Compressed part of research of theory of androgenic/anabolitic balance. AGA h-responders analytic. Theory of physio-metabolitic method of anti AGA treatment. By Vadim Danilenko, Orekhovo-Zuyevo, Russia.
Brief explanation of the physio-metabolic treatment method for AGA (antiandrogen+minoxidil+muscle stress+cold temperature stress).
The essence of my AGA treatment method is to do the following during the period of using FDA-recognized medications for androgenetic alopecia (finasteride 0.25-1.25 mg everyday, minoxidil 5% topical 2ml or(and) oral minoxidil 2.5-5 mg everyday) physiotherapeutic actions:
- Do jogging, running, jump rope, running uphill, cycling, sports (football, etc.), swimming, weightlifting (squats, deadlift), calf raise, leg press and leg extension. You need to exercise in such a way that you experience failure, heavy and rapid breathing, muscle pain, and sweating, pulse->145b/m. You need to work out intensively. It is enough to use different exercises 2-3 times a week, avoiding injuries and overtraining.
- On exercise days it is necessary to use cold stress i.e. Exposure to uncomfortable temperatures may include:
A) Performing exercises (working outside, sport, run, hike) in temperatures of -10 to +15 Celsius.
B) Use of a cold shower on the whole body and always on the hair (thermal effect with cold water from +5 to +15 Celsius. Possible dousing with water from a bucket or tap. The effect is short, 10-20 seconds.
B1)Update of the new method of exposure to cold: It is necessary to treat the follicle muscle as a biceps or triceps or any other muscle. Therefore, you need to take a tap with cold water (or a bucket of cold water, you can with ice so that it is less than +15C, the less the better). Pour water on the scalp for 5 seconds, then 20-30 seconds of rest. Repeat 6-12 times in one approach. So we repeat the muscle training as in the gym, and if there is even vellus hair, it gets wet and the weight of the water is used as the weight of dumbbells or a barbell. Piloerection is actually an exercise for the hair muscle (APM). From this point of view, the “thicker” and heavier the water, the better. The density of water can be increased if you cool it to +4С and increase the salinity, salty cold water is heavier than usual. Moreover table salt in water could influence on Na+ channels of cold receptors.
C) Drying the body without a towel in a room with a temperature of +18 to +22 degrees Celsius, preferably in a draft or outside in the wind. It is advisable to see traces of piloerection (raising of hair on the skin) and goosebumps on the body, this means that everything is correct. After partial drying and feeling cold, you can dry yourself with a towel as usual, the main thing is to feel the cold from drying in order to activate natural heat regulation.
To enhance the effect of piloerection (for TRPA1 receptors) ), you can use (eat) hot spicy soup of the Kim Chi, hot dishes with wasabi and mustard, other hot dishes with red chili pepper and black pepper for cold. According to the author’s experience, this affects the piloerection on the top of the head even without cold. To enhance the effect of piloerection for TRPM8 cold receptors, you can use a menthol ointment (levomenthol) .Menthol works better on the front line of the hair.
If there is no time, money, or opportunity for treatment, then use at least minoxidil, a virtual (imaginary) jump rope to failure, and immediately after finishing the exercise, wash your hair with cold water (+10 to +15 C) or a cold shower with natural drying of the body.
The essence of the method is to increase the metabolism (anabolism) of your body to the maximum and reducing the androgenic effect taking minoxidil and finasteride. At the same time, exercise maximizes the effects of minoxidil, and since androgens no longer harm the follicle, a growth window appears. When performing exercises and during the period of muscle recovery, many unique anabolic effects appear in the human body: activation of stem cells, improvement of fat metabolism, gene emission, emission of unique proteins, the appearance of growth and regeneration factors. Without training large muscle groups, such effects will not occur in the body of a person who does not exercise and leads a sedative lifestyle. Main pathways of muscle stress: SHH, sympathetic nerves, Foxp1, Fgf18, Adrb2, APM hypertrophy, CXCL12, FGF21, BNDF, Hedgehog-SCUBE3-TGF-β, COL17A1, Lipid metabolic acceleration, SULT1A1, IGFBP-rP1, JNK-1( cold) and others. Also, leg exercises from weightlifting (squats, deadlifts), which have a high androgenic potential, help combat the side effects of finasteride.
At the same time, the activation by cold of the piloerection mechanism and goose bumps as part of the thermoregulation mechanism gives a signal to the follicle and the muscle of the follicle to raise the hair, if it is not there, then the body reacts accordingly, taking into account the absence of obstacles to hair growth (DHT). Cold relief has an anabolic effect and a mobilization effect on cells and the nervous system, enhancing the effects of muscle stress. Pathways of cold exposure: SHH, sympathetic nerves, Lipid metabolism acceleration, JNK-1.
The method should work quickly and have an effect in 1-3 months. The method was developed based on personal experience, taking into account the analysis of hyperresponse r/tressless, analysis of a large number of scientific papers from around the world. When analyzing hyperresponders, it turned out that they used finasteride and minoxidil, and also played sports indoors or outdoors, responders usually used their leg muscles. The best results were published when therapy took place during the colder months of the year. In fact, h-responders experienced similar levels of stress to the lives of the Amish and the homeless, who are famous for their hair cause hair its natural thermoregulation mechanism for bad weather environment (not for beauty). Amish and homeless both use leg muscle stress to survive. Previously, I thought that the main thing was muscle stress, but I did not take into account temperature stress. All this makes hyperresponding a unique and rare phenomenon. Moreover, the method has a huge anti-aging effect and helps in mewing.
Table of relationship between exercises and hair regrow here - https://www.reddit.com/r/tressless/comments/1fwmlr7/table_of_the_relationship_between_physical/?utm_source=share&utm_medium=web3x&utm_name=web3xcss&utm_term=1&utm_content=share_button
The method should help most AGA patients achieve the hyperresponder effect. Try this!
Data table of TOP hyperresponders:H responders list - Google Sheets
Additions:
- Intense anaerobic and aerobic leg exercises accelerate negative shedding in AGA patients without the use of antiandrogen and minoxidil.
When applying the physio-metabolic protocol - shedding is positive and sign of deminiturization of the follicle.
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The physio-metabolic protocol can help both AGA patients and those who have other causes of baldness, including those of unknown etymology. Therefore, the use of muscle stress and cold helps with the use of minoxidil and some natural traditional ones (the use of plants and their flavonoids and styrenes).
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The use of proteins, BCAA, omega3, L-carnetine, multivitamins can improve and speed up the result, because they enhance anabolic processes.
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Fasting in addition to the protocol can also speed up the effect because it also affects fat metabolism, which is also enhanced by cold and exercise. Fasting probably also has an androgenic effect, so it is not recommended to fast in AGA without the use of an antiandrogen.
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Muscle stress influence positively on minoxidil treatment cause of improvement pathway: SULT, Nitric Oxid,K+, ATP, metahondrial chanel open. The author’s experience suggests that topical minoxidil and oral minoxidil probably have different metabolisms, oral in the liver, and topical more in the scalp and follicles. Therefore, it is better to use two types of minxidil at once: topical and oral. Oral minoxidil is directly more dependent on muscle stress and its effectiveness is directly proportional to the amount of muscle stress. The author also noted from an assessment of the cases of hyperresponders that topical minoxidil has a greater effect on the crown, and oral minoxidil on the hairline from the front and sides.
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This protocol helps women as well as men, there is no difference. Women can often get results even using minoxidil alone. However, for women it is better to take spironolactone 50-100mg daily or palmetto saw 500mg daily as a atiandrogen. In this case, it is better to abandon contraceptives (especially long-term implants). Mostly hyperresponsive women use only minoxidil, sometimes adding shampoo with ketoconazole.
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If you have dandruff, you need to use shampoo with ketoconazole; besides, ketoconazole has antiandrogenic properties. For scalp diseases, it is advisable to use oral minoxidil. More minoxidil is better than less.
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The best timing for cold stress is within 2 hours after leg exercise during the metabolic window. It is better to use cold stress immediately after stress from leg exercises. Ran - straight into the cold.
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Increasingly, information began to come that some hyperresponders used a sauna (hot bath) during the training period. The effect of the sauna is that when the body is accustomed to an elevated temperature (for example, if you sit in the sauna for 10 minutes or more) and if you leave the sauna, you will not be able to immediately adapt to normal room temperature and for some time the person experiences cold stress (piloerection, goosebumps, feeling cold after leaving a hot and humid room). This is the secret of saunas for hyper responders.
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Internet have many extreme video about training with exercise and cold. This type of activity with antiandrogen and minoxidil give positive results to treatment (anaerobic, aerobic and cold): https://www.youtube.com/watch?v=rnLZyyuEwX4 https://www.youtube.com/watch?v=NaA-HAFDwyc&t=1s . And you could got same effect coincidentally after running exercise and sit under air conditioner and got cold, or sport in winter cold weather. Muscle stress and cold stress are relative - start with small. If you don’t leave the house, start walking outside for at least an hour and rinsing your hair with cold water.
Thoughts on thermoregulation, adaptation, and benefits for the treatment of alopecia here -
Effects of muscle stress over time. Positive hair loss (positive shedding). Exercise shedding and Redditors claim.
According to the author’s observation of hyperresponders, the impact of muscle stress (consequence of exercise) lasts on average from 3 to 7 days and correlates with the concept of compensation and supercompensation. The theory of supercompensation was developed by Russian scientist Nikolai N. Yakovlev (biochemistry of sports 1960-1974) https://ru.wikipedia.org/wiki/Яковлев,Николай_Николаевич(биохимик) , . According to the author, various anabolic and androgenic effects appear and are activated at different stages of muscle recovery (during exercise, an hour after exercise, after three days, after seven days). It is likely that the pathways described by the author for influencing the cellular regeneration of tissues of parts of the follicle are activated differently at different periods of time after receiving muscle stress. In general, scientists working during the Soviet era remained unknown to anyone, but they devoted a lot of time and achieved scientific results in studying the consequences of muscle stress and muscle tissue restoration; many Soviet scientists contributed to the study of the metabolism of muscle stress and were not heard by the world scientific community. The main point of this research - show that muscle stress influence to all body (not only trained muscle groups). Viru A. Early contributions of Russian stress and exercise physiologists. J Appl Physiol (1985). 2002 Apr;92(4):1378-82. doi: 10.1152/japplphysiol.00435.2001. PMID: 11896000. (https://journals.physiology.org/doi/full/10.1152/japplphysiol.00435.2001 ); Kenttä G, Hassmen P. Overtraining and recovery. A conceptual model. Sports Med. 1998 Jul;26(1):1-16. doi: 10.2165/00007256-199826010-00001. PMID: 9739537. (Overtraining and recovery. A conceptual model - PubMed )
At the same time, the visible effect of muscle stress (especially the leg muscles during intense running, weightlifting, intense cycling) on a patient with androgenetic alopecia when observing users of the subreddit /tressless shows that all complaints of intense hair loss generally coincided with receiving intense maladaptive muscle stress. Muscle stress was not always caused by sports; for example, many cases are associated with muscle damage and recovery after the flu (including covid 19). As the author noted, muscle stress increases androgenic activity, incl. through the production of DHT (androgens), but at the same time includes regenerative anabolic mechanisms. Therefore, without suppression of androgenic activity by antiandrogens and the use of minoxidil in a patient with AGA, the condition of the follicles deteriorates, which leads to the replacement of hair in a miniaturized follicle with shorter, thinner and more transparent hair, and with the use of an antiandrogen (finasteride and dutasteride, spironalactone, beta sitosterol) and minoxidil, vice versa in case of hair loss from physical activity, the next hair will be better due to the deminiaturization of the follicle by the anabolic effect and the reduction of androgens.
Reddit users in various hairlost communities have noticed and complained that after sports their hair loss accelerates (becomes noticeable when users begin to wonder), for example, typical user posts (and the same typical comments):
https://www.reddit.com/r/tressless/comments/oee0e1/correlation_between_weight_traininggym_and_hair/
https://www.reddit.com/r/tressless/comments/1c0gk2g/for_those_who_do_weightlifting_and_experience/
https://www.reddit.com/r/tressless/comments/16r923k/does_working_out_affects_hairloss/
https://www.reddit.com/r/tressless/comments/6zn9bh/my_hair_fall_suddenly_reduced_after_i_left_going/
https://www.reddit.com/r/tressless/comments/15g2vy2/workout_and_hairloss_any_connection/
https://www.reddit.com/r/tressless/comments/jxgyhm/gym_weight_loss_and_hair_loss/
https://www.reddit.com/r/tressless/comments/do6rsn/anyones_hair_never_regrow_after_weight_loss/
https://www.reddit.com/r/tressless/comments/9dlwlb/can_working_out_increase_hair_loss_in_my_case/
At the same time, increased hair loss occurs not only from exercise, but for example from the flu/infection, which is accompanied by muscle aches (muscle damage), as well as fasting, which promotes the breakdown of fat reserves (lipid metabolism pathway).
According to the author’s theory, the result of sudden hair loss from the above reasons will depend on whether the patient uses antiandrogen and minoxidil or not. Thus, it is necessary to separate positive shedding (with antiandrogen and minoxidil) and negative shedding, which was in the experience of SubReddit users.
Theory of the androgenic effect of muscle stress regarding the hair follicle of an AGA patient.
The author proposes a theory of the androgenic effect of exercise on the course of androgenic alopecia. The theory is that a patient with AGA, receiving muscle stress, accelerates the course of the disease and leads to accelerated baldness, because in fact exercise increases DHT and 5AR both at the time of training and after. This increase demilitarizes the follicle even faster and larger. The author believes that without the use of antiandrogens and minoxidil from exercise there is great damage to the condition of the follicle.
Serum DHT increase in placebo treatment immediately post maximal aerobic exercise and return to basal values at 60 min of recovery according Sgrò P, Minganti C, Lista M, Antinozzi C, Cappa M, Pitsiladis Y, Pigozzi F, Di Luigi L. Dihydrotestosterone (DHT) rapidly increase after maximal aerobic exercise in healthy males: the lowering effect of phosphodiesterase’s type 5 inhibitors on DHT response to exercise-related stress. J Endocrinol Invest. 2021 Jun;44(6):1219-1228. doi: 10.1007/s40618-020-01409-z. Epub 2020 Sep 18. PMID: 32946077. ( Dihydrotestosterone (DHT) rapidly increase after maximal aerobic exercise in healthy males: the lowering effect of phosphodiesterase's type 5 inhibitors on DHT response to exercise-related stress - PubMed )
5α-dihydrotestosterone (DHT) were locally synthesized in skeletal muscle from dehydroepiandrosterone (DHEA). Moreover, in animal and human studies, the sex steroidogenesis enzymes and sex steroid hormone levels in skeletal muscle are upregulated by acute and chronic exercise stimulation. The enhanced muscle sex steroidgenesis is associated with glycemic control via upregulation of muscle glucose transporter-4 (GLUT-4) signaling in obese and diabetic rats and with muscle mass and strength in older men. Thus, an exercise-induced increase of sex steroid hormone in muscle may positively impact age-related concerns such as life-related diseases and sarcopenia. Stated by Sato K, Iemitsu M. Exercise and sex steroid hormones in skeletal muscle. J Steroid Biochem Mol Biol. 2015 Jan;145:200-5. doi: 10.1016/j.jsbmb.2014.03.009. Epub 2014 Apr 3. PMID: 24704257. (Exercise and sex steroid hormones in skeletal muscle - PubMed )
Repeat sprint exercise is capable of inducing an increase in circulating DHT in healthy active young men, particularly when sprinting cadence is high. According Smith AA, Toone R, Peacock O, Drawer S, Stokes KA, Cook CJ. Dihydrotestosterone is elevated following sprint exercise in healthy young men. J Appl Physiol (1985). 2013 May 15;114(10):1435-40. doi: 10.1152/japplphysiol.01419.2012. Epub 2013 Mar 7. PMID: 23471952. ( https://journals.physiology.org/doi/full/10.1152/japplphysiol.01419.2012?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org ).
Muscular DHEA, free testosterone, and DHT levels were increased in both sexes after the exercise. According Aizawa K, Iemitsu M, Maeda S, Otsuki T, Sato K, Ushida T, Mesaki N, Akimoto T. Acute exercise activates local bioactive androgen metabolism in skeletal muscle. Steroids. 2010 Mar;75(3):219-23. doi: 10.1016/j.steroids.2009.12.002. Epub 2010 Jan 4. PMID: 20045012. (Acute exercise activates local bioactive androgen metabolism in skeletal muscle - PubMed ).
The author believes that DHT as the main trigger of androgenic alopecia is significantly increased by the androgenic effect of exercise as opposed to the anabolic (regenerative) effect of muscle stress (exercise), which, on the contrary, is beneficial for the follicle and other human tissues and organs. Typically, people who exercise do this for a long time without stopping and with the effects of the metabolic window, compensation and hypercompensation for the purpose of muscle growth - they are constantly exposed to increased exposure to androgens. The AGA patient, having a reduced abstract barrier of androgen sensitivity, receives increased damage to the follicle. However, the follicle simply enters a state of hibernation and waits for its chance. Moreover, hot weather conditions and sports activities increase the effect of androgens (reduce protective wnt pathway and SSH drived pathway).
Lipid profile in AGA, obesity, h-responders and /tressless users.
The author has been observing users of hairlost communities for a long time and believes that fat metabolism plays a significant role in alopecia. So much can be said about the visual changes of h-responders in the musculature of the face and body during the period of anti-AGA therapy (before and after achieving results in hair regrowth). That is, an h-responder is a person who has increased muscle mass and decreased body fat through exercise and sometimes diet. Often those who have achieved success in therapy have simultaneously achieved great results in the fight against obesity and purposefully wanted to lose weight at the time of hair treatment. In general, the average portrait of a bald or balding user is a loss of facial geometry compared to a young age, i.e. obesity of the face (rounding), obesity of the chin, visual sagging of the chin towards the neck, obesity in the abdominal area. In general, a balding /tressless user looks like this (compared to how the progression of alopecia has not yet begun) - https://www.reddit.com/r/tressless/comments/wj6knm/i_know_bro_i_know/ .
The author, after long-term observation of users, believes that in general, baldness is visually accompanied by a violation of fat metabolism. Including increased oily skin, acne, increased oily hair, dandruff. Very often, for example, users state that their hair falls out with a white base (ie fat). AGA correlated with high mastrubation/sex rate (more then 3 times per week). Mastrubation not a cause of AGA but symptomatic.
Analytic h-responders said that the most androgenic period of life is 17-35 years. 30 years old ears peak of androgenic activity, then decreased. Meanwhile anabolic activity is until 25 years old. Thats why in 17-24 years old treatment is most fast and looks more unbelievable (40 days results, 2-5 months)…
. In special research noticed that androgenic alopecia (AGA) is a hereditary androgen-dependent disorder, characterized by gradual conversion of terminal hair into miniaturized hair and defined by various patterns. Common age group affected is between 30 and 50 years. Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that include diabetes and prediabetes, abdominal obesity, dyslipidemia, and hypertension. The relationship between androgenic alopecia and MetS is still poorly understood. MetS was seen in 5 (10%) cases and 1 (2%) control (P=0.092). Abdominal obesity, hypertension, and lowered high-density lipoprotein were significantly higher in patients with androgenic alopecia when compared to that of the controls. Vora RV, Kota RKSK, Singhal RR, Anjaneyan G. Clinical Profile of Androgenic Alopecia and Its Association with Cardiovascular Risk Factors. Indian J Dermatol. 2019 Jan-Feb;64(1):19-22. doi: 10.4103/ijd.IJD_526_16. PMID: 30745630; PMCID: PMC6340244. ( Clinical Profile of Androgenic Alopecia and Its Association with Cardiovascular Risk Factors - PMC ) .
Gopinath H, Upadya GM. Metabolic syndrome in androgenic alopecia. Indian J Dermatol Venereol Leprol. 2016 Jul-Aug;82(4):404-8. doi: 10.4103/0378-6323.174421. PMID: 27279298. (Metabolic syndrome in androgenic alopecia - Indian Journal of Dermatology, Venereology and Leprology ) metabolic syndrome was seen in 19 (22.4%) patients with androgenic alopecia and 8 (9.4%) controls (P = 0.021). Abdominal obesity, hypertension and lowered high-density lipoprotein were significantly higher in patients with androgenic alopecia versus their respective controls.
AGA patients showed statistically significant abnormal lipid profiles, and this might partly explain the association between AGA and cardiovascular diseases. Kim MW, Shin IS, Yoon HS, Cho S, Park HS. Lipid profile in patients with androgenetic alopecia: a meta-analysis. J Eur Acad Dermatol Venereol. 2017 Jun;31(6):942-951. doi: 10.1111/jdv.14000. Epub 2016 Nov 2. PMID: 27717019. (Lipid profile in patients with androgenetic alopecia: a meta-analysis - PubMed ).
Bi L, Wang C, Du Y, Lu C, Zhao M, Ding Y, Sun W, Fan W. Causal Effects of Lipids-Related Metabolites on Androgenic Alopecia: A Mendelian Randomization Study. Clin Cosmet Investig Dermatol. 2024 Feb 12;17:409-416. doi: 10.2147/CCID.S445453. PMID: 38371329; PMCID: PMC10871140. ( Causal Effects of Lipids-Related Metabolites on Androgenic Alopecia: A Mendelian Randomization Study - PMC )
The important role of weight loss coupled with therapy using minoxidil is noticeable in hyperresponder women.
Subtheory of accelerated cooling of follicle deminiaturization through the pilar muscle (APM) activation mechanism to enhance the SHH- pathway. Cold stress, thermoregulation and fat metabolism.
It is interesting to note that Harvard University scientists (Cell types promoting goosebumps form a niche to regulate hair follicle stem cells - PMC ) tested their mechanism for activating stem cells by placing the follicle and hair muscle in a cold temperature. The follicle muscle is evolutionarily designed for thermoregulation, that is, “blowing up the hair” to create an air gap between the hair. The main purpose of hair in nature is thermoregulation. When it’s cold, animals become more fluffy. Harvard experts did their experiment involving processes at cold temperatures. As author notice - if you influence to APM by cold you indeed pump APM like u training your biceps in gym.
So experts noticed that they placed mice in cold conditions to activate goosebumps.
The arrector pili muscle and the sympathetic neuron form a dual component niche that regulates hair follicle stem cells— the sympathetic neuron regulates stem cells directly with norepinephrine via synapse-like structures, while the arrector pili muscle maintains sympathetic innervation to stem cells. Through these three connected cell types, cold stimulates not only goosebumps but also stem cell activation.
Cold Exposure Individually caged were housed at an ambient temperature of 5°C for a period of 2 hours or 2 weeks.
At the same time, the analysis of the top10 best and shortest results of h-responders using minoxidil and finasteride in the time period coincided with predominantly in the cold season (the publication of incredible results always occurred in the spring months). That is, they not only ran, did weightlifting and sports, but did it mainly in the cold season. Most of the rapid results of 2-6 months of therapy occurred when the results were published in March, April or May. 7 out of 10 Reddit users showed their results in therapy during the cold period. Cold affects many aspects of biology, medicine, agriculture, and industry.
Also interesting that JNK-1 activate in cold stress, meanwhile lack of JNK-1 for mice displayed more signs of alopecia and hair depigmentation, perhaps JNK1 activity may protect against skin aging. Mice without JNK-1 fed an fat food are predisposed to skin damage and inflammation. Becattini B, Zani F, Breasson L, Sardi C, D’Agostino VG, Choo MK, Provenzani A, Park JM, Solinas G. JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage. FASEB J. 2016 Sep;30(9):3124-32. doi: 10.1096/fj.201600393R. Epub 2016 May 26. PMID: 27230858; PMCID: PMC6191003. (JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage - PMC )
Like in researches said: “ Here, we identify a conserved endoplasmic reticulum (ER) stress response, distinct from the canonical unfolded protein response, that maintains lipid homeostasis during extreme cold. We establish that the ER stress sensor IRE-1 is critical for resistance to extreme cold and activated by cold temperature. Specifically, neuronal IRE-1 signals through JNK-1 and neuropeptide signaling to regulate lipid composition within the animal. This cold-response pathway can be bypassed by dietary supplementation with unsaturated fatty acids. Altogether, our findings define an ER-centric conserved organism-wide cold stress response, consisting of molecular neuronal sensors, effectors, and signaling moieties, which control adaptation to cold conditions in the organism. Better understanding of the molecular basis of this stress response is crucial for the optimal use of cold conditions on live organisms and manipulation of lipid saturation homeostasis, which is perturbed in human pathologies. IRE-1 promotes cold resistance independently of its ribonuclease activity and XBP-1. NLP-3 is part of the IRE-1/JNK-1 axis. IRE-1 increases the levels of MUFA vaccenic acid to promote cold resistance.
Additionally, IRE1 acts as a scaffold for the binding of signaling proteins, including the death-domain protein TRAF, which in turn activates the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). Together, these parallel ER stress pathways are adaptive responses that dictate the fate of cells and hence the organism.”
Dudkevich R, Koh JH, Beaudoin-Chabot C, Celik C, Lebenthal-Loinger I, Karako-Lampert S, Ahmad-Albukhari S, Thibault G, Henis-Korenblit S. Neuronal IRE-1 coordinates an organism-wide cold stress response by regulating fat metabolism. Cell Rep. 2022 Nov 29;41(9):111739. doi: 10.1016/j.celrep.2022.111739. PMID: 36450261. (https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01617-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124722016175%3Fshowall%3Dtrue )
Cold stress help to exercise (muscle stress) to accelerate fat metabolism. Compared with men, women have significantly higher value and rely more on fat oxidation to supply energy in the cold environment, although the increasing level of fat oxidation was similar between the sexes. These factors may have important implications in the individualization of exercise prescription in cold conditions for both men and women. Niu X, Han P, Tang Z, Huang J, Li L, He H, Zhang W, Zhao L, Zhao L. Cold Stress Induced a Higher Level of Fat Oxidation in Women. J Strength Cond Res. 2023 Jan 1;37(1):114-122. doi: 10.1519/JSC.0000000000004160. Epub 2021 Oct 27. PMID: 34711769. (Cold Stress Induced a Higher Level of Fat Oxidation in Women - PubMed )
Cold stress and muscle stress increase metabolism changes. Munten S, Ménard L, Gagnon J, Dorman SC, Mezouari A, Gagnon DD. High-intensity interval exercise in the cold regulates acute and postprandial metabolism. J Appl Physiol (1985). 2021 Feb 1;130(2):408-420. doi: 10.1152/japplphysiol.00384.2020. Epub 2020 Dec 3. PMID: 33270513. ( https://journals.physiology.org/doi/full/10.1152/japplphysiol.00384.2020?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org )
Hairs also like a fat have main thermoregulation properties. Tansey EA, Johnson CD. Recent advances in thermoregulation. Adv Physiol Educ. 2015 Sep;39(3):139-48. doi: 10.1152/advan.00126.2014. PMID: 26330029. ( https://journals.physiology.org/doi/full/10.1152/advan.00126.2014?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org )
Cold stress and muscular stress (including oxidative stress from exercise) lead to increased fat metabolism, which appears to be one of the main pathways to treating and understanding androgenetic alopecia.
It is also interesting that too much ambient temperature affecting the body can inhibit the wnt pathway as it described in Zhou JY, Huang DG, Zhu M, Gao CQ, Yan HC, Li XG, Wang XQ. Wnt/β-catenin-mediated heat exposure inhibits intestinal epithelial cell proliferation and stem cell expansion through endoplasmic reticulum stress. J Cell Physiol. 2020 Jul;235(7-8):5613-5627. doi: 10.1002/jcp.29492. Epub 2020 Jan 21. PMID: 31960439. ( Wnt/β-catenin-mediated heat exposure inhibits intestinal epithelial cell proliferation and stem cell expansion through endoplasmic reticulum stress - PubMed ) .
The use of cold salt water (table salt) itself can directly affect skin cells, including cold receptors in the part of the Na+ ion channel (as does minoxidil, for example), restoring their reaction to cold. The use of Na+, K+, Ca+, N+ salts/nitrats or other elements form and their natural content in water as salts and other compounds (cations/ions) can affect the ion channels of the cellular methochondria, including cold receptors. Tap water is not as simple as it seems and its composition varies in different places on the planet. The author continues experiments with artificial mineralization of cold water and use of rain water (melt snow) as cold water for scalp cooling.
!PATHWAY OF PHYSIO-METABOLITIC METHOD!
SHH, sympathetic nerves, Foxp1, Fgf18 and Adrb2 pathways.
In next research : Shwartz Y, Gonzalez-Celeiro M, Chen CL, Pasolli HA, Sheu SH, Fan SM, Shamsi F, Assaad S, Lin ET, Zhang B, Tsai PC, He M, Tseng YH, Lin SJ, Hsu YC. Cell Types Promoting Goosebumps Form a Niche to Regulate Hair Follicle Stem Cells. Cell. 2020 Aug 6;182(3):578-593.e19. doi: 10.1016/j.cell.2020.06.031. Epub 2020 Jul 16. PMID: 32679029; PMCID: PMC7540726. (Cell types promoting goosebumps form a niche to regulate hair follicle stem cells - PMC ) was stated next:
Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by down-regulating cell cycle and metabolism while up-regulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages and demonstrate sympathetic nerves can modulate stem cells through synapses-like connections and neurotransmitters to couple tissue production with demands. The arrector pili muscle and the sympathetic neuron form a dual component niche that regulates hair follicle stem cells— the sympathetic neuron regulates stem cells directly with norepinephrine via synapse-like structures, while the arrector pili muscle maintains sympathetic innervation to stem cells. Through these three connected cell types, cold stimulates not only goosebumps but also stem cell activation. APMs serve as a critical structural support to which sympathetic nerves can remain anchored while both the epithelial and mesenchymal compartments undergo periodical remodeling. Under steady state, this nerve-APM-HFSC connection primes HFSCs for activation by lowering the expression of quiescence regulators Foxp1 and Fgf18. Under cold conditions, the sympathetic nervous system is elevated, triggering not only goosebumps but also accelerating HFSC activation to produce new hair coat, coupling tissue growth with environmental changes. The sympathetic nerve regulates HFSCs directly through norepinephrine-Adrb2 signaling. Moreover, overexpression of Fgf18 through injection of Adeno-Associated Viruses (AAVs) expressing Fgf18 under the control of a CAG promoter suppressed anagen entry. Together, our data show that upon Adrb2 deletion, HFSCs enter a deep quiescent state governed in part by up-regulation of the Foxp1-Fgf18 axis. These findings link a quiescence pathway with an upstream neuronal signal.
At the same time, analysis of the studies leads to the fact that physical exercise (muscle stress) activates all the mechanisms that are indicated in the study above. So in the study Hibler E, Huang L, Andrade J, Spring B. Impact of a diet and activity health promotion intervention on regional patterns of DNA methylation. Clin Epigenetics. 2019 Sep 11;11(1):133. doi: 10.1186/s13148-019-0707-0. PMID: 31506096; PMCID: PMC6737702. ( Impact of a diet and activity health promotion intervention on regional patterns of DNA methylation - PMC ) it is directly indicated that when using exercises in the IPA pathway analysis, identified pathways related to carcinogenesis (e.g., PI3K/AKT signaling, Wnt/β-catenin, sonic hedgehog, and p53 pathways).
It has been pointed out that exercise induces activity intracellular signaling molecule (SHH). Neurogenesis in the hippocampal dentate gyrus and the subventricular zone occurs throughout the life of mammals and newly generated neurons can integrate functionally into established neuronal circuits. Neurogenesis levels in the dentate gyrus are modulated by changes in the environment (enrichment, exercise), hippocampal-dependent tasks, NMDA receptor (NMDAR) activity, sonic hedgehog (SHH) and/or other factors. NMDAR availability was altered in the hippocampus of mutant animals after exercise. All together our results indicate that PN-1 controls progenitors proliferation through an effect on the SHH pathway and suggest an influence of the serpin on the survival of newly generated neurons through modulation of NMDAR availability. Lino MM, Vaillant C, Orolicki S, Sticker M, Kvajo M, Monard D. Newly generated cells are increased in hippocampus of adult mice lacking a serine protease inhibitor. BMC Neurosci. 2010 Jun 8;11:70. doi: 10.1186/1471-2202-11-70. PMID: 20529321; PMCID: PMC2896953. ( Newly generated cells are increased in hippocampus of adult mice lacking a serine protease inhibitor - PMC ). Exercise influence on SHH.
Exercise have positive influence on sympathetic nerves regeneration, that also participate in hair follicle grow Sonkodi B, Berkes I, Koltai E. Have We Looked in the Wrong Direction for More Than 100 Years? Delayed Onset Muscle Soreness Is, in Fact, Neural Microdamage Rather Than Muscle Damage. Antioxidants (Basel). 2020 Mar 5;9(3):212. doi: 10.3390/antiox9030212. PMID: 32150878; PMCID: PMC7139782. ( Have We Looked in the Wrong Direction for More Than 100 Years? Delayed Onset Muscle Soreness Is, in Fact, Neural Microdamage Rather Than Muscle Damage );
Maugeri G, D’Agata V, Trovato B, Roggio F, Castorina A, Vecchio M, Di Rosa M, Musumeci G. The role of exercise on peripheral nerve regeneration: from animal model to clinical application. Heliyon. 2021 Oct 29;7(11):e08281. doi: 10.1016/j.heliyon.2021.e08281. PMID: 34765794; PMCID: PMC8571504. ( The role of exercise on peripheral nerve regeneration: from animal model to clinical application - PMC ).
Exercise promote FGF18. Aerobic exercise causes secretion by skeletal muscles of proteins (myokines) that may contrast cachexia. Media conditioned by peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α)-expressing myotubes, reproducing some metabolic adaptations of aerobic exercise, as increased mitochondrial biogenesis and oxidative phosphorylation, restrained constitutively active Forkhead box-containing subfamily O3 (caFoxO3)-induced proteolysis. Microarray analysis identified fibroblast growth factor 18 (FGF18) as myokines highly induced by PGC1α. Re Cecconi AD, Forti M, Chiappa M, Zhu Z, Zingman LV, Cervo L, Beltrame L, Marchini S, Piccirillo R. Musclin, A Myokine Induced by Aerobic Exercise, Retards Muscle Atrophy During Cancer Cachexia in Mice. Cancers (Basel). 2019 Oct 12;11(10):1541. doi: 10.3390/cancers11101541. PMID: 31614775; PMCID: PMC6826436. ( Musclin, A Myokine Induced by Aerobic Exercise, Retards Muscle Atrophy During Cancer Cachexia in Mice ).
Foxp1 is also upregulated in skeletal muscles during the postexercise period during which myocytes replenish their energy stores but not during the exercise period. Lactate has been regarded as a metabolic end product typically generated when there is not enough oxygenation to allow for full mitochondrial oxidation, for example, during physical exercise, instead cytosolic glycolysis will reduce pyruvate to form lactate. Interestingly, it has been known for many years that lactate can also be taken up and oxidized by tissues such as the myocardium skeletal muscle. show that Foxp1 is induced during a shorter period of fasting/starvation (mice were without food for 16 h) and postexercise. Ma H, Sukonina V, Zhang W, Meng F, Subhash S, Palmgren H, Alexandersson I, Han H, Zhou S, Bartesaghi S, Kanduri C, Enerbäck S. The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes. J Biol Chem. 2023 Jun;299(6):104795. doi: 10.1016/j.jbc.2023.104795. Epub 2023 May 5. PMID: 37150320; PMCID: PMC10244703. ( The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes - PMC ).
Exercise give Adrb2 expression. Exercise training resulted in a threefold increase in ADRB2. Azadpour N, Tartibian B, Koşar ŞN. Effects of aerobic exercise training on ACE and ADRB2 gene expression, plasma angiotensin II level, and flow-mediated dilation: a study on obese postmenopausal women with prehypertension. Menopause. 2017 Mar;24(3):269-277. doi: 10.1097/GME.0000000000000762. PMID: 28231078. ( http://nek.istanbul.edu.tr:4444/ekos/TEZ/56858.pdf ); de Souza E Silva S, Leite N, Furtado-Alle L, de Souza RLR, Corazza PRP, Tradiotto MC, Milano GE, da Silva LR, Pizzi J, Lopes MFA, Lopes WA, Tureck LV. ADRB2 gene influences responsiveness to physical exercise programs: A longitudinal study applied to overweight or obese Brazilian children and adolescents. Gene. 2022 Apr 30;820:146296. doi: 10.1016/j.gene.2022.146296. Epub 2022 Feb 8. PMID: 35149152. ( ADRB2 gene influences responsiveness to physical exercise programs: A longitudinal study applied to overweight or obese Brazilian children and adolescents - ScienceDirect ) .
Thus, physical exercise through SSH, sympathetic nerves, Fgf18 and Adrb2 pathways can directly influence follicle deminiaturization when using antiandrogen and minoxidil as an additional factor of metabolism (anabolism).
Arrector pili muscle (APM) hypertrophy
In research Torkamani N, Rufaut NW, Jones L, Sinclair RD. Beyond goosebumps: does the arrector pili muscle have a role in hair loss? Int J Trichology. 2014 Jul;6(3):88-94. doi: 10.4103/0974-7753.139077. PMID: 25210331; PMCID: PMC4158628. ( Beyond Goosebumps: Does the Arrector Pili Muscle Have a Role in Hair Loss? - PMC ) stated next:
The arrector pili muscle (APM) consists of a small band of smooth muscle that connects the hair follicle to the connective tissue of the basement membrane. The APM mediates thermoregulation by contracting to increase air-trapping, but was thought to be vestigial in humans. The APM attaches proximally to the hair follicle at the bulge, a known stem cell niche. Recent studies have been directed toward this muscle’s possible role in maintaining the follicular integrity and stability. This review summarizes APM anatomy and physiology and then discusses the relationship between the follicular unit and the APM. The potential role of the APM in hair loss disorders is also described, and a model explaining APM changes in hair loss is proposed. APM differentiation and anchorage to the bulge is thought to be mediated by components of the follicle basement membrane. Tendon genes such as Scx (scleraxis), Mitf, Igfbp5, Fbln1 (fibulin-1), Postn (periostin), Tnc (tenascin-C), Sparc, Igfbp6, and Fgf18 are expressed by bulge stem cells. These cells are known to highly express periostin, which is a major component of the tendon extracellular matrix (ECM). Accordingly it has been concluded that bulge stem cells serve as tendon cells for the APM. The stem cells necessary for hair regeneration reside in the follicle bulge. It has been shown that coordinated signaling between epithelial stem cells in the bulge and the underlying mesenchymal DP is present during hair development, and also in adult follicle cycling. This signaling induces stem cell proliferation and provokes the cell differentiation cascade, eventually leading to regeneration of a new lower follicle that replaces the regressed catagen follicle. Although never directly investigated, the co-expression of nephronectin in the bulge, APM and DP raises the possibility of common signaling pathways in these structures.
In research Yazdabadi A, Whiting D, Rufaut N, Sinclair R. Miniaturized Hairs Maintain Contact with the Arrector Pili Muscle in Alopecia Areata but not in Androgenetic Alopecia: A Model for Reversible Miniaturization and Potential for Hair Regrowth. Int J Trichology. 2012 Jul;4(3):154-7. doi: 10.4103/0974-7753.100069. PMID: 23180923; PMCID: PMC3500053. ( Miniaturized Hairs Maintain Contact with the Arrector Pili Muscle in Alopecia Areata but not in Androgenetic Alopecia: A Model for Reversible Miniaturization and Potential for Hair Regrowth - PMC ) stated next:
The arrector pili muscle (APM) attachment to the hair follicle bulge, a recognized repository of stem cells may be necessary for reversal of hair follicle miniaturization. In conclusion, we have identified loss of contact between the APM and the ORS in miniaturized hairs in MPHL and FPHL. In FPHL, the persisting terminal hair maintains contact with the APM. In contrast, all the miniaturized hairs in AA maintain contact with the APM. We propose that the persisting contact between the APM and ORS predicts reversibility of miniaturization.
Physical exercise involving the leg muscles affects the growth of other untrained muscles. In other words, training the leg muscles can increase the growth of the follicle muscle and restore its attachment to the follicle, promoting the activation of stem cells.
Swensen TC, Howley ET. Effect of one- and two-leg training on arm and two-leg maximum aerobic power. Eur J Appl Physiol Occup Physiol. 1993;66(3):285-8. doi: 10.1007/BF00235108. PMID: 8477686. ( https://www.researchgate.net/publication/14721001_Effect_of_one-_and_two-leg_training_on_arm_and_two-leg_maximum_aerobic_power ); Hansen S, Kvorning T, Kjaer M, Sjøgaard G. The effect of short-term strength training on human skeletal muscle: the importance of physiologically elevated hormone levels. Scand J Med Sci Sports. 2001 Dec;11(6):347-54. doi: 10.1034/j.1600-0838.2001.110606.x. PMID: 11782267. (https://paulogentil.com/pdf/TREINO%20DE%20FORÇA/Hormonios/The%20effect%20of%20short-term%20strength%20training%20on%20human%20skeletal%20muscle%20-%20the%20importance%20of%20physiologically%20elevated%20hormone%20levels.pdf ).
To restore muscle tissue, the human body produces many regenerative factors Schoenfeld BJ. The mechanisms of muscle hypertrophy and their application to resistance training. J Strength Cond Res. 2010 Oct;24(10):2857-72. doi: 10.1519/JSC.0b013e3181e840f3. PMID: 20847704. (The Journal of Strength & Conditioning Research ).
Regular exercise has been reported to protect the skin from free radicals, irregular endurance training of extreme duration or intensity, together with lack of training, may actually mediate oxidative stress and contribute to skin carcinogenesis. Lastly, not only does exercise increase androgen release but it has also been suggested to generate oxidative stress, which may increase dihydrotestosterone entry into dermal papillary cells, resulting in hair loss in patients with AGA. Although exercise may actually have a deleterious effect on patients with AGA, its causality could not be determined because of the observational nature of the study. According Yeh C, Flatley E, Elkattawy O, Berger L, Rao B. Exercise in dermatology: Exercise’s influence on skin aging, skin cancer, psoriasis, venous ulcers, and androgenetic alopecia. J Am Acad Dermatol. 2022 Jul;87(1):183-184. doi: 10.1016/j.jaad.2021.07.023. Epub 2021 Aug 17. PMID: 34416293. (https://www.jaad.org/article/S0190-9622(21)02156-3/fulltext ) .
CXCL12 pathway
In research Zheng M, Kim MH, Park SG, Kim WS, Oh SH, Sung JH. CXCL12 Neutralizing Antibody Promotes Hair Growth in Androgenic Alopecia and Alopecia Areata. Int J Mol Sci. 2024 Jan 30;25(3):1705. doi: 10.3390/ijms25031705. PMID: 38338982; PMCID: PMC10855715. ( CXCL12 Neutralizing Antibody Promotes Hair Growth in Androgenic Alopecia and Alopecia Areata - PMC ) stated next:
Investigated the expression and functional role of C-X-C Motif Chemokine Ligand 12 (CXCL12) during the hair cycle progression. CXCL12 was highly expressed in stromal cells such as dermal fibroblasts (DFs) and inhibition of CXCL12 increased hair growth. Therefore, we further investigated whether a CXCL12 neutralizing antibody (αCXCL12) is effective for androgenic alopecia (AGA) and alopecia areata (AA) and studied the underlying molecular mechanism for treating these diseases.
According research CXCL12 and exercise influence - acute exercise enhances circulating stem and precursor cells (CPCs) in the peripheral blood. The responsible mechanisms and molecular pathways, however, have not been fully identified. The aim of the present study was to investigate a pathway related to elevated levels of apoptotic peripheral blood mononuclear cells (MNCs) and their secretome. An increased uptake of miRNA126 in MNCs was suggested to lead to reduced levels of RGS16 mRNA and, in turn, an enhanced translation and secretion of CXCL12. Eighteen healthy, young men underwent two identical incremental cycling exercises of which the first served as control while the second was preceded by a 7-day-long antioxidative supplementation. Blood samples were collected at baseline (−10min) and several time points after exercise (0, 30, 90, 180, and 270min). Relative concentrations of miRNA126 in MNCs and CXCL12 levels in plasma were determined at all time points while RGS16 mRNA was assessed in MNCs at baseline and 30min after exercise. CXCL12 increased after exercise and strongly correlated with CPC numbers. MiRNA126 increased 30min and, to a lesser extent, also 180 and 270min after exercise but only with supplementation. RGS16 mRNA decreased 30min after exercise independent of the intervention. The amount of RGS16 mRNA inversely correlated with levels of miRNA126, but not with plasma CXCL12. In conclusion, even though plasma CXCL12 correlated with CPC numbers, the increase in CXCL12 cannot be explained by the increased concentration of miRNA126 and lower RGS16 mRNA in MNCs that would have allowed for an enhanced translation of CXCL12. Schmid M, Martins HC, Schratt G, Kröpfl JM, Spengler CM. MiRNA126 - RGS16 - CXCL12 Cascade as a Potential Mechanism of Acute Exercise-Induced Precursor Cell Mobilization. Front Physiol. 2021 Dec 9;12:780666. doi: 10.3389/fphys.2021.780666. PMID: 34955891; PMCID: PMC8696198. ( MiRNA126 – RGS16 – CXCL12 Cascade as a Potential Mechanism of Acute Exercise-Induced Precursor Cell Mobilization - PMC ).
So CXCL12 directly regulated by exercise.
FGF21 pathway
In research Liu X, Zhang P, Zhang X, Li X, Bai Y, Ao Y, Hexig B, Guo X, Liu D. Fgf21 knockout mice generated using CRISPR/Cas9 reveal genetic alterations that may affect hair growth. Gene. 2020 Apr 5;733:144242. doi: 10.1016/j.gene.2019.144242. Epub 2019 Nov 16. PMID: 31743770. (Fgf21 knockout mice generated using CRISPR/Cas9 reveal genetic alterations that may affect hair growth - ScienceDirect ) stated next:
Fgf21 was shown to affect hair follicle development and growth cycle, which may be associated with Pi3k/Akt and Mapk/Erk signaling pathways.
Exercise generate Fgf21. Even low-intensity activity could have beneficial effects. Fibroblast growth factor 21 (FGF21), a cytokine mainly secreted by the liver, improves glucolipid metabolism, reduces inflammation and oxidative stress, increases insulin sensitivity, and acts on multiple organs through autocrine, paracrine, and endocrine actions. Both clinical trials and animal experiments have shown a high correlation between liver fat content and circulating blood FGF21 levels, and abnormal FGF21 signaling appears to be an important mechanism for the development of NAFLD. FGF21 is an exercise that responds to exercise; therefore, it may be a key target in exercise to improve NAFLD. Wang Z, Sun T, Yu J, Li S, Gong L, Zhang Y. FGF21: A Sharp Weapon in the Process of Exercise to Improve NAFLD. Front Biosci (Landmark Ed). 2023 Dec 27;28(12):351. doi: 10.31083/j.fbl2812351. PMID: 38179757. (https://pubmed.ncbi.nlm.nih.gov/38179757/ ) Torre-Villalvazo I, Alemán-Escondrillas G, Valle-Ríos R, Noriega LG. Protein intake and amino acid supplementation regulate exercise recovery and performance through the modulation of mTOR, AMPK, FGF21, and immunity. Nutr Res. 2019 Dec;72:1-17. doi: 10.1016/j.nutres.2019.06.006. Epub 2019 Jul 2. PMID: 31672317. ( https://www.sciencedirect.com/science/article/abs/pii/S0271531719301356?via%3Dihub ).
BNDF pathway
In Female Pattern Hair Loss have big meaning of lack Brain-derived Neurotrophic Factor (BDNF). Meanwhile exercise induces of emission of BDNF.
Mohamed NE, Soltan MR, Galal SA, El Sayed HS, Hassan HM, Khatery BH. Female Pattern Hair Loss and Negative Psychological Impact: Possible Role of Brain-derived Neurotrophic Factor (BDNF). Dermatol Pract Concept. 2023 Jul 1;13(3):e2023139. doi: 10.5826/dpc.1303a139. PMID: 37557155; PMCID: PMC10412050. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412050/ )
Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 2013 Nov 5;18(5):649-59. doi: 10.1016/j.cmet.2013.09.008. Epub 2013 Oct 10. PMID: 24120943; PMCID: PMC3980968. ( https://www.cell.com/cell-metabolism/fulltext/S1550-4131(13)00377-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS155041311300377X%3Fshowall%3Dtrue )
Hedgehog - SCUBE3 -TGF-β pathway
In research Liu Y, Guerrero-Juarez CF, Xiao F, Shettigar NU, Ramos R, Kuan CH, Lin YC, de Jesus Martinez Lomeli L, Park JM, Oh JW, Liu R, Lin SJ, Tartaglia M, Yang RB, Yu Z, Nie Q, Li J, Plikus MV. Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state. Dev Cell. 2022 Jul 25;57(14):1758-1775.e7. doi: 10.1016/j.devcel.2022.06.005. Epub 2022 Jun 30. PMID: 35777353; PMCID: PMC9344965. ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9344965/ ) stated next:
Hair follicle stem cells are regulated by dermal papilla fibroblasts, their principal signaling niche. Overactivation of Hedgehog signaling in the niche dramatically accelerates hair growth and induces follicle multiplication in mice. On single-cell RNA-sequencing, dermal papilla fibroblasts increase heterogeneity to include new Wnt5ahigh states. Transcriptionally, mutant fibroblasts activate regulatory networks for Gli1, Alx3, Ebf1, Hoxc8, Sox18 and Zfp239. These networks jointly upregulate secreted factors for multiple hair morphogenesis and hair growth-related pathways. Among these is non-conventional TGFβ ligand Scube3. We show that in normal mouse skin Scube3 is expressed only in dermal papillae of growing, but not resting follicles. SCUBE3 protein microinjection is sufficient to induce new hair growth and pharmacological TGFβ inhibition rescues mutant hair hyper-activation phenotype. Moreover, dermal papilla-enriched expression of SCUBE3 and its growth activating effect are partially conserved in human scalp hair follicles. Thus, Hedgehog regulates mesenchymal niche function in the hair follicle via SCUBE3/TGFβ mechanism. SCUBE3 promote hair grow.
Exercise increase TGFβ. Mechanical loading of cells induces the expression of transforming growth factor-beta-1, and acute exercise, which involves mechanical loading of several tissues, could thus increase its circulating level in humans. In conclusion, the resting plasma level of transforming growth factor-beta-1 was stable over time when blood samples were treated appropriately. Exercise increased the plasma concentration, perhaps indicating a release from mechanically loaded tissues. Heinemeier K, Langberg H, Kjaer M. Exercise-induced changes in circulating levels of transforming growth factor-beta-1 in humans: methodological considerations. Eur J Appl Physiol. 2003 Sep;90(1-2):171-7. doi: 10.1007/s00421-003-0881-8. Epub 2003 Jul 9. PMID: 14504950. ( https://pubmed.ncbi.nlm.nih.gov/14504950/ ).
SCUBE3 participate in process of fast muscle grow, and exercise for hypertrophy (like in bodybuilding) could promote SCUBE3 expression. As research said: «To examine whether the function of SCUBE3 in regulating fast muscle development is conserved between zebrafish and mammals, we further determined the effect of overexpression of human SCUBE3 on rescuing myod1 expression defects in scube3 morphants. Forced expression of human SCUBE3 by mRNA microinjection rescued the expression of myod1 in the lateral somites in scube3 morphants (Fig. 11), which suggests that human SCUBE3 may share a preserved function with the zebrafish orthologue, at least for the development of fast muscle» Tu CF, Tsao KC, Lee SJ, Yang RB. SCUBE3 (signal peptide-CUB-EGF domain-containing protein 3) modulates fibroblast growth factor signaling during fast muscle development. J Biol Chem. 2014 Jul 4;289(27):18928-42. doi: 10.1074/jbc.M114.551929. Epub 2014 May 21. PMID: 24849601; PMCID: PMC4081933. ( https://www.jbc.org/article/S0021-9258(20)40481-8/fulltext )
Meanwhile hedgehog signaling also increase by exercise (that was already describe in this research). So exist potential possibility of activate Hedgehog - SCUBE3 -TGF-β pathway by exercise to promote follicle deminiaturization.
COL17A1 pathway
Lack of Сollagen XVII (COL17A1) participate in hair follicle aging. Intensive aerobic exercise provide oxidative stress and oxidative stress provide expression of COL17A1 for improving follicle state.
Matsumura H, Mohri Y, Binh NT, Morinaga H, Fukuda M, Ito M, Kurata S, Hoeijmakers J, Nishimura EK. Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Science. 2016 Feb 5;351(6273):aad4395. doi: 10.1126/science.aad4395. Epub 2016 Feb 4. PMID: 26912707. ( https://www.science.org/doi/10.1126/science.aad4395?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed )
Liu N, Matsumura H, Kato T, Ichinose S, Takada A, Namiki T, Asakawa K, Morinaga H, Mohri Y, De Arcangelis A, Geroges-Labouesse E, Nanba D, Nishimura EK. Stem cell competition orchestrates skin homeostasis and ageing. Nature. 2019 Apr;568(7752):344-350. doi: 10.1038/s41586-019-1085-7. Epub 2019 Apr 3. PMID: 30944469. ( https://pubmed.ncbi.nlm.nih.gov/30944469/ )
Thirupathi A, Wang M, Lin JK, Fekete G, István B, Baker JS, Gu Y. Effect of Different Exercise Modalities on Oxidative Stress: A Systematic Review. Biomed Res Int. 2021 Feb 11;2021:1947928. doi: 10.1155/2021/1947928. PMID: 33628774; PMCID: PMC7892233. ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892233/ )
Lipid metabolism acceleration
AGA patients have fatting in scalp and follicle that replace muscle and follicle tissue. More fat less size of follicle. Exercise and cold – reduce fat and accelerate lipid metabolism. Cold stress burns white and brown fat especially with exercise.
Torkamani N, Rufaut NW, Jones L, Sinclair R. Destruction of the arrector pili muscle and fat infiltration in androgenic alopecia. Br J Dermatol. 2014 Jun;170(6):1291-8. doi: 10.1111/bjd.12921. PMID: 24579818. ( https://pubmed.ncbi.nlm.nih.gov/24579818/ )
Tabatabaiei MR, Ghassemi M, Mohammadi Z, Toufani S, Farshad K, Sadeghzadeh Bazargan A. Sonographic comparison of subcutaneous fat layer thickness in the scalp area in patients with androgenetic alopecia compared to healthy individuals: Cross-sectional. Skin Res Technol. 2024 Jul;30(7):e13837. doi: 10.1111/srt.13837. PMID: 38965829; PMCID: PMC11224495.( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11224495/ )
Morinaga H, Mohri Y, Grachtchouk M, Asakawa K, Matsumura H, Oshima M, Takayama N, Kato T, Nishimori Y, Sorimachi Y, Takubo K, Suganami T, Iwama A, Iwakura Y, Dlugosz AA, Nishimura EK. Obesity accelerates hair thinning by stem cell-centric converging mechanisms. Nature. 2021 Jul;595(7866):266-271. doi: 10.1038/s41586-021-03624-x. Epub 2021 Jun 23. PMID: 34163066; PMCID: PMC9600322. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9600322/ )
Marc T. Hamilton et al, A potent physiological method to magnify and sustain soleus oxidative metabolism improves glucose and lipid regulation, iScience (2022). DOI: 10.1016/j.isci.2022.104869 ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9404652/ )
Gemmink A, Schrauwen P, Hesselink MKC. Exercising your fat (metabolism) into shape: a muscle-centred view. Diabetologia. 2020 Aug;63(8):1453-1463. doi: 10.1007/s00125-020-05170-z. Epub 2020 Jun 12. PMID: 32529413; PMCID: PMC7351830. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351830/ )
Chan WS, Ng CF, Pang BPS, Hang M, Tse MCL, Iu ECY, Ooi XC, Yang X, Kim JK, Lee CW, Chan CB. Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery. Sci Signal. 2024 Mar 19;17(828):eadh2783. doi: 10.1126/scisignal.adh2783. Epub 2024 Mar 19. PMID: 38502732; PMCID: PMC11022078. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11022078/ )
Esperland D, de Weerd L, Mercer JB. Health effects of voluntary exposure to cold water - a continuing subject of debate. Int J Circumpolar Health. 2022 Dec;81(1):2111789. doi: 10.1080/22423982.2022.2111789. PMID: 36137565; PMCID: PMC9518606. ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9518606/ )
Devjani S, Ezemma O, Jothishankar B, Kelley KJ, Senna MM. Association Between LDL-C and Androgenetic Alopecia Among Female Patients in a Specialty Alopecia Clinic. Cutis. 2024 Jan;113(1):E33-E35. doi: 10.12788/cutis.0952. PMID: 38478948. ( https://www.mdedge.com/dermatology/article/267536/hair-nails/association-between-ldl-c-and-androgenetic-alopecia-among )
Muscella A, Stefàno E, Marsigliante S. The effects of exercise training on lipid metabolism and coronary heart disease. Am J Physiol Heart Circ Physiol. 2020 Jul 1;319(1):H76-H88. doi: 10.1152/ajpheart.00708.2019. Epub 2020 May 22. PMID: 32442027. ( https://pubmed.ncbi.nlm.nih.gov/32442027/ )
Wang S, Xu S, Wang S, Fang W, Shi W. Risk factors and lipid metabolism characteristics of early-onset male androgenetic alopecia: A pilot study. J Cosmet Dermatol. 2024 May 13. doi: 10.1111/jocd.16371. Epub ahead of print. PMID: 38738464. ( https://pubmed.ncbi.nlm.nih.gov/38738464/ )
SULT1A1 pathway
In research Dhurat R, Daruwalla S, Pai S, Kovacevic M, McCoy J, Shapiro J, Sinclair R, Vano-Galvan S, Goren A. SULT1A1 (Minoxidil Sulfotransferase) enzyme booster significantly improves response to topical minoxidil for hair regrowth. J Cosmet Dermatol. 2022 Jan;21(1):343-346. doi: 10.1111/jocd.14299. Epub 2021 Jun 25. PMID: 34133836. ( https://rest.neptune-prod.its.unimelb.edu.au/server/api/core/bitstreams/f26e5528-6489-5db5-b647-471da5c1a5fa/content ) stated next:
Twenty-four males with androgenic alopecia (Norwood scale average 4.4, range 2-6) were randomized and completed the trial; 12 in the active arm and 12 in placebo. 75% of the subjects who used the SULT1A1 adjuvant with their daily minoxidil treatments for 60 days regrew hair verses 33% of those using the placebo adjuvant (p=0.023).
In research Pietrauszka K, Bergler-Czop B. Sulfotransferase SULT1A1 activity in hair follicle, a prognostic marker of response to the minoxidil treatment in patients with androgenetic alopecia: a review. Postepy Dermatol Alergol. 2022 Jun;39(3):472-478. doi: 10.5114/ada.2020.99947. Epub 2020 Oct 16. PMID: 35950120; PMCID: PMC9326921. ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9326921/ ) stated next:
It is hypothesized that SULT1A1 enzyme activity in the hair follicle correlates with minoxidil response for the treatment of AGA. It is now important to find novel compounds modulating sulfotransferase activity in the scalp. Then, the SULT1A1 activity assay would be a valuable tool for dermatologists to achieve permanent effects of AGA treatment.
Meanwhile exercise could influence on SULT level. Was declared: Sulfotransferase (SULT) catalyzed sulfation is responsible for hormone regulation and xenobiotic detoxification. Induction of SULTs by various hormones has been reported. Stress regulation of SULTs has not been reported, however. Here we report that rat liver SULTs can be regulated by physical stress (forced running, EX) and chemical stress (the organophosphorus pesticide parathion, PS). Both EX and PS increased rat liver phenol-sulfating SULT1A1 and hydroxysteroid-sulfating SULT2A1 activities. The increase in SULT1A1 activity did not correlate with protein (Western blot) or mRNA (RT-PCR) results but correlated well with increased non-protein soluble thiols. This suggests a possible Cys modification mechanism for stress regulation of SULT1A1. In vitro studies on GSH/GSSG effects on SULT1A1 activity support this conclusion. In contrast, SULT2A1 activity following physical or chemical stress treatments correlated well with protein and mRNA levels. This suggests a stress regulation mechanism of SULT2A1 at the gene transcription level, possibly occurring via hormones. Maiti S, Grant S, Baker SM, Karanth S, Pope CN, Chen G. Stress regulation of sulfotransferases in male rat liver. Biochem Biophys Res Commun. 2004 Oct 8;323(1):235-41. doi: 10.1016/j.bbrc.2004.08.074. PMID: 15351727. (https://www.sciencedirect.com/science/article/abs/pii/S0006291X04018224?via%3Dihub ) . In this research rats forced run and got muscle stress.
IGFBP-rP1 pathway
In research Zhou L, Hu R, Sheng Y, Wang X, Qi S, Zhao J, Miao Y, Zhao Y, Xu F, Wu W, Lu Z, Yang Q. IGFBP-rP1 is a potential therapeutic target in androgenic alopecia. Exp Dermatol. 2024 Feb;33(2):e15024. doi: 10.1111/exd.15024. PMID: 38414091. ( https://pubmed.ncbi.nlm.nih.gov/38414091/ ) stated next:
The available interventions for androgenic alopecia (AGA), the most common type of hair loss worldwide, remain limited. The insulin growth factor (IGF) system may play an important role in the pathogenesis of AGA. However, the exact role of IGF binding protein-related protein 1 (IGFBP-rP1) in hair growth and AGA has not been reported. In this study, we first found periodic variation in IGFBP-rP1 during the hair cycle transition in murine hair follicles (HFs). We further demonstrated that IGFBP-rP1 levels were lower in the serum and scalp HFs of individuals with AGA than in those of healthy controls. Subsequently, we verified that IGFBP-rP1 had no cytotoxicity to human outer root sheath cells (HORSCs) and that IGFBP-rP1 reversed the inhibitory effects of DHT on the migration of HORSCs in vitro. Finally, a DHT-induced AGA mouse model was created. The results revealed that the expression of IGFBP-rP1 in murine HFs was downregulated after DHT treatment and that subcutaneous injection of IGFBP-rP1 delayed catagen occurrence and prolonged the anagen phase of HFs in mice with DHT-induced AGA. The present work shows that IGFBP-rP1 is involved in hair cycle transition and exhibits great therapeutic potential for AGA.
IGFBP-rP1 level increase by exercises. Muscle mass and muscle mRNA levels for certain growth factors are reduced in maintenance hemodialysis (MHD) patients. This study tested the hypothesis that in MHD patient’s endurance exercise training (EET) increases mRNA levels for insulin-like growth factors and reduces myostatin mRNA. With EET, skeletal muscle myostatin mRNA decreased by 51%, mRNA levels increased significantly for IGF-IR (by 41%), IGFBP-2, -4, and -5, and IGFBP-rP1. IGF-I mRNA increased by 35%. Kopple JD, Cohen AH, Wang H, Qing D, Tang Z, Fournier M, Lewis M, Casaburi R, Storer T. Effect of exercise on mRNA levels for growth factors in skeletal muscle of hemodialysis patients. J Ren Nutr. 2006 Oct;16(4):312-24. doi: 10.1053/j.jrn.2006.04.028. PMID: 17046615. (https://pubmed.ncbi.nlm.nih.gov/17046615/ ).
JAK pathway
JAK inhibition in alopecia areata have a healing effect in Alopecia Areata Lensing M, Jabbari A. An overview of JAK/STAT pathways and JAK inhibition in alopecia areata. Front Immunol. 2022 Aug 30;13:955035. doi: 10.3389/fimmu.2022.955035. PMID: 36110853; PMCID: PMC9470217. ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470217/ ).
Meanwhile exercise have JAK inhibitor properties. As claim in research: used the human myobundle system devoid of complex organ-organ interactions present in vivo to first time explore direct effects of IFN-γ on human skeletal muscle structure, function, and cytokine secretion and to unveil potential muscle-autonomous mechanisms underlying anti-inflammatory roles of exercise. We found that IFN-γ treatment induced muscle atrophy and reduced contractile function in human myobundles via up-regulation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway (30), an effect that was directly countered by exercise-mimetic muscle stimulation. We further showed that the block of JAK/STAT up-regulation by IFN-γ with small-molecule JAK inhibitors tofacitinib (31) and baricitinib (32), clinically used for rheumatoid arthritis and in trials for COVID-19 (33), fully prevented muscle wasting and weakness induced by IFN-γ. Chen Z, Li B, Zhan RZ, Rao L, Bursac N. Exercise mimetics and JAK inhibition attenuate IFN-γ-induced wasting in engineered human skeletal muscle. Sci Adv. 2021 Jan 22;7(4):eabd9502. doi: 10.1126/sciadv.abd9502. PMID: 33523949; PMCID: PMC10964957. ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10964957/ ).
Interleukin-15 pathway
Interleukin-15 protected hair follicle and accelerated by exercise.
Suzuki T, Chéret J, Scala FD, Rajabi-Estarabadi A, Akhundlu A, Demetrius DL, Gherardini J, Keren A, Harries M, Rodriguez-Feliz J, Epstein G, Lee W, Purba T, Gilhar A, Paus R. Interleukin-15 is a hair follicle immune privilege guardian. J Autoimmun. 2024 May;145:103217. doi: 10.1016/j.jaut.2024.103217. Epub 2024 Apr 5. PMID: 38581915. ( https://pubmed.ncbi.nlm.nih.gov/38581915/ )
Kurz E, Hirsch CA, Dalton T, Shadaloey SA, Khodadadi-Jamayran A, Miller G, Pareek S, Rajaei H, Mohindroo C, Baydogan S, Ngo-Huang A, Parker N, Katz MHG, Petzel M, Vucic E, McAllister F, Schadler K, Winograd R, Bar-Sagi D. Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer. Cancer Cell. 2022 Jul 11;40(7):720-737.e5. doi: 10.1016/j.ccell.2022.05.006. Epub 2022 Jun 2. PMID: 35660135; PMCID: PMC9280705. ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9280705/ )
TLR2 Pathway
TLR2 regulates hair follicle cycle and regeneration and increases by exercise.
Xiong L, Zhevlakova I, West XZ, Gao D, Murtazina R, Horak A, Brown JM, Molokotina I, Podrez EA, Byzova TV. TLR2 regulates hair follicle cycle and regeneration via BMP signaling. Elife. 2024 Mar 14;12:RP89335. doi: 10.7554/eLife.89335. PMID: 38483447; PMCID: PMC10939499. ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939499/ )
Bahman F, AlSaeed H, Albeloushi S, Al-Mulla F, Ahmad R, Al-Rashed F. The role of TLR2 in exercise-induced immunomodulation in normal weight individuals. Sci Rep. 2023 Jul 3;13(1):10703. doi: 10.1038/s41598-023-37811-9. PMID: 37400578; PMCID: PMC10318094. ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10318094/ )
Zbinden-Foncea H, Raymackers JM, Deldicque L, Renard P, Francaux M. TLR2 and TLR4 activate p38 MAPK and JNK during endurance exercise in skeletal muscle. Med Sci Sports Exerc. 2012 Aug;44(8):1463-72. doi: 10.1249/MSS.0b013e31824e0d5d. PMID: 22330023. ( https://pubmed.ncbi.nlm.nih.gov/22330023/ )
All of these pathways are a part of one giant and difficult mechanism of regenerative process and influence positively to other tissue including nerve, skin, cardiac, vessels, brain. Could be using after insults, stroke, heavy injury and comma. It’s may be 5% of pathways of regeneration that humanity know. But humanity can’t realize may be cause of influence of ways that antiandrogens, minoxidil and cold could solve.
All h- responders become healthier like «new young man» like «crazy transformation». Anti-age therapy in nutshell.