Could Alternate-Day Fasting Help Prevent Age-Related Frailty and Cognitive Decline?

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“Anti-aging” is a phrase I use yet somewhat despise. Nothing is really “anti-aging” — we can’t pause the forward motion of time; whether we speak of time in a biological or chronological sense. All of us are aging by the second. What can be altered, however, is the rate at which we age, and there is good evidence that several different interventions such as exercise, a “healthy” diet, and stress management, can all be effective.

Another method to slow aging includes dietary manipulation, and a popular dietary intervention known as intermittent fasting (IF) is promising and extremely popular. IF is a broad term though and can include iterations such as time-restricted feeding (TRF), 5:2 fasting, weekly 24-48-hour fasts, or another popular form known as every-other-day (EOD) fasting.

Why IF is so popular relates to the fact that it is an “easy” and effective way to reduce caloric intake. Calorie restriction without malnutrition is one of the best-known ways to slow aging (in animals, at least) but is somewhat hard to do — many individuals find that constantly restricting their food intake is unpleasant. It seems that some prefer to use a fasting window to limit their calorie intake at certain times of the day/week, allowing them to eat what they would otherwise like during their “feeding window.”

EOD fasting involves consuming food one day, fasting the other, and repeating. The simple framework and potential effectiveness has led to EOD being looked at for its effects on several health outcomes — aging and longevity perhaps being the most heavily investigated areas.

A new study published in the journal Geroscience aimed to determine the effects of EOD fasting on indices of frailty — which is defined as an “age-related loss of physiological reserve [and]…increased susceptibility to various internal and or external stressors leading to poor health outcomes or death.”

The time of intervention was a key part of this study. Many previous investigations have chosen to initiate a fasting regimen early in life, yet the benefits of fasting implemented later in life are less well-known. Can one start fasting in their 60s, 70s, or 80s and still reap the benefits?

Brief study methods

This study used male and female mice to investigate the effects of fasting on age-related frailty measures and to determine whether a sexual dimorphism exists in these effects. I.e. — does late life-initiated fasting affect males and females differently?

Mice in this study were put on their respective dietary intervention starting at 20 weeks of age, prior to which they had been fed a standard chow diet. The interventions included:

Ad libitum dietary intervention: mice were given unrestricted (ad libitum) access to standard rodent chow throughout the study.

Every-other-day fasting (EOD) intervention: mice alternated days of ad libitum access to standard rodent chow (fed days) and complete removal of food access for 24 hours (fast days.) In other words, they ate every other day and fasted every other day.

Before, during, and after each dietary intervention, outcomes related to frailty were measured and analyzed separately for each sex. The measures included a variety of physical, biological, and cognitive outcomes including: food intake, body weight, % fat mass and % lean mass, fasting blood glucose and glucose tolerance, insulin levels, metabolic rate (oxygen consumption and carbon dioxide production), respiratory exchange ratio (RER; an indicator of what fuels the body is using), short-term and long-term memory, forelimb grip strength, neuromuscular coordination, hydrogen sulfide (H2S) production, and inflammatory cytokine gene expression.

Results

As mentioned earlier, analysis of the data was done in a sex-dependent manner, meaning all outcomes were analyzed separately for males and females. Results were compared within each group at each time point (i.e. post-intervention vs. baseline) as well as between each group at all time points (EOD fasting vs. ad libitum fed groups.)

  • Food consumption: the male EOD group reduced overall food consumption by ~38% compared to the ad libitum fed group. Female EOD mice did not reduce food consumption significantly compared to the ad libitum fed mice.
  • Body weight and body composition: the male EOD mice reduced their body weight throughout the intervention, largely driven by a reduction in fat mass. Female EOD mice lost weight up until day 47 (of 78) of the intervention, but body weight did not change thereafter, nor did body composition.
  • Metabolism: EOD fasting did not affect circadian rhythmicity of heat/energy production, oxygen consumption/carbon dioxide production, or heat production.
  • Metabolic flexibility: EOD led to an increase in “metabolic flexibility” — an ability to shift from fatty acid to carbohydrate oxidation and vice-versa — with the observed effect being larger in female than male mice.
  • EOD fasting improved fasting blood glucose and glucose handling in male (~33%) and female (~20%) mice.
  • Musculoskeletal health: male EOD mice improved their relative grip strength compared to ad libitum fed mice, while female EOD mice experienced no improvement in grip strength.
  • Motor coordination and balance improved in male, but not female, EOD mice.
  • Cognitive health & performance: EOD fasting improved some aspects of short-term and long-term hippocampal-dependent memory in male but not female mice.
  • EOD fasting reduced age-related anxiety and prevented age-related declines in ambulatory behavior (movement) in male mice, but not female mice.
  • Hydrogen sulfide production: hydrogen sulfide production in the kidney was enhanced in male EOD mice, but female EOD mice experienced no change in hydrogen sulfide production
  • Inflammation: EOD fasting reduced levels of some pro-inflammatory cytokine genes in the brain and increased gene expression of a neuroprotective protein known as DJ-1.

A lot of results presented here, but that is definitely one of the strengths of this study. Albeit conducted in a rodent model of aging, this investigation nonetheless provided a comprehensive suite of measurements that have been shown to relate to frailty in mice/rats AND humans. Indeed, the authors do mention how many of the frailty indices utilized in this study have correlates in humans.

Frailty is not a single-measure “syndrome” but rather, an age-related phenomenon that affects all bodily systems including musculoskeletal, cardiovascular, neurohormonal, and nervous, among others. The aim of this study was to investigate the effects of fasting on frailty as a whole entity, and this was accomplished by including biological, cognitive, and performance outcomes into the study design.

Some of the most interesting outcomes, from my point of view, are probably those related to glucose handling, strength/body composition, and the tests of short- and long-term memory. As many are aware, aging brings with it a decline in metabolic health, strength, lean muscle mass, and a drastic reduction in cognitive abilities. To be sure, the declines can be prevented by regular training and maintenance of these systems and don’t happen to everyone. The fact that a regimen of EOD fasting could also prevent (but perhaps not improve) a decline in these measures is very promising. Paired with an exercise and cognitive training regimen, this could make for a potent “anti-aging” stack.

The big question in the study is why female mice did not experience many of the benefits of EOD that were observed in male mice. This all really comes down to energy intake. Many (if not most) of the benefits of any intermittent fasting regimen probably boil down to the fact that this is simply an easier way to reduce overall energy intake. Compared to continuously restricting calories, fasting seems to be more feasible. The female mice in this study failed to reduce their overall energy intake to a considerable degree compared to the ad libitum fed mice, even though they were restricted from consuming any food on half of the study days. This was driven by a massive overconsumption of calories on the fed days (almost twice as much as the control mice.)

For intermittent fasting (specifically EOD fasting) to exert many of its benefits, it seems that complete caloric compensation must be avoided. The energy deficit (which was 30-40% in this study) is what drives many of the beneficial adaptations and protections against aging, or at least that is what can be concluded from the results of this investigation. When the body experiences stress (such as nutrient or energy deprivation) even for a short while, beneficial adaptations take place that make the body more resilient. This is a concept known as hormesis, and applies as much to diet as it does to exercise.

Moral of the story. To slow or prolong aging, it might not matter HOW one chooses to limit their energy intake, just that they do, at least intermittently. Whether this comes from eating one meal a day, every-other-day fasting, or daily time-restricted feeding matters not, and the “diet” utilized may just depend on your willingness or interest to try out any one of the nearly limitless dietary interventions for health and longevity.

Study cited

Henderson YO, Bithi N, Link C, et al. Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner. GeroScience. 2021;43(4):1527-1554.

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