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Stimulation of Hair Growth by Small Molecules that Activate Autophagy

autophagy metabolite hair loss hair regeneration rapamycin metformin mtor ampk α-ketoglutarate α-ketobutyrate

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#1 Engadin

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Posted 20 June 2019 - 06:04 PM


S O U R C E :   Cell Reports

 

 

 

ABSTRACT

 

  • mTOR and AMPK modulation by rapamycin, metformin, and α-KG induces anagen hair growth
  • Autophagy induction is necessary and sufficient for anagen entry and hair growth
  • Autophagy is increased during anagen phase of the natural hair follicle cycle
  • Aged mice fed the autophagy-inducing metabolite α-KB are protected from hair loss

 

 

Summary

 

Hair plays important roles, ranging from the conservation of body heat to the preservation of psychological well-being. Hair loss or alopecia affects millions worldwide, but methods that can be used to regrow hair are lacking. We report that quiescent (telogen) hair follicles can be stimulated to initiate anagen and hair growth by small molecules that activate autophagy, including the metabolites α-ketoglutarate (α-KG) and α-ketobutyrate (α-KB), and the prescription drugs rapamycin and metformin, which impinge on mTOR and AMPK signaling. Stimulation of hair growth by these agents is blocked by specific autophagy inhibitors, suggesting a mechanistic link between autophagy and hair regeneration. Consistently, increased autophagy is detected upon anagen entry during the natural hair follicle cycle, and oral α-KB prevents hair loss in aged mice. Our finding that anagen can be pharmacologically activated in telogen skin when natural anagen-inducing signal(s) are absent has implications for the treatment of hair loss patients.
 
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Introduction

 

The biological and psychological importance of hair is well recognized. Hair loss affects millions worldwide and can occur because of aging, hormonal dysfunction, or autoimmunity or as a side effect of cancer treatment. Mammalian hair growth consists of cyclic repetitions of telogen (quiescence), anagen (regeneration), and catagen (degeneration) phases of the hair follicle. This hair follicle cycle is regulated by both intrinsic and extrinsic signals that control quiescence and activation of hair follicle stem cells (HFSCs). Inadequate hair follicle stem cell activation and proliferation underlie alopecia in numerous biological and pathological conditions, including aging. Molecules that can promote hair follicle stem cell activation and anagen initiation have been intensely searched for, as they may both help reveal how hair regeneration is regulated and provide therapeutic and cosmetic interventions. Here, we postulate that telogen hair follicles may be induced to enter anagen by pharmacologically triggering autophagy.

 

As a fundamental process for degrading and recycling cellular components, autophagy is critical for adaptation to nutrient starvation and other adverse environmental conditions, and it is regulated by such signals. Autophagy is also important for quality control of proteostasis through the elimination of misfolded or damaged proteins and damaged organelles. The loss of autophagy may be causally related to neurodegeneration and other diseases. Autophagy declines with age, likely contributing to the higher prevalence of autophagy-related diseases (e.g., cancer, neurodegenerative diseases) in the elderly. Autophagic clearing of active, healthy mitochondria in hematopoietic stem cells is required to maintain quiescence and stemness

, and autophagy fulfills the nutrient demand of quiescent muscle stem cell activation. In the skin, autophagy is required for self-renewal and differentiation of epidermal and dermal stem cells, but its role in hair follicle stem cells has remained controversial. On one hand, autophagy may be required for hair growth as skin grafts from the autophagy-related gene 7 (Atg7)-deficient mice exhibit abnormal hair growth. On the other hand, Atg7 deficiency in epithelial cells of the skin and hair was reported to be compatible with growth of hair, although sebaceous glands were affected, and male mutant mice developed an oily coat when they aged. It was also reported that psychological stress induced autophagy and delay of hair cycle.

 

Previously, alterations in intrinsic signaling, gene expression, and circadian function were implicated to prevent anagen entry in aged hair follicle stem cells and result in alopecia. The unforeseen finding that supplementation of a metabolite α-ketobutyrate (α-KB) in old mice can increase longevity and prevent alopecia suggests that rejuvenating aging or aging associated deficiencies may restore hair follicle stem cell function and hair growth in skin. We report herein that autophagy is increased during anagen phase of the natural hair follicle cycle and demonstrate that specific small molecules that induce autophagy can be used to promote anagen entry and hair growth from quiescent telogen phase.

 

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#2 Mind

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Posted 20 June 2019 - 08:10 PM

Nice to see some investigation into hair loss, although this seems like a prevention strategy rather than rejuvenation.

 

Hair loss and greying are one of the surest signs of the failure of all anti-aging or "rejuvenation" treatments/supplements to date. I suspect some of the things I am taking are slowing down the aging process, but nothing so far has restored my hair or slowed down my greying. When I look at all of the other people my age and older....same thing...same grey hair and same male pattern baldness. When my hair grows back, I will know that particular rejuvenation therapy is working at a root level.


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#3 Phoebus

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Posted 20 June 2019 - 08:25 PM

 

 

We report that quiescent (telogen) hair follicles can be stimulated to initiate anagen and hair growth by small molecules that activate autophagy, including the metabolites α-ketoglutarate (α-KG) and α-ketobutyrate (α-KB), and the prescription drugs rapamycin and metformin, 

 

 

could any of those compounds be used topically on the scalp? I doubt anyone has ever used rapamycin topically on the scalp but it might be an interesting experiment. 


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#4 Oakman

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Posted 20 June 2019 - 10:24 PM

could any of those compounds be used topically on the scalp? I doubt anyone has ever used rapamycin topically on the scalp but it might be an interesting experiment. 

 

Alpha-ketoglutarate (AAKG is a pre-metabolite form of arginine.) is readily available (Amazon) and not expensive, you could always give it a try topically. Although as mind mentions, the study states, "Our data show stimulation of hair regeneration in the telogen phase but have not been tested for hair regeneration in alopecia.", so anything is possible.


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Also tagged with one or more of these keywords: autophagy, metabolite, hair loss, hair regeneration, rapamycin, metformin, mtor, ampk, α-ketoglutarate, α-ketobutyrate

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