As the first rays of morning sun filter through my curtains, I’m engrossed in a lingering question, one that has baffled many: What difference does the timing of meals over the refeeding period truly make?
And with countless health articles, diet blogs, and fitness forums out there, why is this topic seemingly overlooked? It feels like we’re missing a key element of the fasting puzzle, a component that can either magnify or undermine the very benefits we’re after.
The Fast and the Curious
Avid fasters are often deeply involved in the act of fasting that they sometimes neglect the significant implications of the refeeding phase. There’s a discrepancy rooted in media narratives that extensively cover what to eat before and after a fast but gloss over the crucial aspect of timing.
Common fasting routines, such as the popular 16:8 method, are shaped by specific research objectives which might not always align with personal goals—whether that’s healing, weight management, or longevity.
Most fasting guidelines recommend a refeeding period ranging from 4 to 12 hours after a daily fast. However, a growing body of research—primarily in animals—suggests that extended refeeding durations might counteract some of fasting’s anti-aging effects.
📷 Image generated by AI model Stable Diffusion created by Ivy McRae
We’ve seen studies indicating that prolonged exposure of body tissues to glucose impacts long-term health. This understanding fuels the push for calorie restriction in combination with fasting to slow down the aging process.
Enter Fibroblast Growth Factor 21, or FGF21, a hormone buried deep in scientific literature that could be crucial in optimizing the benefits of breaking a fast.
The Role of FGF21 in Longevity
Originating mainly in the liver, pancreas, and adipose tissue, FGF21 reacts to prolonged fasting by adjusting our metabolic responses. But what’s truly intriguing is its potential role in determining lifespan. For instance, increasing the levels of FGF21 has been observed to significantly extend the lifespan of mice.
Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, and increases insulin
sensitivity. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice
— Zhang et al.
It isn’t solely about living longer; it’s about living better. Elevated FGF21 levels are closely tied to reduced blood sugar levels—a critical factor in aging. Through its control over blood sugar, FGF21 acts as a defense against threats like the formation of advanced glycation end products (AGEs), molecules closely associated with aging.
Our results showed that administration of FGF21 significantly improved behavioral performance of d-gal treated mice in water maze task
and step-down test, reduced brain cell damage in the hippocampus, and attenuated the d-gal-induced production of MDA, ROS, and AGEs
— Yu et al.
How does FGF21 accomplish this? Scientists pinpointed the gene in mice liver responsible for FGF21 protein production and amplified its expression using genetic engineering techniques.
These studies hint at FGF21’s efficacy in modulating the growth hormone/insulin-like growth factor-1 (IGF-1) pathway in the liver, known for its role in aging. By inhibiting this pathway, FGF21 might be contributing to increased lifespan.
Transcriptomic analysis suggests that FGF21 acts primarily by blunting
the growth hormone/insulin-like growth factor-1 signaling pathway in liver
— Zhang et al.
The Fasting-Refeeding Cycle
When glucose levels drop significantly, a sign of extended fasting, the body ramps up the release of FGF21.
Long-term fasting (i.e. greater than 12 hours), a ketogenic diet,
and free fatty acids have been shown to stimulate hepatic FGF21 production
— Spann et al.
Different factors stimulate FGF21 production in various tissues. For instance, an empty stomach triggers its production in the liver, whereas the first post-fast meal can stimulate synthesis in adipose tissue.
While fasting plays a role in FGF21’s expression and its anti-aging properties, this protein also oversees metabolic reactions during future fasting episodes.
For instance, FGF21’s production aids in lipid metabolism, ensuring the efficient absorption of nutrients during the refeeding phase.
FGF21 is induced in the liver in response to fasting and certain agonists.
FGF21, in turn, stimulates lipolysis in white adipose tissue
and ketogenesis in the liver
— Inagaki et al.
The Refeeding Paradox
But here’s the twist: a mere 12-hour fast can surge FGF21 expression by up to 28-fold. However, an equivalent duration of refeeding reverses this effect. This back-and-forth between fasting and refeeding, especially the duration of the latter, seems to be a key factor influencing FGF21’s behavior.
The post-fast refeeding period is crucial. Following a 12-hour fast, a 12-hour refeeding window effectively undoes the FGF21 boost and likely affects other beneficial compounds from fasting.
FGF21 mRNA levels were increased 28-fold after a 12 hr fast.
Refeeding for 12 hrs reduced FGF21 mRNA to prefasting levels
— Inagaki et al.
So, how can we optimize the anti-aging benefits of fasting? Research points towards limiting the refeeding duration to a brief 1-2 hour window during intermittent fasting.
Further, exercise not only augments FGF21 levels but also complements its effects. It’s an angle that’s only now being explored in-depth.
We showed that serum FGF21 level is increased in mice after a single bout of acute exercise. In addition, we observed
increased FGF21 level in serum of healthy male volunteers performing a treadmill run at 50 or 80% VO2max
— Kim et al.
📷 Image generated by AI model Stable Diffusion created by Ivy McRae
Looking Ahead: FGF21 and Fasting Research
The interplay between FGF21, intermittent fasting, and refeeding is a rapidly evolving research field. The mentioned studies have provided crucial insights, but the connection between FGF21, fasting, and refeeding still needs more exploration.
The potential of FGF21 is evident to scientists. Its direct application promises to reshape longevity research, although there are challenges, like the protein’s susceptibility to digestion. But with researchers developing modified FGF21 analogs resistant to digestion, there’s much anticipation.
As we move forward, we expect to deepen our understanding of FGF21’s interactions with fasting and refeeding, potentially unveiling novel therapeutic approaches for metabolic health and extending life.
Sources
The Starvation Hormone, Fibroblast Growth Factor-21, Extends Lifespan in Mice
Fibroblast Growth Factor 21 Protects Mouse Brain Against Oxidative Stress and AGEs Formation
Endocrine Regulation of the Fasting Response by PPARα-Mediated Induction of FGF21
The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Stimulus, Tissue, and Model
Fasting-Induced FGF21 Activates Autophagy and Lipid Degradation via JMJD3 Histone Demethylase
Acute Exercise Induces FGF21 Expression in Mice and in Healthy Humans
Rational Design of a Fibroblast Growth Factor 21-Based Clinical Candidate
Ivy McRae, a Franco-British nutritionist and science journalist, holds MScs in Human Nutrition and an M.A. in Journalism. With a decade of experience in the field of nutrition and health, her work has appeared in The Scottish Sun, Men’s Fitness, Women’s Fitness, and Women’s Health. Ivy co-developed the NHS-recognized Low Carb Program and has lectured at the University of East London on global health challenges. Follow @IvyMcRae@mastodon.social on Mastodon for unfiltered insights.