A Call for Matching Donors for the LEV Foundation "Robust Mouse Rejuvenation 2" Fundraiser

The Longevity Escape Velocity (LEV) Foundation was founded by Aubrey de Grey to address an important missing aspect of the ongoing work to produce treatments that target the underlying mechanisms of aging. While the research and development community has made sizable strides in the past decade, and the first rejuvenation therapies now exist in at least prototype form, it remains the case that next to no-one is conducting combination studies that use two or more of these interventions. When considering therapies that can repair forms of the cell and tissue damage that cause aging, it seems plausible that two different therapies will be additive, producing larger results than either alone.

The LEV Foundation is presently conducting the Robust Mouse Rejuvenation 1 Study, and is raising funds for the next study in line, Robust Mouse Rejuvenation 2, testing other promising interventions to prove that there is synergy between very different forms of repair therapy. These studies, and the many more like them that should be running throughout the research community and industry, but are not, will form the first foundation for the next few decades of medical practice. It has always been apparent that there would be a toolkit of many rejuvenation therapies, each addressing some aspect of aging, and that these therapies would be used in combination. But that conjecture still requires concrete proof to convince the industry and the medical community.

Many of the Fight Aging! audience have in the past supported the SENS Research Foundation annual fundraisers, some of you by offering matching donations to encourage others to donate. It worked well, and collectively our community has raised a great deal of funding over the past decade to support the growth of rejuvenation biotechnology research under the SENS umbrella, helping to fund many promising research programs that went on to spawn biotech startups. All those who have done so in the past, I encourage you to reach out and offer your support again to the LEV Foundation in their present important work, and help make the Robust Mouse Rejuvenation 2 study a reality.

Below, see Aubrey de Grey's comments on current efforts at the LEV Foundation, and a call for matching donors to help with the soon to be launched fundraiser:

A decade ago, five indisputably mainstream luminaries of geroscience published a paper that remains, by far, the most highly-cited publication in the entire field this century: "The Hallmarks of Aging". It had its roots in a paper that I and my collaborators published more than a decade earlier: "Time to talk SENS: Critiquing the Immutability of Human Aging", and laid to rest the debate as to whether the divide-and-conquer, damage-repair approach that the earlier paper introduced was feasible. What remained was to implement it.

Inevitably, some of the component interventions in the SENS rejuvenation biotechnology program are much more challenging to implement than others. That is why, while the field has mostly focused on the lower-hanging fruit, SENS Research Foundation has focused on filling that vacuum by targeting the hardest types of damage to repair, since no divide-and-conquer approach can succeed otherwise.

Now, however, the field has reached a new phase of implementing the SENS program. While the themes that SRF have pursued remain relevant, and are now much better funded as a result of Richard Heart's admirable initiative of 2021 that added $27 million to SRF coffers, it has also become possible to move to the final phase of the implementation of divide-and-conquer, namely the combining - in mice, for now - of interventions that individually show considerable promise.

That is why my new organisation, LEV Foundation, is focusing on combination studies as its flagship research program. I continue to provide regular updates on social media regarding the first such study, which we at LEVF are terming "Robust Mouse Rejuvenation 1", as the study progresses towards the point at which interesting differences emerge in the mortality of the cohorts.

Importantly, there is a long list of promising interventions not included in our current study, and which I and the LEVF team are eager to incorporate into a second study: Robust Mouse Rejuvenation 2. We are now focused on raising the funds for this new project, which like our first study will continue to identify the best combinations, antagonistic interactions, and sex and age differences in the degree to which each intervention can impact aging.

The specifics of the second study are being finalized, and we have conducted extensive work to narrow the options down, as I outlined in my presentation at LEVF's Dublin conference. Many of the remaining decisions, both between these options and concerning their details, come down to cost. Thus it continues to be the nature of our work that every offer of financial support counts. We are immensely grateful to those who have made our past work possible, and those who continue to make our future plans possible. Please reach out if you can help to make a difference!


Considering that Jeanne Kalman and a number of other supercentenarians smoked up to 100 years, it would be interesting to test such geroprotectors from tobacco as niacin and isomyosmin for synergy. Isomyosmin (MyMD-1) targets the root causes of inflammation and regulates the immuno-metabolic system through the modulation of numerous pro-inflammatory cytokines, including TNF-α, IL-6 and IL-17A. Moreover, isomyosamine exhibits similar biological activities to mTOR inhibitors rapamycin, everolimus and sirolimus owing to their largely overlapping mechanisms of action. Furthermore, MyMD-1 even slightly outperformed rapamycin in a mouse longevity study. https://doi.org/10.1093/gerona/glac142
Niacin should preferably be given together with the NADase 78c inhibitor. 78c has been shown to increase lifespan (average by 17% and maximum by 14%) and protect against aging-induced health loss in aged male mice. See: https://doi.org/10.1111/acel.13589

Posted by: Dmitry Dzhagarov at September 23rd, 2023 3:43 PM

Hi there! Just a 2 cents. I wish them good luck,

1. Controls only

2. Rapamycin only

3. Senolytic only

4. mTERT only

5. HSCT only

6. All but Rapamycin

7. All but Senolytic

8. All but mTERT

9. All but HSCT

10. All interventions

I think this will turn out, not True rejuvenation, I mean, it will be robust, but, yeah, it's on the health span thing/avg...healthy aging. They say you can expect maximum liefspan extension, but it iwll not be silver bullet. Rapamycin? Senolytic? HSCT/Hematopoeitic Stem Cell Tranfusion?

This, no. not really; mTERT will do something tangible; but, even there, I'm not so sure; something yes, but something Tangible/(really) substantial.... But, it is Mitochondrial...TERT...so it's better; targeted to mitos. TERT (you have) already does this; when TERT exists nucleus it relocates to mitochondria and 'repairs'/goes in repair mtDNA mode....rather than Telomere Extension mode (on nuclear chromosome telomeric DNA/end-telomeres). Many studies said: ''we cannot detect any TERT in these non-mitotic cells...''; but, that was not always true, or was just below detectable levels....does not meant TERT is not there...'under the radar'..
(level) of detection.
That's what I said before, the worry, is redundancy; many share redundant pathways and are not, necessarily, 'additive' or 'synergistic'....because using near-same regulatory pathways; that just, when done in combination, yield 'diminishing returns' by 'redundancy'.

I predict a 20-30% extension of lifespan from Alll of this combined...at best 50%...in best scenario; mostly, avergage lifespan extension; not maximum; maximum will be, around 20-30 or less; doubtful, to see 50% extension of maximum lifespan with this.

And the reason why.;...is because TERT alone is not enough..we have quadrillions of mitos; TERT is also present in large dose...to 'cover' it all...but this will be a problem of 'coverage'...
quadrillions of mitos...they dictate our life..plus, the little thing, of TERT being both positive - and - negative; it was shown that activation of TERT could cause acceleration of intrinsic epigenetic aging 'when overused/overcalled'; which was strange to say the least; bcause it shouldn't do that; but, I think it is clearly back to the 'Telomere attrition rate -- compared to TERT telomere extension rate'... meaning, there is, clearly, a play...on how fast you lose your telomeres...and how quick TERT comes to extend them ---to nullify the (net) loss. Because, if you don't make (net) gain, in telomere lenght, you make (net) loss. It was demonstrated, that TERT could be activated into 'Hyper-TERT' or like, in hyper/turbo mode...when combined with its catalytic element and some other one; together, now, the telomere extension could 1000% in no time...but that was a specific event, that required several elements of TERT...not just TERT/transcript/telomerase enzyme alone...you needed telomerase's enzyme catalytic 'elongating' element...that contains the TTAGGG (DNA) telomere repeats 'copy'.

But, there it is not about nucleus/nuclear chromosome telomeres/nuclear DNA....it's only about mitochondria; and, there are no telomeres there; there is rather mitochondrial DNA....when telomerase/TERT is there, it switches to repair and antioxidative mode; it acts..like any antioxidant...to scavenge (ETC) ROS....at the mitochondrial innermembrane...this way it mitigates the lipid peroxidation/PUFA ROS cascade chain...of the mitochondrial phospholipids/ PUFAs (long-chain polyunsaturates peroxidation, upon mtROS attack of them).

mTERT, and any other therapies, targeting mitochondrias...are the most central/powerful, if they have the coverage (#...s); if it's just 2-3 mitos...it's hopeless...ROS/mtROS emission...is from mitos. So, targeting TERT to mitos is very good move. But, so far, this has been done already...like, several herbs have mitochondrial antioxidative capacities...and even Call telomerase to the mitos...to the job of repairing mitos and acting as mtROS antioxidant also...
It's just how much the 'reach' (as coverage) is what I wonder....so far, studies, with telomerase have been a mixed bag...more worse than good. They do slow aging...but, yeah, many studies were like : ''makes jacks,...difference.''..,in essence, once againg, DNA damage overtakes things...and telomerase is not sufficient, including its TERT transcript...

Animals that lives centuries have activation of TERT...when their telomeres become too low...tis was demonstrated in quahogs...clams living 4 centuries;; after a while (several decades)...tert is 'called' and it's as if, the (epigenetic) system is able to make telomere elongation..without incurring cancer...and restoring function; or, let's say, elongating 'enough'...to continue.
It is akin to iPSCs..or epigenetic reprogramming; our body (or polar clam's body...) have the possibility to activate this 'dangerous telomere extension' but 'only seldomly'..once per decades.. to avoid tumor formation/excess cell growth (uncontrolled growth, mutations/increase mutational 'somatic DNA mutations' load). I think, our body/cells (like clams) have capacity of that...but when we try to do it/force it...there is a danger...of excess telomerase causing cancer.
Several studies were done on mice...about telomerase/TERT....some did cancer...but, the therapy was honed to remove cancer risk; and, as such, some studies did show mice with elongated teloemres after TERT...and with, no cancer. Mice Already have Long Telomeres...longer than humans; but lose them faster (much faster); TERT was not enough to make mice live...as long as a polar clam..obviously; this means, I am not sure, of mTERT being enough to reverse mitochondiral DNA damage/lesions and accumulation of faulty mitos that make a rising mtROS emission with age...blunt it/slow it/reduce it yes...but how much..not sure.
I think, around 20-40%, sounds abour right (30% avg..). Which, for medical researuch is Spectacular...while, for people, who ACtually want LEV to 'become'...not just pipe dream..it's anything but.

Thanks for reading,
Just a 2 cents.

PS: HSCT....stem cells injection....that was done in mice....15-20% healthspan extension.

''So what exactly are we/they supposed to do?....what solutions do you have (instead of complaining sitting on your doughnut)?''. Well, I would say, m-TERT is there...but it is Sliver..of it...we need much more 'm-'....Mitochondria action. Because, the (real) knot (aging) is there. And, until, we, actually, repair mitochondria (which mTERT will help to reduce damage to them) and scavenge the mitochondrias rising ROS/mutational burden...maximum lifespan won't change much in humans (Plateauing...will stay, and you can expect less than 20-30 years extra; we could reach 130-150, which is great...but not spectacular neither; and orders of magnitude from (anything considered) LEV. The message is this: ''You will get healthy aging, to live 100-150, happy...and you will take it/that that (or nothing else/less).''). Peoole have to remember humans die at 120 or so as Maximum...because of our mitochondrias and so many other things...this, here, is an attempt to slow things down...but, some of them are less consequential...they will reduce cancer, reduce inflammation (like senolytics)...but...on the regular 'normal' healthy aging aspect...it will be limited. Meaning, if we give this therapy to a person that is a Centenarian...or, let's say the Offpsrings of centenarians...get this therapy...how much/how little does it affect them; and before you say: ''but you are using the Best example of a human who lives extremely long in perfect health...use people who die young(er)...unhealthy''. No, it's important to test this on the most Longest Liviing person....to dispell and be able to see 'how muich/little' it has an effect..and thus, if less or not much effect...then, it shows..that there is what I said...redundancy (like mice results...translated to humans..is nilll/redundant..because they get a 'Result'..we already optimized..so don't get muhc..once mice result translated to us). And, centenarians' offsprings..whom will live to a 100+ years old...age slower---than regular population...would/are not getting/or little benefit...because they are already, 'slow agers'. Redundant maybe.. but that proves, that this therapy is 'healthy aging'...and not LEV. It's when we will see the longest living people benefiting that we will know we're on the right track. This, is akin, to seeing effects in progeric mice...but much less in Wild-type/control mice...who live longer...and thus, it is redundant for them and not much benefit. The progeric mice is accelerated (aging)...but now, is juist 'slowed back to control level'...does not mean it 'stopped aging' or 'reversed aging'....it just ages (now) slower...about the same as control, after the therapy done on it. LEV, will only be possible when we tackle the whole mitochondrias problem; the rest also (residues/end products of metabolism/clogging lysosome proteasome/telomere shrinking 'DDR position effect'/ epigenome drifting/inflammation), but, if we do not affect mitochondrias and/or fix cumulating DNA damage...nothing will make `LEV or make substantial gains above MLSP (120-150 years). Because, the (largest) source (cause/problem) is there of our aging. Animals that live centuries...protect their mitos like they are their very heart; making DNA damage/DSB (double strand breaks) a non-issue that stays so, for decades, not changing but maintained 'frozen' as so...a pristine function, means cell keeps forever 'young'.....short of that...and we are 'too short'.

Posted by: CANanonymity at September 23rd, 2023 7:48 PM

I would love to see matching donations and would make an extra donation during such a campaign. (I wish I had the ability to create matching donations myself and am grateful to those who do.)

Posted by: Neil at September 24th, 2023 11:39 AM
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