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Main CALERIE II Results

Michael R

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This is evidently the main report from the CALERIE study, an NIA trial that was billed as a CR feasibility study in humans. Most earlier "CALERIE" reports came from pilot studies, which unfortunately used entirely overweight and obese people, making it impossible to disentangle beneficial effects or effects suggesting CR's translatability from simple obesity-avoidance effects. CALERIE proper was somewhat more selective — "Body mass index averaged 25.1 (range: 21.9–28.0kg/m2)" — but this unfortunately still leaves a lot of suspect data points. Additionally, the degree of CR intended was mild, and that achieved and sustained was even milder.


Anyway, here is the abstract of the CALERIE report:


A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity


Eric Ravussin, Leanne M. Redman, James Rochon,, Sai Krupa Das, Luigi Fontana–, William E. Kraus, Sergei Romashkan, Donald A. Williamson, Simin N. Meydani, Dennis T. Villareal, Steven R. Smith, Richard I. Stein, Tammy M. Scott, Tiffany M. Stewart, Edward Saltzman, Samuel Klein, Manju Bhapkar, Corby K. Martin, Cheryl H. Gilhooly, John O. Holloszy, Evan C. Hadley8, Susan B. Roberts, for the CALERIE Study Group


... Methods. To determine CR’s feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21–51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. Outcomes were change from baseline resting metabolic rate adjusted for weight change (“RMR residual”) and core temperature (primary); plasma triiodothyronine (T3) and tumor necrosis factor-α (secondary); and exploratory physiological and psychological measures.


Results. Body mass index averaged 25.1 (range: 21.9–28.0kg/m2). Eighty-two percent of CR and 95% of AL participants completed the protocol. The CR group achieved 11.7±0.7 %CR (mean ± standard error) and maintained 10.4±0.4% weight loss. Weight change in AL was negligible.


RMR residual decreased significantly more in CR than AL at 12 months (p = .04) but not 24 months (M24). [All available evidence is that reductions in RMR disappear over time once corrected for metabolic mass anyway, so this is both expected and seems like an unproductive thing to have had as a primary outcom -MR]. Core temperature change differed little between groups. [Of course, data from proper human CR documents a significant drop in body temperature -MR]. T3 decreased more in CR at M12 and M24 (p < .001), while tumor necrosis factor-α decreased significantly more only at M24 (p = .02). CR had larger decreases in cardiometabolic risk factors and in daily energy expenditure adjusted for weight change, without adverse effects on quality of life.


Conclusions. Sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.


I should be able to get access to the full text soonish, and will provide more details if someone else doesn't beat me to it.

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  • 1 month later...

There is a paper [1] out this month describing new results from the CALERIE Study - a controlled trial of modest CR in humans. 

Here are the highlights:
  • ~200 subjects were 20-50 years old, male and female, with BMI that averaged about 25.. Split into two groups of about 100 each, CR and ad lib. Reference [2] provides details on the intervention used to assist with compliance, including providing some food, nutritional counselling, food diaries, etc. 
  • They were targeting 25% CR for the CR group, but were only able to achieve about 10% calorie reduction overall.. The intervention and subject motivation apparently wasn't quite up to the task of getting these people to cut calories 25%.
  • There was a (modest) 18% attrition rate for subjects in the CR group by the 2 year mark.
  • At the end of 2 years, CR subjects had lost an average of 17 lbs (~10% of body weight), 69% of which was fat.
  • From the supplemental data, overall bone mineral density wasn't statistically significantly reduced, but spine and hip bone mineral density was reduced in CR participants relative to controls, although in the discussion the authors characterized the drop as "small".. "The change in BMD at the lumbar spine (AL: 0.007±0.004, CR: -0.013±0.003 g/cm2p<.001), and femoral neck (-0.005±0.004 vs.-0.015±0.003 g/cm2p=.03) was significantly greater in the CR group (data not shown)." Probably not surprising, since these were relatively sedentary people, and weight loss is known to be associated with reduced BMD.
  • Resting metabolic rate and body temperature didn't change significantly in the CR group, but total daily energy expenditure dropped more in the CR group relative to controls (~100 kcal/day more).. They may have been fidgeting less, or spending less energy lugging those extra pounds around.
  • CR reduced thyroid hormone and inflammation markers after two years (c-reactive protein dropped 33%) .
  • CR reduced total cholesterol (-9 mg/dl), triglycerides (-25 mg/dl), and blood pressure (-3 mmHg), and increased insulin sensitivity, relative to controls (all P < 0.001).
  • Although in the paper they say there weren't any significant differences in the quality of life measures between the CR and AL groups after 2 years, it appears from the supplemental data that scores of depression were significantly improved in the CR group relative to controls (p < 0.04).. I'm not sure why this wasn't called out, except perhaps because they were looking for (and reporting on) adverse effects of CR on QOL measures, and a mood improvement certainly wouldn't be considered adverse.  Perhaps subjects were pleased with their weight loss.
So overall the results weren't very surprising, given what we already know from members of the CR Society - modest calorie restriction leads to modest improvements in a variety of biomarkers of health, and possibly longevity.
[1] J Gerontol A Biol Sci Med Sci.. 2015 Sep;70(9):1097-104.. doi:10.1093/gerona/glv057.. Epub 2015 Jul 17..

A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility
and Effects on Predictors of Health Span and Longevity..

Ravussin E(1), Redman LM(2), Rochon J(3), Das SK(4), Fontana L, Kraus WE(5),
Romashkan S(6), Williamson DA(2), Meydani SN(4), Villareal DT(7), Smith SR(8),
Stein RI(7), Scott TM(4), Stewart TM(2), Saltzman E(4), Klein S(7), Bhapkar M(5),
Martin CK(2), Gilhooly CH(4), Holloszy JO(7), Hadley EC(6), Roberts SB(4);
CALERIE Study Group..

Full Text: http://biomedgerontology.oxfordjournals.org/content/70/9/1097.full

BACKGROUND: Caloric restriction (CR), energy intake reduced below ad libitum (AL)
intake, increases life span in many species.. The implications for humans can be
clarified by randomized controlled trials of CR..

METHODS: To determine CR's feasibility, safety, and effects on predictors of
longevity, disease risk factors, and quality of life in nonobese humans aged
21-51 years, 218 persons were randomized to a 2-year intervention designed to
achieve 25% CR or to AL diet.. Outcomes were change from baseline resting
metabolic rate adjusted for weight change ("RMR residual") and core temperature
(primary); plasma triiodothyronine (T3) and tumor necrosis factor-α (secondary);
and exploratory physiological and psychological measures..

RESULTS: Body mass index averaged 25.1 (range: 21.9-28.0kg/m(2)).. Eighty-two
percent of CR and 95% of AL participants completed the protocol.. The CR group
achieved 11.7±0.7 %CR (mean ± standard error) and maintained 10.4±0.4% weight
loss.. Weight change in AL was negligible.. RMR residual decreased significantly
more in CR than AL at 12 months (p = .04) but not 24 months (M24).. Core
temperature change differed little between groups.. T3 decreased more in CR at M12
and M24 (p < .001), while tumor necrosis factor-α decreased significantly more
only at M24 (p = .02).. CR had larger decreases in cardiometabolic risk factors
and in daily energy expenditure adjusted for weight change, without adverse
effects on quality of life..

CONCLUSIONS: Sustained CR is feasible in nonobese humans.. The effects of the
achieved CR on correlates of human survival and disease risk factors suggest
potential benefits for aging-related outcomes that could be elucidated by further
human studies..

PMID: 26187233



[2] Contemp Clin Trials.. 2011 Nov;32(6):874-81.. doi: 10.1016/j.cct.2011.07.002.. Epub 2011 Jul 8..

The CALERIE Study: design and methods of an innovative 25% caloric restriction


Rickman AD(1), Williamson DA, Martin CK, Gilhooly CH, Stein RI, Bales CW, Roberts
S, Das SK..

Animal studies have shown that life span is extended by caloric restriction (CR)..

This manuscript describes the design and methodology of an innovative CR
intervention, which is the treatment arm of the CALERIE Study.. This study is a
multi-center, randomized controlled trial examining the effects of 2 years of CR
on biomarkers of longevity among non-obese (BMI ≥ 22 kg/m(2) and <28 kg/m(2))
adults.. CALERIE is the first investigation of the effects of long-term CR on the
aging process in non-obese humans.. 220 healthy volunteers across 3 sites were
recruited beginning in May 2007.. Participants were randomized in a 2:1 ratio
between the CR or control group (i.e., ad libitum diet).. An intensive
intervention was designed to assist participants in adhering to the 25% CR
prescription for a two-year duration.. The intervention was designed to optimize
the likelihood that 25% CR would be achieved through a variety of nutritional and
behavioral strategies, several of which are innovative methods for achieving CR..
The intervention includes the following components: an intensive, "mixed" format
schedule of group/individual sessions, meal provision phase with exposure to
various diets, Personal Digital Assistants to monitor caloric intake, unique
portion estimation training, tailored treatment using a computer tracking system,
toolbox strategies and algorithms, as well as comprehensive coverage of nutrition
and behavioral topics in order to assist participants in meeting their CR goal..

This manuscript provides an overview of the CR intensive intervention and may be
of assistance for other researchers and clinicians in designing future trials..

PMCID: PMC3185196
PMID: 21767664


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  • 1 month later...

There is yet another new paper [1] out on the CALERIE 2-year clinical trial of human CR in normal weight individuals. Its the same study described in the previous post, just with a different focus of analysis. This one focused on the IGF-1, IGF Binding Factors (IGFBF) and cortisol differences between the CR group and controls.


Despite significant weight loss over the 2 years (~17lbs on average), the CR group didn't experience a drop in serum IGF-1 level relative to controls. They strange thing is that IGF-1 dropped in BOTH CR and control groups by very statistically significant amounts, namely -15% in CR group and -19% in controls, (p < 0.001 within-group drop for both groups)). The authors (including Luigi Fontana) didn't give an explanation for this anomaly. The control group didn't lose weight, nor did they decrease their protein intake - either of which might have otherwise explained their drop in IGF-1. The CR group did increase their protein intake by 1-2% of total calories (from 16% at baseline to 17-18% after one to two years), which the authors speculate could potentially have prevented a drop in IGF-1, but that seems like a pretty small change in percentage protein to account for the lack any (relative) effect  on IGF-1 of significant weight loss and CR, given the dramatic drop in IGF-1 reported by long-term human calorie restrictors like us.


They did observe an increase in one of the IGF-1 binding factors, IGFBF-1 (by 25% and 21% at one year and two years respectively), in the CR group, which would significantly reduce the bioavailability of IGF-1, which would presumably be good for health and longevity, per Luigi's hypothesis that IGF-1 is (one of) the major pathways for CR benefits. Cortisol was elevated at 1 year in the CR group, but had returned to baseline by year 2. 


Overall, seemingly more muddled and less-than-earth-shattering results from the only long-term (semi-*)controlled trial of CR in normal weight humans...




*semi-controlled since their calorie intake was self-reported and compliance was said to be somewhat of an issue in the CR group, resulting in less CR than was originally targeted.



[1] Aging Cell. 2015 Oct 6. doi: 10.1111/acel.12400. [Epub ahead of print]

Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding
proteins and cortisol in nonobese men and women: a randomized clinical trial.
Fontana L(1,)(2,)(3), Villareal DT(1,)(4), Das SK(5), Smith SR(6,)(7), Meydani
SN(5), Pittas AG(5), Klein S(1), Bhapkar M(8), Rochon J(8,)(9), Ravussin E(6),
Holloszy JO(1); CALERIE Study Group.
Young-onset calorie restriction (CR) in rodents decreases serum IGF-1
concentration and increases serum corticosterone levels, which have been
hypothesized to play major roles in mediating its anticancer and anti-aging
effects. However, little is known on the effects of CR on the IGF-1 system and
cortisol in humans. To test the sustained effects of CR on these key hormonal
adaptations, we performed a multicenter randomized trial of a 2-year 25% CR
intervention in 218 nonobese (body mass index between 22 and 27.8 kg m(-2) )
young and middle-aged (20-50 years age range) men and women. Average CR during
the first 6 months was 19.5 ± 0.8% and 9.1 ± 0.7% over the next 18 months of the 
study. Weight loss averaged 7.6 ± 0.3 kg over the 2-years period of which 71% was
fat mass loss (P < 0.0001). Average CR during the CR caused a significant 21%
increase in serum IGFBP-1 and a 42% reduction in IGF-1:IGFBP-1 ratio at 2 years
(P < 0.008), but did not change IGF-1 and IGF-1:IGFBP-3 ratio levels. Serum
cortisol concentrations were slightly but significantly increased by CR at 1 year
only (P = 0.003). Calorie restriction had no effect on serum concentrations of
PDGF-AB and TGFβ-1. We conclude, on the basis of the present and previous
findings, that, in contrast to rodents, humans do not respond to CR with a
decrease in serum IGF-1 concentration or with a sustained and biological relevant
increase in serum cortisol. However, long-term CR in humans significantly and
persistently increases serum IGFBP-1 concentration.
PMID: 26443692
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Were any dietary guidlines given at the outset of the study regarding a target macro-nutrient ratio since protein is the determinent for IGF-1 cascade?


Also, the cortisol response seems predictable to me in that the body adapted to a new normal thus alleviating stress; plus, a 10% reduction in calories vs. AL does not seem that great of a stressor compared to what mice are subjected too. 

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The CALERIE Study participants received standard nutritional advice and regular dietary counciling throughout the study. Their protein intake, at around 16 percent of calories, really wasn't THAT high.


You are right that only 10% CR relative to baseline was disappointing, and could explain the lack of typical CR-induced metabolic effects, including a reduction in IGF-1.



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  • 4 weeks later...

Another report from CALERIE:



J Bone Miner Res. 2015 Aug 31. doi: 10.1002/jbmr.2701. [Epub ahead of print]
Effect of Two-Year Caloric Restriction on Bone Metabolism and Bone Mineral Density in Non-obese Younger Adults: a Randomized Clinical Trial.
Villareal DT Fontana L Das SK, Redman L, Smith SR, Saltzman E, Bales C, Rochon J, Pieper C, Huang M, Lewis M, Schwartz AV; CALERIE Study Group.


... Two-hundred eighteen non-obese (body mass index [bMI] 25.1 ± 1.7 kg/m2 ), younger (age 37.9 ± 7.2 years) adults were randomly assigned to 25% CR (CR group, n = 143) or ad libitum (AL group, n = 75) for 2 years. ... Body weight (-7.5 ± 0.4 versus 0.1 ± 0.5 kg), fat mass (-5.3 ± 0.3 versus 0.4 ± 0.4 kg), and fat-free mass (-2.2 ± 0.2 versus -0.2 ± 0.2 kg) decreased in the CR group compared with AL (all between group p < 0.001).


Compared with AL, the CR group had greater changes in BMD at 24 months: lumbar spine (-0.013 ± 0.003 versus 0.007 ± 0.004 g/cm2 ; p < 0.001), total hip (-0.017 ± 0.002 versus 0.001 ± 0.003 g/cm2 ; p < 0.001), and femoral neck (-0.015 ± 0.003 versus -0.005 ± 0.004 g/cm2 ; p = 0.03). Changes in bone markers were greater at 12 months for C-telopeptide (0.098 ± 0.012 versus 0.025 ± 0.015 μg/L; p < 0.001) [a marker of bone resorption], tartrate-resistant acid phosphatase (0.4 ± 0.1 versus 0.2 ± 0.1 U/L; p = 0.004) [an osteoclast activity marker, and thus of bone resorption], and bone-specific alkaline phosphatase (BSAP) (-1.4 ± 0.4 versus -0.3 ± 0.5 U/L; p = 0.047) [marker of bone anabolism, albeit not a strong one] but not procollagen type 1 N-propeptide [a marker of metabolism "of procollagen to collagen ... [which] appears to be a more sensitive marker of bone formation rate in osteoporosis ... [and is]  being developed for clinical use."]; at 24 months, only BSAP differed between groups (-1.5 ± 0.4 versus 0.9 ± 0.6 U/L; p = 0.001).


The CR group had larger increases in 25-hydroxyvitamin D, cortisol, and adiponectin and decreases in leptin and insulin compared with AL. However, parathyroid hormone and IGF-1 levels did not differ between groups [see PMID: 26443692, posted and discussed abovein this thread]. The CR group also had lower levels of physical activity.


Multiple regression analyses revealed that body composition, hormones, nutrients, and physical activity changes explained ∼31% of the variance in BMD and bone marker changes in the CR group. Therefore, bone loss at clinically important sites of osteoporotic fractures represents a potential limitation of prolonged CR for extending life span. Further long-term studies are needed to determine if CR-induced bone loss in healthy adults contributes to fracture risk and if bone loss can be prevented with exercise.

PMID: 26332798

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  • 5 months later...

Those researchers from the CALERIE 2 study keep churning out the publications.


Recall in their last publication (PMID 26443692) they focused on the safety of practicing moderate CR for two years in people who started at the borderline of overweight.  I commented in my analysis of that paper that was surprised they didn't play up the (albeit modest) psychological improvements they observed, burying them in the supplemental material and simply characterizing their results as "no serious psychological side effects".


The reason for downplaying the psychological results is now clear - they had another paper in the pipeline focuses entirely on the psychological effects of CR, which has now been published [1] (popular press story).


What they found shouldn't be very surprising, to us anyway. Over the two years of moderate CR the subjects dropped from an average BMI of around 25 to about 22.5, right to the heart of the "normal" BMI range. In conjunction with the weight loss, they reported modest improvements in measures of subjective well-being pretty much across the board: 


Compared with the AL group, the CR group had significantly improved mood.., reduced tension..., and improved general health... and sexual drive and relationship ... at month 24 as well as improved sleep duration at month 12... (all P < .05). Greater percent weight loss in the CR group at month 24 was associated with increased vigor ... and less mood disturbance..., improved general health ..., and better sleep quality ... (all P < .01).


Those are all nice improvements to see, and should encourage people thinking about modest CR to give it a try. Of course, they aren't especially relevant for many folks around here, who've taken CR farther than a BMI of 22.5. Fortunately most of the psychological benefits continue to obtain at lower BMIs as well, with the possible exceptions of increased sleep duration and sex drive...





[1] JAMA Intern Med. Published online May 02, 2016. doi:10.1001/jamainternmed.2016.1189.


Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and Sexual Function in Healthy Nonobese Adults: The CALERIE 2 Randomized Clinical Trial. 


Martin CK, Bhapkar M, Pittas AG, et al. 


Free full text: http://archinte.jamanetwork.com/article.aspx?articleid=2517920




Importance  Calorie restriction (CR) increases longevity in many species and reduces risk factors for chronic diseases. In humans, CR may improve health span, yet concerns remain about potential negative effects of CR.


Objective  To test the effect of CR on mood, quality of life (QOL), sleep, and sexual function in healthy nonobese adults.


Design, Setting, and Participants  A multisite randomized clinical trial (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 [CALERIE 2]) was conducted at 3 academic research institutions. Adult men and women (N = 220) with body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 22.0 to 28.0 were randomized to 2 years of 25% CR or an ad libitum (AL) control group in a 2:1 ratio favoring CR. Data were collected at baseline, 12 months, and 24 months and examined using intent-to-treat analysis. The study was conducted from January 22, 2007, to March 6, 2012. Data analysis was performed from July 18, 2012, to October 27, 2015.


Interventions  Two years of 25% CR or AL.


Main Outcomes and Measures  Self-report questionnaires were administered to measure mood (Beck Depression Inventory-II [bDI-II], score range 0-63, higher scores indicating worse mood, and Profile of Mood States [POMS], with a total mood disturbance score range of −32 to 200 and higher scores indicating higher levels of the constructs measured), QOL (Rand 36-Item Short Form, score range 0-100, higher scores reflecting better QOL, and Perceived Stress Scale, score range 0-40, higher scores indicating higher levels of stress), sleep (Pittsburgh Sleep Quality Index [PSQI], total score range 0-21, higher scores reflecting worse sleep quality), and sexual function (Derogatis Interview for Sexual Function–Self–report, total score range 24-188, higher scores indicating better sexual functioning).


Results  In all, 218 participants (152 women [69.7%]; mean [sD] age, 37.9 (7.2) years; mean [sD] BMI, 25.1 [1.6]) were included in the analyses. The CR and AL groups lost a mean (SE) of 7.6 (0.3) kg and 0.4 (0.5) kg, respectively, at month 24 (P < .001). Compared with the AL group, the CR group had significantly improved mood (BDI-II: between-group difference [bGD], −0.76; 95% CI, −1.41 to −0.11; effect size [ES], −0.35), reduced tension (POMS: BGD, −0.79; 95% CI, −1.38 to −0.19; ES, −0.39), and improved general health (BGD, 6.45; 95% CI, 3.93 to 8.98; ES, 0.75) and sexual drive and relationship (BGD, 1.06; 95% CI, 0.11 to 2.01; ES, 0.35) at month 24 as well as improved sleep duration at month 12 (BGD, −0.26; 95% CI, −0.49 to −0.02; ES, −0.32) (all P < .05). Greater percent weight loss in the CR group at month 24 was associated with increased vigor (Spearman correlation coefficient, ρ = −0.30) and less mood disturbance (ρ = 0.27) measured with the POMS, improved general health (ρ = −0.27) measured with the SF-36, and better sleep quality per the PSQI total score (ρ = 0.28) (all P < .01).


Conclusions and Relevance  In nonobese adults, CR had some positive effects and no negative effects on health-related QOL.


Trial Registration  clinicaltrials.gov Identifier: NCT00427193

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  • 2 months later...

[Admin Note: I moved this post by Tom (with permission) from the Body-mass index and all-cause mortality thread to this one, since it is about Luigi et al's latest findings from the CALERIE study. I will follow-up Tom's post with an in-depth analysis of this very interesting new study shortly... --Dean]


On the other side of the ledger [from PMID 27406257 discussed here which showed that for people 60+, eating more and weighing more reduces mortality risk - DP], not a direct contradiction, but more of a glancing blow - and caveat: biomarkers study not clinical outcomes - there is this, again by Al Pater (thanks Al!): PMID:27410480 


Aging (Albany NY). 2016 Jul 13. [Epub ahead of print]


Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans.

Meydani SN, Das SK, Pieper CF, Lewis MR, Klein S, Dixit VD, Gupta AK, Villareal DT, Bhapkar M, Huang M, Fuss PJ, Roberts SB, Holloszy JO, Fontana L.


Free full text: http://www.aging-us.com/full/100994


Calorie restriction (CR) inhibits inflammation and slows aging in many animal species, but in rodents housed in pathogen-free facilities, CR impairs immunity against certain pathogens. However, little is known about the effects of long-term moderate CR on immune function in humans. In this multi-center, randomized clinical trial to determine CR's effect on inflammation and cell-mediated immunity, 218 healthy non-obese adults (20-50 y), were assigned 25% CR (n=143) or an ad-libitum (AL) diet (n=75), and outcomes tested at baseline, 12, and 24 months of CR. CR induced a 10.4% weight loss over the 2-y period. Relative to AL group, CR reduced circulating inflammatory markers, including total WBC and lymphocyte counts, ICAM-1 and leptin. Serum CRP and TNF-α concentrations were about 40% and 50% lower in CR group, respectively. CR had no effect on the delayed-type hypersensitivity skin response or antibody response to vaccines, nor did it cause difference in clinically significant infections. In conclusion, long-term moderate CR without malnutrition induces a significant and persistent inhibition of inflammation without impairing key in vivo indicators of cell-mediated immunity. Given the established role of these pro-inflammatory molecules in the pathogenesis of multiple chronic diseases, these CR-induced adaptations suggest a shift toward a healthy phenotype.


PMID: 27410480


Again, these are just biomarkers. If you trust that these biomarkers indeed show "a shift toward a healthy phenotype" then it's noteworthy. A 25% reduction in calories is pretty substantial, leading to a 10.4% weight loss over 2 years. However, this is not the same thing as showing actual morbidity/mortality outcomes (rather than biomarkers), and over a pretty short period of time - how this would shake out over a lifetime is an altogether different question.

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Thanks Tom (and Al)!


This new paper (PMID 27410480) is (obviously) another in the long line of papers stemming from the CALERIE II study that Luigi et al conducted, a randomized control trial of CR in non-obese, healthy adults. This time, they focused on the impact of calorie restriction on markers of inflammation and immune system competence.


First off, I won't discuss the before / after demographics, since I went into details about the subjects and their baseline characteristics in this post above. But I will note in regard to Tom's statement:


A 25% reduction in calories is pretty substantial...


Yes - it would have been. Too bad they came nowhere near achieving that. Read carefully Tom. The abstract says (my emphasis):


218 healthy non-obese adults (20-50 y), were assigned 25% CR (n=143) or an ad-libitum (AL) diet (n=75),


The folks who were assigned to the 25% CR group actually achieved 19.5% CR in the first six months (not bad), but only 9% CR over the remaining 18 months. In short, this was a test of very mild calorie restriction. As a result, as I discussed in the post immediately prior to yours above, the CR folks dropped from a BMI of 25.1 to 22.5. 


In short, the CALERIE folks were doing the kind of mild CR I've been advocating lately (at least for younger folks - subjects were 20-50 years old). I.e. enough net calorie deficit to put and keep a person in the "sweet spot" of the BMI range of 20-23.


So Tom, contrary to your characterization of this study as "on the other side of the ledger" from my perspective, and offering my argument "not a direct contradiction, but a glancing blow" - the positive results of this new CALERIE study are actually completely aligned with my side of the argument. Namely that most of the important benefits of CR can be achieved through a very mild, obesity-avoiding diet and lifestyle.


What were the results Luigi et al reported this time?


Basically that two years of mild CR resulted in reduced markers of persistent, systemic inflammation, while preserving the acute immune response to viral challenges (via several vaccines).


I thought the figures were pretty sneaky and misleading in the magnitude of the effect, so I'm not including images of them. Instead, I'll discuss how the number changed, so we can compare them with our own values for the same biomarkers.


In the CR group (but not control group), several important markers of systemic inflammation dropped as follows after 24 months (eyeballing the graphs, P-values represent significance of change relative to controls):

  • WBC:   5.9 → 5.3 (103/µL) (P = 0.002)
  • CRP:    1.1 → 0.5 (µg/ml)   (P = 0.004)
  • TNF-α: 3.1 → 2.2 (pg/ml)   (P = 0.025)

Note: The drop in these three markers of systemic inflammation only became significant relative to controls after 24 months, i.e. after the subjects had been practicing very mild (9%) CR for 18 months. Earlier in the study, at the 12 month point, when compliance was greater and therefore degree of CR was higher, changes in these three markers (while in the same, beneficial direction) were not significantly different from controls.


One concern has always been that CR results in a "quiescent" immune system (as borne out by this study) and that such quiescence might compromise the ability of one's immune system to respond effectively to an acute challenge, like an infection. We've extensively discussed the legitimacy of this concern when it comes to serious CR in this thread.


Fortunately, this new CALERIE study shows this not to be the case, at least when it comes to mild CR.


Basically, Luigi and co gave various vaccines and a tetanus booster to the subjects during the course of the study, and observed no reduction in the CR group's ability to create antigen-specific immune cells to target the corresponding viruses. In addition, total infections during the 24-months was no greater in the CR group than the control group. In fact, when it came to (important - from a mortality perspective) respiratory infections, the mild CR group exhibited lower infection rates than controls - which is consistent with anecdotal reports and the results of the Cold / Flu Survey of CR Society members. However the CR folks did contract somewhat more eye infections during the study.


Here was how the authors summarized their findings (my emphasis):


We show that 25% CR (<sic>  ~9% CR] for 24 mo persistently reduced circulating inflammatory markers including WBC count. Serum concentrations of CRP and TNF-α were about 40% and 50% lower in the CR group, respectively....
A major finding of this study is the lack of significant negative effects of CR on key in vivo indicators of cell-mediated immunity...
[omitted discussion of studies that show CR may compromise cell-mediated immunity]
This difference [i.e. the lack of compromised cell-mediated immunity demonstrated in the current study] might be due to moderate level of CR (25%) [<sic> - actually 9% CR] administered in the current study compared to that used in several animal studies which can be as high as 40%. Taken together, these results suggest that moderate CR without malnutrition is safe and does not adversely affect immune response to pathogens...
These [mild] CR-induced changes suggest a shift toward a healthy phenotype, given the established role of these pro-inflammatory molecules as risk markers in the development of metabolic syndrome and age-related chronic diseases, in particular CVD, T2D and cancer.


[Editorial comment - I'm disappointed by how the authors (including Luigi) kept referring to "25% CR" in describing this study, when in fact they achieved nowhere near that level. I'm surprised the reviewers didn't make them correct this exaggeration.]


In short, for middle-aged, healthy adults, mild CR sufficient to push one's BMI from ~25 to around ~22.5 was sufficient to reduce key markers of systemic inflammation, without compromising people's ability to mount an immune system response to a viral challenge.


Yet another result supporting my contention that the potential (but unproven) benefits of CR in people can be achieved, and most of the risks of CR avoided, via a healthy, obesity-avoiding diet, without serious calorie restriction.



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  • 10 months later...

Consistent with previous results in humans and extensive work in rodents, comparison of the CALERIE 2 data with the CR Society cohort support a dose-response effect of CR on markers of disease risk and inflammation.




Most CR Society Cohort data from PMID 15096581; most CALERIE 2 data from PMID 26187233. Additional data from 6 mo to one-year CALERIE results in PMID 21841020*; from separate 2-year CALERIE 2 data in PMID 27410480; from Biosphere 2 in PMID 12023257§; from separate CR Society Cohort report in PMID 16720655.

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  • 4 years later...

Here is a recent update:

Effect of Long-Term Caloric Restriction on DNA Methylation Measures of Biological Aging in Healthy Adults: CALERIE™ Trial Analysis


Here we report DNA methylation (DNAm) evidence that CR may also slow biological aging in humans. We analyzed DNAm measures of biological age and Pace of Aging at pre-treatment baseline and at 12- and 24-month follow-ups in a randomized controlled trial of CR in healthy, non-obese humans, CALERIE™. We found that CR slowed Pace of Aging, especially for the DunedinPACE measure, and modestly delayed increases in biological age according to the GrimAge DNA methylation clock. In contrast, the clocks proposed by Horvath, Hannum et al., and Levine et al. (PhenoAge) did not show this effect and sometimes suggested an effect in the opposite direction.

Our findings contrast with reports that aging rates may not be modifiable 43 and advance proof-of-concept that an intervention proven to extend healthy lifespan in animals can slow the pace of biological aging in humans. They contribute gold-standard randomized-controlled-trial evidence to early reports from small and un-controlled intervention studies that DNAm measures of aging can be modified in humans 38,44,45. And they extend to the molecular level of analysis in our prior finding in CALERIE™ that CR slows the rate of increase in blood-chemistry biological age 17.

The significance of DNAm evidence of slowed Pace of Aging/ delayed biological aging in CALERIE is remains to be established. Epigenetic alterations, including changes to DNAm, are among the hallmarks of aging 2,3,46. The DNAm measures of aging we studied are predictive of a range of healthspan metrics in young, midlife, and older adults, including morbidity and mortality 25,27,28,47,48. However, the extent to which changes to DNAm measures of aging in CALERIE reflect CR-induced changes to hallmarks of aging is not certain. And additional follow-up of trial participants is required to determine whether CR-induced slowing of biological aging in CALERIE will translate into disease prevention and increased healthy lifespan.

CR effects varied substantially across the DNAm measures of aging we analyzed. Overall, Pace of Aging measures were more sensitive to intervention as compared to clock measures. Within these categories, DunedinPACE Pace of Aging was more sensitive than DunedinPoAm and GrimAge was more sensitive as compared to the other clocks. This pattern of findings mirrors differences in how the measures were developed and in their measurement reliability. ..."

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The study compares normal weight people with obese people.  Also, there is too much confidence placed in measurements that supposedly are measurements of "rate of aging".  You'd need a very long period of study to measure their efficacy -- since human are studying this, and the subjects are humans.

  --  Saul

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On 10/8/2021 at 12:03 PM, Saul said:
On 10/8/2021 at 12:03 PM, Saul said:

The study compares normal weight people with obese people. ...

  --  Saul

This is not necessarily the case, at least for the majority of the subjects:

"CALERIE Phase-2, was a multi-center, randomized controlled trial conducted at three clinical centers in the USA 14. It aimed to evaluate the time-course effects of 25% CR (i.e. intake 25% below the individual’s baseline level) over a 2-year period in healthy, adults (men aged 21–50 y, premenopausal women aged 21–47 y) with BMI in the normal weight or slightly overweight range (BMI 22.0-27.9 kg/m2)."

You have a point regarding the duration and the markers, but I believe that the study is still a reasonable indicator notwithstanding.

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