Dietary restriction impacts health and lifespan of genetically diverse mice

[helenas]

https://www.nature.com/articles/s41586-024-08026-3

Abstract

Caloric restriction extends healthy lifespan in multiple species1. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored2,3,4,5,6,7,8. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity9. Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice. We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling—an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life. Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials.

a , The study design: 960 female DO mice were randomized to one of five diet intervention groups: ad libitum (AL); one day (1D) or two consecutive days (2D) per week fasting; or CR at 20% (20%) or 40% (40%) of estimated adult food intake. b , Kaplan–Meier survival curves by diet group. The dashed lines indicate the median lifespan. Censoring events are indicated by an ‘X’. c , Kaplan–Meier estimates of median (50% mortality) and maximum (90% mortality) lifespan by diet group, showing the percentage change relative to AL and the 95% confidence intervals (computed using R/survfit). n = 937 mice. d , Mortality doubling times estimated from a Gompertz log-linear hazard model, showing the percentage change relative to AL and the 95% confidence intervals (computed using R/flexsurvreg). n = 937 mice. e , Individual mouse lifespans (points) within diet groups. n = 188 (AL), n = 188 (1D), n = 190 (2D), n = 189 (20%) and n = 182 (40%). The box plots show the median lifespan (centre line), quartiles (box limits) and range (whiskers).

Who wants to start deep-diving this? Not me

[RapAdmin]

So, who’s up for 40% dietary restriction from their current levels?

Full Paper available here:

UNTITLED

Commentary in Nature:

[RapAdmin]

In the Nature Commentary they mention “the way rapamycin is processed by the body (its pharmacokinetics) varies markedly between individuals”, and they reference this paper for the source of this information:

Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus - PubMed

Results: Pharmacokinetic studies in adult renal transplant patients have shown that sirolimus may be characterized as a drug with rapid absorption (t(max) = 1 to 2 hours), low systemic availability (F = 14%), linear dose proportionality (2 to 24 mg), extensive partitioning into formed blood elements (B/P = 36), large apparent volume of distribution (1.7 L/kg), prolonged terminal half-life (62 hours), and large intersubject (CV = 52%) and intrasubject (CV = 26%) variability in oral-dose clearance. Results from phase 111 pivotal trials showed that sirolimus (2 or 5 mg/d) reduced acute renal graft rejection (generally, P < 0.01) without TDM. Although TDM may not be required for a regimen consisting of full-dose cyclosporine and corticosteroids with sirolimus 2 mg/d (4 hours after cyclosporine), it may be warranted in patients (1) with hepatic impairment, (2) who are young children, (3) who are receiving concurrent doses of strong CYP3A/p-glycoprotein inhibitors or inducers, (4) in whom cyclosporine dosing is markedly reduced or discontinued, and (5) who are at a high risk for rejection. A whole-blood sirolimus therapeutic window of 5 to 15 ng/mL (measured by microparticle enzyme immunoassay) is recommended for patients at standard risk of rejection. The large intrapatient variability observed in trough sirolimus concentrations indicates that dose adjustments should be optimally based on more than a single trough sample. Because of the time required to reach steady state, sirolimus dose adjustments would optimally be based on trough levels obtained >5 to 7 days after a dose change.

Conclusions: The effective use of sirolimus in an immunosuppressive regimen for the prevention of acute renal allograft rejection requires an understanding of the drug’s clinical pharmacokinetics, concentration/adverse-effect relationship, concentration-efficacy relationship, and TDM.

Full Paper below:

macdonald2000.pdf (2.4 MB)

[helenas]

thanks i was looking for that commentary

[helenas]

any experts here on mouse chow? been a long time since i looked into any of this stuff. these mice were fed standard LabDiet chow:
https://www.labdiet.com/product/detail/5k20-labdiet-jl-mouse-breeder-auto

I always wonder studies like this show up, how much of it is simply due to mice eating the equivalent of a SAD (standard american diet). nothing about this kind of food impresses me. i’d much prefer to see lifespan effects from mice calorically-restricted from eating equivalent of an organic, non-American-ingredient sourced (maybe Italian, Japan, Greek ingredients only) diet, and then compare their lifespan. until then, i have no clue how much of these effects are simply due to the absence of poor quality ingredients in the diet.

[helenas]

rapamycin, on the other hand, avoids these confounders, and is a single variable. i don’t think the CR story will be settled any time soon.

[RapAdmin]

If anyone wants to jump in and try 40% Caloric Restriction for 6 months - feel free. I’ve tried it and its painful, as I’ve described in this forum before (you’re skinny, hungry, cold, weak and your libido drops through the floor). And if I remember correctly, CR in mice later in life didn’t improve lifespan much if at all.

For most of us, a caloric restriction mimetic (as rapamycin is sometimes described) is probably the best bet. Rapamycin is not a perfect CR mimetic, but its a venn diagram with a lot of overlap.

[AnUser]

@RapAdmin

If anyone wants to jump in and try 40% Caloric Restriction for 6 months - feel free. I’ve tried it and its painful, as I’ve described in this forum before (you’re skinny, hungry, cold, weak and your libido drops through the floor).

It’s about the same caloric reduction as the Minnesota Starvation Experiment.

Emotional Changes. During the semi-starvation and the rehabilitative phases, participants were recorded developing new anxiety and depressive symptoms not present at the beginning of the study. Using the Minnesota Multiphasic Personality Inventory (MMPI), Keys et al. (1950) recorded significant increases on the Hysteria, Hypochondriasis, and Depression scales indicating increased anxiety related to somatic concerns and depressive symptoms. Especially during the semi-starvation period, some participants endorsed becoming more sensitive and argumentative with others. Over the first 6 weeks of the rehabilitation period, many men reported feeling even more depressed than the semi-starvation phase; especially those individuals in the rehabilitation group that were fed less calories in the beginning of the phase to test refeeding strategies. Keys et al. (1950) remarked that the only times these participants showed positive emotional reactions were in response to discussing their weight, food, or hunger.

The Starvation Experiment

[RapAdmin]

And probably just as fun.

[AnUser]

… Of the original core group that did hard core longer term CR I can only think of a few names, Dean now eats like 3,000 calories a day, we haven’t heard from Michael in a while but I’ve been told his diet damaged his thyroid, no idea if he has had any other issues, Al and Saul and Paul all have osteoporosis, didn’t Al have a heart attack last year? Matt is fighting for his life with a deadly bacterial infection, Paul doesn’t answer inquiries on his own website/forum anymore, and of course the godfather of CR Roy Walford himself died at age 79. A reporter asks for just ONE case study of long term CR to step forward and gets crickets, haha. Saul why don’t you volunteer for this reporter? I would definitely read that article!

Omitted is the webadmin of the CR society forum passing away making the forum unavailable for 4 months recently.

Journalist in UK (Daily Telegraph health pages) is looking for case studies

It makes me think that CR, at least hardcore CR isn’t good. But I don’t know. Small reductions and careful measurement over time including DEXA scans seems important.

[CronosTempi]

I’ve been on that list, and interacted with these people and many more who went on the CR journey longer or shorter term. I’ve been on strict CR for some 8 years, but am no longer so. I still don’t overeat, but my view of CR in humans has evolved over the years and has become far more nuanced than in the early days, decades ago where the enthusiasm based on Walford’s work led to the “it’s all about the calories” mantra.

It’s funny, but most of the insights from this study were already explored on the list over the decades. Nothing new. Been there, done that. In particular the decoupling of healthspan and lifespan. There were intense arguments about exercise, with the general acknowledgement that it squares the survival curve but does not extend it, and that at the extremes it can be actually counterproductive; if you want to go for the records, it’s CR all the way, abandoning any exercise beyond the simple functional movement. I personally have always been a proponent of “it’s the genes” view, in keeping with the unromantic adage of “it’s better to be lucky than good”… I’ve gotten into many long arguments over this view, and the persistance of the just world fallacy (in this context: surely if I do everything right I’ll be rewarded with a long and healthy life). I could never get over the real life evidence: countless paragons of good health practices living not that long, and the huge variety of lifestyle among the true supercentenarians. Since such diverse lifestyles (icluding the quite unhealthy!) all can end up with 110+ years, clearly it’s not about lifesyles but the blind luck of genes… which is why asking the very old “how did you do it” makes no sense, they can’t give us any actionable advice (be lucky!), and have traditionally been all over the place.

You can fiddle at the margins, boost healthspan, but in the end you have a set physiological potential, and lifestyle interventions (diet, exercise, smoking etc.) will at best allow you to reach it in full, whether yours is 75, 85, 105 or 125. Your genes set your limit, whatever it may be. Only pharma, and ultimately genetic manipulation can truly affect lifespan beyond your natural limits. Pharma in turn depends on individual response (driven by your genes!), so rapa or drug X, will work on a spectrum from very well to not at all and even counterproductive. Luck of the draw. In the long run, it’s all about genetic manipulation, and we are still nowhere on that journey.

Speaking for myself, I’m about to roll the dice with rapa and hope for the best, while keeping an eye out for better drugs. Genetic manipulation - not within my lifetime (I’m 66), and suspect not within yours either, even if you were born just this morning. We’ll see where this strange and wondrous jorney of life takes us…

[RapMet]

What was your daily calorie intake (i.e.2200@60%=1300-1400)? I think it depends on what kind of food you are eating also. It would be different eating two 12 OZ steaks (one lunch and one for dinner) as opposed to eating 3 large muffins LOL. I haven’t tried for too long of periods, but I’ve done up to 20 days eating exactly 2 organic steaks per day with veggies (lunch and dinner), and I was neither hungry, nor felt cold. BTW, It was when Covid hit and our company closed doors for 25 days and had plenty of time to cook, otherwise I would have literally done it for 6 months or longer. The calories were exactly 1500 (about 1350 from steaks and 100-150 from vegies) and while I felt great didn’t lose much, maybe about 1.5lbs.

[Joseph_Lavelle]

My CR plan is to remain able to fit into my high school waist size pants. I weight a few pounds more than my 18 year old self, but I have more muscle mass. I was lifting hard in HS but only upper body. No doubt I could cut calories back to slow down some (which?) of my bodily processes but I’m unconvinced so far. I have used FMD periodically with good effect on visceral fat (and joint pain). I have also cut way back on protein (via low protein days in schedule) to get closer to the “least necessary” for my activity and body plan. Previously I was on the “most protein possible” plan with good effect on body composition but possibly accelerated aging.

[RapMet]

@Joseph_Lavelle

I have also cut way back on protein (via low protein days in schedule) to get closer to the “least necessary” for my activity and body plan.

I guess you missed the part on Attia podcast where he says you need like 5kg of meat per day hahaaa, maybe he doesn’t quite say 5kgs but he did say some really high protein amount daily is important for longevity. I myself do have my doubt that we need that much protein, but who knows.

[RapMet]

@Joseph_Lavelle

My CR plan is to remain able to fit into my high school waist size pants

wouldn’t recommend you do that. I don’t know about other people but for me would be practically impossible to fit into my 18 year old pants. I had way less body mass (muscles and bones) than I have now (not including the fat). As matter of fact, I had very little fat, if any till I hit about 30-33 but my size pants were way bigger at 26 (my best composition) than when I was 18 (a toothpick lol). Probably I wouldn’t mind fitting into my 18-year-old pants when I’m 105, but not at 50 nor even 70. I would however love to be able to fit into the size I was at 26 years old.

[Joseph_Lavelle]

I already fit into my HS pant size 34. I wore 36 in my late 20’s and then needed 38’s in late 30’s. I bought a pair of 38’s but never wore them. I stewed over the bigger pants for a few days before deciding I would never wear bigger pants. I got down to 36 and eventually 34’s where I have stayed (mostly) for the last 20 years.

Now that I’m on Rapa and focused on losing all visceral fat, I have no “love handles”. My pants are loose. I have to wear a belt to keep my pants from falling down. I don’t mind.

[RapMet]

@CronosTempi

You can fiddle at the margins, boost healthspan, but in the end you have a set physiological potential, and lifestyle interventions (diet, exercise, smoking etc.) will at best allow you to reach it in full, whether yours is 75, 85, 105 or 125. Your genes set your limit, whatever it may be. Only pharma, and ultimately genetic manipulation can truly affect lifespan beyond your natural limits.

I agree with most of your message, but I tend to believe that the “genes” effect while very real/true it can’t give too long of a span/difference in lifespan (unless born with some defect). Assuming that all people did everything right lifestyle wise (this may not be exactly same for everyone, what is good for me may not be so good for some) then everyone could possibly live 100-110 (as an example) but I doubt some will die at 75 and some will live to 120 on genes alone.

[RapMet]

Ah it seems you matured fast, but for me I kept growing till about 24 (maybe 3/4 of inch taller at 24 than 18, but much stronger and built, had naturally six pack even though I didn’t exercise much, lost the 6pack around 34-36 years old). I wore 30 in HS and 33-34 at age 25.

[JuanDaw]

There seems to be evidence in humans, not for maximal lifespan, but for reduction in mortality.

Calorie restriction in humans: an update

Calorie restriction without malnutrition in World War I and II

Involuntary episodes of CR are not uncommon in human history, but only few of these events were not accompanied by malnutrition, because the local governments wisely enforced food restriction with an adequate consumption of essential nutrient-dense foods. During World War 1 in 1917, Danish men and women were forced to reduce food consumption for 2 years, but with a well-planned and adequate consumption of whole grain cereals, vegetables, and milk. The result of this undesired experiment was an impressive 34% reduction in death rates (Hindhede, 1920). Similarly, in Norway during World War 2, the citizens of Oslo underwent a forced 20% CR without malnutrition (i.e. Norwegians were provided with adequate intake of fresh vegetables, potatoes, fish and whole cereals) for approximately 4 years (1941–45). In this forced experiment, mortality dropped by 30% compared to the pre-war level in both men and women (Strom and Jensen, 1951).

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Is it possible that a brief CR episode in life can sustain the benefits, similar to how short-term rapamycin-taking benefits mice for life? How brief is brief? Do we do take the proportionate brief period in mice? That is a long time. Three months of 36 months (mouse lifespan) is eight years in humans (ten percent).

Transient rapamycin treatment can increase lifespan and healthspan in...

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

[AnUser]

Cryonics might be the most promising longevity intervention: “Just freeze me in a tank in liquid nitrogen and resurrect me in a few hundred years if civilization makes it”.

I wonder what the endpoints should be for drugs like rapamycin, are you going to monitor all of your biomarkers: liver, kidney, blood cells, etc, and see if they go into or out of the optimal range? Like Lustgarten, or are you using some other measure of efficacy? We don’t know ex-ante if it works, while we are more sure of drugs with clinical trials (without even such measurement). Or do you just forget measurement and go for drugs in the literature with potential like rapamycin, and more proven benefit, like statins?