Short-term protein restriction at advanced age stimulates FGF21 signalling, energy expenditure and browning of white adipose tissue.

Marleen B Dommerholt,Marcel A Vieira‐Lara,Maaike Blankestijn,Theo H Van Dijk,Henk Wolters,Johan W Jonker,Mirjam H Koster,Albert Gerding,Barbara M Bakker,Vincent W Bloks,Ronald P Van Os,Janine K Kruit

doi:10.1111/febs.15604

Marleen B Dommerholt, Marcel A Vieira‐Lara + Show 10 more

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https://doi.org/10.1111/febs.15604

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Abstract

Dietary protein restriction has been demonstrated to improve metabolic health under various conditions. However, the relevance of ageing and age-related decline in metabolic flexibility on the effects of dietary protein restriction has not been addressed. Therefore, we investigated the effect of short-term dietary protein restriction on metabolic health in young and aged mice. Young adult (3months old) and aged (18months old) C57Bl/6J mice were subjected to a 3-month dietary protein restriction. Outcome parameters included fibroblast growth factor 21 (FGF21) levels, muscle strength, glucose tolerance, energy expenditure (EE) and transcriptomics of brown and white adipose tissue (WAT). Here, we report that a low-protein diet had beneficial effects in aged mice by reducing some aspects of age-related metabolic decline. These effects were characterized by increased plasma levels of FGF21, browning of subcutaneous WAT, increased body temperature and EE, while no changes were observed in glucose homeostasis and insulin sensitivity. Moreover, the low-protein diet used in this study was well-tolerated in aged mice indicated by the absence of adverse effects on body weight, locomotor activity and muscle performance. In conclusion, our study demonstrates that a short-term reduction in dietary protein intake can impact age-related metabolic health alongside increased FGF21 signalling, without negatively affecting muscle function. These findings highlight the potential of protein restriction as a strategy to induce EE and browning of WAT in aged individuals.

Highlights

Ageing and age-associated changes in lifestyle are known to affect a wide range of metabolic processes
Effect of dietary protein intake on physical health in young adult and aged mice To evaluate the effects of dietary protein content on metabolic health in the context of ageing, young adult (3 months old) and aged (18 months old) mice were given an isocaloric diet with either a reduced protein content (LP, 7%) or an elevated protein content (HP, 40%) compared to a control diet with medium-protein content (MP, 20%) (Fig. 1A)
Effects of dietary protein intake and age on subcutaneous white adipose tissue In the absence of major effects on brown adipose tissue (BAT), we investigated whether the observed metabolic improvements could be mediated by changes in scWAT

Summary

Introduction

Ageing and age-associated changes in lifestyle are known to affect a wide range of metabolic processes. With the worldwide increase in life expectancy and median lifespan over the last few decades, understanding the mechanisms by which ageing affects metabolic processes has become an increasingly important research focus [4,5]. Caloric restriction (CR) is one of the most effective strategies to delay the symptoms of ageing and to extend longevity in a wide variety of animals [6]. CR, is difficult to maintain, and its long-term success has been limited by the poor adherence to this diet. Long-term dietary protein restriction without reducing total caloric intake has been shown to have similar beneficial effects on metabolic health and extension of longevity in mice as CR [11]. Within 1 week after the dietary switch, mice were protected against obesity and resistant to cold stress as a result of increased energy expenditure (EE) and increased utilization of free fatty acids and glucose in brown adipose tissue (BAT) [12,13,14,15]

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