This study has shed new light on how intermittent fasting affects somatic stem cells and the regeneration of peripheral tissues, especially in the skin. The discovery that fasting alters communication between organs and causes apoptosis in activated hair stem cells reveals a previously unknown mechanism that may have important implications for dietary practices and hair health.
Fasting is a practice with ancient roots, adopted in various religious and cultural traditions throughout history. In recent years, intermittent fasting, which consists of alternating periods of fasting and eating, has gained worldwide popularity, both for its benefits to metabolic health and as a strategy for weight control.
In addition to improving blood sugar regulation and promoting fat loss, studies suggest that intermittent fasting also directly influences the health of the body's tissues.
Despite this, the mechanisms that explain these impacts are still poorly understood, leaving many questions unanswered.
Within the body’s tissues, somatic stem cells play a key role in maintenance and regeneration. They are located in specialized structures called “niches,” which provide the environment necessary for their survival and function.
The niche integrates internal and external signals to decide the fate of stem cells, enabling them to aid in tissue regeneration and adaptation to physiological and environmental changes.
While previous studies have shown that fasting improves stem cell function in tissues such as the intestine, muscle, and hematopoietic system, the effects on other tissues, such as the skin, remain largely unexplored.
The skin, which houses hair follicles, offers an ideal model for investigating how intermittent fasting affects stem cells and tissue regeneration, especially given the visible nature of hair growth.
Hair follicles follow a growth cycle organized into three distinct phases. The first is anagen, which corresponds to the active growth phase of the hair. During this stage, the hair follicle stem cells are activated, promoting the formation and elongation of the hair strand.
The follicle then enters catagen, a regression phase. During this stage, hair growth is interrupted, and the follicle begins to prepare for a period of inactivity.
Finally, telogen occurs, known as the resting phase. During this stage, hair stem cells, called HFSCs (Hair Follicle Stem Cells), remain in a quiescent state, that is, inactive. They await specific signals to be reactivated and restart the regeneration cycle, returning to the anagen phase.
HFSCs do not act alone. They are inserted in a highly specialized environment, the hair niche, composed of several adjacent cells and structures. The niche plays a key role in regulating the regenerative activities of HFSCs.
It interprets external signals, such as changes in diet or environmental factors, and adjusts the behavior of stem cells in response to these changes. This interaction between HFSCs and the niche is essential for the healthy and continuous regeneration of hair follicles.
Clinical observations indicate that people who undergo extreme diets for rapid weight loss often experience hair loss. However, the impact of intermittent fasting on hair regeneration was not yet known.
This study was designed to fill this gap and investigate how different intermittent fasting regimens affect HFSC behavior and hair regeneration in animal models.
To investigate the effects of intermittent fasting, the researchers used two popular fasting models in mice. The first model was Time-Restricted Feeding (TRF), in which mice had a daily feeding period limited to 8 hours, followed by 16 hours of fasting.
The second model was Alternate-Day Fasting (ADF), which consisted of alternating between a full 24-hour fasting day and a day of unrestricted feeding.
The mice were subjected to these fasting regimens starting on day 60 of life (P60), when their hair follicles were in the extended telogen phase, i.e., resting. Before starting the treatment, the researchers shaved the skin on the animals’ backs to monitor hair growth throughout the study.
Monitoring was conducted for 96 days, during which the mice underwent the fasting regimens and hair regrowth was observed and documented. Mice fed regular diets began to regrow their hair rapidly, entering the anagen phase by P80 and regaining most of their hair by P100.
In contrast, those fed the TRF or ADF regimens had significantly impaired hair regeneration, with only partial hair growth observed by P156.
Histological examinations (with hematoxylin and eosin staining) revealed that the hair follicles of these mice were stuck in a prolonged telogen phase or in an incomplete transition to the anagen phase, resulting in a lack of new hair growth. This effect was observed in both male and female mice, regardless of the age at which the regimens were initiated.
Despite this, the intermittent fasted mice showed improved glucose tolerance, indicating that the metabolic benefits of fasting were present, even with the negative effects on hair regeneration.
Intermittent fasting inhibits hair follicle regeneration. (A) Schematic of dietary intervention paradigms including AL, 16/8 TRF, and ADF. Feeding begins at zeitgeber time (ZT) 12 after lights out. (B) Progression of hair regrowth in female mice subjected to AL, 16/8 TRF, and ADF between P60 and P156. Mice were shaved prior to treatments. (C) Quantification of hair regrowth in mice in (B). (D) Hematoxylin and eosin staining of skin. (E) Cage metabolic data from mice under AL, TRF, and ADF over a 72-h period starting at ZT0. Fasting periods are shaded in gray. Measured parameters: food intake (gram), body mass (gram), water intake (gram), respiratory quotient (VCO2/VO2), volume of oxygen consumed VO2 (mL/min) and energy expenditure (kcal/h, n = 3).
The researchers investigated the mechanisms by which intermittent fasting affects hair regeneration and found that it inhibits this process by inducing programmed cell death, known as apoptosis, in activated hair stem cells.
This effect was observed independently of common factors, such as total calorie reduction, changes in circadian rhythm, or regulation by the cellular mechanism mTORC1, which is responsible for sensing nutrients and regulating cellular processes based on food availability.
Rather than relying on these factors, fasting activated a specific communication between the adrenal glands and dermal adipocytes (fat cells in the skin). This communication caused the adipocytes to rapidly release free fatty acids into the hair niche, the environment surrounding the stem cells.
These fatty acids, in turn, caused oxidative stress in hair stem cells (HFSCs), increasing levels of reactive oxygen species and generating cellular damage that resulted in apoptosis, or the death of the stem cells responsible for hair regeneration.
The effects observed in mice were corroborated by a randomized clinical trial (NCT05800730), which showed that intermittent fasting also inhibits hair growth in humans.
While fasting is widely promoted as beneficial for metabolic health, this study highlights a potential negative consequence: inhibition of tissue regeneration, particularly in hair follicles.
This study sheds new light on how intermittent fasting affects somatic stem cells and the regeneration of peripheral tissues, especially in the skin.
The discovery that fasting alters organ communication and causes apoptosis in activated hair stem cells reveals a previously unknown mechanism that may have important implications for dietary practices and hair health.
While the metabolic benefits of intermittent fasting are clear, it is essential to consider these adverse effects when evaluating its application in different contexts.
READ MORE:
Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration
Han Chen, Chao Liu, Shiyao Cui,Yingqian Xia, Ke Zhang, Hanxiao Cheng, Jingyu Peng, Xiaoling Yu, Luyang Li, Hualin Yu, Jufang Zhang, Ju-Sheng Zheng, and Bing Zhang
Cell. December 13, 2024
DOI: 10.1016/j.cell.2024.11.004
Abstract:
Intermittent fasting has gained global popularity for its potential health benefits, although its impact on somatic stem cells and tissue biology remains elusive. Here, we report that commonly used intermittent fasting regimens inhibit hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). This effect is independent of calorie reduction, circadian rhythm alterations, or the mTORC1 cellular nutrient-sensing mechanism. Instead, fasting activates crosstalk between adrenal glands and dermal adipocytes in the skin, triggering the rapid release of free fatty acids into the niche, which in turn disrupts the normal metabolism of HFSCs and elevates their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. A randomized clinical trial (NCT05800730) indicates that intermittent fasting inhibits human hair growth. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration and identifies interorgan communication that eliminates activated HFSCs and halts tissue regeneration during periods of unstable nutrient supply.
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