When a calorie is not just a calorie: Diet quality and timing as mediators of metabolism and healthy aging

Abstract

An epidemic of obesity has affected large portions of the world, increasing the risk of developing many different age-associated diseases, including cancer, cardiovascular disease, and diabetes. In contrast with the prevailing notion that "a calorie is just a calorie," there are clear differences, within and between individuals, in the metabolic response to different macronutrient sources. Recent findings challenge this oversimplification; calories from different macronutrient sources or consumed at different times of day have metabolic effects beyond their value as fuel. Here, we summarize discussions conducted at a recent NIH workshop that brought together experts in calorie restriction, macronutrient composition, and time-restricted feeding to discuss how dietary composition and feeding schedule impact whole-body metabolism, longevity, and healthspan. These discussions may provide insights into the long-sought molecular mechanisms engaged by calorie restriction to extend lifespan, lead to novel therapies, and potentially inform the development of a personalized food-as-medicine approach to healthy aging.

Keywords: calorie restriction; fasting; isoleucine; ketogenesis; methionine; protein restriction; time-restricted feeding.

Figure 1.. Key findings from discussed studies on caloric and nutrient restriction paradigms in fly and mammalian studies.

This schematic summarizes some of the key takeaways from presenters of the NIH workshop, summarizing major findings of studies involving time-restricted feeding, fasting and other feeding paradigms across files, mice, nonhuman primates (NHPs) and humans. In flies, several feeding paradigms were described. Time-Restricted Feeding (TRF) in flies can reduce triglyceride content and improve cardiac and skeletal muscle health under aging and obesity. Intermittent fasting regiment (iTRF) from 10–40 days of age extends lifespan of flies 10–15%, however applied too early or late in life can lead to negative consequences for fly health. Additionally, iTRF can delay age-related climbing inability and intestinal dysfunction. In mice, many different time-restricted and nutrient type-restricted studies were described. In particular, the fasting component of Caloric Restriction (CR) is necessary for many of the improvements observed with CR like insulin sensitivity, lifespan extension and reduced frailty. Fasting can improve intestinal stem cell function and serine and glycine deprivation affects muscle stem cells. TRF can protect from obesogenic, western diets and intermittent ketogenic diets improve healthspan measurements. Twice a day feeding in the dark cycle (TAN) remodels metabolic tissues and increases energy expenditure. Multiple amino acid-restricted diets were discussed; restriction of either methionine or branched-chain amino acids (BCAAs) improves metabolic health and cognition, and extends lifespan. In NHPs, meal spacing matters for healthspan measurements and fasting in between meals can improve survival. In humans, adherence to various forms of caloric restriction and time-restricted feeding can be challenging. While some healthy people with obesity can tolerate 4–12 hour feeding windows, shorter windows do not produce long-term adherence. Restricting eating to 12 hours also did not produce significant improvements in cardiovascular health. Caloric restriction sustained over two years can improve thymic function and reduce oxidative damage, however long-term effects of extended caloric restriction on immune cell function remains to be further elucidated. (Parts of this figure were created with BioRender.com)

Figure 2.. Challenges for translating dietary and pharmaceutical interventions into the clinic.

1) Genetic background and sex play a major role in the response to dietary and pharmaceutical interventions in the pre-clinical studies discussed here; 2) we are only beginning to understand the physiological and molecular mechanisms engaged by these interventions, and many questions remain; and 3) while it is clear that timing and diet composition are critically important regulators of metabolic health, the intersection of timing and diet composition has not been deeply explored. Finally, age, obesity and daily energy expenditure may be important factors in the response to different dietary interventions, and some interventions may be less beneficial or even deleterious in older individuals. This figure was created with BioRender.com.

Figure 3.. Molecular mechanisms of dietary restriction.

Dietary restriction encompasses reduced consumption of macronutrients such as carbohydrates and amino acids to alter their blood levels and, subsequently, insulin and IGF levels. These changes are sensed across different cell types and impinge on several conserved nutrient sensors, such as mTOR complex 1 (mTORC1) and AMP- activated protein kinase (AMPK). Reduced mTORC1 activity, due to lower levels of certain amino acids, leads to decreased protein synthesis and ribosomal biogenesis. AMPK acts as a sensor of cellular energy by sensing changes in intracellular AMP, ADP and ATP levels. Glucose deprivation activates AMPK which in turn can phosphorylate and regulate several downstream substrates. AMPK and mTORC1 both converge on regulating autophagy in opposing ways. AMPK-dependent phosphorylation of Unc-51-like kinase 1 (ULK1) is required for mitophagy, a specific type of autophagy that involves degrading damaged mitochondria that may be impaired in aged tissues. Dietary restriction of carbohydrates or overall calorie restriction can also reduce metabolic activity through PI3K and AKT pathways. Reduced AKT activity will increase forkhead box protein O (Foxo)-dependent transcriptional programs involved in glucose and lipid signaling. Additionally, mTORC1 and AKT regulate sterol regulatory element-binding protein (SREBP) 1 and 2, which regulate fatty acid and cholesterol metabolism, respectively. Inhibition of mTORC1 through Rapamycin can mimic some of the beneficial effects of dietary restriction, but it remains to be seen if Rapamycin affects different tissues and cell types to the same extent. This figure was created with BioRender.com.