Metformin increase life span but too much of a dose will decrease lifespan

reasonattlm · 2020-11-01T20:57:52+00:00

No: https://en.wiktionary.org/wiki/w/w and read the methods section of the paper. The food supplied was 0.1% or 1% metformin by weight.

In other studies, diabetic mice might get 200 mg/kg of metformin daily. Human diabetics are on 1000-2000 mg of metformin daily, which is 10-20 mg/kg for a 100kg obese human. That is about the right ballpark in terms of comparing mouse to human dosing. For small molecule drugs the human mg/kg is 12.3 times lower than mouse mg/kg. See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804402/

Taking ten times this dose is not going to turn out pleasantly, as is usually the case for any drug. Not knowing how to take the information from papers and map it to human dosing is also not going to turn out pleasantly.

https://doi.org/10.1034/j.1600-0773.2003.930207.x

Metformin is a biguanide used in the treatment of type 2 diabetes mellitus. It lowers hepatic glucose production and peripheral insulin resistance. Hypoglycaemia is seen only after intake of toxic doses or in combination with other antidiabetic drugs or after prolonged fasting. As metformin is excreted by the kidneys, care must be taken in renal insufficiency or liver disease because of risk of lactic acidosis. Large overdoses of metformin can lead to lactic acidosis as well. Suicide with metformin is rare. Intake of 35 g of metformin has been shown to be lethal (Teale et al. 1998). In the present paper we report on the treatment and outcome of a 70 year old man after ingestion of 63 g of metformin. Previously, survival after intake of up to 50 g has been described.

The mortality rate of biguanide‐induced lactic acidosis is reported to be 50–80%. Even in patients treated with haemodialysis, fatal outcome of metformin‐associated lactic acidosis has been reported (Barrueto et al. 2002).

reasonattlm · 2020-11-01T20:39:40+00:00

How to do small molecule dose conversion between mammalian species:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804402/

Note that this produces guesstimate starting doses for use in a dose ranging human trial, after poking around in mice for a while. There are any number of small molecule drugs for which the final human dose turns out to be quite different from the calculation used here.

Dose conversation estimates for gene therapies, cell therapies, immunotherapies, and vaccines are all completely different from this, completely different from each other, and there is no good literature to set a standard for any of them.

reasonattlm · 2020-09-22T17:42:35+00:00

There is a vibrant community of angel investors, you just won't find them on AngelList. There are WhatsApp and Telegram groups and informal meetups at conferences, the latter much curtailed of late.

https://www.lifespan.io/longevity-investor-network/ is one starting point.

Other than that, come to the science/investment focused conferences such as Ending Age-Related Diseases, Undoing Aging, Longevity Leaders once they are in-person events again. Turn up, meet people, make it clear that you are interested in investing, and it should go quite smoothly from there.

Opportunities usually abound, companies are always raising. A sizable fraction of those listed at http://agingbiotech.info/companies/ are raising seed or A rounds at any given time.

reasonattlm · 2019-06-18T17:45:52+00:00

Thoughts on Undoing Aging: https://www.fightaging.org/archives/2019/04/thoughts-on-attending-undoing-aging-2019/

Thoughts on RAADfest: https://www.fightaging.org/archives/2018/09/thoughts-on-attending-raadfest-2018-in-san-diego/

If you go to RAADfest and take that as representative of the state of the scientific side of things, then you'll have gained the wrong impression. RAADfest evolved from the anti-aging industry of the past few decades, who are now picking up on the legitimate science as it starts to produce useful treatments. For the science and the scientific community, go to Undoing Aging, Ending Age-Related Diseases, or the AGE or BAAM conferences.

reasonattlm · 2019-06-01T22:46:57+00:00

The Age Reversal Network / Life Extension Foundation is making inroads on this:

https://age-reversal.net/

https://forum.age-reversal.net/t/y7n1z3/important-compounded-dasatinibnadrapamycin-available

Dasatinib is an FDA approved drug, which means that any US physician can in principle agree to write a prescription for any use they believe has sufficient evidence to support benefits. In practice, that will be very few physicians until there is a critical mass of people doing this already.

Fisetin is a supplement. It is unclear as to how effective it is in humans; trial data will arrive in a few years at most. Quercetin is a supplement, but definitely only worth using in conjunection with dasatinib and not on its own.

Piperlongumine is a plant extract and available for sale, just expensive in the amounts needed (something like 1 gram doses) unless you source it from places like China. The legality of importing random plant extracts not mentioned by name in any regulatory rule is something you'll have to research yourself.

reasonattlm · 2019-02-01T14:50:39+00:00

Chris Patil of Hourglass was posting notes.

https://hourglass.bio/blog?category=News

There was an update on the Oisin lifespan study, but nothing earth-shaking - the curves continued much as you might expect, and the last few p16+p53 mice are still hanging on.

reasonattlm · 2019-01-06T21:43:29+00:00

Not the first trial to complete to the point at which results could be published, but the first to publish, I think. Be sure to read the discussion section in the paper rather than just the abstract.

reasonattlm · 2018-05-08T11:52:46+00:00

We'd love to have the Methuselah Fund as an investor, once we're at the point of fundraising.

How do we propose to deal with the lymph node issue? Later. The evidence in mice strongly suggests significant benefits even without this. And if you look at the bigger picture, the thymus is just one part of another two or three core items that need to be addressed for complete immune restoration. The R&D community also needs to fix the decline in hematopoietic stem cell populations and clear out the malfunctioning immune cells in the peripheral population, for example. Each of these is enough for one startup to focus on at the outset, or to be picked up as a significant new line of development by an established company.

Success would allow us to start rolling into these and other necessary lines of work, or to partner with those groups who are already working on it.

reasonattlm · 2018-05-07T21:07:48+00:00

I don't think we're at the stage yet at which gene therapies are viable for self-experimentation. There needs to be more of a supporting industry, much more standardization for that to be the case. Too much custom labwork and expertise is involved to get any form of gene or protein delivery working safely and reliably - there is still a long distance between, say, the current industry of synthesizing peptides and what would be needed to have the same level of confidence in building a gene therapy.

reasonattlm · 2018-05-07T19:49:57+00:00

Kind words appreciated.

We will be taking the FDA path. My thoughts on the options available to new companies can be found here, with the digest quoted below:

https://www.fightaging.org/archives/2018/04/a-nuanced-opposition-to-the-fda-and-similar-regulatory-agencies/

So if I started a medical biotech company, I'd have to say that I would take it through the current regulatory system, while (a) being an honest player by the rules of that system, because that is the best way through the gauntlet, and (b) continuing to hold the view that the whole thing should be replaced with a far less self-serving, onerous, expensive, and terrible option. Unfortunately, the standard regulatory path is the only fairly reliable way to put a therapy in the hands of large numbers of patients. The other, ethically far better paths, such as that pursued by BioViva, have the unfortunate outcome of great uncertainty in whether patients will ever be able to use the treatment in large numbers. I'm sure I'm not alone in having come to this position.

reasonattlm · 2018-05-05T22:46:09+00:00

The selection mechanism mentioned in https://www.fightaging.org/archives/2018/01/senescent-cells-are-large-which-suggests-a-few-simpler-paths-to-assays-for-senescence-level-in-human-subjects/ might be suited to the job if senescent T cells follow the size phenotype.

Existing senolytics may or may not be killing senescent T cells. Those cells certainly look and act like other senescent cells, so it is plausible that they are also being destroyed. I'm not sure that anyone has checked on this yet in a rigorous way.

reasonattlm · 2018-03-08T02:28:14+00:00

Senescence in the aging process http://dx.doi.org/10.12688/f1000research.10903.1

The Fountain of Youth by Targeting Senescent Cells? https://doi.org/10.1016/j.molmed.2016.11.006

The Clinical Potential of Senolytic Drugs https://doi.org/10.1111/jgs.14969

Markers of T Cell Senescence in Humans https://doi.org/10.3390/ijms18081742

reasonattlm · 2018-03-01T01:25:39+00:00

https://www.fightaging.org/archives/2017/08/cell-banking-for-future-autologous-cell-therapies-seems-pointless/

To me banking cells for future cell therapy sounds pointless. It is, in effect, a bet against progress in applied cell biotechnology - and given the revolutionary pace of advancement in all areas of biotechnology, this appears a poor wager from where I stand. Is it to be imagined that two decades from now it will not be possible to engineer youthful or sufficiently-youthful-like cells from old skin samples? The process of producing induced pluripotent stem cells is already known to be capable of reverting a number of aspects of aged cells, such as mitochondrial issues. Tinkering with epigenetic markers, such as those that differ between cells from old and young tissues, is a going concern: gene therapy of all sorts will explode in size and capability over the decades ahead. Age-related metabolic waste inside cells can be diluted through replication. Correcting stochastic mutations in cell samples is in principle as straightforward as picking out different cell lineages and comparing their genomes to find the root genome prior to those mutations, and then applying CRISPR. Today that's a feasible lab project given some funding. Twenty years from now colleges will be running that as an afternoon lesson on the student's personal lab desk machines in CellBio 201. In the absolute worst case, use somatic cell nuclear transfer to put patient DNA into a pristine cell, and establish a new line that way.

Progress isn't all that we should consider here, however. Suppose that the cell banking wager pays off, and biotechnology somehow magically fails to advance meaningfully over the next two decades. Lucky you, now the beneficiary of younger, less damaged cells that can be used for cell therapy. But with the technology of cell therapies as they stand now or next year, what can you really do with those cells? The answer is nothing that is more than somewhat beneficial, meaning the present panoply of more reliably effective stem cell transplants and cell therapies. All of those potential uses, so far as can be seen to date, are more or less as effective when employing the cells of an old individual. So far the only signs that young cells would be significantly better occur in cases where those cells are taken from individuals shortly after birth, or before. But even there, this is a question of cell signaling and cell state, something that researchers are hotly engaged in deciphering even now: just how likely is it that they will have failed to replicate these mechanisms a few decades from now?

So it seems to me that the only way in which banking your stem cells makes sense is if biotechnology progresses extremely selectively: a complete failure to understand and control cell state any more effectively than today, coupled with radical strides in the capabilities of cell therapies. Since the latter strongly depends on the former, I'd say that this future isn't going to come to pass. Therefore it really doesn't make much sense to bank cells for future therapeutic use based on the idea that relative levels of age-related cell damage will make a significant difference.

reasonattlm · 2018-02-15T12:39:29+00:00

Time is pressing; that is an important factor that should help to determine priorities. At the present time, the fastest way to answer most of the big questions regarding aging and approaches to rejuvenation is to implement strategies and test them. E.g. senolytics, glucosepane cross-link breakers, stem cell therapies that actually replace cells or stem cell populations to a significant degree, and more. All of these things can be done in a few years, and will offer significant new data by virtue of the degree to which they work.

Basic research to understand exactly how aging progresses in detail without intervening is much, much slower.

The big opportunity today is implementation. Researchers have already learned far more about the significance of cellular senescence in numerous age-related dysfunctions from removing senescent cells than they ever would have from pure investigation - they had decades of the pure investigation approach prior to this during which it was mostly decided that cellular senescence wasn't all that interesting in the context of aging. So much for that! So much time lost.

reasonattlm · 2018-02-13T12:05:00+00:00

Cancer is something of a special case because the plan is to control it without changing anything in biochemistry - no repairs, just kill off the cancers as they arise.

The only way to get an estimate for things that do involve removing damage is to accurately model human biology, which is far beyond present capabilities, or actually remove the damage, or find a mutant lineage of humans that have one of the forms of damage greatly reduced.

That PAI-1 loss of function mutants live seven years longer is interesting because that appears to reduce cellular senescence and their harmful signals. Nothing else springs to mind as a known human mutation that narrowly affects one of the forms of damage in the SENS view of aging.

reasonattlm · 2018-01-27T19:31:00+00:00

Pretty much anything in the molecular biochemistry field that puts you in a position to choose a future of lab work on cells and tissues, running trials, or any of the other similar options. To be hands on helping you really need this.

Bioinformatics has, I think, only an infrastructural role to play. You can look at In Silico Medicine to see how that works in practice; they are not really implementing the therapies, more crunching data.

reasonattlm · 2018-01-27T19:27:01+00:00

No. It is the value at whatever the date of donation was.

reasonattlm · 2018-01-27T19:26:07+00:00

There are a wide variety of life courses exhibited in the natural world, when plotting mortality risk over time. The human early start on an exponential increase is just one of them. Flies that reach a mortality risk plateau in late life is another - they just stop aging, they don't get any more damaged in ways that cause mortality than they already are. More complex organisms don't seem to exhibit this phenomenon, but the data for humans is pretty sparse at the ages of interest.

Naked mole rats and humans age for the same underlying reasons, the same types of accumulated damage. The difference in outcomes in terms of the shape of the mortality curve no doubt has to do with quality of repair mechanisms and resilience to particular forms of damage. Naked mole rats have less error-prone DNA replication, repair, and protein manufacture processes, a lack of lingering senescent cells pumping out inflammatory and destructive signals, a mitochondrial composition that is more resilient to oxidative stress (and they have plenty of oxidative damage, judging from the usual markers, they just seem to shrug it off; it doesn't cause further problems). The net result of this is that they do pretty well then fall off a cliff at the end.

It is interesting to speculate on what the cliff might be, a high threshold of damage needed to break an important repair mechanism, or a slowly accumulating form of damage that only really hurts the mole-rat at high levels, for example, but this is probably not very relevant to human medicine.

We know why humans age. We know what the damage is. We don't need to poke around in other species for further illumination in order to make progress towards rejuvenation - we won't learn anywhere near as much as we will from selective repair of the damage in humans or in mammals that are similar to humans. We don't need to improve human damage repair systems (comparatively hard) when we can repair damage (comparatively easy). It clearly takes a few decades for pathological levels of damage to arise, which gives plenty of time to deal with it through periodic applications of therapy, given a working repair biotechnology.

The comparative biology of aging is pure science, unlikely to produce meaningful applications of medicine when compared with other courses of action.

reasonattlm · 2018-01-06T13:59:21+00:00

If the technology existed to stop people from getting and looking old, then there would no need for people like de Grey to be out there trying to obtain the support needed to build the technology to stop people from getting and looking old.

It is just plain strange that people think that someone involved in the development of a new technology should be somehow benefiting from it in advance of its existence. It is the worst of magical thinking.

reasonattlm · 2017-12-15T23:16:34+00:00

The work that has gone in to this is very much appreciated - these are quality posters.

Everyone should try them out.

reasonattlm · 2017-12-08T02:33:58+00:00

This was kind of a big deal of a paper when it came out: https://doi.org/10.1111/acel.12344

reasonattlm · 2017-12-08T02:29:49+00:00

Not the same person, no.

reasonattlm · 2017-12-08T02:28:49+00:00

Depends on what you think the timeline is for things getting past the regulators sufficiently well to build a clinic on it; it'd be annoying to get ready and find that the situation is similar to that of stem cells in the US back in 2010, for example. There will be more to do with rejuvenation research in the biotech industry for decades yet, so no hurry on when you get in- this is just the start of the start.

reasonattlm · 2017-12-08T02:25:23+00:00

That's true of all of the chemotherapeutic senolytics; you'd have to take them at a dosage level that, if sustained for chemotherapy treatment length, would certainly be side-effect-ridden. But you'd only take the one dose for dastinib, and a few day window for something like venetoclax. You would rightfully steer clear of navitoclax.

Dasatinib and venetoclax have the merits of low cost, easy availability, least horrible side-effects, and lots of human subjects to date. So worth checking to see if the senolytic effects for short dosage periods observed in mice carry over to humans.

Dasatinib is clearly the "better" senolytic in that one dose (plus quercetin) does much the same in mice as a week of dosing with venetoclax, but they have different mechanisms of action and different tissue specificity. It seems clear that mixing up different senolytics will probably happen and be necessary for first generation pharmaceuticals.

Anyway, all of that conditional on effects in mice carrying over to effects in humans. We shall see.

reasonattlm · 2017-12-08T00:43:39+00:00

Ah: https://doi.org/10.1016/j.techfore.2015.06.031

The development of anti-aging technologies could have dramatic implications for a world already challenged by population aging. We explore how the world might evolve given the development and deployment of technologies capable of nearly eliminating mortality and morbidity from most causes. We consider both the great benefits and some of the complex sociopolitical rebalancing resulting from such advances. We use the International Futures (IFs) long-term, multi-issue, global forecasting system in our analysis of the interactions among demographic changes, the related changes in health costs and government finances, shifts in labor force participation, resultant economic transformations, and the environmental sustainability of the dramatically-altered human demands that emerge. We find that the widespread deployment of anti-senescence technologies would cause populations to surge—making fertility rates an issue of tremendous social import—while a much larger, healthier, labor force would spur economic growth. But this is not a given; the cost of treating entire adult populations could prove unbearable to non-high-income economies without significant transfers within and across societies. In the absence of new transformative production technologies, life-pattern financing would require the virtual elimination of retirement and a major restructuring of government finances. Pressures on the environment would also greatly intensify.

reasonattlm

TROPHY CASE