2 years of mild caloric restriction significantly reduces biological age

[WJ_PhD]

Here’s the relevant methods section on the CR being practiced. It sounds like they were shooting for 25% CR, only hit 12% on average but still saw strong CVD benefits. (I could do 12%!)

One important application for aging clocks is to evaluate the impact of intervention strategies on BA. The CALERIE phase 2 randomized controlled trial was designed to test the effects of moderate (25%) calorie restriction (CR). A cohort of 220 healthy non-obese volunteers between the ages of 20 years and 50 years were randomly assigned to either CR or ad libitum (AL) control groups and followed over 2 years55. Although, in practice, subjects from the CR group achieved only relatively moderate CR (12%), this nevertheless resulted in a significant reduction in several known CVD risk factors56

[desertshores]

Coincidentally I have been using a ~12% calorie reduction based on the average of various online calculators.

I am surprised that using a calorie restriction calculated from my age activity etc reaches a stasis. Has my metabolic rate slowed down? I have maintained a body weight of 175 lbs. for a long time with little fluctuation. BTW this is my Devine weight.

After starting rapamycin I lost weight in the first few months and seem to have reached stasis.

This of course is my ideal weight based on the calculators.

[AlexKChen]

Well how is LinAge different from PhenoAge/GrimAge and why does CR help LinAge but not the two others?

[Neo]

@Joseph_Lavelle

I cannot tell if a constant CR is the key.

Not sure. From much of the mechanistic aging literature it might or even appears to be that good want it at least a material portion of the time.

Yes, transition to better body composition and having had a period of autophagy, IGF-1 down, mTOR down, other key nutrient sensing pathways dialed towards longevity instead of towards growth, etc that can be had from a transient period of CR should be valuable as you suggested.

At the same time for maximal effect, one might have either do it most of the time or at least come back and re-enter that state meaningfully often and for a meaningful percent of the time.

(Anecdotally it seems that Michael Lustgarten and the Blueprint medical team/Bryan Johnson have reached that conclusion).

The Yale professors behind the above NIH funded CR clinical trial and/or Prof Longo and/or Prof Fontana could be amazing people to discuss these questions with - perhaps at some point they could be part of your podcast even…

The classical papers (and books) by Roy Walford that Matt Kaemberlin often refers to might also help shed some light on your question.

[Neo]

Besides this latest clock, LinAge, the mild, short term CR study also found it impacts the third generation clock, DunedinPace. Other methylation studies have also found positive impacts from CR.

Generally, think it’s about what the different clocks are designed to be able to pick up and the limitations of the older, second gen clocks and what they hence are not able to pick up.

The key thing is that the latest (third generation) clocks like Dunedin are PACE clocks - they are designed to identify the rate of aging*.

The older, second generation clocks like Pheno and Grim are AGE clocks, they are designed to predict total, cumulative biological age.

So Dunedin provides a short term, current snap shot of raging rates, while Grim and Pheno are the cumulative effects of a person entire lifetime.

More holistically:

Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5,6,7, and is established to increase healthy lifespan in multiple species8,9

Caloric restriction delays age-related methylation drift (Ref 5)

https://www.nature.com/articles/s41467-017-00607-3

Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism (Ref 6)

Dietary restriction protects from age-associated DNA methylation and induces...

Using DNA Methylation Profiling to Evaluate Biological Age and Longevity Interventions (Ref 7)

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30168-7?

More in detail

You are right that this mild, 2 year (so not yet long term) CR study found that:

CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge.

At the same time

However, these DNAm measures were developed using different methods and reflect different models of aging. The PhenoAge and GrimAge clocks [both only second generation clocks] were developed to predict mortality risk at a single timepoint in mixed-age and older adults. This approach quantifies aging as a static construct of risk accumulated across the lifetime. In contrast, DunedinPACE [a third generation clock] was developed to predict multi-system physiological decline over two decades of follow-up from early adulthood to midlife. This approach quantifies aging as a dynamic construct reflecting change in risk accumulation.

Said differently

A third generation of DNAm measures of aging are referred to as pace-of-aging measures. In contrast to first- and second-generation DNAm clocks [such as PhenoAge and GrimAge], which aim to quantify how much aging has occurred up to the time of measurement, [third generation clocks like DunedinPACE] pace-of-aging measures aim to quantity how fast the process of aging-related deterioration of system integrity is proceeding.

DunedinPACE may therefore be more sensitive than PhenoAge and GrimAge to changes induced by 2 yr of CALERIE intervention.

Treatment effect estimates may therefore represent a lower-bound of the true impact of CALERIE intervention on biological aging.

Our dose–response and TOT analyses indicated that participants who achieved higher doses of CR experienced more pronounced reductions in DunedinPACE.

The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14,15,16 and contrasting with reports that biological aging may not be modifiable17

Above is from this paper published last year by Yale in Nature Aging - it’s a good read about both CR and how to think about first vs second bs third generation clocks and how they can be used in clinical clinical trials (and in N=1 biohacking):

Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial

https://www.nature.com/articles/s43587-022-00357-y#ref-CR5

And now there is also the new clock published this week showing effect of even just the mild CR: 2 years of mild caloric restriction significantly reduces biological age

See also here for a lot of color how these later, 3rd gen rate of aging clocks have a lot of advantages vs the older 2nd gen cumulative amount of age clocks:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8853656/

[Joseph_Lavelle]

@Neo thanks. It’s a worthy topic for investing attention.

As you say, I should pose my questions to the experts in the field. I will plan to do that. Right now my mind is wondering about the importance of the living on as little calories (or maybe just protein) as possible. And what does “possible” mean? Certainly there are underfed people who continue living but who are not healthy (or healthy enough to live a good life).

So how can we determine what is too much calories or protein even if body fatness is good (no metabolic issues)? And how do we determine what is too little calories or protein (RED-S issues for example)? And how do we really know if this is a thing or are the studies confounded by test subjects who are benefiting from losing body fat or the tests are too short to tell if too little calories is causing a RED-S type problem or a sarcopenia type problem?

For now I am just focusing on getting my body comp as good as possible by feeding (and more) to reduce visceral fat while maintaining muscle mass and quality. I will try to learn more about this topic.

[Joseph_Lavelle]

For contex, here is a post that continues to shape my thinking. From a video of Luigi Fontana MD

Calorie Restriction, Exercise, And Longevity: Luigi Fontana, MD PhD

It struck me like a bolt of lightning when he said the rats that died of starvation in CR experiments were “perfectly healthy”. They died of too much autophagy. Not too little and not too much (“U shaped curve”) applies to everything?

[Neo]

Sounds good - will be amazing to listen to any such future podcasts.

One thing, that may be interesting when you look into things is that similarly to rapamycin (and perhaps in even more studies), CR has shown maximal lifespan extension across a massive evolutionary distance and across many, many types of species.

[Neo]

Yes, totally believe in a U shape here! (Edit: But almost everyone in the western world is at the point where less calories likely still would be good for longevity and very few overdo it on the other end of the U).

[Joseph_Lavelle]

@Neo We are experimenters here so each of us can make our bets. I am currently heavily influenced by Matt Kaeberlein on this topic who always says not every animal model shows improvement with CR, that people don’t live in laboratory cages (IRL gives lots of need for immune health), and no one can ask the mouse how it feels about CR.

My bet is on cycles of calorie surplus and calorie shortage. My bias is that CR sounds like a shitty life.

[Neo]

100% that we all our figuring out our own paths

I’m just trying to convey my best thinking on what likely works / how does aging work based on my understanding of what the world knows today

I personally do actually not do a lot of CR at this point, perhaps hovering about -10% half of the time and around 0% the rest of the time

But that is because of the enjoyment value of eating / avoidance of hunger feelings (that I totally agree with you on) and not because I don’t think that a Michael Lustgarten / Bryan Johnson / Oliver Zolman approach of a bit more CR would be more physically optimal for my longevity.

Btw, not sure how much it’s worth, but I think we have a bit different read on Matt Kaeberlein’s view on CR.

I agree that he sees potential safety and adherence issue for humans of extreme levels of CR a la the extreme mouse max lifespan studies

But he clearly often talks about CR as one or even the best supported max life span increasing mechanism I the literature

Just this week:

And this chart he often uses:

[desertshores]

“My bias is that CR sounds like a shitty life.”

Not for everyone.
At the age of my retirement, I was overweight.
I lost the weight by using a keto diet and intermittent fasting. The reason it was great for me is because (maybe my Scandinavian background) is that I generally don’t like vegetables and fruit.
Some people find it hard to skip breakfast but I didn’t. I didn’t like eating breakfast even as a child.

I eat two meals a day between 12 and 6 PM. I think intermittent fasting might shrink your stomach a little bit, because I now have to force myself to eat enough calories to maintain my weight.

My diet is high in protein with some fat and carbohydrates. I still don’t eat enough protein to agree with some of the studies that say I need so much protein to stave off sarcopenia. The studies may be wrong at least for people taking rapamycin. I have not had any strength or muscle loss that I can detect.

I have the memory of being very hungry after arduous exercise such as playing tennis for hours or hiking, etc. High physical activity results in increased appetite.

That said: I think exercise is as or more important than CR.
The studies lack a comparison with mice forced to use an exercise wheel every day to get fed a non-calory-restricted diet versus mice who were calorie-restricted but not forced to exercise.

[Joseph_Lavelle]

@Neo Sure. He says that. But he also says what I’ve repeated. The context is the key. I interpret Kaeberlein as not being a follower of CR

Does CR mean to not overeat, then I agree. Does CR mean to eat so little that the body has to down regulate the immune system and other organ functions? That might also be useful if we have over active function. But surely there is a level so low that is a mistake. It is far safer to cycle it to get the benefits of both retrenchment / autophagy / lower inflammation AND the benefits of growth / strength/ high energy. That’s my bet anyway.

[Neo]

@desertshores

That said: I think exercise is as or more important than CR.

Actually, think you summarized it more correctly here:

The tide turns on vo2max?

Calorie restriction extends lifespan. Exercise extends healthspan. That’s why I do both.

—

@desertshores

The studies lack a comparison

These probably speak to that question:

Exercise has been shown to protect from many age-related diseases but fails to extend maximum life span in rodents (16, 17, 21).

Although the evidence clearly shows a greater benefit from calorie restriction compared with exercise on longevity, there remains a significant gap in the literature explaining this disparate effect. The effects of calorie restriction (40) and exercise (6) on age-related diseases and markers of aging have been exhaustively studied independently, while only a limited number have examined calorie restriction and exercise in tandem (26, 36).

Rodent (17) and human studies (32) suggest that increasing energy expenditure via exercise fails to mimic the life-prolonging benefit of consuming fewer calories.

These results showed that mild and moderate calorie restriction were more effective at lowering fasting IGF-1 and insulin levels than exercise, and animals on moderate calorie restriction most closely resembled young animals for measures of hormones and stress-related proteins. In contrast, exercised animals were leaner than calorie-restricted mice and exhibited greater tissue levels of HSPs and oxidative phophorylation complex content in skeletal muscle mitochondria.

Thus, it is possible that some harmful byproduct(s) or consequence(s) associated with exercise “interferes” with the beneficial effects of being lean. Alternatively, calorie restriction may extend life span by a mechanism(s) independent of leanness, and exercise may fail to activate these critical pathways to the same scope or magnitude.

Recently, Fontana and colleagues (10–12) have examined systemic biomarkers in individuals on a selfimposed low-calorie or low calorie-low protein diet vs. individuals engaged in high-volume exercise for several years. Despite a similar body mass index (10, 12) or fat content (11), long-term calorie restriction and exercise resulted in disparate effects on various parameters related to aging, including thyroid function, systemic inflammation, and growth factors. For instance, individuals engaged in voluntary calorie restriction were found to have lower levels of serum T3 and TNF-α levels than exercisers or a control group consuming a typical Western diet (11). In another study, individuals consuming a low calorie-low protein diet were shown to have a more favorable cancer risk profile than endurance runners or controls, including lower serum IGF-1 and greater levels of dehydroepiandrosterone sulfate and sex-hormone-binding globulin (10). Furthermore, a low-calorie vegan diet resulted in lower blood pressure than exercisers (12). Taken together, the present investigation, coupled with these related studies in humans suggest that at the same relative energy deficit, exercise fails to completely mimic the beneficial changes associated with calorie restriction.

Therefore, the available evidence demonstrates that an increase in energy expenditure can attenuate disease risk (20, 22) but does not presently support the notion that an energy expenditure-induced energy deficit slows the rate of biological aging (20).

• Rats that exercise regularly will, on average, live longer compared to a group that eats the same amount but does not exercise. This is because exercise prevents some diseases, which allows more individual animals to live out their expected life span.

• However, when comparing the rats in these two groups that eat the same amount, the longest-lived animals in the exercise group don’t live any longer than the longest-lived rats in the non-exercise group. Taken together, these findings indicate that exercise can prevent an early death from disease in some rats, but does not extend the maximal lifespan of any of the rats.

• When comparing rats that exercise to those that don’t exercise but eat much less, the longest-lived rats are from the group that ate less.

For above and more see:

The tide turns on vo2max?

A. As mentioned, there is not good clinical trial or MR studies that have been provided on this topic B. So we have to triangulate as best we can and make decision under uncertainty The human correlations studies are one source The rich geroscience literature is another It seems that you either do not agree with A and B or do not think 2 is relevant. Below are some think you might want to consider / leads to look more into things: Exercise has been shown to protect from many age-related diseases but fails to extend maximum life span in rodents (16, 17, 21). Although the evidence clearly shows a greater benefit from calorie restriction compared with exercise on longevity, there remains a significant gap in the literature explaining this disparate effect. The effects of calorie restriction (40) and exercise (6) on age-related diseases and markers of aging have been exhaustively studied independently, while only a limited number have examined calorie restriction and exerci…

[Neo]

@Joseph_Lavelle

surely there is a level so low that is a mistake

Agree (and I said when agreeing that there almost certainly is a U-curve here).

@Joseph_Lavelle

It is far safer to cycle it to get the benefits of both retrenchment / autophagy / lower inflammation AND the benefits of growth / strength/ high energy. That’s my bet anyway.

I can see value to a cycling protocol (but think less data to guide).

Question is what the “highs” should look like in a cyclical protocol? It does not seem to be a binary choice and have to be extreme CR or no CR or extreme CR or surplus calories. It might be that our highs in a cyclical protocol should still be something like what Mike Lustgarten, Bryan Johnson (after he decreased the degree of CR to a more mild CR) and the NIH / Yale CALORIE trial participants on average actually ended up doing - those are much more tolerable/enjoyable and should have less of the in the moment immune system lowering effect.

[Joseph_Lavelle]

@neo. I agree that the amplitude of highs and lows matter. Too much protein at once (24 hours?) is just converted to calories to store or burn. Too much of a calorie deficit can lead (me) to overeating once the dam breaks.

I think the main idea is to maintain a healthy body fatness and muscle mass (and organ function) over time but not every day. Stress is good. Recovery is good. Adaptation is good.

I think short cycles of small excess and deficit are best for older people to minimize the muscle losses and to minimize the fat gain…which get harder to compensate for in aging. To get to the ideal body comp is hard. Staying there requires a permanent change in identity… to become the person who lives that life easily. But be careful what you wish for.

Have you seen @ConquerAging diet? I can’t help but think he “likes” it because he is starving. The most delicious meal I ever had was half of a freeze dried Hawaiian pineapple chicken camping meal that a random stranger gifted my climbing partner and I after a 8 hour climb up the Diamond of Longs Peak. I would have eaten an old shoe with cheese on it to be fair.

[Joseph_Lavelle]

I had to share this. It’s too funny.

“You might not live longer, but it’ll feel like it.”

Mark McCormick tells @mkaeberlein (X handle) his views on caloric restriction as a longevity intervention:

Solving the "Lack" of Anti-aging Discovery & Ranking Current Interventions | 42 - Mark McCormick

[Neo]

All of these points seem good/reasonable, at the macro level. The main thing I’d add is that there appear to be a whole cascade of value from CR at the more micro / molecular/ cellular aging level and we may not want to ignore or under value those.

[desertshores]

I started a CR diet by reducing about 12% of my caloric needs and I lost over 12 pounds of body weight until I reached a stasis point of 175 pounds.
I have kept my food choices that I eat and the amount of calories that I eat the same I am in excellent health. My eating window is 2 meals a day between 12 and 6 PM. I can only conclude that my metabolism has slowed down. Do you think this is true?

When the body experiences a prolonged calorie deficit, it can initiate adaptive mechanisms to conserve energy and slow down the metabolic rate. This metabolic adaptation is a natural response to perceived starvation,

The point is I think people can practice caloric without too much trouble or pain.
Just start slow by gradually reducing your eating window to no more than 8 hours. Changing from a high-carb diet to a low-carb diet. Eggs, beef, poultry, pork, fish, etc. reduce hunger pangs for longer periods than carbs.
An old saw that most of us older folks have heard: “Eat at a Chinese restaurant and you are hungry an hour later”.

An old maxim actually taught in health class was: “Eat slowly and chew your food thoroughly and your stomach and health will thank you for it” They even specified that you should chew each bite twenty times. There is some truth to this advice.

It’s obvious that calorie restriction for many is too hard for various reasons.

[Joseph_Lavelle]

@desertshores nice Certainly your body will shrink to fit your calorie intake. That’s good news and bad news. If you have excess fat in unhealthy places on your body (and maybe just too much in general due to impact on blood flow and brain size, according to Dr Loh), shrinking is good. But the body doesn’t only go after body fat. It will protect body fat. It also goes after sex hormones, and muscles, and organ size, and immune function. This is the RED-S deal. Maybe it’s sarcopenia and osteoporosis related.

So what the right amount of calories? Of protein ? I don’t know. I’m trying to figure that out for myself right now.