• Fasting every other day improves frailty measures including muscle function and cognition for aged male mice.
  • Intermittent fasting also increases the production of a possible anti-aging chemical compound hydrogen sulfide in the kidney.

As the global population over age 65 continues to grow, so too comes the need to extend the number of healthy years lived — what scientists call healthspan. To improve healthspan, researchers have measured the beneficial effects of dietary interventions like calorie restriction and intermittent fasting on the loss of physiological reserve — frailty — that lead to poor health outcomes or death. More research is needed, though, to determine which intervention works best and the optimal age to initiate the dietary regimen. Having a better overall understanding of the effects of these interventions can only help our efforts to increase the aged population’s healthspan.

Hine and colleagues from the Cleveland Clinic Lerner Research Institute published a study in Geroscience where they found that feeding aged mice every-other-day improved signs of muscle frailty and enhanced cognition. This intervention strategy also increased the kidney’s release of a chemical compound called hydrogen sulfide in males, which the researchers speculate provides anti-aging benefits.

“Collectively, these results suggest that late-life initiated [every other day] fasting attenuates multiple components of aging-related frailty in a sex-dependent manner and that these frailty improvements may be due to increased production of renal [hydrogen sulfide],” stated the Cleveland-based research team in their publication.

Why Not Calorie-Restricted Diets?

People have a hard time implementing calorie restriction, let alone studying it. Successfully adhering to calorie restriction requires constant medical oversight to ensure daily calorie intake guidelines are safely followed. Besides, long-term calorie restriction interventions in aged people may lead to malnutrition. For these reasons, Hine and colleagues examined the effects of the more implementable dietary restriction regimen, intermittent fasting, on mouse frailty measures.

Every Other Day Feeding Schedules Enhance Male Muscle Strength and Coordination

To measure the effects of intermittent fasting on parameters of aging like reduced muscle strength and coordination, 20-month-old mice were fed as much they could eat every other day. Following this dietary intervention, the forelimb grip strength of male mice doubled. Using the rotarod test — a measurement of coordination, muscle memory, and balance where mice balance on a rotating rod — Hine and colleagues saw that males substantially improved their duration of balance and the speed at which they could maintain it. However, for female mice, the researchers only saw a trend toward better performance. Overall, these findings suggest that fasting every other day significantly improves male motor coordination and balance.

(Henderson et al., 2021 | Geroscience) Intermittent fasting enhances aged male muscle function. Every other day fasting regimens improved aged male but not female mouse balance duration on a rotating rod (b). The intermittent fasting intervention substantially increased the speed at which males but not females maintained their balance on the rotating rod (c).

Intermittent Fasting Improves Male Cognition

Hine and colleagues also examined whether fasting every other day could improve short-term memory, an indicator of cognitive aging. They utilized a Y-maze that exploits mice’s innate curiosity to explore novel surroundings. On the one hand, since healthy mice remember previously-explored regions, they show a tendency to enter less visited branches of the Y-maze. On the other hand, mice with short-term memory impairment will stick to familiar maze arms, not remembering that they’ve seen these areas before. Following the intermittent fasting intervention, aged male mice spent more time in a novel “target” arm of the Y maze than mice fed each day, indicating that this dietary intervention improved aged male mouse cognition.

(Henderson et al., 2021 | Geroscience) The intermittent fasting dietary intervention improves aged, male mouse cognition. Male mice fed each day (left) spent less time in a novel maze arm (target) than those fed every other day (right). Since healthy mice prefer to explore novel surroundings, these findings indicate that the intermittent fasting mice fed every other day remembered the familiar arms and preferred spending time in the target arm. For these reasons, the findings show that aged, male mice fed every other day had better short-term memory.

Intermittent Fasting Increases Kidney Hydrogen Sulfide

Researchers are constantly on the lookout for new indicators and possible causes of enhanced healthspan and lifespan. Hydrogen sulfide is one such compound, and its levels diminish with age in the liver and kidney. For these reasons, Hine and colleagues measured liver and kidney hydrogen sulfide production following intermittent fasting. Their results showed that fasting every other day enhances kidney but not liver hydrogen sulfide production in males. The research team emphasizes that the correlation between enhanced hydrogen sulfide production and improved frailty measurements does not mean that the increased hydrogen sulfide improves healthspan. It does suggest, though, that future research should explore the possibility of this causal link.

(Henderson et al., 2021 | Geroscience) The intermittent fasting diet enhanced kidney production of the possible anti-aging compound hydrogen sulfide. Feeding aged, male mice every other day substantially increased their kidney hydrogen sulfide production but not liver. These findings indicate that improved kidney hydrogen sulfide production correlates with improved measurements of frailty.

“The present findings did not reveal causation; however, it certainly showed the relationship between these two factors,” said Hine and colleagues in referring to the correlation between improved healthspan measurements and kidney hydrogen sulfide production.

Interestingly, females that underwent intermittent fasting did not exhibit enhanced hydrogen sulfide production.

Explaining Sex-Specific Response Differences

The differences driving the sex-specific benefits from intermittent fasting may center around caloric consumption. Females consumed more calories for their body weights when fed every other day. Along those lines, the stringency and duration of the intermittent fasting regimen may need altering to be effective in females.

Future Intermittent Fasting Research

Clinical studies of intermittent fasting may show that this dietary intervention benefits humans. More research geared toward finding out whether every-other-day fasting regimens benefit females will help determine if the value extends beyond males.

(Henderson et al., 2021 | Geroscience) Intermittent fasting increases aged kidney hydrogen sulfide production which may inhibit frailty onset. Aged male mice fed every other day exhibit enhanced hydrogen sulfide production. They also show improved frailty measurements like muscle function, metabolism, and cognition. Although the correlation between hydrogen sulfide production and improved frailty measurements does not prove causation, it suggests a possible causal link.