Some people say that caloric restriction is a more natural (and therefore better) way of achieving what we achieve with rapamycin. While rapamycin replicates many of the same effects of caloric restriction (and is obviously much easier to follow), there are still many issues with caloric restriction as a longevity strategy.
This paper covers many of these issues (some of which are shared with rapamycin use):
Although the potential benefits of calorie restriction on human lifespan remain uncertain, it is currently one of the most extensively researched non-genetic approaches to extending both lifespan and healthspan in animals. Calorie restriction offers numerous health benefits, including a reduced incidence of age-related diseases. However, calorie restriction also produces a range of negative effects, which are not fully documented and require further investigation, particularly in humans. As the viability of calorie restriction in humans will depend on the balance of benefits and detrimental effects, it is crucial to understand the nature of these negative effects and what drives them. In this Review, we summarize the effects of calorie restriction on wound healing, hunger, cold sensitivity, bone health, brain size, cognition, reproductive performance and infection, primarily based on studies of rodents with some data from other species and from humans. Overall, the detrimental effects of calorie restriction seem to stem directly from prioritization of vital functions and downregulation or suppression of energy-demanding processes, which helps preserve survival but can also lead to impaired physiological performance and increased vulnerability to stressors. The exact mechanisms underlying these effects remain unclear. Whether it might be possible to engage in calorie restriction but avoid these negative effects remains uncertain.
Key points
- Calorie restriction extends lifespan in a wide variety of organisms but it produces a range of both positive and negative impacts; the extent of lifespan extension depends on the balance of positive and negative effects.
- Calorie restriction delays wound healing, increases hunger and decreases metabolic rate, which leads to reduced body temperature and increased cold sensitivity.
- Bone mineral density generally declines in animals under calorie restriction, which might be appropriate relative to the extent of unloading when the animals lose body weight; hence, reduced bone mineral density might not be an adverse outcome.
- During calorie restriction, most organs shrink in size, including the brain (although cognitive impairment does not seem to occur); effects on the immune system are unclear, with some studies showing positive effects and others showing negative effects.
- Most animals under calorie restriction have impaired reproductive functions (with humans showing decreases in libido and quality of sexual life); however, when released from restriction, animals might show improvements relative to age-matched controls.
- Overall, the negative effects of calorie restriction seem to stem directly from the reduced availability of calories to support expensive functions and individuals having to prioritize energy use for immediate survival.
Paywalled Paper:
https://www.nature.com/articles/s41574-025-01111-1
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I would add: water is wet, fire is hot, ice is cold, and could you please tell us something new about CR. Because from the outline here it’s the equivalent of solemnly announcing that the earth is in fact not flat, but round. Thank you Sirs, we have known about this shocking revelation for a few centuries now.
I perked up, hoping to read about CR downsides - not the earth is round variety, but something novel that we haven’t actually known about for literally decades. No such luck from Captain Obvious and Captain YouDontSaySo.
Looking at the institutions the authors are affiliated with, yep, China represent. Most unsurprising. On the bright side, I’m sure this paper counts in the publish or perish churn, thus giving the mediocre authors another lease on academic life. YMMV.
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Haha, a bit harsh. After all, it’s a review article so they’re not going to be writing anything revolutionary. But IMO it’s a nice synopsis to put things together in one place.
In my experience, the majority of Nature Reviews XYZ articles are invited - i.e. the journal contacts the authors about writing an authoritative piece on a certain topic. Others have to go through proposals, where you submit a topic, title, abstract and structure. Then, it may be invited. They are very very selective, so I’m not sure publish or perish comes into it in this case. Though now I feel a little bit annoyed at you because I feel like you just made me defend Chinese research lol
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It sounds like you are complaining about basic science research. This is how it is. Things that we think are obvious still need to undergo scientific testing with rigor, because all too often what we think we know is actually not the case, or has a different mechanism from the expected, or we discover something totally new in the process of investigating something old.
What’s repetitive are the complaints when scientific testing confirms commonly held beliefs. That doesn’t make the research redundant—it makes it foundational. Science isn’t there to surprise you; it’s there to verify reality.
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For me this was helpful, as I can’t do caloric restriction or even intermittent fasting. My Hashimoto’s thyroid disease gets worse, I get migraines, I get extremely fatigued, I get cold, my muscles shrink. I knew this was the case, but it’s good to see evidence. I’m very glad that rapamycin provides an alternative approach to the same goal.
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You are making irrelevant and inapplicable statements. This paper was not “science confirming” anything. It was reviewing what science already established. It wasn’t confirming (or denying) beliefs, whether common or not. So your statements about how science works - including testing common beliefs - are not applicable in this case. But thank you for revealing to me something about how science works that I was aware of since being a child, and something I studied at the uni philosophy of science courses. Instead, you should have applied your remarks about the methodology of science to your own statements in this case, and that way perhaps understood the distinction between studies designed to test a hypothesis and a simple literature review.
My complaints about the paper were not that they “studied” (they studied nothing) commonly held beliefs about CR, but that in their review of the literature they uncovered nothing about CR that wasn’t already widely shown in other reviews, bringing nothing new to the table. It’s as if the paper exists exclusively to churn citations and boost publication counts. It brings no value, but increases noise.
You found it personally educational, bully for you. This is a review behind a paywall. It was not designed for the purposes if educating the public, or it would have been published in a general interest magazine. If printed, I am sure it can also be defended on the grounds that it’s useful as kindling in the fireplace, but again that was not the design of the authors.