Intermittent Fasting: From Calories to Time Restriction

Abstract Classic implementation of calorie restriction (CR) in laboratory animals increases health and longevity in most model organisms. Traditionally, chronic CR is the reduction of daily energy intake without malnutrition. Recently, paradigms have emerged that recapitulate some of the beneficial aspects of this intervention, avoiding some of its challenges. The length of daily fasting length and periodicity have emerged as potential drivers behind CR’s beneficial health effects. Numerous strategies and eating patterns, including prolonged periods of fasting, have been successfully developed to mimic many of CR’s benefits without its austerity. These new feeding protocols range from short mealtimes designed to interact with our circadian system (daily time-restricted feeding) to more extended fasting regimens known as intermittent fasting. We will discuss the current status of knowledge on different strategies to reap the benefits of CR on metabolic health in rodent models and humans without the rigor of chronic reductions in caloric intake.

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NEW DIRECTIONS IN DIETARY RESTRICTION: REMEMBERING EDWARD MASORO Chair: Arlan Richardson
In 1935, Clive McCay reported that severe restriction of food increased the lifespan of male rats. In the following four decades, several laboratories replicated this observation with less sever restrictions, which will be referred to as dietary restriction (DR). However, there were concerns even in the aging community in the 1970s as to whether DR increased lifespan by retarding aging. It was the research of two former Kleemeier Awardees, Edward Masoro and Roy Walford, that conclusively demonstrated in the 1980s that DR retarded aging resulting in improved healthspan and reduced pathology. Ed Masoro's research was focused on lipid metabolism when he was invited to attend a workshop on metabolism and aging in 1969. His interest in aging was piqued such that the more he learned about aging, the more interested he became. In a subsequent workshop in 1973, Ed heard Morris Ross describe his research on restricting food intake on cancer and longevity. Ed was impressed that a relatively simple manipulation had such dramatic effects, and he decided to focus his research on DR. After an extensive review of the DR literature up to the 1970s, Ed established the 40% restriction paradigm, which is used in almost all DR studies to date. Ed's group was the first to study aging and DR under barrier conditions which he established at San Antonio. Over the next two decades, Ed would direct a Program Project that showed DR had a dramatic effect on most age-related pathologies and improved many physiological functions. Studying the restriction of fat, protein, micronutrients, Ed came to the conclusion that total calories consumed was a key factor in the effect of DR on longevity. His group was the first to show that DR significantly reduced circulating levels of glucose and insulin, which was subsequently shown to occur because of increased insulin sensitivity and is now recognized as a hallmark of DR and potentially important in the anti-aging action of DR. Ed was chair of the Biological Sciences Section of GSA in 1979 and President in 1995. This session is dedicated to Edward Masoro who passed away on July 11, 2020 at the age or 95. Dr. Masoro was president in 1995 and BS chair in 1979, Clive McCay was President in 1949.

INTERMITTENT FASTING: FROM CALORIES TO TIME RESTRICTION
Rafael de Cabo, NIA, Baltimore, Maryland, United States Classic implementation of calorie restriction (CR) in laboratory animals increases health and longevity in most model organisms. Traditionally, chronic CR is the reduction of daily energy intake without malnutrition. Recently, paradigms have emerged that recapitulate some of the beneficial aspects of this intervention, avoiding some of its challenges. The length of daily fasting length and periodicity have emerged as potential drivers behind CR's beneficial health effects. Numerous strategies and eating patterns, including prolonged periods of fasting, have been successfully developed to mimic many of CR's benefits without its austerity. These new feeding protocols range from short mealtimes designed to interact with our circadian system (daily timerestricted feeding) to more extended fasting regimens known as intermittent fasting. We will discuss the current status of knowledge on different strategies to reap the benefits of CR on metabolic health in rodent models and humans without the rigor of chronic reductions in caloric intake.

IMPACT OF CALORIC RESTRICTION ON MOLECULAR AND FUNCTIONAL NETWORKS IN RHESUS MONKEYS Rozalyn Anderson, University of Wisconsin-Madison, Madison, Wisconsin, United States
Caloric restriction (CR) delays aging and the onset of age-related disease in diverse species. Several diseases of aging including diabetes, cancer, and neurodegeneration, have an established metabolic component. Although the mechanisms of CR remain unknown, numerous factors implicated in longevity regulation by CR converge on regulation of metabolism. The reprograming of metabolism with CR is tissue specific, but mitochondrial activation and changes in redox metabolism are among the shared features. Changes in non-coding miRNA and in processing of transcripts are contributing mechanisms in integrating metabolic and growth pathways. Our studies in simple cell culture shows that small changes in metabolic status can precipitate large-scale multi-modal functional changes across cellular processes. We propose that modest failures in metabolic integrity with age broadly impact homeostasis and adaptation, creating shared vulnerability to diseases and conditions despite differences in their etiology, and that CR harnesses this same axis to promote health and enhanced longevity.

CIRCADIAN ALIGNMENT OF FEEDING REGULATES LIFESPAN EXTENSION BY CALORIC RESTRICTION
Victoria Acosta-Rodriguez, 1 Filipa Rijo-Ferreira, 1 Mariko Izumo, 1 Pin Xu, 3 Carla Green, 1 and Joseph Takahashi, 1 1. UT Southwestern Medical Center,Dallas,Texas,United States,3. Icahn School of Medicine at Mount Sinai,New York,New York,United States Caloric restriction (CR) promotes longevity in several species. Classic CR protocols often lead to chronic cycles of 2h-feeding/22h-fasting, raising the question whether calories, fasting or time of day are causal. To address this, we tested an AL control group and five CR protocols with different timing and duration of feeding/fasting cycles. C57BL/6J male mice were subjected to 30% CR as one single meal a day at the beginning of the day or night (classical protocols with < 2h feeding, CR-day and CR-night), or smaller meals distributed for 12h (CR-day-12h and CR-night-12h), or evenly spread out throughout 24h (CR-spread) to abolish the otherwise daily feeding pattern adopted by nocturnal animals. We found that CR alone is sufficient to extend lifespan without Innovation in Aging, 2021, Vol. 5, No. S1