The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent

eLife · 21 authors, 11 centres

AI SUMMARY

FIDELITY 60%

POPULATIONC57BL/6NCrl and C57BL/6JCrl mice (young: 9 weeks old; aged: 78 weeks old) and overweight/obese humans (BMI 26–42 kg/m², age 21–61 years)

INTERVENTION30% caloric restriction (CR) for 6 weeks in mice; individualized hypocaloric diet (~1500 kcal/day for women, ~2000 kcal/day for men) for 4 weeks in humans

COMPARISONAd libitum (AL) feeding vs CR; males vs females; young vs aged

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TL;DR

This study demonstrates that the metabolic effects of caloric restriction (CR) are highly sex- and age-dependent. In young mice and humans, females resist CR-induced fat loss and improvements in glucose homeostasis compared to males, but these sex differences are largely absent when CR is initiated in aged subjects. The findings highlight that sex and age are critical determinants of CR outcomes, yet over 95% of published CR research overlooks potential sex differences.

Full summary

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**Background:** Caloric restriction (CR) extends lifespan and reduces risk of age-related diseases, but its effects on metabolic function may differ between sexes. Most preclinical CR studies use only males, and the influence of sex and age on CR outcomes remains poorly understood. This study aimed to systematically quantify sex bias in the CR literature and experimentally determine the extent and basis of sex- and age-dependent metabolic responses to CR in mice and humans.

**Methods:** A systematic PubMed search identified mouse and human CR studies published from 2003–2021, classifying them by sex inclusion and analysis. Experimentally, young (9-week-old) and aged (78-week-old) C57BL/6 mice of both sexes were fed ad libitum (AL) or 30% CR for 6 weeks. Body composition (TD-NMR), glucose tolerance (OGTT), insulin sensitivity (HOMA-IR, Matsuda Index), energy expenditure and respiratory exchange ratio (indirect calorimetry), lipolysis (plasma NEFA, HSL phosphorylation), hepatic sphingolipid content (LC-MS), hepatic gene expression (RNA-seq), and tissue glucose uptake (¹⁸F-FDG PET/CT) were assessed. Human data came from 42 overweight/obese adults (20 males, 22 females; mean age 48.6 and 44.7 years, respectively) who underwent a 4-week individualized hypocaloric diet. Body composition was measured by air-displacement plethysmography.

**Key Results:** The literature review revealed that 64% of mouse CR studies used males only, and only 3.4% of mouse and 4.5% of human studies analyzed data with sex as a variable. In young mice, CR decreased body mass more in males than females (significant sex-diet interaction, p<0.001). Males lost fat mass (absolute and relative) while females maintained fat mass. CR decreased adipocyte area in male gWAT (p<0.001) but not females. Plasma NEFA increased in males only (p<0.01), and HSL phosphorylation increased in males but not females. Energy expenditure decreased more in females during week 1 (p<0.001). Postprandial RER exceeded 1.0 in both sexes and was higher in females (p<0.05), indicating greater de novo lipogenesis. Absolute fatty acid oxidation increased more in males (sex-diet interaction p<0.05). CR improved glucose tolerance (tAUC) more in males (p<0.001), and HOMA-IR decreased significantly only in males (p<0.001). Hepatic ceramide:dihydroceramide ratio decreased in males but not females (p<0.05). RNA-seq showed CR activated oxidative phosphorylation and TCA cycle genes in males only, while plasma ketones were higher in females (p<0.001). In aged mice (78 weeks), CR decreased body mass and fat mass similarly in both sexes, and glucose tolerance improvements were comparable. In humans, total weight loss was greater in males regardless of age (p=0.025 for intercept). Fat loss was greater in younger males than younger females, but with increasing age, fat loss increased in females and diminished in males (p=0.007 for slope interaction). Loss of fat-free mass showed the opposite pattern (p=0.0004 for slope interaction).

**Clinical Implications:** This study demonstrates that sex and age are major determinants of CR's metabolic benefits, with young females resisting fat loss and metabolic improvements that are evident in young males and in older individuals of both sexes. Over 95% of CR research overlooks sex as a biological variable, representing a critical gap. These findings suggest that CR-based interventions may need to be tailored by sex and age—for example, younger women may derive less metabolic benefit from CR than older women or men. The data also highlight the liver as a key mediator of sexually dimorphic CR effects, with differences in hepatic acetyl-CoA metabolism and sphingolipid content potentially underlying divergent glucose homeostasis responses. Future research and clinical translation of CR must account for these variables to avoid misleading conclusions and to optimize personalized dietary interventions.

PICO

PPOPULATION

C57BL/6NCrl and C57BL/6JCrl mice (young: 9 weeks old; aged: 78 weeks old) and overweight/obese humans (BMI 26–42 kg/m², age 21–61 years)

IINTERVENTION

30% caloric restriction (CR) for 6 weeks in mice; individualized hypocaloric diet (~1500 kcal/day for women, ~2000 kcal/day for men) for 4 weeks in humans

OOUTCOME

Body mass, fat mass, lean mass, glucose tolerance (OGTT), insulin sensitivity (HOMA-IR, Matsuda Index), energy expenditure, respiratory exchange ratio, lipolysis, hepatic sphingolipid content, hepatic gene expression, plasma ketones, and glucose uptake (PET/CT)

STUDY TYPE

other

SPECIALTY

endocrinology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

60% · C

ORIGINAL PAPER

PMC10171869

The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent

eLife

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ABSTRACT

Abstract Caloric restriction (CR) reduces the risk of age-related diseases in numerous species, including humans. CR’s metabolic effects, including decreased adiposity and improved insulin sensitivity, are important for its broader health benefits; however, the extent and basis of sex differences in CR’s health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young females. Females’ resistance to fat loss was associated with decreased lipolysis, energy expenditure and fatty acid oxidation, and increased postprandial lipogenesis, compared to males. The sex differences in glucose homeostasis were not associated with differential glucose uptake but with altered hepatic ceramide content and substrate metabolism: compared to CR males, CR females had lower TCA cycle activity and higher blood ketone concentrations, a marker of hepatic acetyl-CoA content. This suggests that males use hepatic acetyl-CoA for the TCA cycle whereas in females it accumulates, stimulating gluconeogenesis and limiting hypoglycaemia during CR. In aged mice (18-months old), when females are anoestrus, CR decreased fat mass and improved glucose homeostasis similarly in both sexes. Finally, in a cohort of overweight and obese humans, CR-induced fat loss was also sex- and age-dependent: younger females (<45 years) resisted fat loss compared to younger males while in older subjects (>45 years) this sex difference was absent. Collectively, these studies identify age-dependent sex differences in the metabolic effects of CR and highlight adipose tissue, the liver and oestrogen as key determinants of CR’s metabolic benefits. These findings have important implications for understanding the interplay between diet and health, and for maximising the benefits of CR in humans. Research organism: Human, Mouse

CITATION EXPORT

Karla J Suchacki, Benjamin J Thomas, Yoshiko M Ikushima et al.. The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent. eLife. (2023). https://doi.org/10.7554/eLife.88080

AUTHORS

21 · 11 CENTRES

Karla J Suchacki, Benjamin J Thomas, Yoshiko M Ikushima, Kuan-Chan Chen, Claire Fyfe, Adriana AS Tavares, Richard J Sulston, Andrea Lovdel, Holly J Woodward, Xuan Han, Domenico Mattiucci, Eleanor J Brain, Carlos J Alcaide-Corral, Hiroshi Kobayashi, Gillian A Gray, Phillip D Whitfield, Roland H Stimson, Nicholas M Morton, Alexandra M Johnstone, William P Cawthorn, Mone Zaidi

1University/BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh BioQuarter, Edinburgh, United Kingdom
2Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
3Rowett Institute, University of Aberdeen, Aberdeen, United Kingdom
4Edinburgh Imaging, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh BioQuarter, Edinburgh, United Kingdom
5Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
6Division of Biomedical Sciences, University of the Highlands and Islands, Centre for Health Sciences, Inverness, United Kingdom
7Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, United Kingdom
8Icahn School of Medicine at Mount Sinai, United States
9Icahn School of Medicine at Mount Sinai, United States
1Icahn School of Medicine at Mount Sinai, United States
1Icahn School of Medicine at Mount Sinai, United States