Sebastian Brandhorst

In recent decades, the study of biological aging has evolved from simplistic theories like the free radical theory to more complex and nuanced perspectives. In particular, the identification of evolutionary conserved genes and signaling pathways that can modulate both lifespan but also healthspan has resulted in the expanding understanding of the link between nutrients, signal transduction proteins, and aging along with substantial support for the existence of multiple “longevity programs,” which are activated based on the availability of nutrients. Periodic fasting and other dietary restrictions can promote entry into a longevity program characterized by cellular protection and optimized function, and the activation of regenerative processes that lead to rejuvenation. This review discusses the idea of juventology, a novel field proposing the existence of longevity programs that can maintain organisms in a highly functional state for extended periods of time. Drawing upon research on Saccharomyces cerevisiae and other model organisms, the review explores the distinctiveness of juventology from traditional aging-centered views. The focus on the “age of youth” challenges conventional thinking and opens new avenues for understanding and extending the period of peak functionality in organisms. Thus, a “juventology”‐based strategy can complement the traditional gerontology approach by focusing not on aging but on the longevity program affecting the life history period in which mortality is very low and organisms remain youthful, healthy, and fully functional.

Dietary interventions can ameliorate age-related neurological decline. Decades of research of in vitro studies, animal models, and clinical trials support their ability and efficacy to improve behavioral outcomes by inducing biochemical and physiological changes that lead to a more resilient brain. Dietary interventions including calorie restriction, alternate day fasting, time restricted feeding, and fasting mimicking diets not only improve normal brain aging but also slow down, or even reverse, the progression of neurological diseases. In this review, we focus on the effects of intermittent and periodic fasting on improving phenotypic outcomes, such as cognitive and motor-coordination decline, in the normal aging brain through an increase in neurogenesis and synaptic plasticity, and decrease in neuroinflammation, mitochondrial dysfunction, and oxidative stress. We summarize the results of various dietary interventions in animal models of age-related neurological diseases such as Alzheimer’s disease, Parkinson’s disease, epilepsy, and Multiple Sclerosis and discuss the results of clinical trials that explore the feasibility of dietary interventions in the prevention and treatment of these diseases.

Purpose of Review This article reviews the current literature on dietary interventions, including time-restricted eating (TRE), intermittent fasting (IF), and fasting-mimicking diets (FMD) and their effects on weight loss. Recent Findings Dietary interventions, primarily known for their potential health benefits, are attracting considerable interest also for their effects on weight loss. Summary The literature suggests that many popular diets can induce weight loss but only a limited number of studies actually demonstrate long-term weight loss efficacy. Here we present an update on the latest studies on some of the most popular dietary interventions able to trigger the physiology of fasting and highlight their impact on weight loss in overweight or obese individuals.

The increasingly older population in most developed countries will likely experience aging-related chronic diseases such as diabetes, metabolic syndrome, heart and lung diseases, osteoporosis, arthritis, dementia, and/or cancer. Genetic and environmental factors, but also lifestyle choices including physical activity and dietary habits, play essential roles in disease onset and progression. Sixty-five percent of Americans diagnosed with cancer now survive more than 5 years, making the need for informed lifestyle choices particularly important to successfully complete their treatment, increase the recovery from the cytotoxic therapy options, and improve cancer-free survival. This review will discuss the findings on the use of prolonged fasting, as well as fasting-mimicking diets to augment cancer treatment. Preclinical studies in rodents strongly support the implementation of these dietary interventions and a small number of clinical trials begin to provide encouraging results for cancer patients and cancer survivors.

Purpose of Review Cardiovascular disease (CVD) is one of the leading causes of death globally. Nutrition plays a central role in CVD risk by affecting aging, adiposity, glycemia, blood pressure, cholesterol, inflammation, and other risk factors and can affect CVD risk not only based on calorie intake and dietary composition but also the timing and range of meals. This review evaluates the effects of fasting, fasting-mimicking diets, and time-restricted eating on the reduction of CVD risk factors and provides initial data on their potential to serve as CVD prevention and treatment therapies. Recent Findings Intermittent fasting (IF), time-restricted eating (TRE), prolonged fasting (PF), and fasting-mimicking diets (FMD) show promise in the reduction of CVD risk factors. Summary Results on IF, TRE, PF, and FMD on CVD risk factors are significant and often independent of weight loss, yet long-term studies on their effect on CVD are still lacking. Coupling periodic and prolonged, or intermittent and more frequent cycles of fasting or fasting-mimicking diets, designed to maximize compliance and minimize side effects, has the potential to play a central role in the prevention and treatment of CVD and metabolic syndrome.

Basic preclinical research on the pathophysiology of aging-related and/or metabolic diseases, including type 2 diabetes, largely relies on animal models. Mice, the most commonly used species to study the biological processes that regulate aging and its associated functional decline, have helped researchers to identify pathways, mechanisms, and genes that regulate aging-related diseases and aging itself and thus are intervention targets. Changes in energy metabolism are a central component of the biological processes that undergo significant alterations with age. For example, the prevalence of type 2 diabetes and impaired glucose tolerance increases with aging. Not surprisingly, the characterization of these changes for metabolic phenotyping is commonly found in laboratories around the world. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) do not require surgery, are relatively easy to perform, and, most importantly, are minimally invasive and are thus the preferred method to evaluate glucose homeostasis in the aging animal. Both assays measure blood glucose following the bolus injection of either glucose (for GTT) or insulin (for ITT). Although they are standard procedures, the interpretation of both assays is strongly influenced by laboratory practices and variable experimental conditions. Here, we aim to provide simple guidelines that can be useful to standardize GTT and ITT in the aging mouse.

Dietary modifications, including caloric restriction, dietary restriction, various intervals of fasting, and even limiting the time when food is consumed can have a pronounced impact on longevity. In addition, dietary modifications are powerful interventions to delay, prevent, or treat many aging-related diseases such as cancer and diabetes. Restricting amino acid and protein intake generally decreases aging-related comorbidities and thereby increases health and longevity. However, chronic dietary interventions are likely not feasible for most people due to low adherence to dietary protocols or resistance to drastic changes to lifestyle, and might even cause detrimental effects, possibly by negatively affecting the immune system and wound healing. The periodic use of low-protein, low-calorie fasting-mimicking diets (FMDs) has the potential to promote health benefits, while minimizing the burden of chronic restriction. Protein restriction and FMDs together have the potential to play an important complementary role in medicine by promoting disease prevention and treatment, and by delaying the aging process at least in part by stimulating stem cell-based regeneration in periods of normal food intake after periodic FMD cycles. The aim of this narrative review is to summarize research on the impact of protein restriction on health and longevity in model organisms and to discuss the implementation of an FMD in mice and in human clinical trials and its effects on biomarkers of healthy aging. Taking into account the importance of sex on aging and diet, we include this information in all discussed studies. Whereas for some model organisms of aging, such as rodents, many studies are available, results are more limited for primates and/or humans.

A periodic fasting diet improves markers of metabolic dysfunction, particularly in people already at risk.