem to have produced anything.

Posted by: Steve Hill at February 11th, 2017 10:07 AM

@Steve Hill: Calico is a disappointment. To all appearances they are taking a mix of reinforcing CR mimetic-like research, analogous things that also look like standard issue drug discovery to modestly slow aging, plus an expanded version of what the Ellison Medical Foundation did, which is to say funding more NIA-like programs of mapping cellular biology in the context of aging.

So given this, the prediction is that they will essentially function as an adjunct to NIA research programs until they are made irrelevant by the introduction of therapies based on damage repair that actually work.

Posted by: Reason at February 11th, 2017 10:21 AM

IMHO, I believe that SENS should put most of all their energies and moneys on oncoSENS therapy, WILT is not enough, curing cancer will be huge but to cure 'healthy normal intrinsic aging/death' you need to target 'at the source' : nucleus/nuclear DNA/nuclear chromosome/chromatin/nuclear epigenetics. Nuclear failure is causal to accelerated aging model (progeria like HGPS, Down's Syndrome, Werner, Trisomy 21/Chromosome breakage) and the downward chain damages from it (senescent cells, MDA, AGEs, carbonyls, prostane, lipofuscin, DNA DSBs, mitochondrial DNA lesions, accelerated telomere loss, stem cell dysfunction, cell cycle arrest). AdG said that nuclear failure is causal to aging and it's 100% true.

Posted by: CANanonymity at February 11th, 2017 10:22 AM

> IMHO, I believe that SENS should put most of all their energies and moneys on oncoSENS therapy

Yes, cancer is important (#2 in causes of death) and there are already some ways to tackle it - don't smoke, don't get fat, don't get sunburn, maybe senescent cell clearance.

Killer #1 is still cardiovascular disease - heart attack and stroke. Seems even more important to me. What's the progress on the AGE breaker front, btw.? I've heard of alagebrium and rosmarinic acid but nothing for glucosepane.

Posted by: Matthias F at February 11th, 2017 10:47 AM

@CANanonymity "means that the body is a self-adapting system carefully balanced, thus tinkering the balance can lead to reverse (new/unforeseen) problems in the long run."

It could but that is the nature of all medicines and as such a very questionable argument.
Why voice it in this instant and not in relation to the treatment of any other disorder.

Every pill has side effects. No one has implied anti aging medicines would be different - definitely not the first couple of generations of them.

Posted by: Anonymoose at February 11th, 2017 11:32 AM

More great writing from you. I think what you're doing here is very important, both to society as a whole and as an educational resource I can use to compliment my current academic curriculum.

Posted by: Brendan at February 11th, 2017 12:10 PM

Hi Matthias F !

One more, try avoiding cancer-causing foods (processed foods, refined foods (nutrients devoid/lost during heating/refining process/fractionation), avoid fatty/sugary/salty junk food like the plague (McDonald's, Donuts, Chips, Soda, BBQ, processed Candy and other vending machine chocolate bars), certains chemicals in food (synthetic dyes/coloring/ benzenes/ conservation agents like BPC BPH, GMO food, gluten celiac causing foodss (grains), artificial sweetners (Splenda, sucralose, aspartame, acesulfame), excessively raw foods (fumonisin, aflatoxin, lectins, and other natural foods toxins/bacteria infected), overcooked foods (acrylamides/AGEs formation in-food from heat exposure), red meat/animal protein (Bbq grilled/charred food (full of acrylamides/AGEs), Bacon (grilled AGEs/acrylamides, unstable bovine meat animal protein, sodium overkill hypertension, fat filled with trans/saturated fats and cholesterol contributing to silent deadly atherosclerosis and arterial embolism (I would know I suffer of atherosclerosis and had embolisms) and eggs (cholesterol ladden - eggs Nearly Killed me, arterial vLDL plaque formation), animal protein in fat filled butter or non/hydrogenated petroleum margarine) as for dairy avoid fat filled cheeses or fatty 1%-3.25% milk, only fat-free yogurt from fat-free/cholesterol-free 0% skim milk (because you want cow milk's lactoferrin and IgA immunoglobulins that boost immune system, plus cheese and yogurt contain polyamines like Putrescine or Spermine from the bacterial fermentation/putrefaction process).

One other big contributor to cancer - is constant Stress (taxing your adrenal system and producing excess cortisol hormone (overstressed/constantly 'alert/fearing or angry/constantly activating the adrenergic life-threath 'Fight or Flight' auto-defense system increasing lactate use for muscle demand exceeding O2 energy throughput (muscle pseudo-hypoxia)/muscle lactic acidic production, which is highly damaging in the constant-long run as your body becomes acidic in its cells' cytosols, losing alkalinity to keep the cytosolic pH in check: cells become senescent as the cytosolic pH drops below 7.4; plus lactic acide must be disposed as long-term exposure breaks down muscle tissue fibers creating sarcopenia/muscular dystrophy)), this in turn messes your epigenetics course towards accelerated epigenetics aging (cancer was shown as accelerated epigenetics aging (hypermethylation of CpG-rich islands oncogenes) and telomere dynamics changes (mostly demethylations in subtelomeres and centromeres; along with possible accelerated telomere shortening)).

Plus, genetic family inheritance (if your parents/close ancestors had cancer) and doing exercise/CR.

Yes, exactly, heart disease is #1 killer, and nuclear failure is causal to it, as seen in HGPS who die of heart failure at 15 years or before that (HGPS is nuclear failure by lamin/lamina failure to assemble histones and chromatin leading to decondensed/unpacted chromosomes = chromosome dysfunction = accelerated epigenetics aging/progeric aging).

AGEs progress seems dormant except for glucosepane characterization.
Alagebrium is akin to Carnosine, Benfotiamine, Carnosic acid/Rosemarinic acid (Rosemary spice) AGEs blockers. Their effect are weak to moderate in reduction AGEs formation, but sadly nothing to write home about.

AGEs (glycoSENS) reduction is mostly partial patchup work (for example it will help reduciung T2D AGEs overload).

Posted by: CANanonymity at February 11th, 2017 12:30 PM

@Anonymoose

I'm only repeating what he is saying, but you are right to say that there was always going to be some (unforeseen) side effects in almost all medical advance, the question that begs is can these (unforeseen) side effects be surmounted (enough) that it's tolerable and thus feasible (I guess it will depend on the gravity of these (unforeseen) side effects)).

The biggest (unforeseen) side effect, obviously : death from usage of said therapy(s).
Still, nothing is certain in medicine; just like you can die, being operated, on the hospital operation table.

Posted by: CANanonymity at February 11th, 2017 1:01 PM

I don't think anyone can bow out and not bother to support rejuvenation biotechnology at present.

The SENS RF and their supporters can probably largely bow out of senescent cell clearance without slowing that area down at all. But what about the other 6 categories of damage? Stem Cells and Cancer are well funded, but extra cellular and intra cellular junk, glucosepane, and mitochondrial mutations are all not at a self sustaining level.

I think some strong in vivo results are still needed in the last four categories to get them onto a self sustaining pathway. And then you'd have to hope those categories don't run into technological problems like RNAi did. Not running into technological problems in any of those four categories is really like going out and hitting four home runs, possible, but unlikely.

Extra cellular junk - aside from Alzhiemers there seems to be a bit of a lack of interest from the pharma industry in this area. I know that one big pharma is slowly pursuing TTR amyloid. More interest in this area could be peaked by putting amyloid into model animals and observing the negative effects, much like the addition of senescent cells seemed to cause osteo arthritis.

Intra cellular junk - the SENSRF has funded 2-3 in vitro demonstrations, hopefully an in vivo demonstration for each type of junk will kick off self sustaining research for that type of junk.

Glucosepane - could go either way. If a molecule that breaks it safely is found then this area could boom. But surely this area is the one most at risk of unknown technological challenges?

Mitochondiral mutations - the key technology of powerful efficient somatic gene therapy is still not here in 2017, any updates on how close this technology is are always interesting.

Posted by: Jim at February 11th, 2017 1:15 PM

Anonymoose said: "Every pill has side effects. No one has implied anti aging medicines would be different - definitely not the first couple of generations of them."

By its own nature, damage repair treatments will have much less side effects than usual medicine (i.e. treatments that tinker with metabolism). That doesn't mean that they will have no side effects, only much less. Metabolism is hugely complex, with many mechanisms influencing each other, and any attempt to adjust or change it is almost guaranteed to produce a cascade of undesired effects.

Posted by: Antonio at February 11th, 2017 2:43 PM

@Antonio Everything worth removing does affects metabolism. If it's a completely inert entity it wouldn't be damaging to the function of the organism either. Furthermore we still don't know how we're going to digest or metabolise any of the junk that needs to be removed.
Making a prediction like - it will have less side effects is premature.

There will be side effects. The benefits should outweigh them. Typical medicine.

Posted by: Anonymoose at February 11th, 2017 2:57 PM

"Everything worth removing does affects metabolism."

Affecting metabolism is not the same that being part of metabolism. The latter is what I was referring to. For example, sirtuins are part of metabolism. They participe in some pathways of normal metabolism. Trying to regulate them would likely affect many pathways. Amyloid aren't part of normal metabolism. They don't play any necessary role on human metabolism, and thus their removal will not cause dysregulation of metabolism but the opposite, metabolism returning to its normal, young state.

"Furthermore we still don't know how we're going to digest or metabolise any of the junk that needs to be removed."

To digest or metabolise it, as you call it, IS to remove it. If we design, say, an AGE breaker, that breaker will digest it, by definition.

Posted by: Antonio at February 11th, 2017 3:56 PM

@Antonio
>Amyloid aren't part of normal metabolism.
There are enough papers saying exactly that. That it is a part of normal metabolism and it does serve a physiological function. Otherwise amyloid precursor proteins wouldn't be so abundant in the brain.

Posted by: Anonymoose at February 11th, 2017 4:22 PM

@Matthias F: AGE-breaker work on glucosepane funded by SRF is in the stage of actively searching for credible drug candidates, and will be until one is found. There are some other people tinkering in this area, but they are not anywhere near as far along. I think we should expect the median outcome, absent surprises, to be an initial drug candidate from the Spiegel lab within a few years.

Posted by: Reason at February 11th, 2017 4:35 PM

Anonymoose: for example?

Posted by: Antonio at February 11th, 2017 4:35 PM

There's another "public" company, Centagen, Inc., who is doing research in aging along with providing several neutraceutical products for their followers intended to maximize their current health. Was curious to know your opinion about Dr. Bryant Villeponteau, the President and CSO. He has an impressive background in microbiology and, apparently, a different approach to research than deGray. He has predicted the end of biological aging to come about in the next quarter century. Appreciate your response.

Regards, Patti Harter

Posted by: Patti Harter at February 11th, 2017 8:22 PM

@Patti Harter

Hi Patti !

Just my 2 cents. This company sells products intended to improve stem cell function/self-division/differentiation thus increase tissue and organ healing/rejuvenation-like effect. Stem Cell 100, Stem Cell 100+, TeloMax, EpiMax, Memex. The ingredients are largely herbal extracts, a good thing and indeed herbs contain elements that are senolytic (clear senescent cells) or anti-senescence (reverse cell senescent state to youth-like proliferating state) or promote bone marrow stem cell division to rebuild aged tissue, thus act as like rejuvenating compounds. But that's where it stops, herbal extracts would never make humans reach much beyond current human Maximum Lifespan limit (122 years). You may take all these herbal extracts and never reach 120. Although, you could buy yourself 7-10 years healthy life extension on them (optimistically, 20 to 30 years if more unlikely). And the reason for that is because no human ever lived to 130+ by herbs (the Chinese botanist who lived 256 years on 'herbs' was proven as a hoax, he lived below 120; but Chinese love to mythicize in Chinese Lore and 'agrandize' the age to spur tourism $ from well-intentioned (if gullible) foreigners 'who buy it' and think the Chinese herbal mixes and lotions will make them immortal). Plus, a 100% life extension of fruit flies on Centagen nutraceuticals does not translate in an identical life extension in humans (because of diverging evolutionary specie goals), the effect is always weaker in terms of humans lifespan extension (because humans are already genetically hyper-adapted to extreme longevity, thus there is no real gain for them). And also, mice received Mesenchymal stem cell injections for their full life, lifespan extension was about the rejuvenating-like effect of Calorie Restriction, 20% lifespan extension only. This could translate as 5-10 healthy years extra in humans longevity.

Mr.Villeponteau is right biological aging will be cured at some point, unlikely in the next 25 years, perhaps in the next 50, but in a century quite possible. We may not be alive to see it, that's the crux of it; time is of essence for us (already) older people.

And Centagen's nutraceuticals will never make SENS LEV (Longevity Escape Velocity, possible Immortality). SENS therapies have that remote possibility (since they patch/repair damages), not Centagen's current nutraceuticals/supplements optic.

Posted by: CANanonymity at February 11th, 2017 11:14 PM

@Jim: "Senescent cell removal always looked like one of the easier forms of damage to deal with, given the body tries to remove the cells anyway,"

The fact that the body tries to remove senescent cells is a relatively recent discovery, first hinted in ≈2008. I can assure you that when the first SENS Roundtable paper was published ("Time to Talk SENS"), it was thought to be a quite difficult challenge, and Dr. Campisi was unsure that it would be a viable approach.

@Steve Hill: "Epigenetic changes we know thanks to SALK and Blasco this year are important and when you reset epigenetic changes we see increased lifespan and cells restored to younger function. Almost certainly a pathway worth pursuing."

I take it you're referring to this paper (in FightAging! here). There was no increased lifespan in this report: there was partial normalization of the miserably-short lives of mutant progeroid mice. Since these mice suffer a variety of phenotypes caused by severe premature stem cell depletion, it makes sense (though I wouldn't suggest that it was obvious) that intermittently partially restoring pluripotency in a subset of their cells would help to ameliorate their severe phenotype - and even there, doing so chronically actually shortened it. It makes even more sense that a one-time short-term application of the same factors normal life enhanced regenerative response to injury in aged mice. But none of that meaningfully suggests that the cyclic lifelong protocol used in the mutant mice would be a net benefit in actual aging.

And remember, in any case, that there are no such semi-pluripotent cells in somatic tissues in a mature adult body, so nothing about this experiment is informative about age-related epigenetic changes or their reversal, as your comment seems to imply.

Finally, note Blasco wasn't on that paper - is there a second paper by her to which you refer?

@CANonymity: the problem with the Kyriazis analogy of lipofuscin to ROS is that ROS are useful as a signaling molecule precisely because of their high chemical reactivity and rapid and easy intermolecular transfer and movement: none of this applies to lipofuscin or other kinds of aging damage.

@Anonymoose: the existence and poorly-understood biological functions of amyloid precursor protein doesn't in any way suggest that beta-amyloid itself has a biological function, any more than the widespread presence of TTR implies a biological function for senile cardiac amyloid, or than the presence of damaged car parts inside an automobile components factory implies a beneficial use for the damaged uits. Their local presence explains why they accumulate locally when they are damaged - that's all.

The inclusion of nutrient sensing as a Hallmark - and its discussion of CR - is an example of the problematic intermingling of causes and effects of aging in the paper, and in turn to confused discussion of points of intervention.

Posted by: Michael at February 12th, 2017 12:07 PM

The main problems of Hallmarks are that it doesn't list all of the hallmarks of aging (like crosslinks and the junk covered by LysoSENS) and most of its proposed solutions are based on messing-with-metabolism approaches which will never lead to rejuvenation.

Posted by: Florin Clapa at February 12th, 2017 5:21 PM

I think that is a very gross simplification but im not going to waste my time debating it with you.

Posted by: Steve Hill at February 12th, 2017 7:15 PM

The hard truth is that SENS, in its current form, is obsolete - b-amyloid anti-bodies, cross link breakers, stem cells etc. all exist independent of SENS initiatives and have taken on a life of their own in the biotech space - there is no reason for SENS to continue to function as a pass through entity for such work - for SENS to survive it needs to transform its business model to focus solely on developing the bleeding edge stuff in its portfolio that has not caught on yet - the rest of its chearleading activity is a distraction

Posted by: senstruth at February 13th, 2017 7:19 AM

It's not truth at all. For example, the only funding body for AGE breakers is SRF.

Posted by: Antonio at February 13th, 2017 8:43 AM

@senstruth @Anotonio - The SRF is also the only group I know of that is funding research into the removal of intra-cellular Tau. Which would surprise me if I was new to this topic given the billions that have been poured into beta amyloid research over the past decade.

It is also the only group providing funding to try and express the genes for remaining 10 mitochondrial proteins in the nucleus.

Posted by: Jim at February 13th, 2017 9:10 AM

Very few groups are working on AGE specifically Glucosepane it is absolutely critical SENS supports this though they can now ease off senescent cell removal, stem cells and some other SENS categories as these are moving foward well. I am sure this is what they doing anyway. Whilst it is true there are other groups working on glucosepane including a friend of mine the work isnt as far advanced as David's at Yale which is supporting by SENS, it is absolutely critical that this continues to be supported.

Posted by: Steve Hill at February 13th, 2017 9:51 AM

@Antonio, @senstruth:

There is only one or two groups that have worked on ALT before SRF.

Posted by: Norse at February 13th, 2017 10:09 AM

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