reasonattlm (u/reasonattlm)

reasonattlm commented on A primer on the current state of longevity research owlposting.com/p/some-que... · Posted by u/abhishaike

reasonattlm · a year ago

It is hard to cover everything related to longevity, given that there is a vast diversity of approaches, and a lot of work presently taking place.

https://www.agingbiotech.info shows how much work goes into just making lists for just the industry side of the house.

Read a few of the lengthy end of year posts at Fight Aging! to see just how much there is to comment on (e.g. https://www.fightaging.org/archives/2023/12/a-look-back-at-2... ), and Fight Aging! only covers an opinionated selection of the full spectrum of research and development.

reasonattlm commented on Effect of gut microbiome modulation on muscle function and cognition nature.com/articles/s4146... · Posted by u/gnabgib

caycep · 2 years ago

the last time I looked at microbiome stuff, someone at Stanford tried to chop up all the microbes in poop and sequence all the RNA/DNA sequences they could collect from that soup. It amounted to several petabytes of data or something ridiculous. Has anyone come up w/ a better way of analysis?

reasonattlm · 2 years ago

The 16S rRNA sequencing you are referring to is now quite cheap and efficient. [1]

Viome is one of many companies offering this as a service. Viome isn't so good at giving you the underlying data, some of the others may be better; look at their example reports or ask their support. Ombre, BIOHM, Tiny Health, Floré, etc.

In terms of whether the add-on services they offer are valuable (tailored prebiotics / probiotics / diet advice based on their reading of the literature) I think only time and randomized controlled trials will tell. Not that any of these services have any incentive to run trials! But it may be a useful time-saver for a self-experimenter who would have been digging through the literature to try to come to the same conclusions on things to test.

[1]: https://doi.org/10.1038/s41467-019-13036-1

reasonattlm commented on Effect of gut microbiome modulation on muscle function and cognition nature.com/articles/s4146... · Posted by u/gnabgib

reasonattlm · 2 years ago

It is interesting that they achieved any positive results with prebiotics. The animal study evidence suggests that these are weak interventions compared to fecal microbiota transplant (FMT) from a young individual or flagellin immunization. Weak in the sense that they don't last long for one dose, whereas both FMT and flagellin immunization are essentially years-long to permanent effects, and also weak in the sense of a small effect size on the gut microbiome and health measures compared to FMT and flagellin immunization.

In principle it should be possible to produce some sort of one-time high dose oral probiotic that produces results that are in the same ballpark for effect size and duration as FMT. In practice, it doesn't look like anyone is rushing to get that done, and it might turn out to be very expensive to manufacture 100-200+ distinct microbial populations into a probiotic mix. No-one seems to know whether it would take that many, or whether there are a lynchpin few dozen species one could focus on to get an 80/20 outcome. But that sounds like a question that could be answered in the next decade or two at the present pace.

reasonattlm commented on People who live past 105 years old have genes that stop DNA damage newscientist.com/article/... · Posted by u/awb

reasonattlm · 4 years ago

We should treat this study and the discussion of the relevance of the results as being highly speculative.

Firstly, near all genetic variants that have been found to correlate with age in one study population fail to replicate in other study populations, and this is true of studies with cohorts consisting of thousands of individuals. The study here used a primary cohort of less than 100 individuals over the age of 100. This is ever the challenge in research focused on extreme old age: very few people make it that far. There was a secondary validation cohort of a few hundred centenarians, but I'm not sure that should increase our confidence in the data, given the existence of other studies that did much the same thing and still failed to replicate.

Secondly, given the identification of a genetic variant, near everything one can say about it is quite speculative in advance of much more detailed research into how exactly that variant changes cell behavior.

Lastly, the most robust data established to date on the contributions of genetic variants to human longevity, with studies pulling from very large national databases such as the UK Biobank, suggests that genetics has only a minor role to play. Lifestyle choices and exposure to pathogens are the dominant factors. In the case of long-lived families, cultural transmission of lifestyle choices relating to longevity seems a more plausible explanation than genetics, given the rest of the literature as it presently stands.

reasonattlm commented on Why Does the Pandemic Seem to Be Hitting Some Countries Harder Than Others? newyorker.com/magazine/20... · Posted by u/irtefa

reasonattlm · 5 years ago

An entire article pondering regional differences in COVID-19 mortality and severity without saying anything about differing demographics of (a) aging and its comorbidities and (b) obesity and its comorbidities.

SARS-CoV-2 is severe in old people and obese people, and very few outside that demographic. Wealthy nations have a much higher obesity rate than poorer nations. The US has ten times the number of obese individuals than India, three times as many as Nigeria. Wealthy nations have a larger proportion of the population in older age cohorts. The US has five times as many 65+ people as Nigeria.

I have no idea why the media persistently chooses to avoid these points. The research community has been turning out review papers by the score to point out, very bluntly, that COVID-19 mortality falls near entirely on the old and the obese.

reasonattlm commented on European startups hacking the ageing process sifted.eu/articles/europe... · Posted by u/tdmckinlay

reasonattlm · 5 years ago

For a fairly inclusive list of longevity industry companies:

https://agingbiotech.info/companies

reasonattlm commented on How to Start a Biotech Company on a Budget blog.ycombinator.com/how-... · Posted by u/flipchart

reasonattlm · 5 years ago

If you can get into an incubator lab space that isn't in a major market like SF or Boston, where the rents are insane, one can expect to set up a reasonable wet lab for most uses given $200k in equipment and reagent costs and a couple of months of time. Then expect $5-10k/month in operating costs outside of salaries.

reasonattlm commented on Sight restored by turning back the epigenetic clock nature.com/articles/d4158... · Posted by u/evo_9

reasonattlm · 5 years ago

Several research groups and companies are working on in vivo applications of cellular reprogramming. Since its discovery, reprogramming has been used to produce induced pluripotent stem cells from any other type of cell. That process has been found to reverse age-related changes in epigenetic patterns and mitochondrial function characteristic of cells in old tissues.

Introducing the factors capable of reprogramming cells into a living animal may produce effects akin to stem cell therapy by converting a small number of cells into induced pluripotent stem cells, followed by stem cell signaling that beneficially affects tissue health more broadly. Alternatively, many cells may have their epigenetic markers reset to a more youthful state without losing their identity to become induced pluripotent stem cells. Or both. Beyond this, there is certainly the threat of cancer or structural damage to tissue through the conversion of too many cells, and this class of therapy will require careful development to ensure safety, even as the mouse data continues to look quite interesting.

David Sinclair has been pushing an epigenetic-centric view of aging of late, with analogies to information systems and computing. The most interesting part of the the supporting work suggests that DNA repair of double strand breaks has the side-effect of driving alteration of the epigenome in characteristic ways with age. That will be an important connection between stochastic nuclear DNA damage and deterministic global effects throughout the body, should the evidence continue to hold up.

As this illustrates, however, epigenetic change is a downstream issue in aging, a reaction to events and a changing environment, not a first cause. Fixing it may or may not turn out to be particularly useful in the broader picture of aging, depending on exactly where it sits in the web of cause and consequence. As a comparable example, hypertension is a major downstream issue in aging. It is far removed from root causes such as cross-link formation and inflammation, but is also a proximate cause of many forms of further dysfunction, such as pressure damage to delicate tissues in the brain. Controlling hypertension without addressing its causes is both possible and beneficial - but the benefits are limited by the fact that those root causes are still there, chewing away at the body in a thousand other ways.

reasonattlm commented on Hyperbaric oxygen therapy increases telomere length in isolated blood cells aging-us.com/article/2021... · Posted by u/generalizations

reasonattlm · 5 years ago

This interesting open access paper recently published reports on the effects of hyperbaric oxygen treatment on telomere length and cellular senescence in immune cells taken from blood samples. I use the word "interesting" quite deliberately, because that is exactly and all that this research is. The paper is appropriately formal and modest on that front, but this attitude doesn't extend to the rest of the publicity, unfortunately. When one runs a business based around offering hyperbaric oxygen treatment, one must make hay while the sun shines, and extract every last drop of marketing juice from every study funded. Hence there are media articles out there at the moment breathlessly telling us that hyperbaric oxygen treatment reverses aging. This is ridiculous, and only makes it harder for the better end of the longevity industry to make progress.

Per the paper, hyperbaric oxygen treatment causes average telomere length to grow by ~20% and markers of cellular senescence to decrease by ~35% in populations of circulating immune cells. This doesn't tell us that hyperbaric oxygen treatment is an amazing rejuvenation therapy, any more than the NAD+ and mitochondrial function data for exercise tells us that exercise is an amazing rejuvenation therapy. In both cases we already know the bounds of the possible. We know that these interventions don't turn older people into notably younger people. If we're calling exercise and hyperbaric oxygen treatment rejuvenation therapies, then the term "rejuvenation therapy" is meaningless.

What this does reinforce is the point that peripheral blood immune cell parameters can be very disconnected from the overall state of aging. We know that telomere length as assessed in these cells is a truly terrible measure of aging. Circulating immune cells are prone to large variations in the pace of celular replication in response to circumstances. Immune cells replicate aggressively when provoked by the presence of pathogens or other issues requiring a coordinated immune response. Telomere length shortens with every cell division in somatic cells: in immune cells, telomere length thus has a very wide spread across individuals, varies day to day, is just as influenced by infection status and other environmental factors as it is by aging. It is just not all that helpful as a measure of aging, and downward trends with age are only seen in the statistics for large study populations.

It seems plausible that the same is true of cellular senescence in immune cells. Cells become senescent when they hit the Hayflick limit on cellular replication. Throughout much of life, the senescence of immune cells is likely more determined by replication pace (and thus immune challenges, the burden of infection) than by aging. And that is before we even get to the point that the authors of this paper used a less than standard measure of senescence, one for which it is possible to argue that it may or may not actually be representative of the burden of senescent cells in immune populations. Overall this data is all interesting, but I suspect that it tells us more about the poor relevance of the metrics chosen to anything other than the deeper aspects of immune function.

If hyperbaric oxygen treatment removed ~35% of senescent cells throughout the body, it would already be well known as a reliable therapy for arthritis, a way to reverse chronic kidney disease, a way to suppress inflammatory conditions, and an effective treatment for numerous chronic diseases of aging. In mice, removing a third of senescent cells via senolytic drugs produces reliably large and beneficial outcomes, while hyperbaric oxygen treatment does not. So clearly it is not globally clearing senescent cells - and nor should any responsible party be trying to present reductions in senescent immune cells as indicative of global senolytic effects throughout the body. What is observed here is an effect limited to the way in which the immune system is functioning. There is some evidence for hyperbaric oxygen treatment to improve resistance to infectious disease such as influenza, and that is interesting in and of itself, but I feel that much of what is going on here is an attempt by certain parties to jump onto the longevity industry bandwagon, rather than responsibly focusing on a realistic view of what can be achieved with their chosen intervention.

reasonattlm commented on Learnings from Running a Longevity Startup celinehh.com/year-1-learn... · Posted by u/sarthakjshetty

reasonattlm · 5 years ago

Some of the more noteworthy lessons I have learned to date as a result of running a longevity industry biotech startup, most of which likely apply to any biotech initiative, were incorporated into the "Notes on Starting a Biotech Company" section of this document:

https://www.fightaging.org/pdf/how-to-start-a-biotech-compan...