JCC So, how long do you want to live?

Update from Aubrey.

Here's update #2 on LEVF's "round 1" attempt to achieve robust mouse rejuvenation!
Yesterday we started the treatment of cohort 2. As I explained two weeks ago, this cohort consists of 300 mice, rather than the 200 that we have in cohort 1. The three 100-mouse treatment groups that have just begun their journey are:
- only senolytic
- levf.org - but eventually, as I've mentioned in a few recent interviews, we decided on galactose-conjugated Navitoclax. Navitoclax has a reasonable pedigree as a senolytic, but it's quite toxic to platelets, so several years ago Manuel Serrano had the brilliant idea of improving its specificity for senescent cells by encasing it in galactose. His logic was that galactose will be broken down (and the drug thus liberated) preferentially in senescent cells, on account of their (non-universally, but typically) high level of expression of lysosomal beta-galactosidase. It worked pretty well, and in more recent work Manuel and his colleagues made a further improvement by, rather than encasing the drug, covalently conjugating it to a single galactose molecule to create an inactive, but galactosidase-activatable, "prodrug". We worked with a top chemistry CRO in Europe to synthesise this prodrug at the scale we needed. We are replicating the treatment regimen used in prior work, which entails injecting the stuff every day for ten days. In due course we will make a decision on whether to repeat the protocol, based on data as to the rate of re-emergence of senescent cells, but that won't be for at least six months.

So to the HSCs. One of the most high-profile lines of research in the biology of aging over the past decade or two has been the rejuvenating impact on old animals of blood from young animals. More recently, this work has mostly focused on the contribution of the cell-free component of the blood, i.e. plasma. (I won't opine here on the debate as to whether it's good stuff in young plasma or bad stuff in old plasma that matters more.) But it also turns out that cells from young blood matter, as shown by a couple of studies that transplanted HSCs from young mice to old ones and obtained very good life extension. So we are doing that. The process is quite involved, consisting of two separate steps: first recipients undergo a 5-day preconditioning regimen, using G-CSF and Mozobil (AMD3100) to mobilize old HSCs into the blood; then, at the end of the 5th day, mice receive HSCs from young donors. I should also explain what I mean by "HSCs": we isolate cells using a standard procedure termed lineage-depletion. Some groups go further and specifically isolate "long-term repopulating" HSCs, but the above studies didn't, so we chose not to do so either.

Finally there's the first multi-treatment group, consisting of rapamycin, senolytic and HSCs. There's nothing different here about the specifics of administration, but I do want to mention one thing: we are not administering the injected treatments all on the same day(s). There are various reasons for this. The first is that injections are rather stressful to the mice, and based on decades of experience it has become standard practice to do at most two injections per day; since the mobilisation protocol involves twice-daily G-CSF, that means the senolytic needs to be before or after. We've chosen to do the HSCs first, followed by the senolytic; there were arguments both ways, but we decided that the main consideration was the possibility that mobilisation would have some similarities to a wound, with the implication that having a bit of SASP around might facilitate re-engraftment.

In that connection I may as well mention telomerase, even though that isn't coming until cohort 3 two weeks from now. We've decided to do the telomerase gene therapy last of the three injected treatments, after both rejuvenation of the stem cell niche and ablation of senescent cells, in order to avoid inadvertently "de-senescing” cells that became senescent for a beneficial reason, such as to stop themselves becoming cancerous.

I'll also mention that this sequencing of interventions has been very much ongoing for the past two weeks, in cohort 1, even though none of those 200 mice were/are rceiving any of the injected interventions. That's because of our choice to evaluate the impact of the method of delivery of an intervention, independently of the intervention itself, by doing two types of control, mock and naive. See my post of two weeks ago for more details, but the upshot is that half the mice in each of groups 1 and 2 (group 2 is getting rapamycin, remember) are getting mobiliser without HSCs, senolytic vehicle without senolytic, and empty (i.e. lacking the telomerase gene) virus, while the other half are getting none of those.

Now for the final topic: deaths. I've decided to be quite expansive here, because we've committed to giving very frequent updates on this, but those of you who are not utterly immersed in the project (which means all of you!) are at risk of overinterpreting the very early data. So I want to go into some depth, concerning not only how things are going but also how we are monitoring the data.
First the bald facts. As of now, two weeks in for the first 200 mice, we have had four deaths. The first was 11 days ago, so only three days into the experiment, and it was an "all controls" animal, which had received only a few doses of G-CSF. The other three, of which one was getting rapamycin and the other two were getting all controls, died early this week.

Now for how we are thinking about these deaths. The overall statistical significance of the above numbers is of course negligible. However, at this initial stage we are being absolutely eagle-eyed concerning any possibility that one or other of our treatments might be doing harm to our animals. That possibility divides into two options: that the treatment itself is toxic, or that the mode of delivery is toxic. (See above!) In the latter case, it is not wrong to respond by adjusting the mode of delivery, if an alternative is available. So, early this past week we looked very closely at the three more recent deaths - and we were rather worried; we noticed that all of them were in the mock-control group (for everything injected; as noted, they were split as regards rapamycin), not the naive group. Unlike the mouse that died 11 days ago, they had just started receiving the senolytic vehicle (which is a cocktail of solvents, because Navitoclax is quite hydrophobic), having completed their course of G-CSF and Mozobil. These coincidences must be evaluated at once in order to decide what to do. But the thing I must massively stress is that any such evaluation must consider how many alternative ways in which a similarly conspicuous coincidence could have occurred, in order to decide whether it is suspicious enough to act upon. Our option, in this case, is to retreat to a simpler vehicle, pure PBS, even though Navitoclax may not dissolve so well. I decided that we should delay doing that, pending further data; if we saw no more deaths fitting the pattern of those three, let's not change anything, but if we see a few more, let's go to PBS, with the adjustment of statistics that that implies. Fortunately, there were no more deaths in the next three days, so controls continue to receive the vehicle formulation as planned.

As the experiment proceeds, these judgement calls will continue to need to be made, but they will become progressively easier because they'll be based on more data. But I wanted to fill you in on the above - partly for full disclosure, but mostly to let you know how much care we’re taking here. We are conducting the most ambitious mouse lifespan experiment of all time, and we're not doing it blindly.

 

Here's update #3 on LEVF's "round 1" attempt to achieve robust mouse rejuvenation!

Yesterday we started the treatment of cohort 3, which consists of 200 mice, 100 of each sex. The two treatment groups within this cohort are:
- only telomerase
- senolytic, telomerase and HSCs (so, not rapamycin)

As a reminder: we don't do all the therapies at the same time, partly because of stress on the animals and partly because of our intuition as to how they will most productively interact. In particular, we have decided that the telomerase gene therapy will be administered last, after completion of the HSCs and senolytic regimens, because we don't want to risk the possibility that telomerase will temporarily "de-senesce" (hence, render resistant to the senolytic) cells that we want the senolytic to take out. So while this cohort includes the first group to be receiving mTERT therapy, it will be some time yet before the virus is actually administered.

Other than that, there's not much to say about cohort 3. However, I do want to mention a tweak that we've made starting with cohort 2. In my last update I mentioned that we had seen three deaths in cohort 1 that we felt might have been caused by the senolytic vehicle. We worked very hard to analyse the problem (even though it was only three mice), and we came to the conclusion that one possibility was excessive stress caused by so many injections in quick succession, because the deaths were all in the "mock" subgroups rather than "naive", i.e. they were receiving sham injections. So for cohorts 2, 3 and 4 we are inserting a two-week gap between HSC and senolytic. With the nicely large number of mice we're working with, we'll be able to discern with good statistical power whether this made a difference. However, we anticipate that if there really was a problem with cumulative stress of the two treatments, it will have been transient, i.e. all the mice that got the senolytic immediately after the mobilisation and survived will recover and be just as healthy a month after treatment as those that got the two-week recovery period. Let's see!

The only other thing to report is that last week we had some hardware problems which limited the number of HSCs we were able to purify per day. But the Ichor team brilliantly coped with that in a manner that has meant no consequence for the overall experiment other than shuffling a few mice between treatment groups. Three cheers for Ichor!

 

First anti-aging pill by 2028?

This is sparked by Sam Altman's 180 million dollar investment last month. This sounds like a "make you really healthy" pill as he stated the goal was to get people to live 10 years longer. Personally I'm a bit surprised rapamycin isn't more readily available.

Here's an FAQ

 

From Aubrey:

Here's update #5 on our study!
The more timekeeping-inclined among you may have noticed that this time I'm a full week late, relative to the two-week interval that I've been religiously adhering to until now. That's mostly just because there is less to say right now than originally expected, on account of the two-week interval that we inserted (see update #3) between the HSC treatment and the senolytic treatment, so as to allow the animals a little time to recover. Arguably that has now become unnecessary, given the switch to oral gavage for the senolytic (see update #4), but once we had made the change to the schedule there was no reason to change back.

So, well, cohort 3 (i.e. treatment groups 6 and 7) have now had all their treatments. These groups are the first ones to receive telomerase gene therapy; group 6 is getting only that, while group 7 is getting that plus HSCs plus senolytic, so all but rapa. Cohort 4, consisting of the all-but-senolytic, the all-but-HSCs and the all-four, is still part-way through.
But other than that, the good news is that there's no news! No new hiccups.

 

Very extended life expectancy scares me because then most governments will raise the retirement age. And I don’t wanna work into my 900s like Yoda.

 

Interesting enough, if you give the GOP the dystopia they are obviously trying to make you'll never have to worry about it since they would just hoard the tech for them and keep everyone else rotating through work and making babies and death, rinse and repeat. I am however optimistic.

 

Rapamycin is an immunosuppressant and is teratogenic besides. It is unconscionable, sociopathic lunacy for a bunch ultra-wealthy people to push for deregulation of tangibly dangerous substances just so they can live out their childhood fantasy of living longer than Yoda.

 

It works its life extension properties without side effects at lower doses than organ transplant patients must take. And again, no one is going to force you to participate.

 

That's extremely cynical. They are not talking about going through legal process and getting an FDA indication for this drug. They literally have a list of doctors on their website that are willing to prescribe it to people off-label. They are openly advocating doctor shopping to use a drug when there's no good clinical evidence it will work as they are claiming. They may as well say "DO YOU WANT TO HAVE FUN AND BE COOL?! HERE'S A LIST OF DOCTORS IN YOUR AREA THAT WILL PRESCRIBE COCAINE"

My lack of participation doesn't change how corrosive and wrong-headed it all is.

 

Actually rapamycin is well tested and has many more tests going on at this time

Not to mention many researchers use it in small doses every day. No side effects.

So only those who dismiss such research say it doesn't have much research. And however wrong headed you might think it is isn't relevant, especially since you tend to just piss on everything anyway. If every problem you think will happen happens it won;t be your concern because you'll be dead.

 

Not just for mice anymore

Vision loss in primates restored by making their eyes young again.

 

For those of you who didn't follow his link. some of the cutting edge research highlighted is improving dental health in rodents. You know, alongside other excellent treatments like "gnawing on a block of wood."

. . .

 

I assume you're being sarcastic? Nothing like that in the link provided.

 

Ahem.

 

1. This is not on the page I am looking at.

2. This is about the rejuvenation in eyes with links throughout.

3. And what you're seeing is what happens in such research, where they experiment on rodents and then go on to people, which is a great thing, which is what you have posted, but for some reason is a negative? Yeah ok.

 

The primary reason this wonder drug has not had investors pushing it forward...it's off patent.

 

We're at an open air concert with the CSO tonight breathing in the Canadian wildfires. So we may all be taking a longevity hit.

 

So I used to be in meetings every once in a while with an excellent CDC epidemiologist who has since retired, but sometime it was difficult to pay attention to his startling level of expertise because of a dense, tangled forest of hair growing out of his ears. I'd never seen anything like it. It was like he had a marmot or some other similarly furry creature nesting at the entrance to his ear canal. He could get away with sporting ear beards because of who he was and his position in the field.

But I felt the need to try to keep my own ear hair contained. I have a trimmer. I'd go in occasionally and do the work. As I get older, however, I feel I am starting to lose the battle. The hairs grow long quickly, like ear tentacles reaching out to greet people. They're thicker and coarser now too. I wonder if I have some kind of ear hair virus developed in a secret CDC lab and spread by this since retired CDC epidemiologist. If there is ear hair biowarfare I may be an early victim.

The point of this is that these kinds of indignities are starting to build up and sap my will to live to an extended old age. If I make it to 80, I will be able to braid my ear hair and put bows in it and little pieces of fuse that I light to look like Edward Teach going into battle, a kind of BlackEarBeard, though mostly gray at that point probably. The future is bleak.

 

I obsessively tweeze out ear hair daily.

 

Ok i haven't read this thread at all, but to answer the question:

1 day less than the first war for fresh water ownership

 

Nose hair trimmers work just fine in your ears... according to a friend of mine...

 

that's what I use for now but I may soon need something more powerful.

 

I too have ear hair but it's outside on the end of the tragus.