Hangry hairs: intermittent fasting linked to hair loss | Cell Research

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Chen and colleagues explore links between intermittent fasting (IF) and skin health, focusing on the effect of IF on hair growth, and discover that hair regeneration is blocked during IF periods.

Intermittent fasting (IF) is a dietary pattern relying on extended periods of fasting each day. This pattern has shown to be almost universally beneficial to overall health in experimental organism models promoting longevity, gut health, and cognition.1 However, more recent data from murine and human models paint a more nuanced picture.2,3,4 Some of the purported positive effects from this regimen have been linked to the regeneration of different types of stem cells throughout the body such as intestinal and hematopoietic stem cells.5 Chen et al.6 performed a comprehensive study of the effect of IF on hair growth as controlled by hair follicle stem cells (HFSCs). HFSCs are present in each hair follicle and serve to initiate the production of an active hair germ which then creates a new growing follicle and hair shaft. Chen et al. explored the effect of IF on HFSCs and uncovered connections between neurological signals induced by fasting and hair growth.

The authors employed two commonly used IF regimen: 16/8 time-restricted feeding and alternate-day fasting, both of which consistently show similar effects throughout the study. 16/8 time-restricted feeding equates eating during an 8 h period and fasting for 16 h. Alternate-day fasting involves alternating between eating days and fasting days. The authors found that mice on these fasting regimens exhibited disrupted hair growth compared to mice with constant feeding. Interestingly, the mice displayed positive metabolic benefits from the fasting regimen, and yet still hair growth was negatively affected. Delving deeper into the cause of hair growth disruption in the fasting mice, the authors examined HFSCs and found that they underwent cell death by apoptosis in the fasting mice. The authors found that longer periods of fasting prompted increased numbers of dying HFSCs, and a longer time required to complete a hair cycle. To illuminate the cause of HFSC apoptosis during fasting, the authors first focused on nutrient sensing pathways known to be important for HFSCs, however, they found that cellular nutrient sensor such as mTORC1 was not involved.

Chen et al. then explored a relation to adipocytes because fasting triggers the breakdown of fats and the skin harbors a robust adipocyte layer, in or near HFSC niches, and these are known to play a role in hair growth and stem cell maintenance. They hypothesized that adipocytes were communicating with HFSCs and somehow driving them to become apoptotic. They discovered that during fasting, adipocytes underwent lipolysis, a process where fat cells are broken down. During lipolysis, triglycerides were broken down releasing free fatty acids into the HFSC niche. Through a variety of genetic knockouts manipulating fatty acid oxidation, they found a reduction of HFSC apoptosis when fatty acid oxidation was blocked. To verify this, they injected free fatty acids into the skin of mice that were not fasting and found that this induced apoptosis in HFSCs. Moreover, Chen et al. identified fasting as the cause of lipolysis which then caused HFSC apoptosis. While others have shown that the adipocyte layer in the skin is a key regulator of HFSC homeostasis, this was not previously linked to lipolysis and diet.7

This prompted a rigorous exploration of the contribution of adrenal glands, which are known to respond to fasting by releasing hormones such as cortisol and epinephrine into the bloodstream. Previous work from the Hsu lab showed that these hormones have a strong effect on HFSC activation.8,9 Here, Chen et al. showed that both hormones can function to induce lipolysis in the skin, and that both of these hormones were increased during fasting in mice (Fig. 1). This is interesting in light of the Hsu studies showing that increases in cortisol associated with stress blocked the hair cycle. After injecting cortisol and epinephrine into the skin, Chen et al. found widespread lipolysis in the skin and apoptosis in HFSCs, further confirming the direct relationship between these hormones and the downstream effects observed throughout the study. These interesting findings emphasize that communication between multiple organs can occur in response to physiological changes such as dietary alteration.

The authors report that upon fasting, adrenal glands produce hormones, cortisol and epinephrine, which then cause lipolysis to release free fatty acids. The release of these free fatty acids near the hair follicles causes apoptosis of HFSC and subsequently blocks hair growth. Figure created with BioRender.com.

Chen et al. then explored ways to prevent HFSC apoptosis and alopecia. When isolating and profiling HFSCs from fasting mice, the pathways most notably changed in fasted HFSCs were oxidative stress response, mitochondrial dysfunction, and apoptosis. Further characterization of these cells demonstrated elevated mitochondrial reactive oxygen species (ROS) in response to fasting. Antioxidants like vitamin E can combat oxidative stress, and topical application of vitamin E on the skin of fasted mice indeed effectively prevented HFSC apoptosis and allowed hair growth to a similar degree to control mice. While these mechanistic insights were made in animal models, there is obviously a compelling interest in understanding how fasting affects hair follicles in humans. The authors extended this study to include a clinical trial on a number of people undergoing IF and then asked how hair follicles responded to this regimen. In this clinical trial, subjects on IF demonstrated elevated levels of lipolytic hormones and a halt in hair growth, as seen in mice. The authors were even able to show elevated levels of fatty acids in the human subjects, consistent with the mechanism identified in mice.

The findings from this remarkable study go beyond effects of fasting, and touch on interorgan communication and stem cell maintenance. In the setting of aging or alopecia, these mechanisms can be further explored in these settings to manipulate HFSC activation to potentially promote hair growth. Although stem cells in various tissues could respond differently to environmental signals and dietary manipulation, this study elucidates how changes in overall physiology are sufficient to impact stem cell survival and activation. It is worth noting that dramatic weight loss by any means is also known to be associated with hair loss, known as telogen effluvium.10 The authors noted this correlation, but also that weight loss due to IF had not previously been connected to alopecia. It will be interesting to see whether weight loss in response to GLP1 agonist therapy also exerts the same stress on HFSCs, as telogen effluvium is a known side effect of this therapy.

Similarly, the Yilmaz group showed recently that IF also has an effect on stem cell proliferation and tumorigenesis in the intestine, suggesting further systemic effects of caloric restriction on stem cells11; and Matta et al. showed that IF can disrupt β cell maturation in the pancreas.2 Ketogenic and high-fat diets are known to induce lipolysis and increase circulating free fatty acids,12 and therefore it will be important to determine the effects of other specific diets and feeding regiment to further understand the effect on HFSCs and the hair cycle as well as stem cells in all other tissues. This new area of research further enforces the idea that physical changes to diet or exercise can have specific effects on potentially any organ in the body. Therefore, as previously shown for neural stem cells and exercise, IF could be impacting stem cell function in a positive or negative capacity throughout the body.

Longo, V. D. & Mattson, M. P. Cell Metab. 19, 181–192 (2014).