Short-Term Intermittent Fasting Induces Long-Lasting Gut Health and TOR-Independent Lifespan Extension

摘要

class="head no_bottom_margin" id="sec1title">IntroductionIntermittent fasting (IF), an umbrella term for diets that cycle between a period of fasting and non-fasting, has become increasingly popular as a weight loss regime (e.g., “every-other-day fasting” and the “5:2” diet) [, ]. Advocates of IF argue that it shows many of the benefits seen with traditional daily energy restriction diets but with a simplified nutritional regime and increased compliance []. One study on the clinical outcomes of fasting in young overweight women described significant weight loss as a result of the IF regime, as well as reduced fat mass and waist circumference, and lowered serum cholesterol, triglycerides, and C-reactive protein []. More recent, pilot, clinical trials used a fasting mimicking diet (FMD) (consisting of monthly cycles of a 5-day fast during which daily food intake was reduced to ∼50% normal caloric intake), which reduced multiple health risk factors during the post-fast recovery period, including lowered blood pressure, and reduced blood glucose and insulin-like growth factor-1 (IGF-1) levels [, ]. However, systematic reviews of the clinical benefits of fasting regimens in humans found that study designs were heterogeneous and compliance data limited, making it difficult to draw definitive conclusions [, ].IF can extend lifespan in a variety of organisms, including bacteria, yeast, nematode worms, and mice []. In animal models, IF has been shown to reduce the risk of developing a variety of age-related pathologies [, ]. IF is effective in preventing neurodegeneration in rodents [, , , , href="#bib15" rid="bib15" class=" bibr popnode">15] and can attenuate cancer [href="#bib16" rid="bib16" class=" bibr popnode">16] and cardiometabolic diseases, such as type II diabetes [href="#bib4" rid="bib4" class=" bibr popnode">4, href="#bib17" rid="bib17" class=" bibr popnode">17, href="#bib18" rid="bib18" class=" bibr popnode">18, href="#bib19" rid="bib19" class=" bibr popnode">19, href="#bib20" rid="bib20" class=" bibr popnode">20, href="#bib21" rid="bib21" class=" bibr popnode">21]. FMD was recently found to increase pancreatic β cell regeneration in mouse models of diabetes [href="#bib22" rid="bib22" class=" bibr popnode">22].DR, a chronic reduction of food intake without malnutrition, is an evolutionarily conserved method of improving health during aging and extending lifespan [href="#bib23" rid="bib23" class=" bibr popnode">23]. However, many studies of DR, particularly in rodents, also involve intermittent access to food, with the DR animals gorging their reduced meal as soon as it is supplied, leaving extended periods of time in a fasted state [href="#bib24" rid="bib24" class=" bibr popnode">24]. The beneficial health effects seen in DR may therefore be attributable, at least in part, to intermittent starvation. Supporting this idea, performing DR without the extended fasting periods by diluting the food of the DR mice with non-digestible cellulose, thus restricting total energy intake but allowing constant access to food, did not extend lifespan compared to fully fed animals [href="#bib25" rid="bib25" class=" bibr popnode">25]. In contrast, many studies in invertebrate organisms, including yeast, worms, and Drosophila, where the DR treatment involves continuous access to diluted food, result in robust lifespan extension [href="#bib26" rid="bib26" class=" bibr popnode">26]. Therefore, periodic fasting may be important for, but is likely not the only contributor to, the pro-longevity effects of DR, at least in these invertebrates.Reduced activity of nutrient-sensing pathways, with corresponding decrease in global protein translation, is implicated as an important mechanism underlying the pro-longevity effects of dietary interventions, such as DR [href="#bib23" rid="bib23" class=" bibr popnode">23]. Reduced TOR signaling is a hallmark of pro-longevity interventions, including DR, and treatment with the TOR inhibitor rapamycin extends healthy lifespan in a range of organisms [href="#bib27" rid="bib27" class=" bibr popnode">27]. Although DR may exert some of its pro-longevity effects through reduced fecundity, DR can still extend lifespan in sterile, ovo^D mutant Drosophila, implying that fecundity and lifespan can be uncoupled and that other mechanisms are also important [href="#bib28" rid="bib28" class=" bibr popnode">28]. A recent study highlighted the importance of gut homeostasis in DR-induced longevity in Drosophila, because DR both rescued age-related gut pathologies and extended lifespan in females and in males with feminized guts, but not in wild-type males, which do not undergo significant age-related gut pathology [href="#bib29" rid="bib29" class=" bibr popnode">29]. Diet composition and fly food transfer schedule are also known to affect the abundance and diversity of fly-associated bacteria [href="#bib30" rid="bib30" class=" bibr popnode">30], and periods of fasting may be expected to modulate the associated microbiota.Invertebrate model organisms provide powerful contexts in which to establish the molecular mechanisms mediating the pro-longevity effects of IF. In yeast, Rim15, a key integrator of signals transduced by the Sch9, Ras, and TOR pathways, is important for starvation-induced lifespan extension [href="#bib31" rid="bib31" class=" bibr popnode">31] while in the nematode worm Rheb-1, with a key role in TOR signaling, is essential for the pro-longevity effects of IF [href="#bib32" rid="bib32" class=" bibr popnode">32]. Interestingly, the findings with both organisms imply the existence of additional underlying mechanisms mediating the pro-longevity effects of IF. It is unclear whether Rim15/Rheb-1 and their interactors mediate the effects of IF in mammals.Previous studies examining potential pro-longevity effects of IF in flies have produced mainly negative results [href="#bib26" rid="bib26" class=" bibr popnode">26, href="#bib33" rid="bib33" class=" bibr popnode">33, href="#bib34" rid="bib34" class=" bibr popnode">34]. The first studies, almost 90 years ago, found that 6 hr of starvation in every 24 hr was beneficial and could extend lifespan [href="#bib34" rid="bib34" class=" bibr popnode">34]. However, the effects of this IF regime may be strain or food medium specific, because a similar, more rigorous experiment ∼80 years later found that daily bouts of either 3 hr or 6 hr starvation throughout the adult life of the fly had neither a positive nor a negative effect on lifespan [href="#bib26" rid="bib26" class=" bibr popnode">26]. Interestingly, short-term fasting can increase resistance to severe cold stress [href="#bib35" rid="bib35" class=" bibr popnode">35] and facilitate long-term memory formation in flies [href="#bib36" rid="bib36" class=" bibr popnode">36]. Time-restricted feeding (TRF) in Drosophila improves sleep consolidation as well as a variety of cardiac output functions that normally decline with age, despite the caloric ingestion/expenditure of TRF flies being the same as ad-libitum-fed flies [href="#bib37" rid="bib37" class=" bibr popnode">37]. Thus, health improvements can result from various IF regimes in Drosophila, but the mechanisms at work await elucidation and the evidence for a pro-longevity phenotype from IF is more mixed.Here, we investigated a variety of IF regimes in flies and their effects on a range of health outcomes, including feeding behavior, gut and metabolic health, survival after stress, and lifespan. Importantly, short-term IF (the “2:5” diet) confined to early life robustly increased subsequent lifespan, particularly in females, independent of TOR signaling. Short-term IF also led to long-lasting health improvements, including increased stress resistance and a lower incidence of gut pathology that was associated with reduced bacterial abundance.