Oral Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

An ad libitum-fed diet that matches the beneficial lifespan effects of caloric restriction but acts via opposite effects on the energy-splicing axis (131877)

Amanda Brandon 1 2 3 , Tamara Pulpitel 1 2 , Carsten Schmitz-Peiffer 1 2 , Lewin Small 1 2 , Alister M Senior 1 2 , sophie Stonehouse 1 2 , Letisha Prescott 1 2 , Alyssa Face 1 2 , Saiful Islam 1 2 , Jenny E Gunton 4 5 , Jacob George 6 , David Raubenheimer 1 2 , Gregory J Cooney 1 2 , David G Le Couteur 1 3 7 , Stephen J Simpson 1 2
  1. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
  2. School of Life and Environmental Science, The University of Sydney, Sydney, NSW, Australia
  3. ANZAC Research Institute, Sydney, NSW, Australia
  4. Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia
  5. Centre for Diabetes, Obesity and Endocrinology Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
  6. Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital Sydney, Sydney, NSW, Australia
  7. 7School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sysney, NSW, Australia

Caloric restriction (CR) with fasting extends lifespan but is difficult to maintain in humans. Here we compared conventional CR (20%; 18% protein, 67% carbohydrate, 15% fat; fed at 3pm) with periods of fasting to an ad libitum-fed low-protein, high-carbohydrate (LPHC) diet diluted 25% with non-digestible fiber (6% protein, 79% carbohydrate, 15% fat) and control fed mice (18% protein, 67% carbohydrate, 15% fat). Due to the cellulose, LPHC mice had an increase in food intake, but an overall decrease in energy intake (~15% CR) compared to controls. Both dietary approaches similarly enhanced longevity and metabolic health (e.g. adiposity, glucose tolerance, fatty liver) relative to controls. Proteomic analysis of liver tissue revealed that CR alone increased proteins associated with energy and mitochondrial pathway. By contrast LPHC diet reduced these pathways but increased abundance of proteins associated with RNA metabolism and spliceosome pathways. These results for LPHC support the “energy-splicing resilience” axis theory of aging. Our results suggest that ad libitum-fed diets can be designed to replicate, and potentially enhance, the geroprotective benefits of CR, albeit via different mechanisms, potentially offering a more sustainable dietary approach to longevity extension.