Twelve Months of Time-Restricted Feeding Improves Cognition and Alters Microbiome Composition Independent of Macronutrient Composition

Abstract

Declining health, gut dysbiosis, and cognitive impairments are hallmarks of advanced age. While caloric restriction is known to robustly extend the healthspan and alter gut microbiome composition, it is difficult maintain. Time-restricted feeding or changes in dietary macronutrient composition could be feasible alternatives for enhancing late life cognitive and physical health that are easier to comply with for extended periods of time. To investigate this possibility, 8-month-old rats were placed on time-restricted feeding with a ketogenic or micronutrient- and calorically matched control diet for 13 months. A third group of rats was permitted to eat standard chow ad libitum during this time. At 22 months, all rats were tested on a biconditional association task and fecal samples were collected for microbiome composition analysis. Regardless of dietary composition, time-restricted-fed rats had better cognitive performance than ad libitum-fed rats. This observation could not be accounted for by differences in motivation, procedural or sensorimotor impairments. Additionally, there were significant differences in gut microbiome diversity and composition between all diet conditions. Allobaculum abundance was associated with cognitive task performance, indicating a link between gut health and cognitive outcomes in aged subjects. Overall, time restricted feeding had the largest influence on cognitive performance in aged rats.

A long-term ketogenic diet in young and aged rats has dissociable effects on prelimbic cortex and CA3 ensemble activity

“…Due to this time-restricted feeding, both groups experienced intermittent fasting. Intermittent fasting, even with a normal control diet, can affect gene expression in the brain (Castrogiovanni et al, 2018;Spezani et al, 2020;Ng et al, 2022), confer neuroprotection (Halagappa et al, 2007;Mattson et al, 2017;Anton et al, 2018), and alter the gut microbiome (Hernandez et al, 2022a;Hernandez et al, 2022b). Because all rats received intermittent fasting, it is possible that potential diet by age interactions were less than would have been observed with free feeding animals.…”

“…Because all rats received intermittent fasting, it is possible that potential diet by age interactions were less than would have been observed with free feeding animals. In fact, rats the receive ad libitum feeding from middle-to old-age have worse cognitive performance compared to both ketogenic and control-fed rats that received intermittent fasting during the same time period (Hernandez et al, 2022b).…”

“…Previous studies have shown that a KD diet with medium chain triglyceride oil as the primary fat source is able to improve cognitive performance in both young and aged rats on both spatial alternations and WM/BAT (Hernandez et al, 2018a). Additionally, the KD leads to increased expression of vesicular GABA transporter in both the hippocampus and frontal cortex (Hernandez et al, 2018b), and alters the gut microbiome composition (Hernandez et al, 2022a; Hernandez et al, 2022b). Importantly, biochemical effects of the KD have been reported to differ between the hippocampus and the frontal cortex.…”

Fasting: From Physiology to Pathology

“…Rhythmic SFB attachment drives diurnal rhythms in the expression and activation of signal transducer and activator of transcription 3 (STAT3), a key regulator for immune response, which modulates the rhythms of antimicrobial proteins, including regenerating islet-derived protein 3𝛾 (REG3G), lipocalin-2 (LCN2) and S100A8, and thus stimulates intestinal innate immunity. [73] Other studies also showed that TRF can adjust the gut microbiota, [74][75][76] however the relationship with circadian rhythms is currently unknown. Although increasing evidence suggests that the benefits of TRF are dependent on a functional circadian clock, a previous study showed that TRF can still alleviate metabolic stress and prevent metabolic disorders in mice lacking a circadian clock.…”

Circadian‐mediated regulation of cardiometabolic disorders and aging with time‐restricted feeding

“…TRF is also beneficial in middle‐aged flies, as it prevents age‐dependent body weight gain and leads to better consolidated nighttime sleep [31]. This extends to other aging‐related dysfunction, as TRF prevents age‐associated cognitive decline in rats [43]. Obesity and weight are risk factors for other cardiometabolic and age‐associated diseases, and TRF ameliorates both along with improving circadian rhythmicity, highlighting its broad therapeutic potential for cardiometabolic diseases.…”