Thoughts on Near Term Rejuvenation Therapies

At this year's RAADfest event, the interviewer noted here was taking an informal survey of optimistic versus pessimistic attitudes towards progress in the decades ahead. Apparently I was on the pessimistic end of the spectrum. Once past the present highly active development of senolytic therapies to remove senescent cells from old tissues, I think it quite plausible that we'll see a gap of a decade before the next class of SENS-like rejuvenation therapy arrives at the point of availability via medical tourism. The likely candidates include clearance of cross-links and restoration of the immune system via thymic regrowth.

Surprise progress in advance of the end of the 2020s seems implausible, with the exception of the discovery that an existing small molecule drug or otherwise widely available low cost compound breaks down significant amounts of some form of molecular waste, such as oxidized cholesterol or glucosepane cross-links. That is possible to engineer, given the resources, but so far as I know next to no-one is screening the compound libraries with this in mind. It is an expensive task with uncertain chances of success. This present state of the market, that there is a gulf of further required development ahead, is perhaps a little obscured by the excitement over senolytics. There is, however, a continued need for philanthropic support of lines of research that remain poorly funded. If senolytics are to be closely followed by the rest of the rejuvenation toolkit, then we still have a great deal of work to do.

What are the most promising near-term therapies that may actually turn back the clock on biological aging?

Senolytic treatment, obviously, is the one that is here already and is presently available. It is fortunate that some of the first drugs identified to have this effect are, to a significant degree, already widely used and cheap. The animal results are far better in terms of robustness and reproducibility than any of the calorie restriction mimetic and other stress response tinkering work. The first human data from formal trials will arrive late this year or in early 2019. These first-generation approaches are killing only about half of the senescent cells at best (and far fewer than that in some tissues) but are nonetheless very effective in comparison to any other approach to age-related inflammatory disease.

The next approach to arrive that will likely have a similar character and size of effect is breaking of glucosepane cross-links, but since that involves a completely new enzyme-based therapy, we're unlikely to see it in people any sooner than a decade from now. If there is interest in that field, someone might uncover a useful small molecule prior to then, but it seems unlikely.

Other than that, over that same timeframe: (a) advances in stem cell medicine, moving beyond the simple transplantation therapies that do little other than suppress inflammation towards ways to actually replace damaged populations and have them get to work; (b) removal of amyloids through means other than the immunotherapies that are the present staple of that field; (c) forms of immune system restoration, such as via thymic regrowth, replacement or enhancement of hematopoietic stem cells, and clearance of problem immune cells.

I'm not convinced that there is an enormous benefit to be realized from approaches to enhance mitochondrial function, such as NAD+ precursors and mitochondrially targeted antioxidants, that get a lot of hype and attention. They may have a small positive effect on metabolism in later life, which would make them worth taking when cheap and safe. They are not in any way reversing aging - they are forcing a damaged machine to work harder without addressing any of the causes of failure. One can paint the same picture when discussing ways to enhance stem cell function without addressing the underlying damage, such as telomerase therapies and the use of signaling molecules. It may meet the cost-benefit equation, but it also may not, since these are much more expensive propositions.

Why is breaking extracellular crosslinks so important?

This is important because cross-links cause stiffening of tissues. The stiffening of blood vessels is the cause of hypertension, and hypertension is (like inflammation) a major way in which low-level biochemical damage is translated into many different forms of structural damage: pressure damage to delicate tissues; rupture of capillaries in the brain; remodeling and weakening of the heart; increased risk of atherosclerotic lesions causing stroke or heart attack. High blood pressure is very damaging. It is so harmful that ways to reduce blood pressure that work by overriding signaling systems - which do absolutely nothing to eliminate the root cause, the biochemical damage of aging - can still produce large reductions in mortality risk.

All of that can be greatly reduced by cross-link breaking, and there is only one major class of cross-links in humans that needs targeting to obtain that benefit: those involving glucosepane. Thus, like senolytics, once there is some motion towards achieving this end, we should see a very rapid expansion of the industry and delivery of benefits to patients. Glucosepane is hard to work with, so very few groups have done anything meaningful - the first big advance that the SENS Research Foundation achieved in this field was to fund the creation of the tools needed to move forward at all in this part of the field. Even now, there is really only one group working earnestly on it that I know of, David Spiegel's team at Yale, with a couple of others doing some investigative work around the edges of the challenge. The Spiegel approach is to mine the bacterial world for enzymes that degrade glucosepane and then refine the successes into therapeutic drugs. His team is a fair way along, and work is progressing in a funded startup company at this point.

Link: https://www.leafscience.org/an-interview-with-reason-near-term-life-extension-therapies/

Comments

"Apparently I was on the pessimistic end of the spectrum" - lol have you been being scientifically grounded and appropriately cautious again? ;)

Posted by: Steve Hill at December 14th, 2018 8:38 AM

I would say that there is some foundation for optimism. Once human senolytic therapies are reproduced in humans the industry will attract a lot of attention and funding. And by extension all other SENS topics will gain some credit and attention. So there might be a gap of a few years but the extra money and attention should bring more discoveries at the end of the next decade...

Posted by: cuberat at December 14th, 2018 11:55 AM

@ Reason and everyone. I was reading the article with a great interest. However how can we define the term "Near Term"? How many years exactly from now? Also I'm very curious to know how many extra years of life the senolytic therapies can give to humans? I understand it's very difficult to make predictions, but let's be specific. Thanks.

Posted by: Aleks Aleks at December 14th, 2018 12:40 PM

@Aleks Aleks: Near term means before I become aged and haggard. Long term means well after I become aged and haggard. Very long term means too late, barring success in the near term and long term.

Posted by: Reason at December 14th, 2018 1:30 PM

Thank you, Reason, for your very clever definition of the terms, which means the terms should be estimated for every person individually depending on his/her age and health condition. What's about my second question? Can we hope that senolytic therapies will give us one additional decade of life?
What's your thoughts about it? Thanks.

Posted by: Aleks Aleks at December 14th, 2018 5:06 PM

@Aleks Aleks, probably, no, if you mean monotherapy. Any organism is as weak as the weakest chain. For now the weakest chain is vascular pathologies. While senolitics are more for chronic inflammation. Hovewer, they very likely improve health span of many people. The main mistake is a belief in a myth of a silver bullet -- any single therapy that can rejuvenate whole organism, improving human lifespan. Senolitics is just a piece of a complex rejuvenation panel, very important piece, but only a piece.

Posted by: Ariel at December 14th, 2018 5:43 PM

@Aleks Aleks: As @Arial noted, I'd doubt it. Five years may be plausible, for a suitably large reduction in inflammation starting your 50s and persisting on, but we'll have to wait and see on the data.

Posted by: Reason at December 14th, 2018 5:46 PM

Proclara bio are progressing to human trials for treatment of systemic amyloidosis, in addition to Alzheimer's. I think what they are doing is very exciting.

Posted by: Link at December 14th, 2018 7:04 PM

You would think that Mellon and others with deep pockets who are concerned with their own selfish desires would fund the most critical next step beyond the solyntics to extend our lives. And, as cuberat mentioned, once solyntics treatments are well known and received, funds and the publicity should be pouring in from all directions. Lets face it, at this point, most people don't know what is possible, yet.

Posted by: Robert at December 14th, 2018 7:54 PM

@Reason, wasn't there some sort of advance in MitoSENS and a fundraiser after the first of the year? How long do you speculate for this advancement?

Posted by: Morpheus at December 14th, 2018 8:15 PM

@Steve Hill: are they hoping to get a lifespan increase in mice even by only intervening on a few genes?

Posted by: space_cowboy at December 15th, 2018 4:59 AM

@Reason, exactly! Being pessimistic or optimistic have sense in context only. That is why people before 40 are more optimistic and after are more, well, pessimistic.

Posted by: Ariel at December 15th, 2018 12:54 PM

@space_cowboy, I believe that minimal rejuvetaion panel which can meaningfully improve health span and lifespan of average people is as follows -- senolytics + 7KC breaker + glucosepane breaker + some preventive cancer therapy like OncoSenX.

Posted by: Ariel at December 15th, 2018 12:59 PM

Once the industry takes off, it is wild how far things can go in the span of 20 years. Look at how far and fast cell phones developed once the industry started flying.

Posted by: aa3 at December 15th, 2018 1:56 PM

@Ariel
What is 7KC BREAKER ?
PS my father is getting older can you suggest something for him ?

Posted by: Salman at December 15th, 2018 3:37 PM

I can't see how senolytics will be a game changer for R&D if they *may* (and just may) add a measly 5 years to median life expectancy. That's what calorie restriction does, which means that we shouldn't expect any acceleration in funding or change in public opinion.

It is either senolytics perform a hell of a lot better, or they get lumped with any other piecemeal or tinkering-type approach (e.g. NAD+, gene silencing, maybe working CAR-t for solid tumors) out there.

There's serious cognitive dissonance between enthusiasm for this approach and expected results here.

Posted by: Barbara T. at December 15th, 2018 3:45 PM

@Barbara T.: The game-changing nature of senolytics is more in the fact that they produce near-immediate significant reversal of symptoms in at least inflammatory age-related degrees, something that cannot be achieved through any other present day approach. Once the human trial results are out, there's going to be a very sizable amount of interest.

Posted by: Reason at December 15th, 2018 3:50 PM

I'm wondering whether fasting (not just calorie restriction) can reduce a level of senescent cells in the human body? Here I'd like to clearly distinguish just calorie restriction from fasting. Fasting is when a person doesn't eat at all and drink only water during few days (14 days). I understand this is a very inhumane and rude method of life extension, but nowadays we have no options. The idea is when a person has a fast, he losses weight, for example 10 kg/21 stones, and senescent cells dies the most, while healthy cells survive during the fast.

Posted by: Aleks Aleks at December 15th, 2018 4:21 PM

@Barbara
Calorie traction had to be filled for the whole life, while with senolytics it is just a bunch of pills or, probably, injections done at most on monthly basis. Adhering to a strict diet love CR is very hard. Both psychologically and phisiologically. For example, last night I did 8 days of fasting and, believe me, it was much harder than popping a few pills...

And even 5 years is a lot. It is on the scale of eradicating cancer or heart attach. Cutting one or the other would increase the life expectancy by 5 to 7 years. Not too shabby... But most importantly it will be a proof of principle that anti-aging is not a pipe dream and the rejuvenation folks are not some quasi-new age crack heads. It will bring credibility to the field and the researchers will not be embarrassed to espouse these ideas.

Posted by: Cuberat at December 15th, 2018 5:00 PM

Hi Aleks ! Just a 2 cents.

Yes, CR does reduce senescent cells in the body, the accumulation of new ones; but, it depends on severity of CR % of CR, and not one body reacts the same to CR. I tried doing CR and nearly died of it, because of my disease and because I am thin already, was becoming a skeleton on CR. IT's just too hard of a weaker body, if your health is great and can take it; yes, otherwise no. It may accelerate the disease progression and accelerate frailty; which is Very bad when you are diseased. You need your nutrients and minerals, and yes a certain amont of calories; so don'T be extreme with this and carefully check your body's responses as you do it; CR increases ROS production immediately and this activates autophagy (proteasome activated by 'stressors' like CR, heat, cold and ROS; this means cleansing of the junk, senescent effete), TCA/ketosis mechanism via PGC-1a and peroxisome fat lipid burning to use as fuel instead of glucose (when you are thin your WAT/BAT can be pretty small and not much lipid left to burn; if you are obese/fat this can help for sure, but take caution`even obese people whom lost many pounds show age acceleration from previous 'fat' state despite losing the fat after; but, at least, now they are in better shape; for thin frail diseased people (like me), it's another problem). If you are not overweight and thinner, losing 21 stones/10kg can be substantial, too much even as you will strain yourself and make frailty possible; very BMI (body mass index).

Just a 2 cents.

PS: Merry Christmas and Happy New Year (in health and longevity to all, one of the best way is too keep a positive optimistic outlook on one's health (which I know I don't always do very much) but, it's a juggle between being realistic and self-optimisic 'placebo' (the more you fake yourself that it is going better the more you make your body believes it, even if not true, 'Convince Yourself'...laern to play pretend and be ok with it about your health, Lying to yourself, you are not lying you are learning how to rig your body; this was demonstrated with people with higher pain threshold; happy people have higher pain threshold because of decreased pain signals; while irate/stressed people have increased activation of brain pain receptors; (test cold water test, happy people tough longer their hands in cold water than angry/stressed people, endure more pain) they get it full pin and that can kill you overtime ('over stressed' leading to chronic inflammation and pain, health decline and frailty,; thus disease, death). It is also demonstrated in people whom 'decide to die' in older age, after a traumatic loss of a loved one or shocking event; they 'just let go'; so yes, mind is supreme over body and you must tough it if you want live long (I have atherosclerosis, I had to, or I was dead).
The Will to Live, the Need to Live...if you don't see any point to living and it hurts too much...you must Make One. Keeping a more positive outlook means better pain resilience when it happens because you exposed yourself to Less Pain; Too Much Pain, will kill you. Thus, avoid pain...the saying : 'what doesn't kill you makes you stronger'; is quite true, but don't play heromatcho bs, the pain may harden you and you survive it; but too much of it and will succomb. It's why, reduce pain at all time and keep positive thoughts, always. Talking about negative things is normal but when talking about your health, a positive outlook gives you a chance of living longer. Positive outlook won't stop anything, but give you chances of staving the problems later; so go ahead smile your problems away, laugh it up - yes LAUGH in the face of utter seriousness of this, because you need it (there is a time for joy, humor, laughter, celebration, a time for pain, grieving, and moving on, and time for being serious; just don'T be too serious, all the time; centenarians are people who took life as it comes and always smiled/laughed and forgot about their problems soon (unlike the overstress population whom live shorter lives) - 0 stress helping to live fuller, longer).

Posted by: CANanonymity at December 15th, 2018 5:10 PM

@salman
7KC stands for 7-ketocholesterol

Posted by: Nina at December 15th, 2018 10:37 PM

@Aleks,@CANanonymity
I wouldn't name a 14 days fast a mild one. The individual tolerance is very different, though.

I find that following a strict CR regimen is very hard and it is to eat to fall off the wagon. Fasting is hard but at least is time limited to at most a few weeks, and you see some of the benefitial effects immediately. As
CANanonymity said, it works best for obese and overweight people, at least that's my experience. A few months ago, I did a 5 days fast ( instigated by some weird abdominal pain, with some of the symptoms researched by a lay person matching cancer). After the fasting ended, i had no pain, experienced somehow better vision, and a bit smoother skin.

Last month I did an 8 day fast. This time the improvements were less pronounced and more subtile. I did tolerate it well, though. but apart of being , 45 and being obese, with some sings of metabolic syndrome, I don't have anything serious.

So probably 14 days are the minimum you have to do to have a SC clearing. I did 22 days 12 years ago. After the day 17 it was quite hard and I had no energy. Since I was more than 10 years younger, I didn't witness any relative effects , except that my skin looked much younger , and of course losing about 40 pounds ( a tad less than 20 kg)

Some people claim dining over 40 days and having profile effects. But nothing scientific. And the success stories have selection bias, even if the claims are true.

I hope that senolytics can be combined with a couple of weeks fasting to enhance the effects.

Unfortunately, a rigorous self experimentation with well measured effects requires a couple of thousand USD for lab testing and equipment. That's on top of finding the time and will power to do it...

Posted by: Cuberat at December 15th, 2018 11:18 PM

To Reason

I like the interview where you consider the programmed aging theory (the theory that I personally favor):

Q: What is your preferred umbrella theory for aging? Do you agree with the notion that we are in various ways programmed by evolution to age and die?
A: For me, the old-school view of aging as a side-effect of relentless evolutionary optimization of reproductive success in earlier life works just fine. Systems have evolved that (a) function exceptionally well out of the gate but (b) have limited capacity to run indefinitely. This is because running indefinitely would require resources to be directed to maintenance rather than reproductive success, and mutational drift in that direction will be promptly out-competed. Selection pressure in later life exists (see the grandmother hypothesis), but it clearly isn't enough to select for anything that will devote resources to greater life-long repair rather than reproductive success while young.

Please clarity the sentence that starts with "This is because . . ."

I gather that the idea is that late life selection would be too small ("isn't enough"), and life-long repair would be outcompeted by reproduction in youth.

Posted by: Anthonie Muller at December 16th, 2018 3:49 AM

"The game-changing nature of senolytics is more in the fact that they produce near-immediate significant reversal of symptoms in at least inflammatory age-related degrees, something that cannot be achieved through any other present day approach."

This is unfortunately just not so - maybe 30 years ago; but not today

If your product is just about effecting signs and symptoms of disease, you will never get approval in this day and age

It is all about "disease modification" in today's therapeutics world - especially as it is related to chronic inflammatory disorders - DMARDS in auto-immunity; DMOAD in OA (a holy grail never yet achieved in the last 100 year of pharma) etc.

And disease modification takes time - current FDA requirements dictate long term studies in these areas to show prolonged effects

If you can't show it, you won't get approved by regulators, prescribed by clinicians, or reimbursed by payers.

Posted by: Ira S. Pastor at December 16th, 2018 4:59 AM

@Ira S. Pastor: Who said anything about regulatory approval? No-one will wait around on an approval process for compounds that cost so little. That is part of why these are so game-changing - the gatekeepers cannot hold this back, they cannot forbid this. When it becomes well known that combinations of cheap compounds such as dasatinib, quercetin, fisetin, piperlongumine, etc, produce large, immediate, recognizable differences in disease state and quality of life, there will be a landslide. And are the regulators going to step in to tell people that they are forbidden from turning back their arthritis, their inflammatory bowel disease, and so forth? Good luck with that.

Posted by: Reason at December 16th, 2018 8:17 AM

@Anthonie Muller: Yes, that is my point. Late life selection probably exists, and is probably why humans are significantly longer lived than other similarly sized primates. But this is just a matter of degree. Why are humans not living for a thousand years with negligible senescence like naked mole rats? Because the size of the effect isn't large in comparison to the size of the antagonistic pleiotropy effect of selection for mechanisms that do well in early life but decay later.

Posted by: Reason at December 16th, 2018 8:21 AM

@Reason

Sorry - you stated "Once the human trial results are out, there's going to be a very sizable amount of interest."

I assumed you were talking about large institutional investor interest / big pharma interest, to commit to getting these compounds fully registered - and, yes, unfortunately they will have to meet the clinical hurdles of regulators, per indication, no matter how unfair they may seem

Unity, as an example, will have to prove disease modification in the joints in OA; not just signs and symptoms, or they will be seen as just another anti-inflammatory agent

If you are only talking about "self-experimentation interest", that's another thing - I'm sure that will proceed, and grow to some extent

Posted by: Ira S. Pastor at December 16th, 2018 10:59 AM

@Ira S. Pastor

Once there is a verified result there inevitably will be a lot of scientific interest. There will be more publications, more articles. And some investor will will try to be part of it. One way or another. If it does work, and is cheap enough, almost any entrepreneur could set up a thriving business to shipping people for medical tourism. This business will be much less controversial then uber. So the big pharma will want to invest to at least be up to date, and probably, find more efficient formulations. When the general public realizes that such treatments work well there will be an immense pressure to make them legal. And there will be a lot of money there too. If the annual cost is a couple of thousands dollars but you could capture half of the population , we are talking about more than half a trillion dollar's market in US alone. The health insurers will prefer to pay for sonolytical therapies as a form of cheap prevention instead of the expensive treatments. If the senolytics don't really increase the lifespan but only the health-span it means less money spent on expensive palliative treatments and having a healthier population at the very same time. If it increases the lifespan, then it becomes even more important. Look at how much money was poured in bitcoin and the related blockchain mania. The investors have an appetite for risky moonshots but need at least some proof of concept.

Posted by: cuberat at December 16th, 2018 12:12 PM

lol CANanonymity has spent so many 2 cents on here over the years he could fund the end of ageing

Posted by: scott emptage at December 16th, 2018 2:59 PM

The pace is too slow. When there is a new idea, we need it in human trials within 3 months and the results with 12 months. Now it can take decades.

There is no urgency.

Compare to virus outbreaks where countries and private corporations spend billions on new drugs. Given the number of people who die of aging every year, hundreds of billions should be spent to prevent it.

This is not the case. Thus progress is extremely slow.

Posted by: Peter Lind at December 16th, 2018 5:12 PM

@Peter Lind senolytics are already in clinical trials.

Posted by: scott emptage at December 16th, 2018 6:08 PM

@Ira Pastor: Ah, I see the point of confusion. No, I was referring to the current very small initial trials, soon to be published.

Posted by: Reason at December 16th, 2018 6:39 PM

@Salman, 7KC is 7-ketocholesterol, the main cause of atherosclerosis

Posted by: Ariel at December 17th, 2018 1:35 PM

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