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Abstract: >The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1,2,3. 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. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10). We 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. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11,12,13. 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. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18,19,20.

A while ago I saw an interview with a group of seniors who practiced calorie restriction for health reasons. They all moved and spoke like they lacked energy and looked generally miserable though that might have been the upper middle-class snobbery.

Given the poor quality of most Western diets which have been well established as conducive to inflammatory diseases, the results of this study might be a good example of correlation not indicating causation. Eating less food might improve health because of a reduction in inflammation caused by a poor quality diet, not necessarily because less calories are consumed. To my knowledge, calorie restriction has not been associated with longevity or any positive health outcomes in so-called blue zones:

https://en.wikipedia.org/wiki/Blue_zone#/media/File:3_blue_zones_venn_diagram.svg

We're at a point where we know what leads to healthy, long lives, there's no need to rewrite the alphabet in that sense, or more precisely, to eat less calories than we should, we simply need to restructure society so that we can practice what we know is good for us.

That's very interesting, thanks for sharing! I would be interested to see if this is related to autophagy modulation and oxidative stress given that prolonged periods of feast vs. fast may result in lower cellular turnover, and as a result, higher incidence of mutation, degradation, and greater levels of stored toxins.

Anecdotal evidence suggests intermittant and medium-term fasting promotes not only autophagy in general, but release and processing of toxins from freed lipids with ketosis. With more new cells, less malformed or damaged DNA should be present, so would that affect the DunedinPACE DNAm algorithm? For those with more time and interest, I noticed some relevant sources cited at the bottom of the report. Of particular interest are the ones regarding telomeres, the validity of the different DNAm clocks, and intermittant fasting.

I hate misspelled acronyms

Did you just refute this research with an anecdote about a conversation with hungry seniors and a venn diagram in a Wikipedia article?

He did alright.

The developed world is suffering from severe overeating. So seeing that calorie restriction can actually have beneficial effects on top of losing fat is great to hear isn't it, why would you want less of that?

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Because the diets of the participants were not analyzed, only a caloric deficit was tracked, and the results therefore can't be used to claim that sustained caloric restriction itself is a necessary predictor of better health outcomes. Someone eating an appropriate amount of calories from a good diet might have the same or better health than someone eating an unhealthy calorie restricted Western diet. In other words, it's not necessary to eat less calories than recommended to be healthy, calorie restriction is not practiced in areas known for health and longevity. There are various factors that go into good health and a long life that have been identified in blue zones but calorie restriction is not one of them.

At least that's more evidence than most politicians use to form major policies

The scientific community has known for decades that calorie restriction increases longevity in mammals, but the exact mechanisms weren't well understood. It seems like we might be narrowing down the way it works.

What does healthy or unhealthy mean in this regard? The researchers made sure that the participants were a randomized group of people in a CR and with all of their nutrients met. So that points to a really strong association between CR and this slowing in aging. Thats all this study was saying really. Of course there are various factors that go into good health and now we have potentially found an additional factor, which is why I'm suprised by your opposition to it.

Personal anecdotes have no value

Question: They say that

"In the CALERIE Trial, the %CR achieved by participants in the treatment group varied, with most participants achieving doses below the prescribed 25% (mean = 11.9)"

This seems to indicate this is not being achieved by a standardized diet. They're hitting varied reductions and most are off by 200+ calories. Wouldn't that raise some confounding issues? If the cut is hard to achieve, the fastest ways to do it are dropping junk food and calorie heavy drinks.

Smart ppl who've read the link. Yes or no?

Smart people, please explain for the rest of us.

I don't think humans evolved with an abundance of food so periods of not eating help with many biological processes I think

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Yes, we know caloric restriction works, my point wasn't to point out that it doesn't work, my point was to point out that we don't know that it leads to better health because of the lower caloric intake or because of other associated factors as was profusely discussed in the study you linked.

Your second link discussed research suggesting that when we eat is important as well, which we have also known for a while, but this has nothing to do with determining the reason why caloric restriction leads to better health and longevity. We still don't know if it's the associated factors that are responsible rather than the lower intake of calories itself.

I feel better when I'm slightly hungry, there you go with another pointless personal anecdote. Bring data or shut up

TLDR: calorie restriction of the type described in the article slowed aging but didn't change age markers.

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A healthy diet is one which contains a low amount of animal products and highly processed foods along with a good amount of fiber. In recent years we have become aware of the effects of highly processed foods in our gut microbiome and how chronic diseases are linked to inflammation caused by poor diets.

Calories being equal, a serving of plainly cooked farro is healthier than a serving of white bread in the same manner that a serving of grapes is healthier than a serving of wine, etc. because of the inflammatory effects and associated chronic diseases linked to highly processed foods.

We have known for a while that calorie restriction works, we don't know why it works, there are various competing theories. People do not like to be hungry, it affects their mood and their cognitive abilities. The point of my comment was to stress that it may not be necessary to restrict calories in order to promote health, that link has not been definitively established because the cause for improved health and longevity through caloric restriction has not been determined.

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Thank you for pointing this out. It was exactly my point in my comment. How can caloric restriction be said to lead to better health and longevity when it's inextricably linked to better diets? Wouldn't the better diet be assumed to be the real determinant? Is calorie restriction necessary at all or is it simply better diets that lead to better health and longevity? I think the answers are pretty clear, particularly when you consider what's known about the diets and cultural factors of so-called blue zones.

Irrelevant whether I'm in the minority or not (and congrats for failing to read and understand my pointless personal anecdote claim, where I mention being slightly hungry but whatever), it is still a personal anecdote which has no value. Just like yours. Go educate yourself about how science works

Its possible to over eat on food considered healthy. Its easier to feel sated on low calorie, high density foods, but you cant say eating the equivalent number of calories in burgers with toppings, wouldnt lead to the same result, without a study anyway.

TLDR if you eat less, you might live longer!

We can say that it wouldn't lead to the same result. There have been numerous studies linking highly processed foods to disturbances in the gut microbiome that lead to inflammation and chronic diseases which are far less prevalent in societies that have maintained their traditional cuisines, free or nearly free from highly processed foods.

And what proof do we have than any of that is specifically related to longevity?

Because we have studies showing that people who consume less processed foods, who have maintained their traditional cuisines, live longer on average than people who eat highly processed Western diets.

I feel crappy if I don't eat very much though.

try a fast, your body gets used to it quickly and you stop feeling hungry so easily

These are facts. Consider it a challenge and you are doing it for a good reason, helps motivate ya. In the end, a little hunger isn’t going to kill ya… at least not for many many days.

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As the authors noted, this can be seen in multiple species. In animal trials, caloric intake is often achieved by manipulating quantity of food, not type. This could suggest that energy would independently impact longevity, and that it's not simply a matter of eliminating highly processed foods. While animal studies are not the highest degree of evidence, they are often useful for determining mechanisms of action when confounding variables like this can be accounted for. This is not to say that diet quality does not also have an independent or synergistic effect on longevity, but it would point toward energy intake being a piece of the puzzle, at least.

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I don't think that's accurate. The specific question we're asking is if you control for calories can you achieve the same longevity regardless of diet. Observational studies on people who tend to eat more calorie dense refined food do not control for calorie intake.

On the Huberman Lab podcast, an interesting note he made was that in a mouse study, obese mice that fasted lived as long as healthy BMI mice that fasted and both outlived mice that did not fast/did not calorie restrict

Even if you don't live longer, it will feel longer.

Not necessarily, the reason being that animals are fed more fiber to keep them from being hungry in these studies and we already know that fiber is beneficial to health.

This particular study did not monitor diet so no, that question has not been answered. It's not understood why caloric restriction improves health and longevity, there are various competing theories which were outlined in a study someone else linked in a comment.

Diet composition compared to energy intake has also been investigated in animals. Read the introduction to the linked study and the authors discuss previous findings demonstrating CR working independently from diet composition.

“We recently completed a longitudinal study in male C57BL/6J mice (B6) initiated at 4 months of age in which the effects of the two diet compositions under ad libitum (AL) and CR conditions were measured (Mitchell et al., 2019). Independent of diet, male B6 mice on 30% CR exhibited significant improvements in health, survival, and a delayed onset of cancer with respect to AL-fed mice.”

https://www.sciencedirect.com/science/article/pii/S1550413120302357

Friendly reminder than less calories doesn't imply less volume. I love grapefruit, berries, air popped popcorn, boiled potatoes, brussels sprouts and snack on them frequenly. Just look for food that is very filling for the ammount of cals

I don't see any diet specifics listed. As I said, fiber is given to animals to account for the missing calories in these studies and we already know that fiber has beneficial effects on health, as was pointed out by this study.

I'll also add that we don't see the mood and cognitive effects of caloric restriction monitored in these studies. We already have several studies demonstrating that "hangryness" is real and has negative effects on mood and cognition which once again, circles back to my original comment. Just because we can recognize the benefits of certain practices even if we don't precisely understand them doesn't mean that those practices are sustainable or that they don't affect other areas negatively.

I do not dispute that fiber has health promoting benefits. I do feel that it’s a bit of a straw man from the original point, though. The discussion seemed to be that the less processed food, in the blue zones, was responsible for increases in longevity, independent from CI. From that perspective, I believe the animal studies, where diet composition is the same (degree of processing isn’t different) and CI is the IV, are useful. I believe they provide evidence that energy intake affects longevity independent processed food consumption.

It's not a straw man, my point was that diet is not monitored in most of these studies as was noted in the study you linked and even when diet is monitored, it is still not equal because fiber is used to supplement the diets of the animals eating the calorie restricted diet, therefore the diets are not equal in nutritional value. There's more to a good diet than low amounts of highly processed foods as I noted in a different comment, a low amount of consumed animal products along with a good amount of fiber and adequate consumption of all essential amino acids, proteins, fats, carbs, vitamins and minerals is also needed.

There has not been a study that has established why caloric restriction results in increased health and longevity therefore we can't say that it's not the co-factors associated with caloric restriction (i.e., better diets, intermittent fasting, fasting correlated with circadian rhythms, etc.) that are primarily responsible for the beneficial effects rather than the restriction of calories itself.

My purpose in pointing out blue zone diets was to demonstrate that health and longevity do not require caloric restriction. My point was also to demonstrate that caloric restriction leads to hunger and hunger leads to impaired mood and cognition which has also been well documented in other studies. Caloric restriction has benefits but we can reap those benefits through a good diet, without restricting calories, without going hungry, and without affecting our mood and cognitive abilities.