Metabolic switching is impaired by aging and facilitated by ketosis independent of glycogen

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>The ability to switch between glycolysis and ketosis promotes survival by enabling metabolism through fat oxidation during periods of fasting. Carbohydrate restriction or stress can also elicit metabolic switching. Keto-adapting from glycolysis is delayed in aged rats, but factors mediating this age-related impairment have not been identified. We measured metabolic switching between glycolysis and ketosis, as well as glycogen dynamics, in young and aged rats undergoing time-restricted feeding (TRF) with a standard diet or a low carbohydrate ketogenic diet (KD). TRF alone reversed markers of insulin-related metabolic deficits and accelerated metabolic switching in aged animals. A KD+TRF, however, provided additive benefits on these variables. Remarkably, the ability to keto-adapt was not related to glycogen levels and KD-fed rats showed an enhanced elevation in glucose following epinephrine administration. This study provides new insights into the mechanisms of keto-adaptation demonstrating the utility of dietary interventions to treat metabolic impairments across the lifespan.</jats:p>

Time-restricted feeding from adulthood to old age improves biconditional associative learning in geriatric rats regardless of macronutrient composition

“…When initiated at 8 months of age, normal rats show little metabolic dysfunction from lifelong ad libitum feeding with a standard diet. In contrast, rats that are allowed to consume food ad libitum into old age gain excessive weight, acquire aberrant amounts of white adipose tissue, as well as show disrupted insulin signaling and a reduced ability to utilize glucose in the brain (5,6,13,14). The current data suggest that timerestricted feeding throughout adulthood, regardless of the macronutrient composition, may be able to prevent these metabolic deficits in old age and lead to resilience against age-related cognitive decline.…”

“…Furthermore, we observed that nutritional ketosis, which has been shown to improve metabolic health in aged rats (5,6), did not confer an additive benefit to time-restricted feeding with a standard control diet in regards to multitasking performance on a biconditional association task. Shorter term ketogenic diets initiated in old age (21 months), which is an age at which rats on lifelong ad libitum feeding have age-related declines in metabolic function, have demonstrated improved cognitive outcomes on a similar task as well as reduced anxiety-like behavior (9).…”

“…Importantly, both diets had equivalent caloric and micronutrient content and were given once per day. Critically, the aged animals in this previous study had metabolic impairments, including hyperinsulinemia and excess visceral white adipose tissue (5). The possibility therefore exists that diet-induced cognitive benefits are directly related to the efficacy of different diets at reversing metabolic deficits that lead to impairments in brain function.…”

“…These rats were given ~51 kcal of food once daily. All animals consumed the full ration of calories within 3 hours, resulting in ~21 hours of fasting (5). Among the rats given timerestricted feeding, one group was fed a ketogenic diet, while the other group was fed a micronutrient and calorically equivalent control diet (6).…”

“…A third group of rats was fed ad libitum until 21 months of age, at which time they were fed standard rodent chow once daily to encourage appetitively-motivated participation in cognitive testing. A previous study has reported that rats of the Fischer 344 x Brown Norway hybrid strain develop hyperinsulinemia and metabolic impairments when allowed unrestricted access to standard laboratory rodent chow from adulthood into old age (5).…”