Integrated Chronofasting:up,down and all around healthy aging pathways modulation.
Aging is associated with a host of biological changes that contribute to a progressive decline in cardiovascular,neuro-endocrine-immune and physical function, ultimately leading to a loss of independence,disability,frailty and increased risk of mortality.To date, prolonged caloric restriction (in which daily calorie intake is reduced by 20–40%, and meal frequency is unchanged without malnutrition) is the only non-genetic intervention that has consistently been found to extend both mean and maximal life span across a variety of species. Most individuals have difficulty sustaining prolonged caloric restriction, which has led to a search for alternative approaches that can produce similar benefits as caloric restriction. A growing body of evidence indicates that short fasting periods and intermittent/periodic fasting regimens in particular can trigger similar biological pathways as caloric restriction. For this reason, there is increasing scientific interest in further exploring the biological and metabolic effects of intermittent fasting periods, as well as whether long-term compliance may be improved by this type of dietary approach. In lower eukaryotes, chronic fasting extends longevity, in part, by reprogramming metabolic and stress resistance pathways. In rodents intermittent or periodic fasting protects against diabetes, cancers, heart disease, and neurodegeneration, while in humans it helps reduce obesity, hypertension, asthma, rheumatoid arthritis and promotes healthy aging.Different dietary regimens are proposed by fasting strategies world scientists: (i) intermittent energy restriction (IER), which involves eliminating (fasting) or greatly reducing (e.g., 500 calories per day) daily intake food/caloric beverage intake intermittently,for example 2 d/wk with intervening periods of normal food intake, on a recurring basis;(ii) time-restricted feeding (TRF), which involves limiting daily intake of food and caloric beverages to a 4- to 8-h time window;(iii) Short term (ST) and prolonged periodic fasting (PF) to refer to IF with ciclical straight days of fasting or fasting mimicking diets lasting< 3 days (ST) to more days (3 or more )(PF).In laboratory rats and mice IF and PF have profound beneficial effects on many different indices of health and, importantly, can counteract disease processes and improve functional outcome in experimental models of a wide range of age-related disorders including diabetes, cardiovascular disease, cancers and neurological disorders such as Alzheimer's disease Parkinson's disease and stroke. Studies of IF (e.g., 60% energy restriction on 2days per week or every other day), PF (e.g., a 5day diet providing 750-1100kcal) and time-restricted feeding (TRF; limiting the daily period of food intake to 8h or less) in normal and overweight human subjects have demonstrated efficacy for weight loss (preserving muscle mass)and improvements in multiple health indicators including insulin-leptin resistance,adiponectin level, and reductions in risk factors for cardiometabolic diseases; we find also positive promising reports in the health and aging related biomarkers like oxidative stress,glycation and inflammation in some TRF studies(Ramadam and resistance-trained males studies).Fasting has been practiced for millennia, but, only recently, studies have shed light on its role in positive aging. The different kind of fasting strategies exert both common and different effects.The cellular and molecular mechanisms by which IF, ST,PF and TRF improve health and counteract disease processes involve adaptive cellular responses(generated by a hormetic effect) that reduce oxidative damage and inflammation, optimize energy metabolism, enhance mitochondrial health, DNA repair and autophagy and boosts cellular protection.Other effects are mediated by the antinflammatory,antioxidant, vagotonic actions exerted by the body ketones produced during longher period of fasting or when shorter fasting times are integrated by a ketogenic diet.Many beneficial health effects of ketones are also mediated by their promoting actions on the release of BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) by the neurons which exerts both neurotrophic and positive cardiometabolic effects.PF also promotes stem cell-based regeneration while TRF produces its positive actions also through the optimizzation of microbiota composition,balance and its biological rhytms.In this lecture, the multilevel healthy aging actions of Chronofasting( CF) are explored; CF ideated by our scientific group Regenera Research Group for Aging Interventions, is the expression of the integration of the most important fasting strategies integrated by a diet rich in superfoods( foods that activates antiaging pathways like ampk,sirtuin,pgc-1alpha,foxo and nrf2) and by the treatment with phytochemicals(hormetins),supplements and drugs that mimic the actions of CR and Fasting on antiaging pathways.These are compounds that mimic CR and fasting effects by targeting metabolic and stress response pathways affected by energy restriction interventions.For example, drugs that inhibit glycolysis (2-deoxyglucose),enhance insulin action (metformin), or affect stress signaling pathways (resveratrol,curcumin,poliphenols,astaxanthin), are being assessed as CR mimetics (CRM).We quoted our project with the term Chronofasting because we propose a ciclical fasting that mirrors circadian rhytms (five days of TRF or circadian fasting, alternated with two days of Energy Restriction (ER) or weekly fasting and 3-5 straight days of ER two times/year during the seasonal change(seasonal fasting).The name Chronofasting has been proposed also because we know today that CR and the different fasting strategies exert many of their positive effects on aging process through the reset of central(CR,IF) and peripheral clocks(CR,IF,TRF) of our body and microbiota clocks(TRF) that are closed linked to our biological clocks in the regulation and promotion of health,aging and aging related diseases.Last researches have also proved similar conclusions in the mechanism of actions of old and new ones geroprotectors that so could be named Chronogeroprotectors.Thus, chronofasting that boostes the positive healthy aging effects of single different fasting strategies(multilevel circadian hormesis) integrated by the support of a personalized superfoods nutrition and supplementation program,has the potential to delay aging and help prevent and treat diseases while minimizing the side effects and compliance limit of chronic energy restriction interventions.It’s clear that we are in the infancy of fasting research so randomized controlled clinical trials of CF and IF versus PF and isoenergetic continuous energy restriction in human subjects will be required to establish the real efficacy of these nutritional strategies in improving general health, and preventing and managing most common diseases of aging.
