A long‐term obesogenic high‐fat diet in mice partially dampens the anti‐frailty benefts of late‐life intermittent fasting

The global obesity pandemic coupled with ever-growing life expectancies equates to hundreds of millions of individuals with potentially longer but not healthier lives. Aging is one of the risk factors for numerous maladies such as metabolic dis- order and frailty, which are exacerbated under obesity. Thus, therapeutic approaches that address obesity to ultimately improve afected individuals’ quality of life and extend their lifespan are needed. We previously reported that the every other day (EOD) fasting initiated late-life improved metabolic, musculoskeletal, and cognitive endpoints in standard rodent diet-fed mice. In the present study, using the same dietary intervention methodology, we tested if 2.5 months of EOD fasting could improve metabolic, physiological, and cognitive endpoints in mice after an 18 month obesogenic high-fat diet (HFD). The positive efects of EOD fasting were generally consistent across the endpoints; EOD fasting decreased total body mass, maintained more %lean mass, improved glucose tol- erance and utilization, and improved neuromuscu- lar function. In contrast to our previous study, grip strength, hippocampal-dependent memory, and renal hydrogen sulfde (H2S) production were not improved by the HFD EOD fasting. Thus, efcacy for late- life initiated intermittent fasting to improve specifc frailty markers may be partially dependent on nutritional compositions of the diet

Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex

Background: Dietary sulfur amino acid restriction (SAAR) improves body composition and metabolic health across several model organisms in part through induction of the integrated stress response (ISR). Objective: We investigate the hypothesis that activating transcription factor 4 (ATF4) acts as a converging point in the ISR during SAAR. Methods: Using liver-specific or global gene ablation strategies, in both female and male mice, we address the role of ATF4 during dietary SAAR. Results: We show that ATF4 is dispensable in the chronic induction of the hepatokine fibroblast growth factor 21 while being essential for the sustained production of endogenous hydrogen sulfide. We also affirm that biological sex, independent of ATF4 status, is a determinant of the response to dietary SAAR. Conclusions: Our results suggest that auxiliary components of the ISR, which are independent of ATF4, are critical for SAAR-mediated improvements in metabolic health in mice

Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex

BACKGROUND: Dietary sulfur amino acid restriction (SAAR) improves body composition and metabolic health across several model organisms in part through induction of the integrated stress response (ISR). OBJECTIVE: We investigate the hypothesis that activating transcription factor 4 (ATF4) acts as a converging point in the ISR during SAAR. METHODS: Using liver-specific or global gene ablation strategies, in both female and male mice, we address the role of ATF4 during dietary SAAR. RESULTS: We show that ATF4 is dispensable in the chronic induction of the hepatokine fibroblast growth factor 21 while being essential for the sustained production of endogenous hydrogen sulfide. We also affirm that biological sex, independent of ATF4 status, is a determinant of the response to dietary SAAR. CONCLUSIONS: Our results suggest that auxiliary components of the ISR, which are independent of ATF4, are critical for SAAR-mediated improvements in metabolic health in mice