42 ms·

Beginner's guide to longevity research

361 points by sajid 9y ago

joekrill 9y ago
Very interesting and informative! As someone who knows nothing about this field, this was a really great summary! (I can only assume it's accurate unless someone chimes in to claim otherwise).
Jemmeh 9y ago
This is a pretty fantastic writeup, short and simple on each topic with loads of sources. For those looking for something actionable, you may want to head to the reddit board for intermittent fasting. It's a good way to lower your caloric intake and increase autophagy. People doing intermittent fasting often also eat a keto diet that is mentioned in the writing as well. https://www.reddit.com/r/intermittentfasting/ https://www.reddit.com/r/intermittentfasting/ https://www.reddit.com/r/keto/ https://www.reddit.com/r/keto/
- agumonkey 9y ago
  My diet is almost small these days but I'm very curious about IF... Hoping I'll have willpower to do one
  - fbr 9y ago
    Just try. For me that was way easier than expected.
  - Jonovono 9y ago
    Honestly, it takes less willpower to do IF than to not do it :p 1. Wake up 2. Make Breakfast 3. Go on with day vs 1. Wake up 2. Go on with day.
    - agumonkey 9y ago
      one shot are easy, it's the semblance of regularity that is important
    - phaus 9y ago
      Less work doesn't necessarily mean less willpower. Maybe you don't get very hungry, but some people do and for them that's what makes it take more willpower to fast than not fast. Another thing to consider is that many people who don't feel like spending the effort to make breakfast will just buy something and eat it. Doesn't take much effort or willpower to stop at Dunkin Donuts or Starbucks on the way to work.
      - naasking 9y ago
        First there's the adaptation period. Even after you're adjusted you'll experience hunger sometimes, but once you start moving and have a coffee, tea or water, the hunger subsides. The only will power you'd need is just to have your morning drink before acknowledging you're hungry.
  - Jemmeh 9y ago
    This is partially why I mentioned keto, keto keeps your blood sugar level very even so you don't get hungry as much. I find eating once per day to be quite easy as long as I eat the correct ratio of fat/protein/carbs. Also I worked up to eating once per day so that helped. (14 hrs for 2 weeks, then 15 hrs for 2 weeks, 16 hours for 2 weeks, etc.)
- deleted 9y ago
  [deleted]
- jbob2000 9y ago
  I have made many attempts at fasting. I'm skinny as a rake and get very weak without some kind of constant caloric intake. I also get "hangry" and make bad decisions on an empty stomach. Is this just me? Or is this a thing that everyone has and just works through?
  - Jonovono 9y ago
    I'm like you pretty skinny. I started IF and also going to the gym to try and put on weight. I never liked eating breakfast but did it because I thought it was something I had to do. It took me maybe a week or two of not eating breakfast until it felt normal - but now I could never go back. I feel much more in control. Before if I missed breakfast i'd be a mess and my stomach would be making all kinds of noises in meetings. Another plus I can eat massive lunches and dinners to make up for what I didn't eat at breakfast. I've still been able to gain weight this way!
    - projektir 9y ago
      I might try this, not because I believe in IF, but just because breakfast is annoying. Does coffee count as breakfast here, though?
      - mtgx 9y ago
        Not if it's black.
      - Jonovono 9y ago
        Ya, black coffee is fine. I can't remember the number but if it's under like 50kcal I think you'll stay in the fasting state, so you can even have like a small fruit. Definitely double check this though :p
      - Jemmeh 9y ago
        Black is fine. But protein (creamer) or sweetener(sugar/artificial) both spike your insulin which lessens autophagy. As the OP Article points out, autophagy leads to longevity in mice and lessens your chance of neurological disease. In 2016 a Nobel prize was given to Yoshinori Ohsumi for his work on autophagy. "After infection, autophagy can eliminate invading intracellular bacteria and viruses. Autophagy contributes to embryo development and cell differentiation. Cells also use autophagy to eliminate damaged proteins and organelles, a quality control mechanism that is critical for counteracting the negative consequences of aging. Disrupted autophagy has been linked to Parkinson's disease, type 2 diabetes and other disorders that appear in the elderly. Mutations in autophagy genes can cause genetic disease. Disturbances in the autophagic machinery have also been linked to cancer. Intense research is now ongoing to develop drugs that can target autophagy in various diseases." [1] That said, Dr. Jason Fung says black is better but he allows creamer if needed so that people stick with their fasts. [1]https://www.nobelprize.org/nobel_prizes/medicine/laureates/2016/press.html https://www.nobelprize.org/nobel_prizes/medicine/laureates/2...
- Jonovono 9y ago
  Also, a good subreddit for IF and weight training: https://www.reddit.com/r/leangains/ https://www.reddit.com/r/leangains/
- AnIdiotOnTheNet 9y ago
  I've lost about half my bodyweight, so I feel like my experience qualifies to me to offer my opinion that Keto's supposed anti-hunger effects are broscience crap. Ephedrine or amphetamines, those work.
  - TACIXAT 9y ago
    Omega-3 fats are known to control hunger. That is probably where the claim that a high fat diet like keto can regulate appetite. https://www.livestrong.com/article/296534-omega-3-as-an-appetite-suppressant/ https://www.livestrong.com/article/296534-omega-3-as-an-appe...
    - Jemmeh 9y ago
      It's not about that. Here's a good youtube video explaining it. https://www.youtube.com/watch?v=Dan8qtgQRi8 https://www.youtube.com/watch?v=Dan8qtgQRi8
  - QAPereo 9y ago
    I’ve never actually talked about this online before, but now I’m going to. I used to weigh over 560lbs, and I’ve lost 190 of that, with more going every week. I spent a lot of time on this, tried a lot of diets, tried medication, and ultimately considered surgery. In the end a ferocious commitment to eating less, eating better, and moving around more was what worked, and continues to work. Years ago I went to a medically supervised weight loss program, twice, and met a loooot of people of all ages, all with serious weight problems. A few found success with surgery, and maybe half of those kept it off. Of the half that did, they knew going in that they were ready for the hard work, but they were so big they needed a boost to get moving. The people who used drugs never kept it off. The the people who thought the magic was in some special way of eating never kept it off. The people who committed to lifelong lifestyle change kept it off, and it didn’t seem to matter if it was Keto, Atkins, Paleo, or any permutation of potentially healthy lifestyles. The active ingredient is not the plan, it is the desire to commit to the plan with all of your being... for years, forever. For me at least, it was also a matter of growing the fuck up, really taking responsibility for my negative patterns of thought and behavior, and relentlessly working on them in a positive way. It’s hard, but I went from barely being able to walk, to jogging up stairs. Everyone is a bit different, everyone has different issues with food and exercise, and everyone probably has to use a slightly different approach. Still, some constants for me were the need to ditch fast food completely, and soda is now a very rare treat. More than that however, I had to slowly alter my mental habits about food, and really pay attention to how I felt, especially after an unhealthy meal. I basically tried to form new habits to take the place of old destructive habits. Anyway, enough babble from me, I just wanted to add my own perspective as someone doing the work to live, and live well. Edit: I forgot to mention what actually made me post this in the first place, that I found intermittent fasting genuinely helpful. In particular I tend not to have cravings until after I’ve had my first real meal, so I just start a bit later, and have a defined cut-off. I have something with plenty of fiber in the morning, and then just lay off until lunch. More protein with each meal, less sugar, and plenty of fiber, and normal portions.
Asdfbla 9y ago
Very interesting research, but trying to derive actionable recommendations for humans seems a bit laughable at this point. Still seems tough to become immortal these days. Harvesting young blood, a rigid diet, castration and starving yourself occasionally - lots of effort your self-absorbed wealthy investor with a desire to live forever has to go through. But then again, Sam Altman recently praised China for having fewer ethical concerns in that regard, so maybe they will get some longitudinal human studies going. The population scale full-genome analyses that are currently underway might also be helpful.
- reasonattlm 9y ago
  Actionable things for humans at the moment appear to look like trying senolytic drug candidates in rational self-experimentation, with before/after tests of metrics linked to tissue stiffness, inflammation, kidney and heart function. Clearing senescent cells very clearly produces a degree of rejuvenation in mice, and can turn back progression of aging and specific age-related diseases via a sizable number of metrics. Of those senolytic drug candidates, dasatinib plus quercetin if you're fine with short burst of chemotherapeutics, or FOXO4-DRI if you are fine with using peptides lacking human data. Both of which should be filed under the "risk that needs to be well understood" category. Or you could wait a few years for the first human trials to run through and more data and better drug candidates to arrive. But these things are on the menu of possibilities, and are not expensive at all to carry out as exploratory tests.
  - danieltillett 9y ago
    The problem with all potential senolytic drugs is cancer. Looking at all the animal models (and spontaneous human mutations) where senescence is reduced there is a corresponding increase in cancer. We really can't do much about ageing until we can cure or prevent cancer.
    - reasonattlm 9y ago
      That would only be the case in the models where senescence is blocked completely. If instead for a short time killing some fraction of all currently existing senescent cells, the effect on cancer risk should be a reduction, due to decreased inflammatory signaling from those cells. The senescent cells that are hanging around at any given moment in time aren't helping you in any way; they're not reducing the risk of cancer. If there are enough of them, they are in fact increasing the risk of cancer due to messing with the surrounding environment. If those senescent cells ever actually helped, then that help was applied at the time the cell became senescent - and shortly thereafter it became a liability that should be destroyed. There are emerging exceptions to that view, such as adaptive senescence in the immune system and possibly in support cells in the brain, but fortunately both of those should be largely moot points for the early senolytic therapies, and don't seem to be obstacles in old mice.
MMTP 9y ago
Yes this is a great introduction into the topic. I would also recommend checking out www.leafscience.org home of the LEAF foundation. They are the guys who did that great video with Kurzgesagt last year and their website is packed with great info about aging and research. https://www.youtube.com/watch?v=MjdpR-TY6QU https://www.youtube.com/watch?v=MjdpR-TY6QU
agumonkey 9y ago
"long" interview with aubrey de grey from last december: https://medium.com/@arielf/wake-up-people-its-time-to-aim-high-b0c2bcac53f1 https://medium.com/@arielf/wake-up-people-its-time-to-aim-hi...
fbr 9y ago
You may enjoy Dr Rhonda Patrick's podcast as well. https://www.youtube.com/user/FoundMyFitness/ https://www.youtube.com/user/FoundMyFitness/
reasonattlm 9y ago
The author of this overview, Laura Deming, runs the Longevity Fund, and has a research background in the study of aging. She merits congratulations for being, I think, the first by a few years to put together a longevity-focused fund, now joined by e.g. Jim Mellon's Juvenescence venture, Methuselah Fund, Apollo Ventures, etc. Rejuvenation research after the SENS Research Foundation model of repairing the known root causes of aging is a massive arbitrage opportunity. It remains the case that most people just don't get it, and are thus enormously undervaluing research and companies in this space. That is changing in senescent cell clearance, but six or seven other nascent areas of research and development are in exactly the same position senescent cell clearance was in back in 2010 - no attention, little funding, low valuation, huge potential for breakout gains in said valuation on producing a technology demonstration for rejuvenation in animal models. It seems likely that the Longevity Fund will do well on the basis of having invested in Unity Biotechnology alone, even putting aside any other successes. The article linked here is a useful overview, with copious references, of the type of work presently taking place in the aging research community. It well illustrates that, aside from senescent cell clearance, nearly everything that counts as a major interest by funding and number of scientists involved is a form of tinkering with stress response biochemistry to modestly slow aging - not addressing root cause molecular damage by repairing it, but rather messing with metabolism to slow damage accumulation. Nowhere near as helpful. Given what we know, where the data exists to compare outcomes between short-lived and long-lived species, the approach of altering metabolic processes to enhance beneficial stress response mechanisms is not going to move the needle all that far in humans. The results should be exercise-like and calorie-restriction-like in that they have worthwhile effects on long-term health, assuming that the cost of development and treatment is low, but they won't add much more to life expectancy than those two items are capable of achieving - which means perhaps the low end of five to ten years at best in our species, assuming life-long commitment to the intervention. Given that senescent cell clearance is a going concern, and other damage repair approaches such as cross-link breaking should follow in the years ahead, we can hope that the focus of the research community will shift as other approaches prove themselves much more cost-effective and successful.
Sir_Cmpwn 9y ago
I know they're for illustrative purposes but I really would have appreciated some scales on those graphs.
onuralp 9y ago
I recommend Peter Attia's highly engaging and informative talk [0] on the same topic, which I think does a better job at articulating the motivation behind possible approaches to attacking the issue of health- and life-span. [0] https://www.youtube.com/watch?v=vDFxdkck354 https://www.youtube.com/watch?v=vDFxdkck354
- roystonvassey 9y ago
  I second this. I think Attia is one of the clearest thinkers on health, longevity and nutrition currently. Moreover, he is a trained doctor AND an ex-McKinsey consultant, a combination that marries a strongly analytical and numerical lens to a field (medicine) that notoriously isn't.
deleted 9y ago
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the_economist 9y ago
This is an awesome write-up. Regarding the experiment on monkeys that showed calorie restriction led to a longer life, there is one key point that I think damages the conclussion. Both groups of monkeys were fed an extremely unhealthy diet that was very high in sugar. So the conclusion would be that eating fewer unhealthy calories leads to a longer life, not that calorie restriction in itself does.
robbomacrae 9y ago
It would be interesting to see a lab focussed on reproducing these findings and then running all the various combinations to see how those incremental improvements stack. Seems like something we should get ahead of before people run into unknown consequences of trying their own combinations.
akuma73 9y ago
Dr. Greger's talk is excellent with respect to how diet can influence longevity. https://www.youtube.com/watch?v=7rNY7xKyGCQ https://www.youtube.com/watch?v=7rNY7xKyGCQ
cies 9y ago
Really well written article! And a lot of things I've never heard of. While keto is mentioned, I do think that another diet deserves a mention here: WFPB (whole food plant based). In the book, How Not To Die, Dr Greger bring together the science that underpins this diet. Some one switching to this from a standard american diet can expect to add some healthy years to their lives, based on sci evidence.
- pdfernhout 9y ago
  Good point. See for example: The Whole Foods Diet: The Lifesaving Plan for Health and Longevity" by John Mackey, Alona Pulde, Matthew Lederman" https://www.goodreads.com/book/show/34837239-the-whole-foods-diet https://www.goodreads.com/book/show/34837239-the-whole-foods... Based on research studies cited there, the typical US American stitching from a SAD diet to a whole foods plant-based diet would live about ten years longer, and additionally have a much healthier and happier twenty years or so at the end with much lower likelihood of chronic illness or dementia. See also: https://bluezones.com/live-longer-better/ https://bluezones.com/live-longer-better/ For example: https://bluezones.com/exploration/loma-linda-california/ https://bluezones.com/exploration/loma-linda-california/ "Today, a community of about 9,000 Adventists in the Loma Linda area are the core of America’s Blue Zone region. They live as much as a decade longer than the rest of us, and much of their longevity can be attributed to vegetarianism and regular exercise. ... Adventists tend to spend time with lots of other Adventists. They find well-being by sharing each other’s values and supporting each other’s habits." But even as good diet is essential, it is aspects of community and infrastructure that help people keep eating healthy together. Likewise, community and infrastructure can help promote daily exercise. So, ultimately, for most people, longevity is not an individual thing. It is a community thing. That point on community is also made in the sequel to "Fat, Sick and Nearly Dead": https://en.wikipedia.org/wiki/Fat,_Sick_and_Nearly_Dead https://en.wikipedia.org/wiki/Fat,_Sick_and_Nearly_Dead and is even made by Dean Ornish in the trailer: http://www.fatsickandnearlydead2.com/ http://www.fatsickandnearlydead2.com/
semi-extrinsic 9y ago
I'll offer a contrarian view: longevity research, as in the current scope, is about as accurate and useful as Ray Kurzweil's predictions from the 90s. Let's take caloric restriction, for instance, which is all the rage. Trouble is, all of the evidence we have is in mice or lesser animals, and the comparison is animals on caloric restriction against animals being force fed to the point of obesity. Let me repeat that: in research that shows caloric restriction increasing lifespan in animal models, they are not comparing to animals on a normal diet. So it's entirely plausible all this caloric restriction research findings is just confirmation of the fact that obesity shortens lifespans. This isn't even touching on the point that correspondence between animal models and humans is abysmally bad. It's the best we have, but there's a very good reason drugs need to go through three stages of human testing after it's been proven successful in animals. With caloric restriction, we don't even have consistent positive results in monkeys, only in rodents. Has any of this longevity stuff ever been tested in humans? Obviously not, since it would take many decades. Some pointers for further reading: https://www.sciencedirect.com/science/article/pii/S0891584914002317 https://www.sciencedirect.com/science/article/pii/S089158491... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765579/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765579/
- reasonattlm 9y ago
  Rejuvenation therapies and treatments that slow the progression of aging won't be tested in humans by waiting to see. They will be tested using quick before/after measures of biomarkers of aging. Those biomarkers are under development, and numerous types exist somewhere in the slow scientific process of standardization and debate. Here applied to calorie restriction, for example: https://academic.oup.com/biomedgerontology/article/73/1/4/3834057 https://academic.oup.com/biomedgerontology/article/73/1/4/38... "We obtained data from the National Institute on Aging CALERIE randomized trial through its public-access biobank (https://calerie.duke.edu/ https://calerie.duke.edu/). The CALERIE trial randomized N = 220 nonobese adults to 25% caloric restriction (n = 145; 11.7% caloric restriction was achieved, on average) or to maintain current diet (n = 75) for 2 years. We analyzed biomarker data collected at baseline, 12-, and 24-month follow-up assessments. We applied published biomarker algorithms to these data to calculate two biological age measures, Klemera–Doubal Method Biological Age and homeostatic dysregulation. Intent-to-treat analysis using mixed-effects growth models of within-person change over time tested if caloric restriction slowed increase in measures of biological aging across follow-up. Analyses of both measures indicated caloric restriction slowed biological aging. Weight loss did not account for the observed effects. Results suggest future directions for testing of geroprotective therapies in humans." That said, it is quite clear that research into provoking stress response isn't going to do much for longevity in humans, even while it may do useful things for long-term health in the same way as exercise and calorie restriction do. In addition to calorie restriction, growth hormone receptor knockout can be compared in mice and humans with Laron syndrome - the large gains in mouse life span don't occur in humans. However, research into repairing the damage that causes aging is a whole different ball game. A completely different strategy, set of mechanisms, overall approach, and effect on the individual. A reversal of aging rather than a slight slowing of aging. We have no idea how results in mice will map to results in humans. So it is worth keeping an eye on the ongoing pilot trials and forthcoming larger trials of clearing senescent cells in human patients.
jcmoscon 9y ago
You guys should look at the "steak and eggs" diet. This is the best diet I did. You loose a lot of weight, feel amazing, no brain fog, you do not get crazy hungry. It's amazing!
- raarts 9y ago
  That's because of the ketogenic aspect of it. Though I would get bored if I only ate Steak & eggs.
  - jcmoscon 9y ago
    It's so easy you don't need to check how many carbs your food has because you only eat steaks and eggs. You can change how you cook your eggs or get different cuts of meat. And you can eat anything in the sixth day. It's the easiest and most efficient diet I tried so far.
659087 9y ago
What's the end game here? A future ruled by 400 year old Zuckerbergs and other multi-trillionaires? Much of the progress in society is possible only because previous generations eventually die off. What happens when that's no longer the case?
- deleted 9y ago
  [deleted]
- darpa_escapee 9y ago
  Hope to God that you're dead by then.
ldeming 9y ago
Thanks everyone for reading! I'll be around if you have any questions.
- beefman 9y ago
  I have 3 questions: 1. Did you see the Park et al report on DNA-PK inhibition from earlier this year? https://news.ycombinator.com/item?id=14301878 https://news.ycombinator.com/item?id=14301878 2. Is anyone working on sleep? https://twitter.com/clumma/status/764842049199898624 https://twitter.com/clumma/status/764842049199898624 3. Have you considered funding low-dose ionizing radiation research? https://www.facebook.com/clumma/activity/10151804061151737 https://www.facebook.com/clumma/activity/10151804061151737
tasty_freeze 9y ago
That table at the end has a column "Median Lifespan Increase (treated/control)". No, it isn't an increase, it is a ratio. Eg, the first entry, scenescent cell removal %135, is a 35% increase, not a 135% increase.
- ekianjo 9y ago
  It would be good to add the base size for the observed effect in each study.
antongribok 9y ago
I'm a bit surprised at no mention of importance of sleep. Why is that? Or is this because that falls outside of scope of what "longevity research" in this case means?
- beefman 9y ago
  Seems to me an obvious target. Soundness of sleep seems to decline monotonically from near birth all the way to death https://twitter.com/clumma/status/764842049199898624 https://twitter.com/clumma/status/764842049199898624
ThankYouByeBye 9y ago
Why starve yourself by calorie restriction for 30 years when some bozo will shoot you dead in the end .
aaavl2821 9y ago
if you are interested in the biopharma industry in general, in addition to the sources she lists on her site, here is a primer i recently put together: http://newbio.tech/blog.html http://newbio.tech/blog.html
watertom 9y ago
Almost all animal testing is done on animals that manufacture L-Ascorbic Acid in their liver. L-Ascorbic Acid is an incredibly powerful hormone and completely discounting it's presence is foolish at best and negligent at worst.

361 points by sajid 9y ago

Very interesting and informative! As someone who knows nothing about this field, this was a really great summary! (I can only assume it's accurate unless someone chimes in to claim otherwise).

Jemmeh 9y ago

This is a pretty fantastic writeup, short and simple on each topic with loads of sources. For those looking for something actionable, you may want to head to the reddit board for intermittent fasting. It's a good way to lower your caloric intake and increase autophagy. People doing intermittent fasting often also eat a keto diet that is mentioned in the writing as well. https://www.reddit.com/r/intermittentfasting/ https://www.reddit.com/r/intermittentfasting/ https://www.reddit.com/r/keto/ https://www.reddit.com/r/keto/

agumonkey 9y ago
My diet is almost small these days but I'm very curious about IF... Hoping I'll have willpower to do one
- fbr 9y ago
  Just try. For me that was way easier than expected.
- Jonovono 9y ago
  Honestly, it takes less willpower to do IF than to not do it :p 1. Wake up 2. Make Breakfast 3. Go on with day vs 1. Wake up 2. Go on with day.
  - agumonkey 9y ago
    one shot are easy, it's the semblance of regularity that is important
  - phaus 9y ago
    Less work doesn't necessarily mean less willpower. Maybe you don't get very hungry, but some people do and for them that's what makes it take more willpower to fast than not fast. Another thing to consider is that many people who don't feel like spending the effort to make breakfast will just buy something and eat it. Doesn't take much effort or willpower to stop at Dunkin Donuts or Starbucks on the way to work.
    - naasking 9y ago
      First there's the adaptation period. Even after you're adjusted you'll experience hunger sometimes, but once you start moving and have a coffee, tea or water, the hunger subsides. The only will power you'd need is just to have your morning drink before acknowledging you're hungry.
- Jemmeh 9y ago
  This is partially why I mentioned keto, keto keeps your blood sugar level very even so you don't get hungry as much. I find eating once per day to be quite easy as long as I eat the correct ratio of fat/protein/carbs. Also I worked up to eating once per day so that helped. (14 hrs for 2 weeks, then 15 hrs for 2 weeks, 16 hours for 2 weeks, etc.)
deleted 9y ago
[deleted]
jbob2000 9y ago
I have made many attempts at fasting. I'm skinny as a rake and get very weak without some kind of constant caloric intake. I also get "hangry" and make bad decisions on an empty stomach. Is this just me? Or is this a thing that everyone has and just works through?
- Jonovono 9y ago
  I'm like you pretty skinny. I started IF and also going to the gym to try and put on weight. I never liked eating breakfast but did it because I thought it was something I had to do. It took me maybe a week or two of not eating breakfast until it felt normal - but now I could never go back. I feel much more in control. Before if I missed breakfast i'd be a mess and my stomach would be making all kinds of noises in meetings. Another plus I can eat massive lunches and dinners to make up for what I didn't eat at breakfast. I've still been able to gain weight this way!
  - projektir 9y ago
    I might try this, not because I believe in IF, but just because breakfast is annoying. Does coffee count as breakfast here, though?
    - mtgx 9y ago
      Not if it's black.
    - Jonovono 9y ago
      Ya, black coffee is fine. I can't remember the number but if it's under like 50kcal I think you'll stay in the fasting state, so you can even have like a small fruit. Definitely double check this though :p
    - Jemmeh 9y ago
      Black is fine. But protein (creamer) or sweetener(sugar/artificial) both spike your insulin which lessens autophagy. As the OP Article points out, autophagy leads to longevity in mice and lessens your chance of neurological disease. In 2016 a Nobel prize was given to Yoshinori Ohsumi for his work on autophagy. "After infection, autophagy can eliminate invading intracellular bacteria and viruses. Autophagy contributes to embryo development and cell differentiation. Cells also use autophagy to eliminate damaged proteins and organelles, a quality control mechanism that is critical for counteracting the negative consequences of aging. Disrupted autophagy has been linked to Parkinson's disease, type 2 diabetes and other disorders that appear in the elderly. Mutations in autophagy genes can cause genetic disease. Disturbances in the autophagic machinery have also been linked to cancer. Intense research is now ongoing to develop drugs that can target autophagy in various diseases." [1] That said, Dr. Jason Fung says black is better but he allows creamer if needed so that people stick with their fasts. [1]https://www.nobelprize.org/nobel_prizes/medicine/laureates/2016/press.html https://www.nobelprize.org/nobel_prizes/medicine/laureates/2...
Jonovono 9y ago
Also, a good subreddit for IF and weight training: https://www.reddit.com/r/leangains/ https://www.reddit.com/r/leangains/
AnIdiotOnTheNet 9y ago
I've lost about half my bodyweight, so I feel like my experience qualifies to me to offer my opinion that Keto's supposed anti-hunger effects are broscience crap. Ephedrine or amphetamines, those work.
- TACIXAT 9y ago
  Omega-3 fats are known to control hunger. That is probably where the claim that a high fat diet like keto can regulate appetite. https://www.livestrong.com/article/296534-omega-3-as-an-appetite-suppressant/ https://www.livestrong.com/article/296534-omega-3-as-an-appe...
  - Jemmeh 9y ago
    It's not about that. Here's a good youtube video explaining it. https://www.youtube.com/watch?v=Dan8qtgQRi8 https://www.youtube.com/watch?v=Dan8qtgQRi8
- QAPereo 9y ago
  I’ve never actually talked about this online before, but now I’m going to. I used to weigh over 560lbs, and I’ve lost 190 of that, with more going every week. I spent a lot of time on this, tried a lot of diets, tried medication, and ultimately considered surgery. In the end a ferocious commitment to eating less, eating better, and moving around more was what worked, and continues to work. Years ago I went to a medically supervised weight loss program, twice, and met a loooot of people of all ages, all with serious weight problems. A few found success with surgery, and maybe half of those kept it off. Of the half that did, they knew going in that they were ready for the hard work, but they were so big they needed a boost to get moving. The people who used drugs never kept it off. The the people who thought the magic was in some special way of eating never kept it off. The people who committed to lifelong lifestyle change kept it off, and it didn’t seem to matter if it was Keto, Atkins, Paleo, or any permutation of potentially healthy lifestyles. The active ingredient is not the plan, it is the desire to commit to the plan with all of your being... for years, forever. For me at least, it was also a matter of growing the fuck up, really taking responsibility for my negative patterns of thought and behavior, and relentlessly working on them in a positive way. It’s hard, but I went from barely being able to walk, to jogging up stairs. Everyone is a bit different, everyone has different issues with food and exercise, and everyone probably has to use a slightly different approach. Still, some constants for me were the need to ditch fast food completely, and soda is now a very rare treat. More than that however, I had to slowly alter my mental habits about food, and really pay attention to how I felt, especially after an unhealthy meal. I basically tried to form new habits to take the place of old destructive habits. Anyway, enough babble from me, I just wanted to add my own perspective as someone doing the work to live, and live well. Edit: I forgot to mention what actually made me post this in the first place, that I found intermittent fasting genuinely helpful. In particular I tend not to have cravings until after I’ve had my first real meal, so I just start a bit later, and have a defined cut-off. I have something with plenty of fiber in the morning, and then just lay off until lunch. More protein with each meal, less sugar, and plenty of fiber, and normal portions.

Asdfbla 9y ago

Very interesting research, but trying to derive actionable recommendations for humans seems a bit laughable at this point. Still seems tough to become immortal these days. Harvesting young blood, a rigid diet, castration and starving yourself occasionally - lots of effort your self-absorbed wealthy investor with a desire to live forever has to go through. But then again, Sam Altman recently praised China for having fewer ethical concerns in that regard, so maybe they will get some longitudinal human studies going. The population scale full-genome analyses that are currently underway might also be helpful.

reasonattlm 9y ago
Actionable things for humans at the moment appear to look like trying senolytic drug candidates in rational self-experimentation, with before/after tests of metrics linked to tissue stiffness, inflammation, kidney and heart function. Clearing senescent cells very clearly produces a degree of rejuvenation in mice, and can turn back progression of aging and specific age-related diseases via a sizable number of metrics. Of those senolytic drug candidates, dasatinib plus quercetin if you're fine with short burst of chemotherapeutics, or FOXO4-DRI if you are fine with using peptides lacking human data. Both of which should be filed under the "risk that needs to be well understood" category. Or you could wait a few years for the first human trials to run through and more data and better drug candidates to arrive. But these things are on the menu of possibilities, and are not expensive at all to carry out as exploratory tests.
- danieltillett 9y ago
  The problem with all potential senolytic drugs is cancer. Looking at all the animal models (and spontaneous human mutations) where senescence is reduced there is a corresponding increase in cancer. We really can't do much about ageing until we can cure or prevent cancer.
  - reasonattlm 9y ago
    That would only be the case in the models where senescence is blocked completely. If instead for a short time killing some fraction of all currently existing senescent cells, the effect on cancer risk should be a reduction, due to decreased inflammatory signaling from those cells. The senescent cells that are hanging around at any given moment in time aren't helping you in any way; they're not reducing the risk of cancer. If there are enough of them, they are in fact increasing the risk of cancer due to messing with the surrounding environment. If those senescent cells ever actually helped, then that help was applied at the time the cell became senescent - and shortly thereafter it became a liability that should be destroyed. There are emerging exceptions to that view, such as adaptive senescence in the immune system and possibly in support cells in the brain, but fortunately both of those should be largely moot points for the early senolytic therapies, and don't seem to be obstacles in old mice.

MMTP 9y ago

Yes this is a great introduction into the topic. I would also recommend checking out www.leafscience.org home of the LEAF foundation. They are the guys who did that great video with Kurzgesagt last year and their website is packed with great info about aging and research. https://www.youtube.com/watch?v=MjdpR-TY6QU https://www.youtube.com/watch?v=MjdpR-TY6QU

agumonkey 9y ago

"long" interview with aubrey de grey from last december: https://medium.com/@arielf/wake-up-people-its-time-to-aim-high-b0c2bcac53f1 https://medium.com/@arielf/wake-up-people-its-time-to-aim-hi...

fbr 9y ago

You may enjoy Dr Rhonda Patrick's podcast as well. https://www.youtube.com/user/FoundMyFitness/ https://www.youtube.com/user/FoundMyFitness/

reasonattlm 9y ago

The author of this overview, Laura Deming, runs the Longevity Fund, and has a research background in the study of aging. She merits congratulations for being, I think, the first by a few years to put together a longevity-focused fund, now joined by e.g. Jim Mellon's Juvenescence venture, Methuselah Fund, Apollo Ventures, etc. Rejuvenation research after the SENS Research Foundation model of repairing the known root causes of aging is a massive arbitrage opportunity. It remains the case that most people just don't get it, and are thus enormously undervaluing research and companies in this space. That is changing in senescent cell clearance, but six or seven other nascent areas of research and development are in exactly the same position senescent cell clearance was in back in 2010 - no attention, little funding, low valuation, huge potential for breakout gains in said valuation on producing a technology demonstration for rejuvenation in animal models. It seems likely that the Longevity Fund will do well on the basis of having invested in Unity Biotechnology alone, even putting aside any other successes. The article linked here is a useful overview, with copious references, of the type of work presently taking place in the aging research community. It well illustrates that, aside from senescent cell clearance, nearly everything that counts as a major interest by funding and number of scientists involved is a form of tinkering with stress response biochemistry to modestly slow aging - not addressing root cause molecular damage by repairing it, but rather messing with metabolism to slow damage accumulation. Nowhere near as helpful. Given what we know, where the data exists to compare outcomes between short-lived and long-lived species, the approach of altering metabolic processes to enhance beneficial stress response mechanisms is not going to move the needle all that far in humans. The results should be exercise-like and calorie-restriction-like in that they have worthwhile effects on long-term health, assuming that the cost of development and treatment is low, but they won't add much more to life expectancy than those two items are capable of achieving - which means perhaps the low end of five to ten years at best in our species, assuming life-long commitment to the intervention. Given that senescent cell clearance is a going concern, and other damage repair approaches such as cross-link breaking should follow in the years ahead, we can hope that the focus of the research community will shift as other approaches prove themselves much more cost-effective and successful.

Sir_Cmpwn 9y ago

I know they're for illustrative purposes but I really would have appreciated some scales on those graphs.

onuralp 9y ago

I recommend Peter Attia's highly engaging and informative talk [0] on the same topic, which I think does a better job at articulating the motivation behind possible approaches to attacking the issue of health- and life-span. [0] https://www.youtube.com/watch?v=vDFxdkck354 https://www.youtube.com/watch?v=vDFxdkck354

roystonvassey 9y ago
I second this. I think Attia is one of the clearest thinkers on health, longevity and nutrition currently. Moreover, he is a trained doctor AND an ex-McKinsey consultant, a combination that marries a strongly analytical and numerical lens to a field (medicine) that notoriously isn't.

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the_economist 9y ago

This is an awesome write-up. Regarding the experiment on monkeys that showed calorie restriction led to a longer life, there is one key point that I think damages the conclussion. Both groups of monkeys were fed an extremely unhealthy diet that was very high in sugar. So the conclusion would be that eating fewer unhealthy calories leads to a longer life, not that calorie restriction in itself does.

robbomacrae 9y ago

It would be interesting to see a lab focussed on reproducing these findings and then running all the various combinations to see how those incremental improvements stack. Seems like something we should get ahead of before people run into unknown consequences of trying their own combinations.

akuma73 9y ago

Dr. Greger's talk is excellent with respect to how diet can influence longevity. https://www.youtube.com/watch?v=7rNY7xKyGCQ https://www.youtube.com/watch?v=7rNY7xKyGCQ

cies 9y ago

Really well written article! And a lot of things I've never heard of. While keto is mentioned, I do think that another diet deserves a mention here: WFPB (whole food plant based). In the book, How Not To Die, Dr Greger bring together the science that underpins this diet. Some one switching to this from a standard american diet can expect to add some healthy years to their lives, based on sci evidence.

pdfernhout 9y ago
Good point. See for example: The Whole Foods Diet: The Lifesaving Plan for Health and Longevity" by John Mackey, Alona Pulde, Matthew Lederman" https://www.goodreads.com/book/show/34837239-the-whole-foods-diet https://www.goodreads.com/book/show/34837239-the-whole-foods... Based on research studies cited there, the typical US American stitching from a SAD diet to a whole foods plant-based diet would live about ten years longer, and additionally have a much healthier and happier twenty years or so at the end with much lower likelihood of chronic illness or dementia. See also: https://bluezones.com/live-longer-better/ https://bluezones.com/live-longer-better/ For example: https://bluezones.com/exploration/loma-linda-california/ https://bluezones.com/exploration/loma-linda-california/ "Today, a community of about 9,000 Adventists in the Loma Linda area are the core of America’s Blue Zone region. They live as much as a decade longer than the rest of us, and much of their longevity can be attributed to vegetarianism and regular exercise. ... Adventists tend to spend time with lots of other Adventists. They find well-being by sharing each other’s values and supporting each other’s habits." But even as good diet is essential, it is aspects of community and infrastructure that help people keep eating healthy together. Likewise, community and infrastructure can help promote daily exercise. So, ultimately, for most people, longevity is not an individual thing. It is a community thing. That point on community is also made in the sequel to "Fat, Sick and Nearly Dead": https://en.wikipedia.org/wiki/Fat,_Sick_and_Nearly_Dead https://en.wikipedia.org/wiki/Fat,_Sick_and_Nearly_Dead and is even made by Dean Ornish in the trailer: http://www.fatsickandnearlydead2.com/ http://www.fatsickandnearlydead2.com/

semi-extrinsic 9y ago

I'll offer a contrarian view: longevity research, as in the current scope, is about as accurate and useful as Ray Kurzweil's predictions from the 90s. Let's take caloric restriction, for instance, which is all the rage. Trouble is, all of the evidence we have is in mice or lesser animals, and the comparison is animals on caloric restriction against animals being force fed to the point of obesity. Let me repeat that: in research that shows caloric restriction increasing lifespan in animal models, they are not comparing to animals on a normal diet. So it's entirely plausible all this caloric restriction research findings is just confirmation of the fact that obesity shortens lifespans. This isn't even touching on the point that correspondence between animal models and humans is abysmally bad. It's the best we have, but there's a very good reason drugs need to go through three stages of human testing after it's been proven successful in animals. With caloric restriction, we don't even have consistent positive results in monkeys, only in rodents. Has any of this longevity stuff ever been tested in humans? Obviously not, since it would take many decades. Some pointers for further reading: https://www.sciencedirect.com/science/article/pii/S0891584914002317 https://www.sciencedirect.com/science/article/pii/S089158491... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765579/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765579/

reasonattlm 9y ago
Rejuvenation therapies and treatments that slow the progression of aging won't be tested in humans by waiting to see. They will be tested using quick before/after measures of biomarkers of aging. Those biomarkers are under development, and numerous types exist somewhere in the slow scientific process of standardization and debate. Here applied to calorie restriction, for example: https://academic.oup.com/biomedgerontology/article/73/1/4/3834057 https://academic.oup.com/biomedgerontology/article/73/1/4/38... "We obtained data from the National Institute on Aging CALERIE randomized trial through its public-access biobank (https://calerie.duke.edu/ https://calerie.duke.edu/). The CALERIE trial randomized N = 220 nonobese adults to 25% caloric restriction (n = 145; 11.7% caloric restriction was achieved, on average) or to maintain current diet (n = 75) for 2 years. We analyzed biomarker data collected at baseline, 12-, and 24-month follow-up assessments. We applied published biomarker algorithms to these data to calculate two biological age measures, Klemera–Doubal Method Biological Age and homeostatic dysregulation. Intent-to-treat analysis using mixed-effects growth models of within-person change over time tested if caloric restriction slowed increase in measures of biological aging across follow-up. Analyses of both measures indicated caloric restriction slowed biological aging. Weight loss did not account for the observed effects. Results suggest future directions for testing of geroprotective therapies in humans." That said, it is quite clear that research into provoking stress response isn't going to do much for longevity in humans, even while it may do useful things for long-term health in the same way as exercise and calorie restriction do. In addition to calorie restriction, growth hormone receptor knockout can be compared in mice and humans with Laron syndrome - the large gains in mouse life span don't occur in humans. However, research into repairing the damage that causes aging is a whole different ball game. A completely different strategy, set of mechanisms, overall approach, and effect on the individual. A reversal of aging rather than a slight slowing of aging. We have no idea how results in mice will map to results in humans. So it is worth keeping an eye on the ongoing pilot trials and forthcoming larger trials of clearing senescent cells in human patients.

jcmoscon 9y ago

You guys should look at the "steak and eggs" diet. This is the best diet I did. You loose a lot of weight, feel amazing, no brain fog, you do not get crazy hungry. It's amazing!

raarts 9y ago
That's because of the ketogenic aspect of it. Though I would get bored if I only ate Steak & eggs.
- jcmoscon 9y ago
  It's so easy you don't need to check how many carbs your food has because you only eat steaks and eggs. You can change how you cook your eggs or get different cuts of meat. And you can eat anything in the sixth day. It's the easiest and most efficient diet I tried so far.

659087 9y ago

What's the end game here? A future ruled by 400 year old Zuckerbergs and other multi-trillionaires? Much of the progress in society is possible only because previous generations eventually die off. What happens when that's no longer the case?

deleted 9y ago
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darpa_escapee 9y ago
Hope to God that you're dead by then.

ldeming 9y ago

Thanks everyone for reading! I'll be around if you have any questions.

beefman 9y ago
I have 3 questions: 1. Did you see the Park et al report on DNA-PK inhibition from earlier this year? https://news.ycombinator.com/item?id=14301878 https://news.ycombinator.com/item?id=14301878 2. Is anyone working on sleep? https://twitter.com/clumma/status/764842049199898624 https://twitter.com/clumma/status/764842049199898624 3. Have you considered funding low-dose ionizing radiation research? https://www.facebook.com/clumma/activity/10151804061151737 https://www.facebook.com/clumma/activity/10151804061151737

tasty_freeze 9y ago

That table at the end has a column "Median Lifespan Increase (treated/control)". No, it isn't an increase, it is a ratio. Eg, the first entry, scenescent cell removal %135, is a 35% increase, not a 135% increase.

ekianjo 9y ago
It would be good to add the base size for the observed effect in each study.

antongribok 9y ago

I'm a bit surprised at no mention of importance of sleep. Why is that? Or is this because that falls outside of scope of what "longevity research" in this case means?

beefman 9y ago
Seems to me an obvious target. Soundness of sleep seems to decline monotonically from near birth all the way to death https://twitter.com/clumma/status/764842049199898624 https://twitter.com/clumma/status/764842049199898624

ThankYouByeBye 9y ago

Why starve yourself by calorie restriction for 30 years when some bozo will shoot you dead in the end .

aaavl2821 9y ago

if you are interested in the biopharma industry in general, in addition to the sources she lists on her site, here is a primer i recently put together: http://newbio.tech/blog.html http://newbio.tech/blog.html

watertom 9y ago

Almost all animal testing is done on animals that manufacture L-Ascorbic Acid in their liver. L-Ascorbic Acid is an incredibly powerful hormone and completely discounting it's presence is foolish at best and negligent at worst.