Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner

Abstract

Global average life expectancy continues to rise. As aging increases the likelihood of frailty, which encompasses metabolic, musculoskeletal, and cognitive deficits, there is a need for effective anti-aging treatments. It is well established in model organisms that dietary restriction (DR), such as caloric restriction or protein restriction, enhances health and lifespan. However, DR is not widely implemented in the clinic due to patient compliance and its lack of mechanistic underpinnings. Thus, the present study tested the effects of a somewhat more clinically applicable and adoptable DR regimen, every-other-day (EOD) intermittent fasting, on frailty in 20-month-old male and female C57BL/6 mice. Frailty was determined by a series of metabolic, musculoskeletal, and cognitive tasks performed prior to and toward the end of the 2.5-month dietary intervention. Late-life EOD fasting attenuated overall energy intake, hypothalamic inflammatory gene expression, and frailty in males. However, it failed to reduce overall caloric intake and had a little positive effect in females. Given that the selected benefits of DR are dependent on augmented production of the gasotransmitter hydrogen sulfide (H2S) and that renal H2S production declines with age, we tested the effects of EOD fasting on renal H2S production capacity and its connection to frailty in males. EOD fasting boosted renal H2S production, which positively correlated with improvements in multiple components of frailty tasks. Therefore, late-life initiated EOD fasting is sufficient to reduce aging-related frailty, at least in males, and suggests that renal H2S production capacity may modulate the effects of late-life EOD fasting on frailty.

The degree of frailty as a translational measure of health in aging

“…In contrast to these findings, a ketogenic diet that mimics calorie restriction has little effect on the level of frailty in aging mice 193 . Other dietary interventions like protein restriction 194 or intermittent fasting 195 also reduce frailty or components of frailty, but only in male mice. This indicates that the effects of frailty interventions can be sex specific, which is important as many intervention studies have used only one sex-generally male (Table 2).…”

Effects of exercise on cellular and tissue aging

“…Additionally, it is currently unclear whether caloric restriction has a positive effect in humans. Current research is exploring intermittent fasting as an alternative with beneficial antiaging effects at a cellular level in animals and humans [ 26 , 27 ].…”

Caloric Restriction May Help Delay the Onset of Frailty and Support Frailty Management

“…Time-restricted feeding may help protect cardiometabolic health; in contrast to CR, it may also be associated with satisfactory compliance as time is relatively easy to monitor ( 69 ). In later life, intermittent fasting on alternate days may increase renal gasotransmitter hydrogen sulfide production, which may help reduce age-related frailty in male mice ( 70 ).…”