Consumption of protein-rich diets and supplements has been increasingly advocated by individuals seeking to optimize metabolic health and mitigate the effects of aging. Protein intake is postulated to support muscle mass retention and enhance longevity, underscoring its perceived benefits in age-related metabolic regulation. However, emerging evidence presents a paradox; while moderate protein consumption contributes to health maintenance, an excessive intake is associated with an elevated risk of chronic diseases, notably obesity and diabetes. Furthermore, recent studies suggest that reducing the ratio of protein intake to macronutrients improves metabolic parameters and extends lifespan. The aim of this study is to review the current evidence concerning the metabolic effects of protein-restricted diets and their potential mechanisms. Utilizing rodent models, investigations have revealed that protein-restricted diets exert a notable influence over food intake and energy consumption, ultimately leading to body weight loss, depending on the degree of dietary protein restriction. These phenotypic alterations are primarily mediated by the FGF21 signaling pathway, whose activation is likely regulated by ATF4 and the circadian clock. The evidence suggests that protein-restricted diets as an alternative approach to calorie-restricted regimes, particularly in overweight or obese adults. However, more research is needed to determine the optimal level of restriction, duration, and long-term effects of such interventions.

Lee S, et al. J Nutr Health. 2025 Aug;58(4):408-420. https://doi.org/10.4163/jnh.2025.58.4.408

Supplementation of nicotinamide adenine dinucleotide (NAD) precursors has been investigated for its potential to counteract age-related physiological decline. While decreased NAD⁺ level is associated with conditions such as obesity and dyslipidemia, few studies have explored its metabolic impact in relatively young animals. Here, we hypothesized that nicotinamide mononucleotide (NMN) could alleviate high-fat diet-induced metabolic stress in young mice and sought to elucidate the underlying mechanisms. We first conducted a secondary analysis of hepatic transcriptome datasets from multiple NMN intervention studies to identify target pathways. Next, 11-week-old lean and obese C57BL/6N mice administrated NMN (500 mg/kg/day) for 1 mon were analyzed for metabolic parameters and gene expression for the target pathways. In vitro study using AML12 cell line was then conducted to confirm the effects of NMN. Additionally, transcriptomic data from liver-specific nicotinamide phosphoribosyltransferase (NAMPT)-deficient mice were analyzed to examine the relationship between NAD⁺ metabolism, endoplasmic reticulum (ER) stress, and circadian rhythm. The secondary analysis of hepatic transcriptome datasets revealed potential target pathways related to circadian regulation and hepatic ER stress. In mouse study, short-term NMN administration significantly decreased body weight and fat mass. NMN also alleviated hepatic ER stress response in vivo and in vitro. Additional analysis revealed that the mice with diet-induced metabolic stress or NAMPT deficiency led to phase shifts of the hepatic circadian core clock oscillation by advancing the peak time, while time-restricted feeding shifted the opposite, indicating the metabolic regulation of the circadian phase. Short-term NMN administration effectively attenuated obese condition in young mice and mitigated hepatic ER stress. The altered ER stress was regulated by NAMPT, potentially through the phase shift of the hepatic circadian rhythm.