23 ms·

The field of longevity biotech is a mess

187 points by deegles 5y ago

williamkuszmaul 5y ago
Interesting post! Small comment on the argument against anti-aging genes existing: "genes only propagate if selected for, and there’s no selective pressure for longevity after reproductive age" (I know that this was just a very minor aside, but I still think it's worth pointing out the flaw.) That's not how evolution works. Even after you have reproduced, you have impact on whether your children survive and reproduce. This means that there could very reasonably be evolutionary pressure in either direction (causing people to die younger that way they stop taking resources from their children or causing people to live longer that way they keep providing support for their children).
- HPsquared 5y ago
  This idea is called group selection [0]. Edit: perhaps kin selection [1] is the more appropriate one here. Still, longevity would affect the group and not only the direct kin. [0] https://en.m.wikipedia.org/wiki/Group_selection https://en.m.wikipedia.org/wiki/Group_selection [1] https://en.m.wikipedia.org/wiki/Kin_selection https://en.m.wikipedia.org/wiki/Kin_selection
  - syllogism 5y ago
    More like kin selection: https://en.wikipedia.org/wiki/Kin_selection https://en.wikipedia.org/wiki/Kin_selection
- skybrian 5y ago
  Effect size is hardly ever zero and surprisingly small effect sizes can be measured. But is this evolutionary pressure large enough to make a difference for a longevity gene when people already live quite long after having children?
  - pharke 5y ago
    I think the idea is that there aren't "longevity" genes only aging genes. Put another way, aging isn't an accident caused by the accumulation of damage. It's a selected for trait, a sort of slow, whole body apoptosis used to get rid of the soma once it's served it's purpose. Lifespan is simply the well timed removal of a generation once it has had the opportunity to reproduce and raise its brood.
    - robwwilliams 5y ago
      Perfect! And reproductive longevity is strongly selected. Mole rats and bats, despite small bodies and quite high metabolic rates live far longer than might be expected from simple allometric relations. Reproductive lifestyles can evolve by bootstrapping on large numbers of DNA variants that modulate and molecular-cellular systems.
    - codeflo 5y ago
      I’m not sure I buy that completely. If this were a neutral choice, why would a gene take the 50% chance of not having made it to the next generation? (Or in the case of many offspring, invest half its resources into a different copy of the gene?) At least in mammals, killing the soma is on the surface such a massive waste of resources that I believe it must be either: (a) biologically implausible to keep an animal reproducing for a longer timespan or (b) caused by mechanisms that are counterweighted by massive reproductive benefits while the animal is young.
      - pharke 5y ago
        > killing the soma is on the surface such a massive waste of resources How is it a waste of resources? Evolutionarily, the goal is to produce another successful generation who then begets another generation and so on. The rate at which that happens is a balance between what is necessary to confer the best chance of survival to each child, the number of children needed to outweigh the mortality rate, and the required mutation and crossover to adapt to the environment. Keeping the same individuals in circulation longer doesn't confer an advantage to their offspring since they already posses the same genes. It would more likely hinder the propagation of their genes by taking resources away from their progeny and competing for mates, territory, status, whatever.
- jakear 5y ago
  The balance point being to live to provide care to the grandchildren while the children are in the height of their career, then die off in order to free up resources?
- codeflo 5y ago
  That’s plausible, but there might be trade-offs involved. There’s a theory — not sure how serious it’s taken by experts — that at least some of the mechanisms involved in aging have other benefits. For example, the fact that telomeres limit the number of cell divisions might also be a defense against cancer. A mutation that increases lifespan at the cost of this mechanism could be a net negative, from an evolutionary point of view.
- jhales 5y ago
  It's also a factual error. There have been longevity genes discovered. Cynthia Kenyon famously doubled the lifespan of a C. Elegans by mutating daf-2: https://www.nature.com/articles/366461a0 https://www.nature.com/articles/366461a0
- pyrrhotech 5y ago
  Also simply because there is no selective pressure for a gene does not mean it does not exist through pure chance.
iandanforth 5y ago
There's an anecdote from AIDS research that I'm frequently reminded of. People started off not knowing what was causing symptoms, then they began to understand the virus, then they started to produce chemicals to attack HIV, prevent its spread, reduce it's harmful effects, until one day when results of a study of a cocktail of these drugs was released showing dramatic reduction in symptoms and increased survival rates. People in the audience when the results were presented had access to these drugs individually and went home and started taking the cocktail regime themselves. They got better. This was only the successful path, along the way innumerable theories were tried and refuted, chemicals produced which did nothing or caused harm, and hopes were raised and dashed over and over. Aging research is in the world before solid theory, before we understand the many causes, but chemicals are being developed and people are taking them. It might be that one of the proposed theories is right, and self-medicators will be the first to know. More likely though is that it will take years and billions of dollars in basic research to develop good theory and better drugs. Unlike HIV/AIDS there probably won't be a single cause and aging (by definition) doesn't impact a young, healthy, active population. In fact, we are so conditioned to accept aging as normal the fight for resources is the fight to convince funders that there is a problem worth addressing. It's a pretty big, and terrifying, mindset change to go from "death from old age is natural and to be accepted" to "death from old age is preventable and tragic."
- Someone 5y ago
  To kill something, you need to know one way to do that. To keep it alive, you need to avoid _all_ the ways of killing it. I think that is a strong argument for preventing aging being a much more difficult problem.
  - AuthorizedCust 5y ago
    Not really. It’s more of a “how do you eat an elephant” problem. Answer: one bite at a time. We’re doing that, even without the anti-aging label. E.g., things we now call “preventable deaths”. Even within that label, there’s a lot of opportunities that are far more tractable than others.
rubyskills 5y ago
Very interesting to get a sneak peak into this world. Over the past year I've been digging deep into research around similar topics but revolving around protocol first changes, with supplements as an optional add on. I had some crazy symptoms develop after realizing I wasn't sleeping enough / properly. Fixing my sleep hygiene and eating habits changed my life. I wonder if more research was dedicated to recovery if this would help the field progress faster as it seems to be the key to preventing and healing all of the major causes of death. If anyone is interested, I stumbled onto this research through professor Andrew Huberman on YouTube. Amazing, life changing stuff.
- swader999 5y ago
  Huberman is the real deal.
robwwilliams 5y ago
Yes, and the tight timelines of VC and high burn rate of startup funds motivates hype and self-delusion. Longevity research requires a 20–30 year time line even if you are using mice. But is there good news? Yes: the NIA Interventions Testing Program is an awesome, systematic, flexible, and rigorous effort to evaluate the impact of dietary supplements on lifespan. And the 10 year studies we have just completed on the genetics of lifespan and longevity in a highly diverse family of mice (the BXD family) provide very strong evidence of gene variants that modulate longevity well after reproductive senescence and under different environments. It is NOT a matter of selection for or against lifespan: it is just a result of high levels of genetic variation affecting all biochemical processes and disease risks. Genetic variants and gene-by-environmental interactions definitely are “in play”. These types of variants are actually inevitable. Want some references for the smoke-free and half-full part of the glass? 1. Hook et al PMC6066442: Genetic cartography of longevity in humans and mice: Current landscape and horizons. 2. Roy et al 2021 in Nature Metabolism: Gene-by-environment modulation of lifespan and weight gain in the murine BXD family; doi.org/10.1101/776559 3. Williams et al in Cell Systems 2021: Multiomic profiling of the liver across diets and ages in a diverse mouse population; doi.org/10.1101/2020.08.20.222968v2 All of the data from the last two paper is available as FAIR data at www.genenetwork.org. You are welcome to map the longevity loci yourself. Some of these loci operate only late in life—some even after two years of age—roughly equivalent to 60 years and older in humans. After your trauma at the meeting, read the papers above to know that solid verifiable progress is being made. And smell the ITP roses at www.nia.nih.gov/dab/interventions-testing-program-itp Rapamycin and acarbose definitely extend lifespan in highly diverse mice (a robust result) and so do several other dietary additives—at least five others at this point. Resveratrol, as you say, is a failure, and this is confirmed by well powered studies by the ITP.
- guzik 5y ago
  I think the correct link is www.nia.nih.gov/research/dab/interventions-testing-program-itp ?
  - robwwilliams 5y ago
    Thanks for correction.
dnautics 5y ago
there is a fundamental problem here. You can guess if some longevity biomarker has a causal effect; but in the end they are only guesses. Suppose your desired endpoint is a human lifespan of 150 years. And you start experimenting on 50 year-olds, now. You cannot truly know if your intervention will work for another 100 years. At best we can start doing interventions on shorter lifespan animals (say, dogs) but there's still no guarantee that the causal factors for dog death match up with those for humans.
- notahacker 5y ago
  Not to mention the fact that even if it works in removing some ageing factors, most of your cohort still probably ends up running into the sort of ailments that terminate most people's lives before the theoretical limit to their lifespan. And those other ailments represent challenging, but more easily testable medical problems to solve first
- D-Coder 5y ago
  This feels like saying that a five-year MTBF estimate for a disk drive is meaningless until it's been tested for five years. No, we don't truly know if the estimate is correct, but nothing in life is truly known: some level of evidence will be good enough.
  - nradov 5y ago
    Yes but what evidence? We don't have any biomarkers that can be measured to determine the longevity effect of a particular intervention. For example if a hypothetical medication reduces blood glucose level (good) but also reduces skeletal muscle mass (bad) will that have an overall positive or negative effect on longevity? Who knows? It's a complex multifactorial issue. Disc drives are much simpler. We have decades of data on failure rates.
    - dnautics 5y ago
      I would say that the simplicity has to do with the linear nature of most failure modes of disk drives. The overall failure curve is nonlinear due to compounding per time probabilities. But those probabilities are only nonlinear/cross-interacting at the point where the drive is already considered to be "a loss", and our engineering/maintenance strategies take advantage of this fact. We do not generally consider a human to be "a loss", if say, they start getting chronic back pain, which can start to precipitate other problems in a compounding fashion.
Andrew_nenakhov 5y ago
One should consider that breakthroughs in longevity research would be disastrous for humanity. The first to benefit from it will be the super rich, and various dictators. Economic inequality will rise, Stalins, Maos, Kim Ir Sens will rule without end. Death is a great equalizer, take it away and people would be split into two castes: immortal super rich, and their short-lived slaves.
- ridewinter 5y ago
  Just like smartphones are only for the super-rich? Technology becomes affordable to all over time. I for one cheer on the billionaires trying to extend their lives - it will benefit us all, and remove much disease & suffering from this planet.
  - Andrew_nenakhov 5y ago
    With smartphones, the super rich so not have the incentive to block everyone else from having them. Extreme pongevity is a whole different deal: those at the top do not want to be replaced, and what better way to do that by making it harder to get on their level? Also, take inheritance. Business shark accumulates a fortune, then leaves it to his less competent children, who waste it, giving others a chance. Imagine a world where sharks do not naturally die from old age and keep their fortunes in best shape over centuries?
    - sokoloff 5y ago
      Many (most?) of those original fortunes were amassed by giving large numbers of people small amounts of something they’d rather have than money. It’s not only that they’d keep their fortunes in shape (what you’re arguing is a negative), but that they’d have a longer period of time to create value (and capture some of it) in the world.
    - sorenn111 5y ago
      How you could stop the greed of someone wanting to sell those treatments to the mass market? I imagine Mark Cubin (or any other "shark" billionaire) would fucking love to be the first trillionaire or quadrillionaire by being the person who made accessible the treatments for aging. Cancer alone: the ego-boost and vast wealth for the person whose company/research helped "cure cancer" (hell, even just 1 type of cancer). these "sharks" would "chomp" at the opportunity I imagine.
dentalperson 5y ago
> The notion that somehow aging is “special” and therefore shouldn’t be regulated like “normal” diseases is not convincing. The same argument could be made about any number of other conditions. For example cancer – for years we’ve been told it’s not one disease but hundreds of diseases, and therefore we need to think about it differently. And yet, cancer medications including personalized therapies such as CAR-T seem perfectly capable of getting approved within the existing framework of the FDA. This seems to miss the main point about regulation that the longevity researchers face. Aging is not recognized as a disease by the FDA, so aging treatments are not allowed to have the same treatment and development pipeline. To 'be regulated like “normal” diseases' is in fact what many longevity companies would benefit from.
- JumpCrisscross 5y ago
  > Aging is not recognized as a disease by the FDA, so aging treatments are not allowed to have the same treatment and development pipeline This is valid but immaterial criticism. There are no treatments reaching their clinical endpoints in a rigorous way. The FDA isn’t blocking anything because nothing has made it to its level. That makes complaining about the FDA putting the cart before the horse at best and a red herring for certain personalities at worst.
- philipkglass 5y ago
  There's no need for the FDA to recognize aging itself as a disease to get a therapy through clinical trials. If you have a working aging-prevention or aging-reversal therapy, pick one of many age-associated diseases like arthritis or osteoporosis. Run a trial showing that it successfully and safely treats that specific condition. Once it's approved for any condition it can be approved off-label for other conditions by a willing physician.
deleted 5y ago
[deleted]
season2episode3 5y ago
It is my sincere hope that anti-aging treatments never become viable. Successful longevity research will only lead the world to resemble Elysium, with two tiers of society: ultra-wealthy immortals and the impoverished, mortal, and expendable masses. "Death by natural causes" (i.e., death linked to old age, as opposed to premature death due to murder, warfare, traumatic accidents, etc) deserves to be approached and treated with grace.
- sorenn111 5y ago
  "Death by natural causes" induced by age include alzheimers, cancer, heart disease, strokes, etc. natural causes are just diseases that medicine isn't great at truly treating, often those diseases are exacerbated by age. I don't want to imply you are pro-cancer (for older individuals), but what "natural cause" deaths are unworthy of attention in your opinion?
  - season2episode3 5y ago
    Hey sorry for the delay in getting back. It's obviously a difficult line to draw because terminal diseases, especially those of the painful/slow degenerative type, are tragic and I would never wish them on anyone. I also understand that it will be a bitter pill for me to swallow were I to develop a terminal illness, and approaching death in that way is no doubt a very difficult. To give you a specific sort of research that I feel is dangerous: preventing oxidative damage to telomeres (stopping one of the primary mechanisms of aging). Even though a breakthrough in that field will generate new therapies for schizophrenia and certain cancers, I believe that it will open a Pandora's box of externalities that, on balance, will outweigh the therapies. I'm thinking about this more on principle: death is important for society in the same way that fire is important for a forest (imperfect analogy, but bear with me). The passing of older generations creates opportunities and mobility for younger generations, as well as room for cultural change that adapts with the rapid pace of technological change. I think in many ways the world would be a far worse place today were there large numbers of 120+ year-old people still around, voting however they would vote. Having a lot of 120-year-olds around would be ecologically untenable too. In the original comment I refer to "grace", and by that I'm referring to the way that Randy Pausch or Morrie Schwartz describe their experiences with terminal disease. To them, death is an inevitability that highlights the value and sacredness of our short mortal lives. In the same way, I also really love the way how certain cultures treat funerals as celebrations of life rather than the somber sad traditions common in the West. Put simply, death is what makes life valuable.
GhettoComputers 5y ago
>genes only propagate if selected for, and there’s no selective pressure for longevity after reproductive age. Couldn’t older men who are still fertile have children that propagates these genes? Wouldn’t this also occur if someone doesn’t lose fertility and keeps having children? > The notion that somehow aging is “special” and therefore shouldn’t be regulated like “normal” diseases is not convincing. Is the fact that innovations have declined since more regulation convincing or making any research needing more barriers a good thing?
stanford_labrat 5y ago
Whenever a rejuvenation/life extension biotech post gets made here I always want to plug Rejuvenation Tech. They’re a YC company working in this space :)
the__alchemist 5y ago
I'm curious about the state of research on longevity for model organisms. Especially C-Elegans, or something else comparatively "simple" to a human. If we can't manipulate lifespan significantly in those, I don't see much hope for it in humans. Phrased a different way: I think extending flatworm lifespan is a prerequisite for extending human lifespan, at least in a systematic way. I'm not optimistic we'll have real breakthroughs in this field within the next century or so, but the gut reactions to the field (See the acerbic tone of the linked article) are born more out of a knee-jerk reaction to what longevity research implies, than a rational take. When the arguments go towards societal sustainability or "I wouldn't want to live any longer than 90", it's a cue you're reading a skin-deep reaction.
- uplifter 5y ago
  Experimenters have been able to extend the lifespan of C-Elegans five-fold by modifying just a few genes[0], though its unlikely that research will translate well to humans. Even interventions in much more closely related mouse models frequently fail to translate to us, but must biologists will agree with you that those organisms are the place to start. [0] https://www.buckinstitute.org/news/five-fold-lifespan-extension-in-c-elegans-by-combining-mutants/ https://www.buckinstitute.org/news/five-fold-lifespan-extens...
- coyotespike 5y ago
  Yes, good question! We have good results for c. elegans, mice, and fruit flies. These have all had their lifespans extended by quite a lot for c. elegans, or iirc about 40% for mice. This, and the existence of several multicellular organisms that do not appear to age, is the basis for optimism for eventual success in extending healthspan. Like, so far we haven't found any fundamental biological reason that living longer is impossible. (it is worth nothing that Blagosklonny's paradigm of programmed aging seems to me to lead to more pessimism, but I don't know if he'd agree) Matt Kaeberlein's Dog Project, and Celine Halioua's company Loyal, are both focused on extending dog lifespan, as a much larger model organism, but are not there yet. I also agree with your second paragraph :)
- _9omd 5y ago
  You might be interested in this paper, "A collective analysis of lifespan-extending compounds in diverse model organisms.[1]" Interestingly, common substances like aspirin and minocycline had a large impact on lifespan in the simple organisms studies. This seems to be due to a systemic impact on the organism's function and ability to heal from age related degeneration. https://pubmed.ncbi.nlm.nih.gov/34687363/ https://pubmed.ncbi.nlm.nih.gov/34687363/
narrator 5y ago
Banting and Best came up with the idea for synthetic insulin, tested it on themselves, tested it on animals, tested it on comatose diabetic children, developed and released a commercial product, and won the nobel prize in a span of 3 years back in the 1930s. Doing things on this kind of timeline now would be totally illegal and they would have lost their medical licenses and been thrown in jail no matter how well the whole thing worked. Longevity science overseas is embracing this no rules, we want the future now, kind of mentality. It's amazing what Bioviva has done with adult gene editing. It's probably some of the more underreported science news in modern history. I could see Bioviva getting shut down by the feds and gene editing for longevity going back to the realm of stuff we don't have anymore like the Concorde or a moon landing capable space program.
- refurb 5y ago
  Diabetes is a near term fatal condition if untreated. Dying of old age isn’t.
  - Robotbeat 5y ago
    Pretty sure dying of old age is a fatal condition if untreated. "Near term" being different depending on your age, but if you're 94 and male, you have a 3 year life expectancy, so pretty dang near term.
    - refurb 5y ago
      Near-term being key. And most longevity work involves early intervention. Convincing the FDA you need to dose a 5-year old with an experimental compound so they live until 100 instead of 90 isn't going to work.
      - solveit 5y ago
        Yes, but you can't convince the FDA to dose a 95-year old either.
        5y ago
GDC7 5y ago
It's no wonder that the field is populated by crackpots. They are trying to solve a problem nobody is worried about and nobody has ever been worried about in the history of the human specie. People who dedicate more than 5 minutes a day to the thought of living to 120 are the usual suspects: Bezos, Ellison, Thiel and so forth. A reputable industry cannot emerge if you can count the potential clients on one hand.
- meroes 5y ago
  Aubrey de Grey said in 2007 and earlier a lot of people alive then will live to be 1000. It's a very catchy thought, but so were Theranos's blood tests. It's almost the perfect scam, way better than Theranos's...investors will all be dead before he's proven wrong. (Cynical take)
  - Terry_Roll 5y ago
    Aubrey is going grey which would suggest to me if he is practising what he preaches, he's not mastered it yet. Maybe he needs to find out what this cancer drug is doing? https://www.theguardian.com/science/2017/jul/21/cancer-patients-grey-hair-unexpectedly-darkens-in-drug-study https://www.theguardian.com/science/2017/jul/21/cancer-patie... He also drinks alcohol, he likes a pint, so perhaps he doesn't know that alcohol dissolves fat soluble vitamins from the liver, which in excess can cause a vitamin A deficiency. What he has is he has done time like a prisoner at these things called university's which generally reward people for academic conformity, having a memory and being able to use logic to argue points when elephants in the room appear. I'm also remind big pharma sponsor uni's in a variety of legal but potentially ethically questionable ways. Now it should be noted that scientists have known a purified diet shortens life span, so arguably diets which restrict your ability to eat a varied diet, like a shake of sorts, could be doing you more harm, than eating top quality food products and then adding some supplements on top, whilst trying to not over eat. Anyway read what you like, this is just one of many amino acids and a right mix of opinion which sort of represents life and the medical experts in general. https://joshmitteldorf.scienceblog.com/2017/02/06/glycine-and-mitochondria https://joshmitteldorf.scienceblog.com/2017/02/06/glycine-an... https://raypeatforum.com/community/threads/aging-in-human-mitochondria-fully-reversed-by-glycine.6823/ https://raypeatforum.com/community/threads/aging-in-human-mi... https://novoslabs.com/novos-anti-aging-longevity-supplement/glycine-anti-aging-supplement-longevity/ https://novoslabs.com/novos-anti-aging-longevity-supplement/... https://pubmed.ncbi.nlm.nih.gov/29136945/ https://pubmed.ncbi.nlm.nih.gov/29136945/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002905/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002905/ There is loads to read up on Glycine too numerous to list here, and there are loads of mistakes in scientific studies which if you read enough you can start to spot. But I will also put this up. https://en.wikipedia.org/wiki/Angus_Barbieri%27s_fast https://en.wikipedia.org/wiki/Angus_Barbieri%27s_fast He had the world record for fasting, there used to be a movement in the 50's in the US called the Hygienists (Herbert Shelton) which was about water only fasting. Guinness make a good point about unsafe practices, you dont want to deplete your body of some things like Glutathione when fasting, which is something the Hygienists never considered and possibly didnt know back then either. http://loveandtruth.net/shelton-fasting.html http://loveandtruth.net/shelton-fasting.html Other factors with water only fasting and Ketogenic diets is Ketoacidosis, too many ketones and the liver cant handle the increase in acetone, you know nail polish remover! LOL This probably sums up our medical knowledge best, the graph in the top left of this link. https://pubmed.ncbi.nlm.nih.gov/?term=glycine&sort=date&ac=yes https://pubmed.ncbi.nlm.nih.gov/?term=glycine&sort=date&ac=y... An explosion of knowledge where perhaps AI and big data can spot things the existing experts have missed? Like where AI can spot the subconscious bias in judges presiding over parole board requests. Other points include, what is being taught is not always up to date, who sets the course work and writes the books and some knowledge being practiced is decades out of date and is likely contributing to worse outcomes. Supermarkets also control the health of the nation because they tell farmers what properties they want in the food they sell, so supermarkets could tell pig farmers, they dont want pigs with a couple of inches of back fat, so the pig farmer goes to the nutritionist, can you reduce back fat, and the nutritionist comes back with a pellet mix which will achieve that objective. Farmer is happy, he is only interested in meeting the supermarkets requirements. He also doesnt know if this pellet mix is affecting the nations health or not. So this lab grown meat will be interesting, it could end up "meating" the minimum legal standard to be called meat missing amino acids and other chemicals which can be found in the cheapest traditional reared meats, or it could become like a super meat containing everything we need that we can contribute to rude health if supermarkets didnt have profit margins to meat. Anyway a contentious subject none the less and a very complex one.
maxander 5y ago
I've been interested in this field long enough that I'm still plenty happy with the fact we now have a longevity biotech field, despite it's issues. :) I agree with the author that longevity biotech is frequently tripping over itself with enthusiasm to bring interventions to market (or some variety of off-label use) well before they're on solid scientific ground. You don't see this in, e.g., cancer research- if a novel kind of anti-cancer drug tests well in mice, you (almost) never see a sudden cottage industry pop up around it the next week. Obviously part of the difference is that most of us aren't expecting to suffer from cancer in the immediate future, whereas everyone expects to age; aging research faces a lot of weird psychological pressures that most industries do not. For all that, though, there are a lot of parts where I think this article is too skeptical. As someone who uses machine learning in (non-aging-related) biotech, the discussion of "garbage-in/garbage-out" put me in mind of "Yes We Have Noticed the Skulls" [0]; we're well aware that data quality coming out of molecular biology is a problem, and anyone working in the field could give you a long list of the kinds of biases, distortions, and gaps that are known to occur in their areas of interest [1]. Not all of the grand claims made about biotech AI/ML are taking this expertise into account, certainly, but certainly many of them are. [0] https://slatestarcodex.com/2017/04/07/yes-we-have-noticed-the-skulls/ https://slatestarcodex.com/2017/04/07/yes-we-have-noticed-th... [1] The list, regardless of what variety of data it applies to, would always end with "sometimes something unknown happened and the data just turned out bad, oh well."
nradov 5y ago
Most longevity biotech companies are following a completely wrong course. At best they might develop some compounds which provide marginal lifespan gains for a subset of people along with negative side effects. The most effective way to actually increase longevity is by delaying the onset of chronic diseases such as hypertension, diabetes, sarcopenia, and arteriosclerosis. If you look at people who actually live past 100 they don't live any longer than others once they have chronic disease. Instead they experience disease onset later in life. And we actually already know how to delay most chronic diseases fairly well. However the interventions aren't consistently applied and patient compliance is often poor.
- steve76 5y ago
  Not prevent, but also deal with the side effects. We just cut out a hog's kidney, grafted it to a guy's leg, and ran gene editing through an IV, and it transplanted. They're gearing up to do heart. Then it's heart/lung, then liver. then likely neural. Level them all. Take all their money, and full speed ahead on that.
- coyotespike 5y ago
  I respectfully disagree - many diseases are diseases of aging, in that they appear only when someone has aged significantly. A drug that increased healthspan would thus treat multiple diseases at once. And in fact, since we still do not have reliable aging clocks - in other words, a good way to tell if a drug has made you younger - one way to assess whether a drug may be treating aging at its root is to see if it is treating multiple diseases at once. A drug that improved outcomes for multiple diseases might turn out to be an anti-aging drug, is the idea (of course, there is no such drug yet!). Anyway, the logic is that instead of delaying multiple chronic diseases separately, we go after aging, which should have that effect anyway (for many people, and for many diseases, but certainly not all).
  - nradov 5y ago
    That's just silly. You're basically talking about a magic drug which doesn't exist even in concept form. It's the equivalent of wishing for cheap fusion power or room temperature superconductors or warp drives. Instead of scifi fantasies, how about working towards something actually achievable?
ummonk 5y ago
> and most notably the opening lecture from Charles Brenner had a great take-down on all of the reasons why longevity genes are unlikely to exist (TL/DR – genes only propagate if selected for, and there’s no selective pressure for longevity after reproductive age). I mean, we don’t just drop dead the minute we pass reproductive age. One would expect there to be genes that affect aging (including past reproductive age), either due to different environments creating different selective pressures or just genetic drift or genes with an adaptive function for reproductive life having a side effect for post-reproductive life. Consider particularly that women have a shorter reproductive window than men, but live longer on average.
dalke 5y ago
I find it interesting to read old publications. It gives a sense of what arguments are new and what are re-treads. Here's an essay from Eugene Garfield from 1983 titled "The dilemma of prolongevity research -- Must we age before we die, or if we don't, will we?" at http://www.garfield.library.upenn.edu/essays/v6p107y1983.pdf http://www.garfield.library.upenn.edu/essays/v6p107y1983.pdf > Medicine men and magicians, alchemists, sages, and physicians have searched for ways to ward off the effects of aging. But to date, scientists and their predecessors alike have been rebuffed. ... > Why has the problem of aging been such an intractable one? Up until recently, the prevalent view of scientists had been that the task of controlling aging was fundamentally impossible. But today, such a consensus no longer exists. Many researchers now believe that their predecessors failed, not because their goals were misguided, but because the tools and the level of sophistication they could bring to the task were inadequate. Moreover, it is argued that progress has been hampered because funding has been scarce, and researchers concerned with aging have been too few and far between. > Indeed, until recently, aging research had been plagued by all of these problems. During most of the first half of the twentieth century, while rapid progress was being made in other areas of biomedicine, only a handful of scientists throughout the world were doing aging research. One of these pioneers was Nathan Shock, who, according to Paul D. Phillips, Wistar Institute, Philadelphia, is considered by many to be one of the “fathers” of modern gerontology. > Growing public and private support for aging research reflects the scientific community’s own increasing commitment. Today, aging research occupies unprecedented numbers of highly talented individuals, not only specialists in gerontology, but researchers from other disciplines as well. These include biochemistry, endocrinology, immunology, neurobiology, genetics, and cell biology, to name only a few. Garfield then lists a number of books advocating longevity research (Ettinger's 1962 "The Prospect of Immortality"; Barrington's 1969 "The Immortalist" ; Comfort's 1964 "The Process of Ageing"; Rosenfeld's 1983 "Prolongevity"), praises the increase in federal funding in longevity research, mentions private sector organizations funding aging research (The American Longevity Association; The American Federation for Aging Research) and lists similar organizations in different countries. He then writes for a few pages more about the current status of longevity research in 1983, written for a technical but non-specialist audience. With an additional 40 years of research, what progress has the field made? I don't know - I claim not even the basic of expertise in the area. But what I can say is that certain arguments sound hollow after being repeated for decades with seemingly limited success.
Guest34988 5y ago
Here is one of the most cited papers in the aging field, published in Cell: https://www.sciencedirect.com/science/article/pii/S0092867413006454 https://www.sciencedirect.com/science/article/pii/S009286741... from OP's article: "..so far it’s all just pre-clinical testing or Phase I trials at the very most." Well, here is a map of the clinical trials corresponding to those hallmarks of aging, many of which are in Phase I and beyond: https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/ https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/
coyotespike 5y ago
I regret that this is not a very good article. For context, I'm not a biologist, but have joined On Deck Longevity Biotech - maybe half the people have biology PhDs, and everyone is interested in (obviously) longevity biotech. Yes, there is more money than ever before flowing into biotech in general, including longevity. Why? For one thing, just a few years ago, people like Aubrey de Grey had successfully branded the field as fit only for crackpots and mediocrities (to be fair, some good people got into the field through de Grey's work, but I am not a fan). Now longevity (or anti-aging, or whatever you want to call it) has attracted many very legitimate researchers, in part thanks to Laura Deming. However, the field is worried about an "AI winter" - there's awareness that someone or other needs to deliver a working drug in the next decade or so to avoid investor flight. Here's where I don't get the article's critique: the author lists many new companies, none of which have yet delivered a working anti-aging drug. Sure - but why is that a problem? Scientists and investors alike are well aware this is a new and speculative field. No one legitimate is promising a working drug. They are promising research, which is normal in biotech (big pharma has largely outsourced research to biotech startups). What is worth debating is the time horizon. These companies are indeed formed on the belief that there's a reasonable chance of a working drug in the next decade or two. If that pans out, of course it will change the culture at large, make billions, and the field will explode. If there's no such reasonable chance, then yes many of these companies shouldn't exist. I was very pessimistic about the chances until I read more of the science, and now I am more optimistic that in a few decades we may see a drug that extends healthspan by say 5 years. Finally, I will note that "90% of anything is crap" and there are many useless and scammy companies and "researchers" in the field. Just don't throw the baby out with the bathwater.
- dorfsmay 5y ago
  I'm not in that field at all but Aubrey de Grey keep saying that since they try to solve or slow down illnesses of old ages,the worse that can happen is that if they fail at curing aging they'll have at least reduced the impact of some illnesses.
- arc-in-space 5y ago
  Agreed, article seems to be of the "vaguely rambling against everything" genre, and of little substance. For instance, what is the paragraph mentioning Aducanumab and ivermectin even trying to say?
mrRA 5y ago
I agree with this claim. After years of hoping a “good” bio company to invest in longevity I finally have hope again. Without shilling here, but if you like thinking and discussing longevity in a decentralized autonomous organization (DAO) manner, a web 3.0 organization, than surely check out vita dao (search on google or twitter). This is not a financial advice or what so ever, dyor for always.
phkahler 5y ago
>> genes only propagate if selected for, and there’s no selective pressure for longevity after reproductive age Because humans are not social animals? Because protecting your own offspring as long as possible is NOT a thing? Everything with even slight benefit is selected for to a degree based on that benefit. Having parents is beneficial. Having grand parents is probably also useful. Having great grandparents... well someone has to get eaten by that lion.
paulcole 5y ago
I often hear people smugly tsk-tsk’ing those who buy lottery tickets as not understanding math. The anti-aging, longevity crew isn’t much different to me. Except I’m hopeful that most of the money wasted on this nonsense is coming from wishful billionaires and rich people.
goopthink 5y ago
YMMV, but a significant amount of real-world and statistically significant contributions can be made to average human longevity by focusing on paths of least resistance, such as tackling gun and car related deaths, then on the individual+average longevity by looking at preventable-but-chronic conditions (such as diabetes) by regulating things like common pollutants, added sugars to foods, and having better access to the outdoors and exercise/activity. Then you can enjoy a long life that will - on average - be healthy and long enough and with decreased risk of dying early. Past that, a lot of the research feels like “solutionism”.
ncmncm 5y ago
The only very good news I have encountered lately came out in April, where a cohort of tens of thousands of US Veterans Administration patients were found to suffer 40% less incidence of dementia if they had got a recent Tdap booster. Nobody knows what was in the booster that made the difference, but it is very hard for a confounder to produce a 40% effect size. (I doubt aspirin would get such an effect size.) A Tdap is safe, and I don't need to know why it helps, only that it (apparently) does, so I went right out to the drug store and got one. I expect at least some of the billionaires are getting transfusions of blood extracted from infants. Which infants, I hate to imagine.
LeanderK 5y ago
Naive Idea, but some mechanisms, like the testosterone-level in males, change with age. Why can't we, as a first step, just try to keep the levels fixed where we have a "reference level"?

187 points by deegles 5y ago

Interesting post! Small comment on the argument against anti-aging genes existing: "genes only propagate if selected for, and there’s no selective pressure for longevity after reproductive age" (I know that this was just a very minor aside, but I still think it's worth pointing out the flaw.) That's not how evolution works. Even after you have reproduced, you have impact on whether your children survive and reproduce. This means that there could very reasonably be evolutionary pressure in either direction (causing people to die younger that way they stop taking resources from their children or causing people to live longer that way they keep providing support for their children).

HPsquared 5y ago
This idea is called group selection [0]. Edit: perhaps kin selection [1] is the more appropriate one here. Still, longevity would affect the group and not only the direct kin. [0] https://en.m.wikipedia.org/wiki/Group_selection https://en.m.wikipedia.org/wiki/Group_selection [1] https://en.m.wikipedia.org/wiki/Kin_selection https://en.m.wikipedia.org/wiki/Kin_selection
- syllogism 5y ago
  More like kin selection: https://en.wikipedia.org/wiki/Kin_selection https://en.wikipedia.org/wiki/Kin_selection
skybrian 5y ago
Effect size is hardly ever zero and surprisingly small effect sizes can be measured. But is this evolutionary pressure large enough to make a difference for a longevity gene when people already live quite long after having children?
- pharke 5y ago
  I think the idea is that there aren't "longevity" genes only aging genes. Put another way, aging isn't an accident caused by the accumulation of damage. It's a selected for trait, a sort of slow, whole body apoptosis used to get rid of the soma once it's served it's purpose. Lifespan is simply the well timed removal of a generation once it has had the opportunity to reproduce and raise its brood.
  - robwwilliams 5y ago
    Perfect! And reproductive longevity is strongly selected. Mole rats and bats, despite small bodies and quite high metabolic rates live far longer than might be expected from simple allometric relations. Reproductive lifestyles can evolve by bootstrapping on large numbers of DNA variants that modulate and molecular-cellular systems.
  - codeflo 5y ago
    I’m not sure I buy that completely. If this were a neutral choice, why would a gene take the 50% chance of not having made it to the next generation? (Or in the case of many offspring, invest half its resources into a different copy of the gene?) At least in mammals, killing the soma is on the surface such a massive waste of resources that I believe it must be either: (a) biologically implausible to keep an animal reproducing for a longer timespan or (b) caused by mechanisms that are counterweighted by massive reproductive benefits while the animal is young.
    - pharke 5y ago
      > killing the soma is on the surface such a massive waste of resources How is it a waste of resources? Evolutionarily, the goal is to produce another successful generation who then begets another generation and so on. The rate at which that happens is a balance between what is necessary to confer the best chance of survival to each child, the number of children needed to outweigh the mortality rate, and the required mutation and crossover to adapt to the environment. Keeping the same individuals in circulation longer doesn't confer an advantage to their offspring since they already posses the same genes. It would more likely hinder the propagation of their genes by taking resources away from their progeny and competing for mates, territory, status, whatever.
jakear 5y ago
The balance point being to live to provide care to the grandchildren while the children are in the height of their career, then die off in order to free up resources?
codeflo 5y ago
That’s plausible, but there might be trade-offs involved. There’s a theory — not sure how serious it’s taken by experts — that at least some of the mechanisms involved in aging have other benefits. For example, the fact that telomeres limit the number of cell divisions might also be a defense against cancer. A mutation that increases lifespan at the cost of this mechanism could be a net negative, from an evolutionary point of view.
jhales 5y ago
It's also a factual error. There have been longevity genes discovered. Cynthia Kenyon famously doubled the lifespan of a C. Elegans by mutating daf-2: https://www.nature.com/articles/366461a0 https://www.nature.com/articles/366461a0
pyrrhotech 5y ago
Also simply because there is no selective pressure for a gene does not mean it does not exist through pure chance.

iandanforth 5y ago

There's an anecdote from AIDS research that I'm frequently reminded of. People started off not knowing what was causing symptoms, then they began to understand the virus, then they started to produce chemicals to attack HIV, prevent its spread, reduce it's harmful effects, until one day when results of a study of a cocktail of these drugs was released showing dramatic reduction in symptoms and increased survival rates. People in the audience when the results were presented had access to these drugs individually and went home and started taking the cocktail regime themselves. They got better. This was only the successful path, along the way innumerable theories were tried and refuted, chemicals produced which did nothing or caused harm, and hopes were raised and dashed over and over. Aging research is in the world before solid theory, before we understand the many causes, but chemicals are being developed and people are taking them. It might be that one of the proposed theories is right, and self-medicators will be the first to know. More likely though is that it will take years and billions of dollars in basic research to develop good theory and better drugs. Unlike HIV/AIDS there probably won't be a single cause and aging (by definition) doesn't impact a young, healthy, active population. In fact, we are so conditioned to accept aging as normal the fight for resources is the fight to convince funders that there is a problem worth addressing. It's a pretty big, and terrifying, mindset change to go from "death from old age is natural and to be accepted" to "death from old age is preventable and tragic."

Someone 5y ago
To kill something, you need to know one way to do that. To keep it alive, you need to avoid _all_ the ways of killing it. I think that is a strong argument for preventing aging being a much more difficult problem.
- AuthorizedCust 5y ago
  Not really. It’s more of a “how do you eat an elephant” problem. Answer: one bite at a time. We’re doing that, even without the anti-aging label. E.g., things we now call “preventable deaths”. Even within that label, there’s a lot of opportunities that are far more tractable than others.

rubyskills 5y ago

Very interesting to get a sneak peak into this world. Over the past year I've been digging deep into research around similar topics but revolving around protocol first changes, with supplements as an optional add on. I had some crazy symptoms develop after realizing I wasn't sleeping enough / properly. Fixing my sleep hygiene and eating habits changed my life. I wonder if more research was dedicated to recovery if this would help the field progress faster as it seems to be the key to preventing and healing all of the major causes of death. If anyone is interested, I stumbled onto this research through professor Andrew Huberman on YouTube. Amazing, life changing stuff.

swader999 5y ago
Huberman is the real deal.

robwwilliams 5y ago

Yes, and the tight timelines of VC and high burn rate of startup funds motivates hype and self-delusion. Longevity research requires a 20–30 year time line even if you are using mice. But is there good news? Yes: the NIA Interventions Testing Program is an awesome, systematic, flexible, and rigorous effort to evaluate the impact of dietary supplements on lifespan. And the 10 year studies we have just completed on the genetics of lifespan and longevity in a highly diverse family of mice (the BXD family) provide very strong evidence of gene variants that modulate longevity well after reproductive senescence and under different environments. It is NOT a matter of selection for or against lifespan: it is just a result of high levels of genetic variation affecting all biochemical processes and disease risks. Genetic variants and gene-by-environmental interactions definitely are “in play”. These types of variants are actually inevitable. Want some references for the smoke-free and half-full part of the glass? 1. Hook et al PMC6066442: Genetic cartography of longevity in humans and mice: Current landscape and horizons. 2. Roy et al 2021 in Nature Metabolism: Gene-by-environment modulation of lifespan and weight gain in the murine BXD family; doi.org/10.1101/776559 3. Williams et al in Cell Systems 2021: Multiomic profiling of the liver across diets and ages in a diverse mouse population; doi.org/10.1101/2020.08.20.222968v2 All of the data from the last two paper is available as FAIR data at www.genenetwork.org. You are welcome to map the longevity loci yourself. Some of these loci operate only late in life—some even after two years of age—roughly equivalent to 60 years and older in humans. After your trauma at the meeting, read the papers above to know that solid verifiable progress is being made. And smell the ITP roses at www.nia.nih.gov/dab/interventions-testing-program-itp Rapamycin and acarbose definitely extend lifespan in highly diverse mice (a robust result) and so do several other dietary additives—at least five others at this point. Resveratrol, as you say, is a failure, and this is confirmed by well powered studies by the ITP.

guzik 5y ago
I think the correct link is www.nia.nih.gov/research/dab/interventions-testing-program-itp ?
- robwwilliams 5y ago
  Thanks for correction.

dnautics 5y ago

there is a fundamental problem here. You can guess if some longevity biomarker has a causal effect; but in the end they are only guesses. Suppose your desired endpoint is a human lifespan of 150 years. And you start experimenting on 50 year-olds, now. You cannot truly know if your intervention will work for another 100 years. At best we can start doing interventions on shorter lifespan animals (say, dogs) but there's still no guarantee that the causal factors for dog death match up with those for humans.

notahacker 5y ago
Not to mention the fact that even if it works in removing some ageing factors, most of your cohort still probably ends up running into the sort of ailments that terminate most people's lives before the theoretical limit to their lifespan. And those other ailments represent challenging, but more easily testable medical problems to solve first
D-Coder 5y ago
This feels like saying that a five-year MTBF estimate for a disk drive is meaningless until it's been tested for five years. No, we don't truly know if the estimate is correct, but nothing in life is truly known: some level of evidence will be good enough.
- nradov 5y ago
  Yes but what evidence? We don't have any biomarkers that can be measured to determine the longevity effect of a particular intervention. For example if a hypothetical medication reduces blood glucose level (good) but also reduces skeletal muscle mass (bad) will that have an overall positive or negative effect on longevity? Who knows? It's a complex multifactorial issue. Disc drives are much simpler. We have decades of data on failure rates.
  - dnautics 5y ago
    I would say that the simplicity has to do with the linear nature of most failure modes of disk drives. The overall failure curve is nonlinear due to compounding per time probabilities. But those probabilities are only nonlinear/cross-interacting at the point where the drive is already considered to be "a loss", and our engineering/maintenance strategies take advantage of this fact. We do not generally consider a human to be "a loss", if say, they start getting chronic back pain, which can start to precipitate other problems in a compounding fashion.

Andrew_nenakhov 5y ago

One should consider that breakthroughs in longevity research would be disastrous for humanity. The first to benefit from it will be the super rich, and various dictators. Economic inequality will rise, Stalins, Maos, Kim Ir Sens will rule without end. Death is a great equalizer, take it away and people would be split into two castes: immortal super rich, and their short-lived slaves.

ridewinter 5y ago
Just like smartphones are only for the super-rich? Technology becomes affordable to all over time. I for one cheer on the billionaires trying to extend their lives - it will benefit us all, and remove much disease & suffering from this planet.
- Andrew_nenakhov 5y ago
  With smartphones, the super rich so not have the incentive to block everyone else from having them. Extreme pongevity is a whole different deal: those at the top do not want to be replaced, and what better way to do that by making it harder to get on their level? Also, take inheritance. Business shark accumulates a fortune, then leaves it to his less competent children, who waste it, giving others a chance. Imagine a world where sharks do not naturally die from old age and keep their fortunes in best shape over centuries?
  - sokoloff 5y ago
    Many (most?) of those original fortunes were amassed by giving large numbers of people small amounts of something they’d rather have than money. It’s not only that they’d keep their fortunes in shape (what you’re arguing is a negative), but that they’d have a longer period of time to create value (and capture some of it) in the world.
  - sorenn111 5y ago
    How you could stop the greed of someone wanting to sell those treatments to the mass market? I imagine Mark Cubin (or any other "shark" billionaire) would fucking love to be the first trillionaire or quadrillionaire by being the person who made accessible the treatments for aging. Cancer alone: the ego-boost and vast wealth for the person whose company/research helped "cure cancer" (hell, even just 1 type of cancer). these "sharks" would "chomp" at the opportunity I imagine.

dentalperson 5y ago

> The notion that somehow aging is “special” and therefore shouldn’t be regulated like “normal” diseases is not convincing. The same argument could be made about any number of other conditions. For example cancer – for years we’ve been told it’s not one disease but hundreds of diseases, and therefore we need to think about it differently. And yet, cancer medications including personalized therapies such as CAR-T seem perfectly capable of getting approved within the existing framework of the FDA. This seems to miss the main point about regulation that the longevity researchers face. Aging is not recognized as a disease by the FDA, so aging treatments are not allowed to have the same treatment and development pipeline. To 'be regulated like “normal” diseases' is in fact what many longevity companies would benefit from.

JumpCrisscross 5y ago
> Aging is not recognized as a disease by the FDA, so aging treatments are not allowed to have the same treatment and development pipeline This is valid but immaterial criticism. There are no treatments reaching their clinical endpoints in a rigorous way. The FDA isn’t blocking anything because nothing has made it to its level. That makes complaining about the FDA putting the cart before the horse at best and a red herring for certain personalities at worst.
philipkglass 5y ago
There's no need for the FDA to recognize aging itself as a disease to get a therapy through clinical trials. If you have a working aging-prevention or aging-reversal therapy, pick one of many age-associated diseases like arthritis or osteoporosis. Run a trial showing that it successfully and safely treats that specific condition. Once it's approved for any condition it can be approved off-label for other conditions by a willing physician.

deleted 5y ago

[deleted]

season2episode3 5y ago

It is my sincere hope that anti-aging treatments never become viable. Successful longevity research will only lead the world to resemble Elysium, with two tiers of society: ultra-wealthy immortals and the impoverished, mortal, and expendable masses. "Death by natural causes" (i.e., death linked to old age, as opposed to premature death due to murder, warfare, traumatic accidents, etc) deserves to be approached and treated with grace.

sorenn111 5y ago
"Death by natural causes" induced by age include alzheimers, cancer, heart disease, strokes, etc. natural causes are just diseases that medicine isn't great at truly treating, often those diseases are exacerbated by age. I don't want to imply you are pro-cancer (for older individuals), but what "natural cause" deaths are unworthy of attention in your opinion?
- season2episode3 5y ago
  Hey sorry for the delay in getting back. It's obviously a difficult line to draw because terminal diseases, especially those of the painful/slow degenerative type, are tragic and I would never wish them on anyone. I also understand that it will be a bitter pill for me to swallow were I to develop a terminal illness, and approaching death in that way is no doubt a very difficult. To give you a specific sort of research that I feel is dangerous: preventing oxidative damage to telomeres (stopping one of the primary mechanisms of aging). Even though a breakthrough in that field will generate new therapies for schizophrenia and certain cancers, I believe that it will open a Pandora's box of externalities that, on balance, will outweigh the therapies. I'm thinking about this more on principle: death is important for society in the same way that fire is important for a forest (imperfect analogy, but bear with me). The passing of older generations creates opportunities and mobility for younger generations, as well as room for cultural change that adapts with the rapid pace of technological change. I think in many ways the world would be a far worse place today were there large numbers of 120+ year-old people still around, voting however they would vote. Having a lot of 120-year-olds around would be ecologically untenable too. In the original comment I refer to "grace", and by that I'm referring to the way that Randy Pausch or Morrie Schwartz describe their experiences with terminal disease. To them, death is an inevitability that highlights the value and sacredness of our short mortal lives. In the same way, I also really love the way how certain cultures treat funerals as celebrations of life rather than the somber sad traditions common in the West. Put simply, death is what makes life valuable.

GhettoComputers 5y ago

>genes only propagate if selected for, and there’s no selective pressure for longevity after reproductive age. Couldn’t older men who are still fertile have children that propagates these genes? Wouldn’t this also occur if someone doesn’t lose fertility and keeps having children? > The notion that somehow aging is “special” and therefore shouldn’t be regulated like “normal” diseases is not convincing. Is the fact that innovations have declined since more regulation convincing or making any research needing more barriers a good thing?

stanford_labrat 5y ago

Whenever a rejuvenation/life extension biotech post gets made here I always want to plug Rejuvenation Tech. They’re a YC company working in this space :)

the__alchemist 5y ago

I'm curious about the state of research on longevity for model organisms. Especially C-Elegans, or something else comparatively "simple" to a human. If we can't manipulate lifespan significantly in those, I don't see much hope for it in humans. Phrased a different way: I think extending flatworm lifespan is a prerequisite for extending human lifespan, at least in a systematic way. I'm not optimistic we'll have real breakthroughs in this field within the next century or so, but the gut reactions to the field (See the acerbic tone of the linked article) are born more out of a knee-jerk reaction to what longevity research implies, than a rational take. When the arguments go towards societal sustainability or "I wouldn't want to live any longer than 90", it's a cue you're reading a skin-deep reaction.

uplifter 5y ago
Experimenters have been able to extend the lifespan of C-Elegans five-fold by modifying just a few genes[0], though its unlikely that research will translate well to humans. Even interventions in much more closely related mouse models frequently fail to translate to us, but must biologists will agree with you that those organisms are the place to start. [0] https://www.buckinstitute.org/news/five-fold-lifespan-extension-in-c-elegans-by-combining-mutants/ https://www.buckinstitute.org/news/five-fold-lifespan-extens...
coyotespike 5y ago
Yes, good question! We have good results for c. elegans, mice, and fruit flies. These have all had their lifespans extended by quite a lot for c. elegans, or iirc about 40% for mice. This, and the existence of several multicellular organisms that do not appear to age, is the basis for optimism for eventual success in extending healthspan. Like, so far we haven't found any fundamental biological reason that living longer is impossible. (it is worth nothing that Blagosklonny's paradigm of programmed aging seems to me to lead to more pessimism, but I don't know if he'd agree) Matt Kaeberlein's Dog Project, and Celine Halioua's company Loyal, are both focused on extending dog lifespan, as a much larger model organism, but are not there yet. I also agree with your second paragraph :)
_9omd 5y ago
You might be interested in this paper, "A collective analysis of lifespan-extending compounds in diverse model organisms.[1]" Interestingly, common substances like aspirin and minocycline had a large impact on lifespan in the simple organisms studies. This seems to be due to a systemic impact on the organism's function and ability to heal from age related degeneration. https://pubmed.ncbi.nlm.nih.gov/34687363/ https://pubmed.ncbi.nlm.nih.gov/34687363/

narrator 5y ago

Banting and Best came up with the idea for synthetic insulin, tested it on themselves, tested it on animals, tested it on comatose diabetic children, developed and released a commercial product, and won the nobel prize in a span of 3 years back in the 1930s. Doing things on this kind of timeline now would be totally illegal and they would have lost their medical licenses and been thrown in jail no matter how well the whole thing worked. Longevity science overseas is embracing this no rules, we want the future now, kind of mentality. It's amazing what Bioviva has done with adult gene editing. It's probably some of the more underreported science news in modern history. I could see Bioviva getting shut down by the feds and gene editing for longevity going back to the realm of stuff we don't have anymore like the Concorde or a moon landing capable space program.

refurb 5y ago
Diabetes is a near term fatal condition if untreated. Dying of old age isn’t.
- Robotbeat 5y ago
  Pretty sure dying of old age is a fatal condition if untreated. "Near term" being different depending on your age, but if you're 94 and male, you have a 3 year life expectancy, so pretty dang near term.
  - refurb 5y ago
    Near-term being key. And most longevity work involves early intervention. Convincing the FDA you need to dose a 5-year old with an experimental compound so they live until 100 instead of 90 isn't going to work.
    - solveit 5y ago
      Yes, but you can't convince the FDA to dose a 95-year old either.
      - 5y ago

GDC7 5y ago

It's no wonder that the field is populated by crackpots. They are trying to solve a problem nobody is worried about and nobody has ever been worried about in the history of the human specie. People who dedicate more than 5 minutes a day to the thought of living to 120 are the usual suspects: Bezos, Ellison, Thiel and so forth. A reputable industry cannot emerge if you can count the potential clients on one hand.

meroes 5y ago
Aubrey de Grey said in 2007 and earlier a lot of people alive then will live to be 1000. It's a very catchy thought, but so were Theranos's blood tests. It's almost the perfect scam, way better than Theranos's...investors will all be dead before he's proven wrong. (Cynical take)
- Terry_Roll 5y ago
  Aubrey is going grey which would suggest to me if he is practising what he preaches, he's not mastered it yet. Maybe he needs to find out what this cancer drug is doing? https://www.theguardian.com/science/2017/jul/21/cancer-patients-grey-hair-unexpectedly-darkens-in-drug-study https://www.theguardian.com/science/2017/jul/21/cancer-patie... He also drinks alcohol, he likes a pint, so perhaps he doesn't know that alcohol dissolves fat soluble vitamins from the liver, which in excess can cause a vitamin A deficiency. What he has is he has done time like a prisoner at these things called university's which generally reward people for academic conformity, having a memory and being able to use logic to argue points when elephants in the room appear. I'm also remind big pharma sponsor uni's in a variety of legal but potentially ethically questionable ways. Now it should be noted that scientists have known a purified diet shortens life span, so arguably diets which restrict your ability to eat a varied diet, like a shake of sorts, could be doing you more harm, than eating top quality food products and then adding some supplements on top, whilst trying to not over eat. Anyway read what you like, this is just one of many amino acids and a right mix of opinion which sort of represents life and the medical experts in general. https://joshmitteldorf.scienceblog.com/2017/02/06/glycine-and-mitochondria https://joshmitteldorf.scienceblog.com/2017/02/06/glycine-an... https://raypeatforum.com/community/threads/aging-in-human-mitochondria-fully-reversed-by-glycine.6823/ https://raypeatforum.com/community/threads/aging-in-human-mi... https://novoslabs.com/novos-anti-aging-longevity-supplement/glycine-anti-aging-supplement-longevity/ https://novoslabs.com/novos-anti-aging-longevity-supplement/... https://pubmed.ncbi.nlm.nih.gov/29136945/ https://pubmed.ncbi.nlm.nih.gov/29136945/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002905/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002905/ There is loads to read up on Glycine too numerous to list here, and there are loads of mistakes in scientific studies which if you read enough you can start to spot. But I will also put this up. https://en.wikipedia.org/wiki/Angus_Barbieri%27s_fast https://en.wikipedia.org/wiki/Angus_Barbieri%27s_fast He had the world record for fasting, there used to be a movement in the 50's in the US called the Hygienists (Herbert Shelton) which was about water only fasting. Guinness make a good point about unsafe practices, you dont want to deplete your body of some things like Glutathione when fasting, which is something the Hygienists never considered and possibly didnt know back then either. http://loveandtruth.net/shelton-fasting.html http://loveandtruth.net/shelton-fasting.html Other factors with water only fasting and Ketogenic diets is Ketoacidosis, too many ketones and the liver cant handle the increase in acetone, you know nail polish remover! LOL This probably sums up our medical knowledge best, the graph in the top left of this link. https://pubmed.ncbi.nlm.nih.gov/?term=glycine&sort=date&ac=yes https://pubmed.ncbi.nlm.nih.gov/?term=glycine&sort=date&ac=y... An explosion of knowledge where perhaps AI and big data can spot things the existing experts have missed? Like where AI can spot the subconscious bias in judges presiding over parole board requests. Other points include, what is being taught is not always up to date, who sets the course work and writes the books and some knowledge being practiced is decades out of date and is likely contributing to worse outcomes. Supermarkets also control the health of the nation because they tell farmers what properties they want in the food they sell, so supermarkets could tell pig farmers, they dont want pigs with a couple of inches of back fat, so the pig farmer goes to the nutritionist, can you reduce back fat, and the nutritionist comes back with a pellet mix which will achieve that objective. Farmer is happy, he is only interested in meeting the supermarkets requirements. He also doesnt know if this pellet mix is affecting the nations health or not. So this lab grown meat will be interesting, it could end up "meating" the minimum legal standard to be called meat missing amino acids and other chemicals which can be found in the cheapest traditional reared meats, or it could become like a super meat containing everything we need that we can contribute to rude health if supermarkets didnt have profit margins to meat. Anyway a contentious subject none the less and a very complex one.

maxander 5y ago

I've been interested in this field long enough that I'm still plenty happy with the fact we now have a longevity biotech field, despite it's issues. :) I agree with the author that longevity biotech is frequently tripping over itself with enthusiasm to bring interventions to market (or some variety of off-label use) well before they're on solid scientific ground. You don't see this in, e.g., cancer research- if a novel kind of anti-cancer drug tests well in mice, you (almost) never see a sudden cottage industry pop up around it the next week. Obviously part of the difference is that most of us aren't expecting to suffer from cancer in the immediate future, whereas everyone expects to age; aging research faces a lot of weird psychological pressures that most industries do not. For all that, though, there are a lot of parts where I think this article is too skeptical. As someone who uses machine learning in (non-aging-related) biotech, the discussion of "garbage-in/garbage-out" put me in mind of "Yes We Have Noticed the Skulls" [0]; we're well aware that data quality coming out of molecular biology is a problem, and anyone working in the field could give you a long list of the kinds of biases, distortions, and gaps that are known to occur in their areas of interest [1]. Not all of the grand claims made about biotech AI/ML are taking this expertise into account, certainly, but certainly many of them are. [0] https://slatestarcodex.com/2017/04/07/yes-we-have-noticed-the-skulls/ https://slatestarcodex.com/2017/04/07/yes-we-have-noticed-th... [1] The list, regardless of what variety of data it applies to, would always end with "sometimes something unknown happened and the data just turned out bad, oh well."

nradov 5y ago

Most longevity biotech companies are following a completely wrong course. At best they might develop some compounds which provide marginal lifespan gains for a subset of people along with negative side effects. The most effective way to actually increase longevity is by delaying the onset of chronic diseases such as hypertension, diabetes, sarcopenia, and arteriosclerosis. If you look at people who actually live past 100 they don't live any longer than others once they have chronic disease. Instead they experience disease onset later in life. And we actually already know how to delay most chronic diseases fairly well. However the interventions aren't consistently applied and patient compliance is often poor.

steve76 5y ago
Not prevent, but also deal with the side effects. We just cut out a hog's kidney, grafted it to a guy's leg, and ran gene editing through an IV, and it transplanted. They're gearing up to do heart. Then it's heart/lung, then liver. then likely neural. Level them all. Take all their money, and full speed ahead on that.
coyotespike 5y ago
I respectfully disagree - many diseases are diseases of aging, in that they appear only when someone has aged significantly. A drug that increased healthspan would thus treat multiple diseases at once. And in fact, since we still do not have reliable aging clocks - in other words, a good way to tell if a drug has made you younger - one way to assess whether a drug may be treating aging at its root is to see if it is treating multiple diseases at once. A drug that improved outcomes for multiple diseases might turn out to be an anti-aging drug, is the idea (of course, there is no such drug yet!). Anyway, the logic is that instead of delaying multiple chronic diseases separately, we go after aging, which should have that effect anyway (for many people, and for many diseases, but certainly not all).
- nradov 5y ago
  That's just silly. You're basically talking about a magic drug which doesn't exist even in concept form. It's the equivalent of wishing for cheap fusion power or room temperature superconductors or warp drives. Instead of scifi fantasies, how about working towards something actually achievable?

ummonk 5y ago

> and most notably the opening lecture from Charles Brenner had a great take-down on all of the reasons why longevity genes are unlikely to exist (TL/DR – genes only propagate if selected for, and there’s no selective pressure for longevity after reproductive age). I mean, we don’t just drop dead the minute we pass reproductive age. One would expect there to be genes that affect aging (including past reproductive age), either due to different environments creating different selective pressures or just genetic drift or genes with an adaptive function for reproductive life having a side effect for post-reproductive life. Consider particularly that women have a shorter reproductive window than men, but live longer on average.

dalke 5y ago

I find it interesting to read old publications. It gives a sense of what arguments are new and what are re-treads. Here's an essay from Eugene Garfield from 1983 titled "The dilemma of prolongevity research -- Must we age before we die, or if we don't, will we?" at http://www.garfield.library.upenn.edu/essays/v6p107y1983.pdf http://www.garfield.library.upenn.edu/essays/v6p107y1983.pdf > Medicine men and magicians, alchemists, sages, and physicians have searched for ways to ward off the effects of aging. But to date, scientists and their predecessors alike have been rebuffed. ... > Why has the problem of aging been such an intractable one? Up until recently, the prevalent view of scientists had been that the task of controlling aging was fundamentally impossible. But today, such a consensus no longer exists. Many researchers now believe that their predecessors failed, not because their goals were misguided, but because the tools and the level of sophistication they could bring to the task were inadequate. Moreover, it is argued that progress has been hampered because funding has been scarce, and researchers concerned with aging have been too few and far between. > Indeed, until recently, aging research had been plagued by all of these problems. During most of the first half of the twentieth century, while rapid progress was being made in other areas of biomedicine, only a handful of scientists throughout the world were doing aging research. One of these pioneers was Nathan Shock, who, according to Paul D. Phillips, Wistar Institute, Philadelphia, is considered by many to be one of the “fathers” of modern gerontology. > Growing public and private support for aging research reflects the scientific community’s own increasing commitment. Today, aging research occupies unprecedented numbers of highly talented individuals, not only specialists in gerontology, but researchers from other disciplines as well. These include biochemistry, endocrinology, immunology, neurobiology, genetics, and cell biology, to name only a few. Garfield then lists a number of books advocating longevity research (Ettinger's 1962 "The Prospect of Immortality"; Barrington's 1969 "The Immortalist" ; Comfort's 1964 "The Process of Ageing"; Rosenfeld's 1983 "Prolongevity"), praises the increase in federal funding in longevity research, mentions private sector organizations funding aging research (The American Longevity Association; The American Federation for Aging Research) and lists similar organizations in different countries. He then writes for a few pages more about the current status of longevity research in 1983, written for a technical but non-specialist audience. With an additional 40 years of research, what progress has the field made? I don't know - I claim not even the basic of expertise in the area. But what I can say is that certain arguments sound hollow after being repeated for decades with seemingly limited success.

Guest34988 5y ago

Here is one of the most cited papers in the aging field, published in Cell: https://www.sciencedirect.com/science/article/pii/S0092867413006454 https://www.sciencedirect.com/science/article/pii/S009286741... from OP's article: "..so far it’s all just pre-clinical testing or Phase I trials at the very most." Well, here is a map of the clinical trials corresponding to those hallmarks of aging, many of which are in Phase I and beyond: https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/ https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/

coyotespike 5y ago

I regret that this is not a very good article. For context, I'm not a biologist, but have joined On Deck Longevity Biotech - maybe half the people have biology PhDs, and everyone is interested in (obviously) longevity biotech. Yes, there is more money than ever before flowing into biotech in general, including longevity. Why? For one thing, just a few years ago, people like Aubrey de Grey had successfully branded the field as fit only for crackpots and mediocrities (to be fair, some good people got into the field through de Grey's work, but I am not a fan). Now longevity (or anti-aging, or whatever you want to call it) has attracted many very legitimate researchers, in part thanks to Laura Deming. However, the field is worried about an "AI winter" - there's awareness that someone or other needs to deliver a working drug in the next decade or so to avoid investor flight. Here's where I don't get the article's critique: the author lists many new companies, none of which have yet delivered a working anti-aging drug. Sure - but why is that a problem? Scientists and investors alike are well aware this is a new and speculative field. No one legitimate is promising a working drug. They are promising research, which is normal in biotech (big pharma has largely outsourced research to biotech startups). What is worth debating is the time horizon. These companies are indeed formed on the belief that there's a reasonable chance of a working drug in the next decade or two. If that pans out, of course it will change the culture at large, make billions, and the field will explode. If there's no such reasonable chance, then yes many of these companies shouldn't exist. I was very pessimistic about the chances until I read more of the science, and now I am more optimistic that in a few decades we may see a drug that extends healthspan by say 5 years. Finally, I will note that "90% of anything is crap" and there are many useless and scammy companies and "researchers" in the field. Just don't throw the baby out with the bathwater.

dorfsmay 5y ago
I'm not in that field at all but Aubrey de Grey keep saying that since they try to solve or slow down illnesses of old ages,the worse that can happen is that if they fail at curing aging they'll have at least reduced the impact of some illnesses.
arc-in-space 5y ago
Agreed, article seems to be of the "vaguely rambling against everything" genre, and of little substance. For instance, what is the paragraph mentioning Aducanumab and ivermectin even trying to say?

mrRA 5y ago

I agree with this claim. After years of hoping a “good” bio company to invest in longevity I finally have hope again. Without shilling here, but if you like thinking and discussing longevity in a decentralized autonomous organization (DAO) manner, a web 3.0 organization, than surely check out vita dao (search on google or twitter). This is not a financial advice or what so ever, dyor for always.

phkahler 5y ago

>> genes only propagate if selected for, and there’s no selective pressure for longevity after reproductive age Because humans are not social animals? Because protecting your own offspring as long as possible is NOT a thing? Everything with even slight benefit is selected for to a degree based on that benefit. Having parents is beneficial. Having grand parents is probably also useful. Having great grandparents... well someone has to get eaten by that lion.

paulcole 5y ago

I often hear people smugly tsk-tsk’ing those who buy lottery tickets as not understanding math. The anti-aging, longevity crew isn’t much different to me. Except I’m hopeful that most of the money wasted on this nonsense is coming from wishful billionaires and rich people.

goopthink 5y ago

YMMV, but a significant amount of real-world and statistically significant contributions can be made to average human longevity by focusing on paths of least resistance, such as tackling gun and car related deaths, then on the individual+average longevity by looking at preventable-but-chronic conditions (such as diabetes) by regulating things like common pollutants, added sugars to foods, and having better access to the outdoors and exercise/activity. Then you can enjoy a long life that will - on average - be healthy and long enough and with decreased risk of dying early. Past that, a lot of the research feels like “solutionism”.

ncmncm 5y ago

The only very good news I have encountered lately came out in April, where a cohort of tens of thousands of US Veterans Administration patients were found to suffer 40% less incidence of dementia if they had got a recent Tdap booster. Nobody knows what was in the booster that made the difference, but it is very hard for a confounder to produce a 40% effect size. (I doubt aspirin would get such an effect size.) A Tdap is safe, and I don't need to know why it helps, only that it (apparently) does, so I went right out to the drug store and got one. I expect at least some of the billionaires are getting transfusions of blood extracted from infants. Which infants, I hate to imagine.

LeanderK 5y ago

Naive Idea, but some mechanisms, like the testosterone-level in males, change with age. Why can't we, as a first step, just try to keep the levels fixed where we have a "reference level"?