Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study

Abstract

The lifespan extension induced by 40% caloric restriction (CR) in rodents is accompanied by postponement of disease, preservation of function, and increased stress resistance. Whether CR elicits the same physiological and molecular responses in humans remains mostly unexplored. In the CALERIE study, 12% CR for 2 years in healthy humans induced minor losses of muscle mass (leg lean mass) without changes of muscle strength, but mechanisms for muscle quality preservation remained unclear. We performed high‐depth RNA‐Seq (387–618 million paired reads) on human vastus lateralis muscle biopsies collected from the CALERIE participants at baseline, 12‐ and 24‐month follow‐up from the 90 CALERIE participants randomized to CR and “ad libitum” control. Using linear mixed effect model, we identified protein‐coding genes and splicing variants whose expression was significantly changed in the CR group compared to controls, including genes related to proteostasis, circadian rhythm regulation, DNA repair, mitochondrial biogenesis, mRNA processing/splicing, FOXO3 metabolism, apoptosis, and inflammation. Changes in some of these biological pathways mediated part of the positive effect of CR on muscle quality. Differentially expressed splicing variants were associated with change in pathways shown to be affected by CR in model organisms. Two years of sustained CR in humans positively affected skeletal muscle quality, and impacted gene expression and splicing profiles of biological pathways affected by CR in model organisms, suggesting that attainable levels of CR in a lifestyle intervention can benefit muscle health in humans.

Metabolomic analysis of dietary‐restriction‐induced attenuation of sarcopenia in prematurely aging DNA repair‐deficient mice

“… 38 These results are consistent with the recent observation in human muscle. 20 One of the detrimental effects of sarcopenia in the elderly is loss of motor coordination. 39 To further investigate the effects of DR on muscle quality, four trials of accelerating rotarod performance were conducted.…”

“…Similar processes were recently also observed in healthy human volunteers following a 2‐year caloric restriction regimen. 20 This comprehensive analysis provides fundamental metabolomics insights into the anti‐aging effects of DR on sarcopenia, and represents a snapshot in the progressive development of the premature aging phenotype at a relatively late stage. In the future it may be interesting to compare this to early stages to better understand the various intermediate steps leading to the development of sarcopenia along with human material.…”

“… 14 , 15 Several lifestyle interventions can affect health and longevity, including dietary intake and exercise. 16 Among those, caloric‐ or dietary restriction (CR/DR; reduced food intake without malnutrition) is currently recognized as effective intervention for extending lifespan and retarding age‐related diseases in numerous species, including mammals 17 , 18 , 19 and humans, 20 and references therein]. Besides the indications of DR attenuating sarcopenia, muscle atrophy, and motor neuron loss, 18 , 21 , 22 the fundamental mechanism of how DR attenuates sarcopenia still needs to be systematically investigated to identify potential biomarkers for monitoring diagnosis, prevention, and treatment of sarcopenia.…”

Effect of long‐term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis

“…The foremost data for the effects of CR in humans comes from the NIA-supported Comprehensive Assessment of the Long-Term Effects of Reducing Energy (CALERIE™) 2 study (Rochon et al, 2011). Prior results from CALERIE™ 2 provide evidence for significant improvements to quality of life, cardiometabolic integrity, liver functioning, skeletal muscle quality, and immune health following moderate CR (11.9 ± 0.7%) over a span of 2 years (Das et al, 2023;Dorling et al, 2021;Kraus et al, 2019;Martin et al, 2016;Meydani et al, 2016). CR in CALERIE™ also reduced the rate of biological aging measured with a panel of clinical biomarkers representing physiological integrity across multiple organ systems (e.g., creatinine, albumin, blood glucose, blood pressure) (Belsky et al, 2017).…”

“…Evidence is mixed for genomic phenotypes of aging. Gene expression analyses in subsets of CALERIE™ participants suggest CR modulates core longevity pathways related to mitochondrial stability, inflammation, and oxidative stress (Das et al., 2023 ; Spadaro et al., 2022 ). In contrast, epigenetic clock analyses yielded mixed results, with the DunedinPACE clock, which was designed to measure the pace of aging (Belsky et al., 2022 ), indicating slowed aging in response to CR while other epigenetic clocks showed no response (Waziry et al., 2023 ).…”