Combining Therapies as the Next Frontier for the Treatment of Aging
There are two activities in medical science in which both the academic research community and clinical development industry are truly terrible at achieving results, or indeed even at getting started at all. The first is transfer of programs from academia to industry. The renowned valley of death in the development of new medical biotechnologies is very real; so very many programs languish undeveloped simply because neither side can effectively coordinate with the other. The second is the testing of synergies between multiple therapies that are applied at the same time to the same patient for the treatment of the same condition. We live in a world in which age-related conditions are the result of multiple distinct contributing mechanisms, so why is it that the exploration and application of combined therapies targeting separate mechanisms is such a rare occurrence?
Firstly, different therapies tend to be owned by different groups (companies or universities) who have only limited incentives to collaborate with one another. Because the biotech field is governed in a very heavy-handed way by intellectual property and other forms of government regulation, setting up a collaboration is a costly matter. Thus in a world in which the expectation is that few efforts will be successful, as is the case for most initiatives in medical science, there is an unwillingness to explore. Secondly, the regulatory process for approval is very, very costly. Taking a candidate drug through to phase III trial success is at least a $150M proposition, and usually more. Companies do all they can to make clinical trials as simple as possible, and there is no incentive to roll the dice on a collaborative trial that depends on another drug outside the control of the company in question.
And yet, aging and all age-related diseases are the consequence of multiple underlying forms of molecular damage. They will require multiple very different therapies to achieve complete reversal or prevention. The perverse incentives in medical regulation and intellectual property are acting to close off the most promising strategy for the treatment of aging, which is to tackle all of its varied causes concurrently. Something must change here. As Aubrey de Grey points out in the short interview below, this is the next frontier for patient advocacy. Now that the first rejuvenation therapies are being actively developed, using them together is a logical next step.
Aubrey de Grey: "Damage repair is the future of longevity medicine"
Aubrey is a plain-speaking biomedical gerontologist who is committed to combating the aging process. We started by asking him about what he was up to at the moment.
SENS Research Foundation suffered a fair amount of slowdown as a result of the pandemic, but we're picking up now. I think the most exciting thing we're doing is continuing to strengthen the pipeline between the really early-stage translational work we do at SENS and the "just investable" stage work pursued by startups in our space, including our own spinouts. Basically, the appetite of some investors is increasingly emphasising projects that are so early that they would historically be viewed as pre-competitive; that boundary is now becoming very blurred.
What isn't getting sufficient exposure?
I would say that the single biggest elephant in the room is the simultaneous administration of multiple therapies. It is subliminally understood that damage repair is the future of longevity medicine, and also that the damage repair paradigm is inescapably a divide-and-conquer one that will entail combination therapies, but the medical industry is really not set up to develop and promote that way of working. At some point that has to change, and I'm hopeful that investors at the more courageous end of the spectrum will soon find ways to start that process in earnest.
Our survey found that most investors appear to prefer seed-to-early-stage investing, have you found this to be case in your networks?
Absolutely. At this point I don't see how things could be otherwise, actually, because the investment opportunities consist almost entirely of startups, which in turn is because the underlying technologies are so new.
We also saw that senolytics are a very popular category for investors - are you seeing an increased appetite from investors?
I do see that tendency too, and it's not surprising to me, because senolytics have two huge things going for them: they are bona fide rejuvenators (i.e. they repair a type of aging damage rather than just slowing down its accumulation), which is much more exciting to people old enough to have money to invest, and they are only just now going into clinical trials and showing impressive results, so they are opportunities for first movers.
Regulatory agencies are beginning to see some light - it's up to companies and investors to have some guts to do it
https://www.fda.gov/combination-products
https://www.ema.europa.eu/en/clinical-development-fixed-combination-medicinal-products
https://www.pmda.go.jp/files/000150384.pdf
Disagree utterly.
Business Plan thinking is required. Think not of pushing drugs and tech from academia to industry and forward. Think of pulling anti-ageing demand for knowledge and products from an industry to a network of knowledgeable front-line clinics (probably private) and sympathetic medical professionals who are integrating such therapies (mostly future) into their front-line appointments and diagnoses with patients looking for increased-health opportunities. It is that 'sucking' sound of low-level, optimistic-but-low-expectation demand in the doctor's office that attracts the ears of industry and their direct supporters. Witness the money piles being heaped upon doctors from big Pharma for sample spreading, conference attendance, and colleague 'discussion' - its practically bribery and coercion. Further, corporate medical plans that nudge products, services, and networks upon employees and employers are one of the biggest monopolistic undertakings in any industry. And still Big Pharma does not see the potential of even senolytics. Start with the Mayo Clinics, etc. Disparage not of an unsympathetic FDA, but hark positive toward a new line of treatments not yet tainted by ravenous ultra-cap Pharmas who will then squash and pervert access. Spread out from anti-ageing Conferences to investment-quality, late winter 'senolytics' conferences along with the scores of other pharma micro-sector conferences. Get Unity Bio, etc., into investor, stock, lime-light exposure opportunities. You are selling a product/ service even below 'entry level' potential, not trying to change the world or other such noble enterprises. Leave 'noble intentions' to the content providers for websites, marketing, and lobbying - success begins with front-line demand. The FDA is only an obstacle for generic knock-off pushers, rare-disease application desperation for sagging pharmas, and bio-similar applications - a big enough potential 'finds away' around the bureaucracy.
Seems to me we ultimately want to stop our bodies from trying to kill us, not just clean up their efforts to do so ("damage repair"). wrt Aubrey, I've been skeptical of his views since 2007 when he wrote (in Ending Aging):
"We know that our genes are our allies, not our foes, in our war against aging - that they exist to postpone aging, not to cause it, and we only age because those life-preserving genetic pathways are not comprehensive." ...and he goes on later to compare body aging with the accumulation of damage to a car over time
Nonsense. Average lifespan is clearly an inherent property of the species (see long-lived mole rats and bats we've been discussing), meaning that your genes are _not_ your allies with respect to aging. And if we're anything like cars, it is cars designed to actively self-destruct on a schedule, which varies between car types (and with car size not being a reliable indicator of car lifetime). At age 67, my genes are trying to kill me by actively turning off repair mechanisms, etc., allowing damage and vulnerabilities to accumulate, with the intent to replace me with a younger version - the net effect (in the past) being to make my species more competitive with others. No thanks! I intend to resist this program of self-destruction as best I can for purely personal reasons. :)
But why aren't combination therapies investigated nearly enough pre-clinical, where it's so much cheaper and faster? Why aren't we doing a lot more combination trials on mice? Why the heck aren't there impressively long-lived mice treated by a blend of 10 or 100 senolytics and stuff? Why is it that every researcher gets their 10% lifespan improvement with mice and then moves on to other things instead of trying how it would work with other known 10% things? Why aren't there more Methuselah Mouse Prizes being offered and won?
Ending the patent system is a required step towards infinite progress in this field as with any other.
Hi there barabtarlo! Just a 2 cents.
''But why aren't combination therapies investigated nearly enough pre-clinical, where it's so much cheaper and faster? Why aren't we doing a lot more combination trials on mice? Why the heck aren't there impressively long-lived mice treated by a blend of 10 or 100 senolytics and stuff? Why is it that every researcher gets their 10% lifespan improvement with mice and then moves on to other things instead of trying how it would work with other known 10% things? Why aren't there more Methuselah Mouse Prizes being offered and won?''
I guess the answer (why) would be summed in one word:
money.
Money makes the world go round, if that is the resource currency to progress; and in capitalistic richer 1st world countries, it is; it is, why there are rich, per say; but poor too (rich class, middle class, ultra-poor class). Because not everyone is rich; and the large majority is middle class/average to low; and there is still a substantial amount of people in poverty or near it.
Money is the crux/problem of it all; because we lack that resource (constantly). This means needing to prioritize things and abandon things just too costly/unaffordable. Namely, expensive therapies and whatnot;
There is an elephant in the room, many future therapies will simply be unaffordable to a large majority of people...Big Pharma wants to profit from it 'somehow'...medical therapies/supplements is a lucrative business....notthing wrong per say with that...the 'wrong' part is that Everyone Needs Access to these health cares/rejuvenation therapies...but Not everyone can. Because not everyone rich/priviledged/flowing with money resource.
like, just to give an example, I saw a telomere supplement bottle sold for 300$ on internet..I mean I know it is quality and would work...but christ...300$? for 1-2 months supply...like...
Reallly...? Not many can afford that....when paycheque to paycheque living; don't have an 'extra 500$' lying around for suplements or therapies...rich people do; not middle class.
And it is the middle class the majory 95% of the 'mass' population. Rich are 5% or less.
You see the conundrum, but that is lacking of capitalism...and we lived with it since. Only few become rich and can afford all supplements/therapies....
I bet these senoyltics therapies will be 'prescribed' need doctor appointment...and then, in USA, they won't be covered so you'll end up paying 5,000$ for a therapy...seriously...am serious.
Who has this money....Not the middle mass class. The upper micro class yes.
Thus, it's all about money/funds....lack of funds, makes the advancement Much slower than it should be (plus the whole FDA approval thing Even More slowing things; albeit, it'S for making sure it is safe for human use..that is a good thing...except...it takes too long 'for approval/clinical trials...'....'getting funds'..for said trial...those funds...From Rich people...wanting the next big thing (they pay with their own money...even for the others as seen in certain clinical trials...that 1 rich people pretty much 'Covers' all by themselves...and in this study there are many middle class people participating as guniea pigs...but they don't contribute any money - because can't...all they can contribute is their self/body/guinea pig/test subject...while the rich person 'pays' the entire study alltogether and 'The 'seats'' of the others (poorer ones) in the trial'; the benefit is that the rich person obtains the supplement/therapy the fastest (because 'funding it'/paying it) - while' helping others' to obtain it down the line (when the price tag of said therapy drops...but that rich person gets it First..because can afford it). And, in aging, it'S all about 'time'...'timely/being timely'..since we age...right now....and time goes/you age...hence, priviledged (financially) people obtain it now/timely quick in their young years (''before old'') and thus, live longer.
Money/being rich...buys time/years of life/healthcare by access (by paying it). Money = Time = Money = Time (in capitalistic world where resource for 'living' is money/dependent on it; the resource Is money; lack of it = die; plenty of it = live).
I mean let me repeat...5000$ of supplement per year...need good enough salary...5000$ - 1 - single therapy itself...and AdG said it is 'combinational therapies/supplements' you Will have to use multiple strategies to defeat aging...that means an Armement/warfare loaded of 'therapies/strategies' to defeat aging... = Costly.
If 1 single therapy is thousands or hundreds of dollars...How can we afford (as midle class) these Many Strategies/therapies/Supplements - All of them - Per Month - For Life...
Answer: We can't. (Afford it). Unless...
like rich people; we become rich/win the lotto.
That is the problem that AdG has not faced/talked of..he did talk of 'we don't have enough funds for SENS...to fund these new ventures/therapies...and it'S why the field is so slow and not moving...while others still get the money (like calorie restriction or mimetic bs....that has no impact on longevity..not much that is) and doctors still obtain large paycheques IF they promote big pharma products (namely ones that do jachksht...or your lifespan...rather they are health promoters or antiaging supplements taht are just not doing much besides slight health improving; certianly not stopping/reversing aging or repairing damages). But the big elephant is that all these services/supplements/therapies cost...and that cost...is 'passed down' to the middle class....(and in USA it's even more dire..with the health cares not funded by taxes...not 'health insurance'...well medicare...but not like Health Canada...where I'm at and it is tax funded/gov; in USA it's dire, if you end up in hospital you can end up with 10,000$ bill after 'your stay' in hospital; and to think these therapies Suddenly will pay from thesmelves).
It means costs costs...if gov/tax/social (health) insurance can'T pay...I mean ..who? is paying...
The rich people?
In the future, I fear, the biggest hurdle is not so much the fda approving/bureaucracie/time taking for the therapies to be mass marketed - ti'S the Cost/affording them for the general populace.
If, already, it's hard to get quality supplements to improve your health/longevity...how do we suppose that we can get these 'next-gen' therapies to save our lifespance/longevity....
It thus means it will be a priviledge - Then - too. A financial one, and rich people will Then be 1st in line; while many poor people will not be able to afford it and will die earlier - 100% sure of that.
This (won't change in capitalistic countries).. will happen. It may be a long time before any of it is affordable to poorer majority (I mean...40 years later...and obtaining a quality supplements costs 500$/month?...yeah...you are going to wait tfor that '500$ cheap therapy' too....maybe another 40 years. until then, 'spit the cash' - 5000-10,000$- ready your wallet (or die, if empty wallet).
Big Pharma Wants money/it is a lucrative business (go thing - makes money - bad thing - run out of money/you die) - the rich people's money First to finance/fund the industry and pay fat salaries to rich ones; poor people be damnned). And that is too long/life is short/can't wait/in that time we age; so, ubetter 'get rich quick' (..good luck).
Just a 2 cents. (Gonna need more than that).
wrt why things aren't moving faster, I think...
(1) we simply don't know what to do yet that makes a significant difference wrt aging
If such solutions were available, does anyone doubt that we (incl. China, India) would find a way to mass produce and distribute them? For example, the cost of NMN and NR at the moment is mostly due to their being unproven to have a significant impact on human health/lifespan, and thus not widely used/desired - not because of some complex structural limitation/conspiracy.
(2) we have been put in the wrong frame of mind by "damage repair" folks (AdG et al.)
iow, if you're left thinking that you're like a car that accumulates damage, then it feels like it's simply your responsibility to maintain/protect the car to extend its life, and that its resulting lifespan is your own damn fault. But if you think that the car is actively trying to destroy itself (end its life), then you might just be pissed off enough to want something done about it, and would insist that the experts get on with discovering how to modify its programming to stop/slow the destruction. Our aging bodies are not the friend of our minds/self, so we should stop giving our bodies and the FDA and the medical establishment a pass when it comes to aging. imho
(I guess the latter also fits Jer's view from above: "It is that 'sucking' sound of low-level, optimistic-but-low-expectation demand in the doctor's office that attracts the ears of industry and their direct supporters.")
It would be interesting to see if the 20-30% lifespan increases in mice for senolytics and epigentic reseting of cells in vivo have any additive or synergistic effect in mice. Would it result in a greater than 30% lifespan extension vs controls?
I guess no one has the money to carry about this experiment?
Bit of an aside, but do mice undergo thymic atrophy and lymph node fibrosis with aging like humans do? I know there were mice or rat experiments done showing the FOXN1 gene expression in the thymus restored it's size. Where there ever any lifespan experiments carried out to see if thymus rejuvenation had any effect? Surely this would be a good candidate for a lifespan.io crowd funding attempt?
Do senolytics have any effect on ~6 month average lifespan killifish? This species might be a cheaper model to investigate if there are any additive or multiplacative effects of combinations of treatments.
Hi jimofoz! Just a 2 cents.
One study had rats put in constant darkness (darkness therapy) and they saw thymus growth (300%); my take is that during constant darkness there is a surplus of melatonin hormone produced and other hormones (tryptophan, serotonin, endorphin, dopamine, opiate...) produced by pineal gland and other glands responsable for mood/brain health/dreams (neuron consolidation/(re)calibration)/sleep/awake cycle (circadian clock) etc...these endocrine hormones regulate quite a lot and have an impact on the immune system; and, namely, the thymus organ; its output of immature T-cells/killer/immune/memory cells (part of the whole body immunity). For some reason, light seems to accelerate thymus athrophy; I guess it would be down to UVs rays and the whole 'process' of circadian clock continuing its process; this process triggers 'night/day switch' gene 'programs' ..that alter function and program is suited for night or day (there are specific genes activate during day and off at night; and vice versa). But, the constant switch and going to day time switch; is an 'aging' trigger for the thymus. The circadian clock 'awake/sleep/day light/darkness' gene program makes 'aging' in the thymus the minute it goes back to day time. It's a combination of UVs (UVa mainly; less so UVb) oxidation/radiation and gene program causing epigenetic 'drifting' and thus, thymus atrophy/immune senescence.
It was incredible because there has been no such huge hyperthorphy of the thymus but this experience showed it; darkness therapy is good; but, in humans, should not do it forever. You need light too; the constant day-night cycle (for circadian clock) function is crucial; they saw in mice that day-night cycle switch was better in the long run (then constant darkness or constant artificial light (phototherapy/light therapy)) for health; thus, our circadian clock (and our immune system/by proxy of thymus) depend on that cycle/switch; but getting more darkness is a positive for your immune system (mainly, I think, due to darkness activating gene program and hormones that are very protective (like melatonin sleep hormone or even, HGH (human growth hormones))). Surely, thymus reversal of atrophy would rejuvenate the body and the immune system...would it reverse all aging..not so sure...but would improve health first and would definitely give longevity boost (we have to remember a 115 year old woman had 3kb telomeres in the leukocytes immune cells...it means she 'toughed her run'...she 'Spent it all'...and there was not much telomere left; and is why she lived this long...because a strong immune system her whole life; no immunosenescence -except at the very very end; 115). Strong thymus/not atrophied = immunorejuvenation = reduction of immunosenescence = you might reach 115 like her (she probably had a non atrophied thymus too; since her leukocytes were aplenty till the end).
I'll try to answer your other questions:
''It would be interesting to see if the 20-30% lifespan increases in mice for senolytics and epigentic reseting of cells in vivo have any additive or synergistic effect in mice. Would it result in a greater than 30% lifespan extension vs controls?''
I agree...it would be interesting to see....I think it would have some additive effect....
I mean epigenetic resetting of cells will be strong in effect, possibly more than any senolytics therapy...senolytics therapy are mostly meant to stop senescent cell from contributing to health degradation and accelerate/'hasten death'....but not so much on the whole specie maximum lifespan thing...that is the domain of replicative senescence/hayflick limit of cells dividing (up to a limit and then arrest/hayflick limit; this will mean impossibility of stem cells to repair tissues anymore; like organs that have high turnoever and highly dividing cells/fast tissue replacement by stem cells from stem cell niches (but stem cells (except gonadal primordial germ stem cells) do not use telomerase much/their telomeres shrink too; and they will arrest too); obviously if we reduce senescence, like replicative senescence that is a good thing; but senolytics do not directly stop that; (though indireclty they may) they reduce the inflammation burden (from senescent cells (SASP/Senescence Associated Secretory Phenotype); by ablating them); they probably also reduce SAHF (Senescence Associated Heterochromatic Foci) indirectly by stopping SASP; which that will have strong impact; because SAHF is highly contributory to replicateive senescence. Anything that is reduced in the chromosomes/end termini nuclear telomeres will have deep impact on lifespan/longevity. Telomeres are the penultimate life deciders of longevity/it was shown that rate of telomere shortening equals to maximum lifespan; DNA is in Telomeres. Because that is where the (nuclear) DNA lies (in cell nucleus), and it dictates lifespan (moreso than the mitochondrial DNA; which that one is mostly for mitochondrial function/quality/stability..to produce mito ATP). The epigenome is like a another layer (on top of DNA) of 'switches' or should I say 'plugs' that activate/deactive genes depending if methylated or not. But the ultimate decider is that DNA content itself; which that, is in the telomere, centromere and sub-telomere of the chromosome (as DNA coil repeats), in nucleus.
I doubt that senolytics in human will give more than 30 years of extra lifespan...it most likely will be roughly 10-25 years (optimistically) or at worse (pessimitiscally) 5-10 years extra.
''I guess no one has the money to carry about this experiment?''
Exactly/pretty much...or no more money left for the 'useful' studies....all the money is put in calorie restruction, metformin...and cancer...so that leaves not much for rejuvenation research.
''Do senolytics have any effect on ~6 month average lifespan killifish?''
I searched but could not find much; I would wager that the effect could be non-existent or very strong (since in small/fast living species; the effect is larger); if in mice senolytics give 15-30% of lifespan extension; I doubt it would give much more than that in killifish. One of the best model is dogs/cats (or even better, apes); albeit it is just too long to wait...dogs live longer and can give us a better indicator of approx. what it will give us; but in humans, it will still be less even; because we still live much longer than dogs/cats/mouse/even apes (and killifish, shortest lived fish; though good for understanding biology; not super good for extrapolating to humans). So, it thus muddies/reduces the effect. Don't hold your breath for double lifepan extension in killifish by them; and even much much less so; in humans (when as said, killifish lives couple months; we live a full century).
It seems obvious to write this, but combined therapy exploration is clearly one area where data mining / deep learning would be a useful tool not just for initial screening but also for seeking synergistic treatments. If I can think of it surely the smarter people involved in research can also?