Beginner's guide to longevity research
ldeming.com
ldeming.com
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/S089158491...
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/). 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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115619/
A simple interpretation of CR would be: “additional leanness from a normal body weight may add health and life span delaying the process of aging.”
Regarding BMI, rule of thumb is 20-ish.
CR in the NIA study reduces body weight by 25%, so the NIA CR “man equivalent” will have a BMI of 20.8 (in the lower half of the normal weight category)
As the OP say, there's very little basis to CR given you're talking mostly animals that are overeating and under exercising by default.
And mice are genetically uniform. CR has been partly tested on monkeys and other animals but it's a lot harder and results less conclusive.
Ad-libitum feeding is not force feeding. Noone goes and shoves the food into mice. The food is just available.
Also, CR has extended lives in many species, including dogs (see https://avmajournals.avma.org/doi/abs/10.2460/javma.2002.220...), not just mice.
Also while comparison to animals can be useful as a starting point it is no proof that it works anything like that in humans.
The dog study you link also highlights another issue with this kind of research: they focus on osteoarthritis, i.e. cartilege in joints being worn out over time, since that was the most common chronic disease. This occurred equally often in both groups, but time until first treatment for this condition was 25% longer in the CR group. That's exactly what you expect just from the 25% reduced body mass of CR fed dogs which they report, since reduced body mass puts less stress on the joints. No attempt is made to account for this, it is not even mentioned as a confounding variable.
Taken together with the fact that they don't observe any significant increase in maximum lifespan of the CR fed dogs, it's again very unclear whether this is anything more than confirming the well-established result that when you inevitably get a chronic disease, higher body mass means you get sick faster.
Not entirely. It's accepted now that caloric restriction helps fighting cancer, so that effect alone means people following caloric restriction will live longer on average. Those feeding the cancers will simply die younger.
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/keto/
1. Wake up
2. Make Breakfast
3. Go on with day
vs
1. Wake up
2. Go on with day.
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.
Is this just me? Or is this a thing that everyone has and just works through?
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!
Does coffee count as breakfast here, though?
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/2...
Sugar / carbs => Insulin spike > insulin drop > hangry within 2-3 hours
Protein / fat => Smooth sailing for 4-5 hours or more, hunger is much less intense
Just my experience.
2.) This is exactly why people who do intermittent fasting are often eating keto, which is a low carb, moderate protein, high fat diet. Carbs spike your blood sugar. Then it comes crashing down and puts you in a relative "low", so your body craves more of that quick energy and boom you are hungry/want carbs again.
Fats and proteins on the other hand give you a more stable energy level by not spiking your blood sugar as much. You stay full. The reason for only moderate protein is because excess protein is also turned into glucose through gluconeogenesis.
For the record my boyfriend is a black hole when it comes to food. He's fairly muscular and active so he gets hungry pretty quickly. But if he eats keto macros he can handle 1 meal a day too. He actually gets a bit sick eating carb heavy meals now.
I've seen people do it without doing keto and still get weight loss success, but a LCHF diet of some sort is the most common diet I see. Also the article mentions specifically keto diet linked to longevity.
Read through the sidebar info on the keto reddit if you want an idea of where to start.
My advice is that starting out, I wouldn't get too hung up on the ratio. It's actually pretty hard to get 75% of calories from fat. IMO, the important part is to limit the carbs. If you're hitting something like 60% fat, 30% protein, 10% good carbs (mostly green veggies, maybe some berries), you'll still see most of the keto benefits in terms of fewer mood swings and cravings, ability to fast more easily, etc.
Healthy eating is one of those areas where a lot of people (myself included) let perfect become the enemy of good. Even moderate low-carb, just eating cutting out sweets and starches, can be enough for a lot of people to see waistline and mood stability improvements.
The discussion about carbs, keto, etc applies to some people, but for the truly skinny, that feeling of weakness is your body slowly starving.
Ephedrine or amphetamines, those work.
https://www.livestrong.com/article/296534-omega-3-as-an-appe...
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.
And for any nutrition plan,ensure you get all your macros in your feeding window too. I've totally found that hunger is suppressed by IF though, but only after a week or so of doing it. Even if you did everything right, maybe it's just not for your body.
All of your post is good but this is the most important bit (IMO). The biggest scam the weight loss industry ever pulled on Western civilisation was the redefinition of "diet" from "what you eat" to "a temporary change in what you eat". To maintain a healthy weight you have to monitor your weight, and what you're eating, and adjust the latter in response to the former, forever. It's not a thing with an end. It's how you have to live.
Yeah, this is the part that people don't get when they talk about weight loss. They make it out like losing weight is the greatest thing, you'll feel better, have more energy, get more attention from the opposite sex, etc.
Truth is those benefits aren't guaranteed and are mostly exaggerated, but worse is the part they never talk about: what you're giving up to get there. Personally, I have to avoid (or leave early) social functions where free food will be available (you wouldn't believe how pushy people get, insisting that you eat), or that takes place at a restaurant (order a salad and everyone acts like you shot their dog). I have to suppress the urge to hit people who bring donuts to work. I spend three nights a week exercising and I eat a single meal a day of steamed vegetables and fake meat. I weigh myself every single morning and I make n effort to count every single calorie. And I have to do this for the rest of my life if I want to maintain where I am.
Weight loss is not a panacea, the tradeoffs aren't going to be worth it for everyone, and I really wish people would stop being such dicks about the whole thing.
> "I tend not to have cravings until after I’ve had my first real meal
Very much the case for me too, to the point that I can "forget" to eat all day so long as I really don't actually eat even a bit.
More importantly, though, I've found I can duplicate this effect to a great extent by strictly eliminating carbs from my first meal, and then a eating a proper square old-fashioned "dinner" in the afternoon. This has other benefits for me as well, the most noticeable being that I don't suffer grinding foggy sleepiness at midmorning or late afternoon. It also lets me be satisfied with a light supper later on, which is critical for my sleep. Big meals before bed leave me tossing and turning until early morning.
A sugary breakfast, on the other hand, will fuck up my whole day.
Also here's a good youtube video explaining it: https://www.youtube.com/watch?v=Dan8qtgQRi8
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.
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.
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.
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.
> senolytic drug candidates, dasatinib plus quercetin if you're fine with short burst of chemotherapeutics, or FOXO4-DRI
How does one go about self-experimentation? FOXO4-DRI is for sale on the internet, but one needs a doctor to read the mouse studies and formulate a treatment plan. The same goes for dasatinib plus quercetin. In the mouse models it needs to be administered monthly. Is there a country one can visit today that has access to these peptides and drugs and willing doctors to create a plan?
https://www.fightaging.org/archives/2017/05/planning-a-singl...
You don't need a doctor to figure out a treatment plan, you just need to put in some time to get familiar with reading research papers, the terminology, how researchers describe things, and the methodology used to move from animal to human exploratory studies. And an understanding of the risk - as doctors are usually pretty bad at explaining that in any case. It really isn't rocket science, and it is all copiously documented in scientific and other literature.
Also D+Q isn't administered monthly, it is a one-off treatment that, assuming it works in humans in the same way it does in mice, certainly wouldn't need to be done more than once every few years. It removes the cells it can remove, and then isn't going to do any more until new senescent cells arise at their slow pace. The people out there taking it frequently as though it were a supplement are just not acting sensibly, and don't understand the research.
What's more interesting is how my health/lifespan is impacted as a transwoman... Fertility is pretty badly hit by hormone therapy for both trans men and women, and in a few decades you should start having enough people to see how that actually affects outcomes. Of course... the social realities of being trans could confound that data. (E.g., being socially isolated is not good for your health)
Why might a loss of fertility particularly matter to a trans person?
Trans people often do desire to have biological children. I wish I had ovaries and a uterus and all of that, but I can't with the current state of medicine, so biologically, I'm limited to playing the male role. Hormones do nuke fertility, but I froze sperm beforehand.
I don't think the desire to have biological children is any different in trans people than it is in cis ones. I find the idea of being a mother much more appealing but that's not the hand I got dealt.
Trans men do become pregnant (look up the man who got pregnant, it was a bit of a news sensation)
Everyone experiences gender in their own way - "the most female thing a person could do" is not a fair way to describe it. Although I desire it, as a trans woman, I don't think of it as the holy grail of femininity. Perhaps biologically it is; but as a social creature how I am received socially matters more.
I also can nurse, it turns out, and if I ever did have children with my cis partner, that duty would probably fall to me.
Plenty of trans people, like cis people, have no interest in having children; still others are not invested in them being biological. It's a personal thing that varies with each individual.
The things that the broad society considers most central to gender stereotypes are not necessarily most central to (or even compatible with) individual gender identity. That’s true for cisgender individuals, and its also (perhaps even moreso) true for transgender individuals.
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.
https://medium.com/@arielf/wake-up-people-its-time-to-aim-hi...
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.
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/
For example: 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 and is even made by Dean Ornish in the trailer: http://www.fatsickandnearlydead2.com/
1. Did you see the Park et al report on DNA-PK inhibition from earlier this year? https://news.ycombinator.com/item?id=14301878
2. Is anyone working on sleep? https://twitter.com/clumma/status/764842049199898624
3. Have you considered funding low-dose ionizing radiation research? https://www.facebook.com/clumma/activity/10151804061151737
Eg, the first entry, scenescent cell removal %135, is a 35% increase, not a 135% increase.
Or is this because that falls outside of scope of what "longevity research" in this case means?
Much of the progress in society is possible only because previous generations eventually die off. What happens when that's no longer the case?