Nutritional quality of calorie restricted diets in the CALERIE™ 1 trial

Abstract

Objectives:

The aim was to determine the nutritional adequacy of calorie restricted (CR) diets during CR interventions up to 12 months.

Methods:

The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE™) phase 1 trial consisted of 3 single-site studies to test the feasibility and effectiveness of CR in adults without obesity. After baseline assessments, participants who were randomized to a CR intervention received education and training from registered dietitians on how to follow a healthful CR diet. Food diaries were completed at baseline and during the CR interventions (~6, 9, and 12 months) when participants were self-selecting CR diets. Diaries were analyzed for energy, macronutrients, fiber, 11 vitamins, and 9 minerals. Nutritional adequacy was defined by sex- and age-specific Estimated Average Requirement (EAR) or Adequate Intake (AI) criteria for each nutrient. Diet quality was evaluated using the PANDiet diet quality index.

Results:

Eighty-eight CR participants (67% women, age 40 ± 9 y, BMI 27.7 ± 1.5 kg/m²) were included in the analysis. Dietary intake of fiber and most vitamins and minerals increased during CR. More than 90% of participants achieved 100% of EAR or AI during CR for 2 of 4 macronutrients (carbohydrate and protein), 6 of 11 vitamins (A, B1, B2, B3, B6, B12), and 6 of 9 minerals assessed (copper, iron, phosphorus, selenium, sodium, zinc). Nutrients for which <90% of participants achieved adequacy included fiber, omega-3 fatty acids, vitamins B5, B9, C, E, and K, and the minerals calcium, magnesium, and potassium. The PANDiet diet quality index improved from 72.9 ± 6.0% at baseline to 75.7 ± 5.2% during CR (p < 0.0001).

Conclusion:

Long-term, calorie-restricted diets were nutritionally equal or superior to baseline ad libitum diets among adults without obesity. Our results support modest calorie restriction as a safe strategy to promote healthy aging without compromising nutritional adequacy or diet quality.

1. Background

Increased enthusiasm for “anti-aging” interventions are contributing to renewed interest in the potential to optimize healthspan by reducing calorie intake. Calorie restriction (CR) has been linked with delaying age-related decline and increasing longevity among various species since the 1950s (Mattison et al., 2007; Weindruch, 1996). The interest in its implications for human health and longevity have intensified as evidence emerges for numerous benefits on biomarkers of aging and age-related pathologies (Barger et al., 2003; Fontana et al., 2004; Ingram et al., 2006; Meyer et al., 2006).

There is controversy, however, regarding the relative benefits and risks of long-term CR among older adults due to concerns about malnutrition and reductions in bone mass and muscle mass that accompany weight loss (Morley, 2007). Advancing age itself poses risks for malnutrition, osteoporosis, and sarcopenia and there is an abundance of evidence that healthy dietary patterns are essential for optimal health among older adults (Bernstein and Munoz, 2012; Roberts et al., 2021). Clinical trials that involve calorie-restricted diets often include micronutrient supplementation to prevent potential nutrient deficiencies. However, it is unclear what nutrient inadequacies exist before initiating a CR diet and whether inadequacies persist, worsen, or are ameliorated during calorie restriction interventions among healthy adults.

The concern that the lower energy intake of a CR diet would hinder consumption of adequate amounts of essential micronutrients is based on the negative effects observed in situations of chronic starvation (Keys et al., 1950) and in eating disorders such as anorexia nervosa (Fontana and Klein, 2007). Previous reports of weight loss diets indicated that the diets generally were not lacking in nutritional adequacy and that nutrient density was higher in the CR diets compared to baseline ad libitum diets (Benezra et al., 2001; Buzzard et al., 1990; Swinburn et al., 1999). Benezra et al. (Benezra et al., 2001) reported that nutrient intakes were maintained in 115 women with overweight or obesity who decreased their energy intakes by 23–36% and Swinburn et al. (Swinburn et al., 1999) confirmed that there were no detrimental changes in micronutrient intake or serum indicators of retinol, α-tocopherol, or beta carotene in middle-aged adults who switched from an ad libitum diet to a fat-restricted diet. While this evidence supports the contention that moderate CR can be implemented safely, data are lacking on the nutritional adequacy of long-term, moderate CR diets in populations without obesity.

The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE™) trial, funded by the National Institute on Aging, was designed to assess the feasibility of CR in human participants and the effects on numerous biomarkers of health, healthspan, and aging (http://calerie.duke.edu). For the present analysis, we evaluated the nutritional adequacy of CR diets self-selected by participants in the CALERIE phase 1 trial.

2. Methodology

2.1. Study design

CALERIE phase 1 was designed as 3 single-site studies to assess the feasibility of CR and its effects on biomarkers of aging. The clinical sites included Pennington Biomedical Research Center (PBRC) in Baton Rouge, LA; the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University (Tufts) in Boston, MA; and Washington University School of Medicine (WUSM) in St. Louis, MO. Each site had its own eligibility criteria, distinct intervention designs, and specific outcome measures. Detailed methodologies for each of the studies have been published previously (Das et al., 2007; Das et al., 2009; Heilbronn et al., 2006; Racette et al., 2006). The unique CALERIE 1 dataset contains adults of varying ages (24–60 y) who were prescribed varying levels of CR (10–30%) for different durations (6–12 months). The trials were conducted between 2002 and 2005. The ClinicalTrials.gov Identifiers for the trials at PBRC, Tufts, and WUSM are NCT00099151, NCT00099099, and NCT00099138, respectively.

2.2. Subjects and interventions

All sites enrolled healthy participants without obesity (BMI eligibility range 23.5–29.9 kg/m²). The age range, CR interventions, and comparison conditions varied by site, as shown in Fig. 1. At PBRC, the 4 groups included control (no intervention), 12.5% CR + 12.5% exercise (CR/EX), 25% CR, and low-calorie diet (LCD); the intervention period was 6 months. Participants in the CR/EX group gradually increased their exercise level until energy expenditure was increased by 12.5%. Exercise included structured aerobic activities (walking, running, cycling) and occurred 5 days/week. At Tufts, the groups were 10% CR and 30% CR and the intervention lasted 12 months. At WUSM, 3 groups included a healthy lifestyle control group, 20% CR, and 20% EX, with the interventions lasting 12 months. Only the CR groups at each site were included in the current analysis of nutritional adequacy; the LCD group at PBRC was not included, because that intervention did not involve moderate CR. All study protocols were approved by the respective Institutional Review Board at each site and written informed consent was obtained from each participant.

Fig. 1.

CALERIE 1 trial eligibility criteria and participant flow by site. CR (calorie restriction), EX (exercise), LCD (low calorie diet). Shaded boxes reflect study groups that were not included in the present analysis.

The CR prescriptions were individualized for each participant based upon their energy intake at baseline, which was assumed to be equal to total energy expenditure (TEE) as determined by the doubly labeled water method (Schoeller, 1988) during 2, 2-week periods, representing average TEE over 4 weeks. CR subjects were provided all foods and beverages on the following schedules: PBRC: weeks 1–12 and weeks 22–24; Tufts: weeks 1–24; WUSM: weeks 4 and 13. All CR participants received comprehensive training on preparing and following CR diets via individual and group sessions led by registered dietitians and licensed counselors. Participants in the control group at WUSM did not receive meals or education about CR; participants in the control group at PBRC did not receive education about CR. Participants at Tufts and WUSM were provided a multi-vitamin and mineral supplement throughout the intervention periods; an additional calcium tablet (500 mg) was provided at Tufts. The nutrient quantities in these supplements were not included in the analyses of nutritional adequacy and quality of the CR diets.

2.3. Nutrition assessment

Participants at the 3 clinical sites were instructed to record all food and beverage intake in food diaries for 1–2 weeks at baseline and 1 week at the subsequent time points. Research dietitians provided detailed instructions on how to weigh, measure, and record foods and then reviewed the completed food diaries with participants at the end of each recording period; they did not provide healthy diet recommendations during these sessions. Food diaries were analyzed for nutrient intake at baseline and several subsequent time points. For the current analysis, we included the following intervention time points during which participants were selecting and preparing their own meals: ~6 months (PBRC and WUSM), 9 months (Tufts), and 12 months (Tufts and WUSM). All food diaries for this analysis were obtained during periods of self-selected feeding.

Nutrition Data System for Research software (NDS-R, developed by the Nutrition Coordinating Center, University of Minnesota, Minneapolis, MN, versions 4.05_33 [2002], 4.06_34 [2003], and 5.0_35 [2004]) was used for the nutrient analyses at Tufts and WUSM; Moore’s Extended Nutrient Database (MENu, PBRC, Baton Rouge, LA, 2000) was used at PBRC. The following nutrients were quantified: carbohydrate, protein, fiber, total fat, saturated fat, polyunsaturated fatty acids (PUFA), omega-3 fatty acids, cholesterol, vitamins A, B1, B2, B3, B5, B6, B9, B12, C, D, E, and K, and the minerals calcium, copper, iron magnesium, phosphorus, potassium, selenium, sodium, and zinc. Vitamin D was excluded from the final analyses because vitamin D was incomplete in NDSR when the food diaries were analyzed and was not included in the PBRC MENu database. The MENu database did not provide estimates of fiber, omega-3 fatty acids, vitamin B5, or selenium; our analyses accounted for these missing nutrients.

2.4. Nutritional adequacy based on EAR or AI

To evaluate the adequacy of individual nutrients in the CR diets, we calculated the mean daily intakes from multi-day food diaries for each participant and expressed the results for each nutrient as a percentage of the sex- and age-specific Estimated Average Requirement (EAR) or Adequate Intake (AI) criteria of the Dietary Reference Intakes (DRI) established by the Institute of Medicine (Institute of Medicine Subcommittee on Interpretation and Uses of Dietary Reference Intakes and Institute of Medicine Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, 2000b) (Table 1).

Table 1.

Nutrient criteria to define adequacy.

	Unit	EAR or AI	Men			Women			RDA	UL
			19–30 y	31–50 y	51–70 y	19–30 y	31–50 y	51–70 y
Macronutrients
Carbohydrate	g/d	EAR	100	100	100	100	100	100	130
Protein	g/kg/d	EAR	0.66	0.66	0.66	0.66	0.66	0.66	0.80
Fiber	g/d	AI	38	38	30	25	25	21
Omega-3 fatty acids	g/d	AI	1.6	1.6	1.6	1.1	1.1	1.1
Vitamins
A	μg/da	EAR	625	625	625	500	500	500	M 900, W 700	3000
B1 (thiamin)	μg/d	EAR	1.0	1.0	1.0	0.9	0.9	0.9	M 1.2, W 1.1
B2 (riboflavin)	mg/d	EAR	1.1	1.1	1.1	0.9	0.9	0.9	M 1.3, W 1.1
B3 (niacin)	mg/d	EAR	12	12	12	11	11	11	M 16, W 14	35
B5 (pantothenic acid)	mg/d	AI	5	5	5	5	5	5
B6 (pyridoxine)	mg/d	EAR	1.1	1.1	1.4	1.1	1.1	1.3	M 1.3/1.7, W 1.3/1.5	100
B9 (folate)	μg/d	EAR	320	320	320	320	320	320	400	1000
B12 (cobalamin)	μg/d	EAR	2	2	2	2	2	2	2.4
C (ascorbic acid)	mg/d	EAR	75	75	75	60	60	60	M 90, W 75	2000
E (alpha-tocopherol)	mg/d	EAR	12	12	12	12	12	12	15	1000
K (phylloquinone)	μg/d	AI	120	120	120	90	90	90
Minerals
Calcium	mg/d	EAR	800	800	800	800	800	1000	M 1000, W 1000/1200	2500
Copper	μg/d	EAR	700	700	700	700	700	700	900	10,000
Iron	mg/d	EAR	6	6	6	8.1	8.1	5	M 8, W 18/8	45
Magnesium	mg/d	EAR	330	350	350	255	265	265	M 400/420, W 310/320
Phosphorus	mg/d	EAR	580	580	580	580	580	580	700	4000
Potassium	mg/d	AI	3400	3400	3400	2600	2600	2600
Selenium	μg/d	EAR	45	45	45	45	45	45	55	400
Sodium	g/d	AI	1.5	1.5	1.3	1.5	1.5	1.3		2.3
Zinc	mg/d	EAR	9.4	9.4	9.4	6.8	6.8	6.8	M 11, W 8	40

Values represent the Estimated Average Requirement (EAR), Adequate Intake (AI), Recommended Dietary Allowance (RDA), or Upper Limit (UL) for each nutrient, updated in 2011 and 2019. Values in bold differ by age (relative to 19–30 y/o); values in italics differ by sex (W, women relative to M, men).

^aRetinol Activity Equivalents (RAE).

2.5. PANDiet diet quality index

PANDiet is a diet quality index that provides a comprehensive assessment of the overall nutritional quality of an individual’s daily diet (Verger et al., 2012). The index is computed as the average of an Adequacy sub-score (0–100%) and a Moderation sub-score (0–100%), with higher values reflecting higher diet quality. As shown in Table 2, the Adequacy sub-score reflects the probability of achieving adequate intake for 26 macronutrients, vitamins, and minerals, defined as meeting the EAR or AI. The Moderation sub-score reflects the probability of achieving moderate nutrient intake for 17 macronutrients, vitamins, and minerals, defined as not exceeding the Recommended Dietary Allowance (RDA) or Upper Limit (UL). The PANDiet index was chosen as the most comprehensive method to assess overall diet quality based on adequacy of individual macronutrients, vitamins, and minerals. Additionally, the PANDiet index is recommended by the Institute of Medicine (Institute of Medicine Subcommittee on Interpretation and Uses of Dietary Reference Intakes and Institute of Medicine Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, 2000a) because this index accounts for: (1) number of days of food diary data, (2) average nutrient intake/day, (3) day-to-day variability of nutrient intake, (4) reference EAR or AI for Adequacy, (5) reference RDA or UL for Moderation, and (6) variability between individuals.

Table 2.

Nutrients included in the PANDiet index.

PANDiet adequacy sub-score			PANDiet moderation sub-score
Nutrient	Unit	EAR or AI	Nutrient	Unit	RDA or UL
Macronutrients			Macronutrients
Carbohydrate	g/d	EAR	Carbohydrate	%	RDA
Protein	g/kg/d	EAR	Fat	%	RDA
Fiber	g/d	AI	Saturated Fat	%	RDA
Fat	%	EAR	Cholesterol	mg/d	RDA
PUFA	%	EAR
Omega-3 fatty acids	g/d	AI
Vitamins			Vitamins
A	μg/d	EAR	A	μg/d	UL
B1 (thiamin)	μg/d	EAR	B3 (niacin)	mg/d	UL
B2 (riboflavin)	mg/d	EAR	B6 (pyridoxine)	mg/d	UL
B3 (niacin)	mg/d	EAR	B9 (folate)	μg/d	UL
B5 (pantothenic acid)	mg/d	AI	C (ascorbic acid)	mg/d	UL
B6 (pyridoxine)	mg/d	EAR	E (alpha-tocopherol)	mg/d	UL
B9 (folate)	μg/d	EAR
B12 (cobalamin)	μg/d	EAR
C (ascorbic acid)	mg/d	EAR
E (alpha-tocopherol)	mg/d	EAR
K (phylloquinone)	μg/d	AI
Minerals			Minerals
Calcium	mg/d	EAR	Calcium	mg/d	UL
Copper	μg/d	EAR	Copper	μg/d	UL
Iron	mg/d	EAR	Iron	mg/d	UL
Magnesium	mg/d	EAR	Phosphorus	mg/d	UL
Phosphorus	mg/d	EAR	Selenium	μg/d	UL
Potassium	mg/d	AI	Sodium	g/d	UL
Selenium	μg/d	EAR	Zinc	mg/d	UL
Sodium	g/d	AI
Zinc	mg/d	EAR

EAR (Estimated Average Requirement), AI (Adequate Intake), RDA (Recommended Dietary Allowance), UL (Upper Limit).

We calculated PANDiet Adequacy and Moderation sub-scores using the probabilistic approach (Institute of Medicine Subcommittee on Interpretation and Uses of Dietary Reference Intakes and Institute of Medicine Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, 2000a), as shown in Fig. 2. Each participant’s probability of adequate intake was estimated for each of the 26 nutrients listed under Adequacy in Table 2 and then averaged to derive the Adequacy sub-score. Likewise, each participant’s probability of moderate intake was estimated for each of the 17 nutrients listed under Moderation in Table 2 and then averaged to derive the Moderation sub-score. PBRC’s PANDiet sub-scores were adjusted to account for missing data for fiber, omega-3 fatty acids, vitamin B5, vitamin K, and selenium.

Fig. 2.

Equation to calculate the probabilities of adequate intake for individual nutrients. Image from Verger et al. (2012).

2.6. Statistical analysis

Descriptive statistics were calculated for baseline characteristics by study site and for all participants collectively. Total energy expenditure (TEE) and total energy intake were compared between baseline and CR by repeated-measures analysis of variance (RM-ANOVA). Sex- and age-specific nutritional adequacy (% EAR or AI) and diet quality (PANDiet index) were also compared between baseline and CR by RM-ANOVA. Nutritional adequacy and diet quality metrics were not adjusted for energy under-reporting in the food diaries. Nutrient intakes and PANDiet probabilities for CR groups within the same site were not statistically different and therefore were combined. Likewise, nutrient intakes and PANDiet scores were not statistically different for the 2 CR timepoints (i.e., Tufts: 9 and 12 months; WUSM: 6 and 12 months) and therefore are reported as one mean value in select tables and figures. Analyses were performed using Statistical Analysis Software (version 9.4, SAS Institute, Inc., Cary, NC). Significance was accepted at p < 0.05.

3. Results

3.1. Baseline characteristics

Table 3 shows the baseline characteristics of study participants (n = 88). Overall, 67% were women, the mean age upon enrollment was 40 ± 9 y (range 25–62) and BMI averaged 27.7 ± 1.5 kg/m². By design, the age of participants was older at WUSM (55 y) than at PBRC (37 y) or Tufts (35 y). The racial distribution (Black/White/Other) was 37%/57%/6% at PBRC, 2%/84%/14% at Tufts, and 8%/85%/7% at WUSM.

Table 3.

Subject characteristics and reported energy intake by study site.

	PBRC		Tufts		WUSM
	12.5% CR/EX	25% CR	10% CR	30% CR	20% CR
N	12	12	12	34	18
Sex: % women	58	50	73	76	61
Age (y): baseline	36 (6)	39 (5)	35 (4)	35 (5)	55 (3)
BMI (kg/m2): baseline	27.5 (1.7)	27.7 (16)	28.6 (1.5)	27.6 (1.4)	27.2 (2.4)
Total energy expenditure (kcal/d)
Baseline	2665 (514)	2846 (589)	2803 (356)	2836 (469)	2503 (452)
CR	2676 (626)	2502 (396)	2612 (390)	2461 (390)	2300 (436)
Self-reported energy intake (kcal/d)
Baseline	1939 (459)	2231 (547)	2224 (542)	2080 (515)	2080 (551)
CR	2097 (453)	2041 (430)	2062 (461)	1801 (444)	1768 (429)

Results are expressed as percentage of the sample for sex and as mean (SD) for the other variables. CR (calorie restriction), CR/EX (calorie restriction + exercise), PBRC (Pennington Biomedical Research Center), WUSM (Washington University School of Medicine).

3.2. Energy expenditure and energy intake

Baseline TEE averaged 2740 ± 486 kcal/day across sites and did not differ among sites (p = 0.15), as shown in Table 3. During CR, TEE averaged 2465 ± 435 kcal/day. Self-reported energy intake averaged 2099 ± 519 kcal/day at baseline, with no difference across sites (p = 0.63). The ratio of energy intake reported in food diaries (kcal/day) to energy intake based on TEE measured by doubly labeled water (kcal/day) averaged 0.78 throughout the study, with no statistically significant differences among sites (p = 0.40) or between baseline and CR timepoints (p = 0.15).

3.3. Nutrient intake

The distribution of macronutrient intake, expressed as a percentage of total energy intake from carbohydrate/protein/fat, was similar across sites during the CR diets: 46%/18%/36% at PBRC, 48%/17%/35% at Tufts, and 47%/18%/35% at WUSM. Fiber, vitamin, and mineral intakes generally increased during CR (data not shown). Fiber intake increased from 9.2 ± 2.9 g/1000 kcal at baseline to 15.0 ± 5.6 g/1000 kcal during CR (p < 0.0001). Relative to baseline, intakes of Vitamins A, B1, B2, B5, B6, B9, C, E, and K, and the minerals copper, magnesium, potassium, selenium, and zinc increased significantly in several CR groups across sites.

3.4. Nutritional adequacy based on EAR or AI

In general, an equal or higher proportion of participants achieved adequacy for each nutrient during CR relative to baseline (Fig. 3). During CR, >90% of participants achieved 100% of EAR or AI for 2 of the 4 macronutrients assessed (carbohydrate and protein), 6 of 11 vitamins (A, B1, B2, B3, B6, and B12), and 6 of 9 minerals (copper, iron, phosphorus, selenium, sodium, and zinc). Nutrients for which <90% of participants achieved adequacy included fiber, omega-3 fatty acids, the vitamins B5, B9, C, E, and K, and the minerals calcium, magnesium, and potassium.

Fig. 3.

Proportion of CR participants across all sites who achieved 100% of Estimated Average Requirement (EAR) or adequate intake (AI) for vitamins (top panel) and selected minerals and macronutrients (bottom panel) at baseline (BL, solid bars) and during calorie restriction (CR, striped bars). Data labels represent the % of participants.

3.5. PANDiet diet quality index

The PANDiet index, which accounts for both Adequacy and Moderation, increased (i.e., improved) from an average of 73 ± 6% at baseline to 76 ± 5% during the CR interventions (p < 0.0001). Results by site and time point are shown in Fig. 4. There were no differences in diet quality by sex (p = 0.93). The mean PANDiet Adequacy sub-scores were 57 ± 10% at baseline and 61 ± 9% during CR across sites. The corresponding Moderation sub-scores were 89 ± 4% at baseline and 90 ± 4% during CR.

Fig. 4.

PANDiet diet quality index at baseline and during calorie restriction (CR) for all participants combined and by site. Data labels within each boxplot represent the median values; the circles outside represent outliers.

4. Discussion

The CALERIE 1 studies were randomized controlled trials that demonstrated the feasibility of long-term CR among healthy adults without obesity. The CR interventions varied in intensity (10 to 30% CR), duration (6 to 12 months), and nutrient composition, which enabled us to examine the nutritional adequacy self-selected CR diets in this unique data set. The major finding of the current analysis was that the nutritional adequacy and diet quality of the CR diets were comparable to or greater than that of the ad libitum, weight-maintaining diets consumed at baseline.

The CR interventions in CALERIE 1 promoted numerous beneficial physiological effects that have been reported previously, including reduced total and abdominal adiposity (Das et al., 2007; Racette et al., 2006) and favorable changes in biomarkers of aging, such as hormones, lipids, (Fontana et al., 2006; Larson-Meyer et al., 2008), immune function (Ahmed et al., 2009), fasting insulin (Das et al., 2007; Heilbronn et al., 2006), glucose tolerance (Das et al., 2007; Weiss et al., 2006), cardiometabolic risk factors (Das et al., 2009; Fontana et al., 2007; Larson-Meyer et al., 2006; Lefevre et al., 2009; Pittas et al., 2006; Racette et al., 2006; Weiss and Holloszy, 2007), oxidative stress, and DNA damage (Das et al., 2017; Heilbronn et al., 2006). Given the positive outcomes of these CALERIE 1 trials (Das et al., 2017) and the subsequent CALERIE 2 trial (Das et al., 2017; Dorling et al., 2021; Ravussin et al., 2015), it is important to consider the potential impact of long-term, CR diets on nutritional adequacy when individuals are self-selecting their diets.

An important concern for older adults in particular is whether CR diets have sufficient calcium and vitamin D to support optimal bone health (Gallagher, 2013; Thorpe et al., 2008). This concern is not unique to CR diets, as calcium intake in the general adult population is commonly below the recommended level (Ma et al., 2007) and only 40% of participants in our sample met adequacy for calcium intake at baseline. Although more participants met adequacy during the CR interventions (52%), the suboptimal calcium intake of many individuals at baseline and throughout the study is cause for concern and runs counter to the National Osteoporosis Foundation’s evidence-based position statement on the importance of dietary calcium and vitamin D for optimal bone health (Weaver et al., 2016). Therefore, calcium and vitamin D supplements generally should be recommended not only during a CR diet (Dwyer et al., 2005), but also for many adults who habitually do not meet recommended intake levels.

Another potential concern of CR diets may be low intakes of nutrients associated with dietary fat intake, such as vitamin E, linoleic acid, and omega-3 fatty acids. The CR diets selected by CALERIE participants were not particularly low in fat, with average reported intakes consistent with the Dietary Guidelines for Americans (U.S. Department of Agriculture and U.S. Department of Health and Human Services, 2020) and recommendations of the American Heart Association (2015). However, vitamin E was the micronutrient with the lowest adequacy at baseline and during CR (15% and 30% of participants, respectively) and omega-3 fatty acid intake did not meet adequacy for more than half of the sample at baseline and during CR. Low plasma levels of omega-3 fatty acids, which are influenced by dietary intake, were associated with dementia in the InCHIANTI study of older adults (Cherubini et al., 2007). As with the calcium and vitamin D, these findings suggest that, although adequacy did not decline during CR, intake levels for vitamin E and omega-3 fatty acids were suboptimal in both the ad libitum baseline diets and the CR diets; these issues should be explored in future investigations.

An important factor is that many participants in the CALERIE 1 trials received a multi-vitamin and mineral supplement, which would be expected to fill the gap for some of the nutrients that did not meet adequacy criteria. Our analyses specifically excluded the nutrient content of the supplements so that we could focus on the diets themselves. It is likely, therefore, that overall nutritional adequacy was higher among many participants in our sample than is reflected by the food and beverage components alone. Another consideration is reporting accuracy, particularly with respect to total energy intake. Consistent with previous analyses (Institute of Medicine Subcommittee on Interpretation and Uses of Dietary Reference Intakes and Institute of Medicine Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, 2000b; Schoeller, 1995), reported energy intake based on food diaries is often significantly lower than that determined objectively from energy expenditure measured by doubly labeled water and changes in body composition. The degree of energy under-reporting (kcal/day) averaged 22% throughout the study, which suggests that individual nutrients also may be underestimated based on food diary data.

There are no direct comparisons to be made between the CALERIE 1 trials and other investigations because previous studies have employed more restrictive diet interventions (e.g., 50% CR) for shorter time periods, had very different target populations (i.e., individuals with obesity, type 2 diabetes, and/or hypertension), and had different primary outcomes than the CALERIE 1 trials. While nutrient inadequacies are an important concern in many diets (Ha et al., 2021), the participants in the CALERIE trials were well supervised and were instructed to follow carefully planned CR regimens. Thus, our findings allay concerns that adopting a CR diet reduces the likelihood of achieving nutritional adequacy. Rather, our results suggest that when appropriate education and counseling are provided, CR diets can be of comparable or superior quality among community-dwelling adults who are consciously reducing their calorie intakes for potential anti-aging benefits. A caveat is that older adults with low socioeconomic status may have greater difficulty meeting nutrient guidelines (Nazri et al., 2021). With growing recognition of the potential for CR to modify human aging (Das et al., 2017), the need to evaluate the “real world” impact of CR diets on health underscores the importance and positive implications of these CALERIE 1 findings on nutritional adequacy and diet quality.

There are strengths and limitations of this study. The CALERIE 1 trials represent the first randomized, controlled trials of CR in humans without obesity. Additionally, the CR interventions were unique and the studies employed state-of-the art methodology. Limitations are that the site-specific CR interventions differed in %CR, macronutrient composition, and duration, and each site had distinct participant eligibility criteria. However, this limitation also provided a range of CR levels and a broader age range, thus improving the generalizability of our findings. Our study population was food secure and the majority was educated; therefore, the results of this study may not be generalizable to individuals of low socioeconomic status, low education, or with food insecurity. The dietary data were not adjusted for plausible intake/reporting; however, adjustment would have improved rather than reduced nutrient adequacy, since intake generally was under-reported. The MENu database used at PBRC didn’t include some nutrients of interest and therefore we were unable to assess their adequacy. Finally, evaluation of adequacy of dietary intake is a standard evaluation approach, but does not account for nutrient bioavailability or the individual’s nutritional status at baseline or at the end of the interventions.

In conclusion, the 3 CALERIE phase 1 trials provide consistent evidence that self-selected CR diets can be nutritionally equal or superior to ad libitum weight-maintaining diets when study participants receive education and training. Together with an impressive array of beneficial physiological effects that have been reported for the CALERIE trials, the current results support modest calorie restriction as a safe strategy to promote healthy aging without compromising nutritional adequacy or overall diet quality.