Epigenetic Roles of Microbiota and Aloe vera in Health and Disease

Akira Yagi1, PhD; Byung Pal Yu2, PhD

1 Professor Emeritus, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Hiroshima, Japan
2 Professor Emeritus, Department of Physiology, University of Texas, Health Science Center, San Antonio, TX, the United States

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Akira Yagi, Editor-in-Chief, 2-10-1 Hanagaura, Kasuya-machi, Kasuya-gun, Fukuoka-ken, Japan 811-2310
Email: 0131akirayagi@gmail.com
Telephone: +81-92-938-2717

Received: May 2, 2019
Revised: February 20, 2019
Accepted: May 22, 2019
Published online: June 21, 2019


Our healthspan is to a great extent epigenetically determined by diets, lifestyle, and various other environmental factors. Gut microbiota has been proven to be the major player in maintaining human health. Our previous report described health benefits of long-term ingestion of aloe vera gel through the modification of the intestinal microbiota. In the present review, we broadly cover the topics of microbiota and aloe vera gel ingestion related to attenuation of reactive oxygen species, prevention of cardiovascular disorders, effects of life-prolonging calorie restriction. Additional data are summarized on prophylactic actions of fermented butyrate, and aloe-emodin related components against obesity. Prophylactic actions of aloe vera gel on healthy aging, skin photo-aging, and the viability and lifespan in Drosophila melanogaster are discussed in relation to the properties of butyrate and its potential effects involved in health and disease.

Key words: Aloe vera gel ingestion; Microbiota interaction; Anti-obesity; Calorie restriction; Healthy aging; Longevity

© 2019 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Yagi A, Yu BP. Epigenetic Roles of Microbiota and Aloe vera in Health and Disease. Journal of Gastroenterology and Hepatology Research 2019; 8(3): 2871-2878 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/2614


It has been shown that long-term aloe vera ingestion increases longevity and suppresses the occurrence and severity of age-related diseases of laboratory animals. More importantly, it attenuates the age-associated functional declines without any harmful or deleterious side effects in these animals as reported by the laboratory of one of us (BPY)[1]. Chandrasheckars et al[2] and Yagi[3] reported that health maintenance with aloe vera in long-term ingestion is influenced by the intestinal microbiota during aging. Rahmani et al[4] described possible mechanisms of action and therapeutic implications of aloe vera in health maintenance. However, the major mechanism underlying such beneficial effects has not been established. The aloe vera’s anti-aging action was more discernible in the skin aging. For instance, the study done by Cho et al[5] on 30 healthy women aged 45 years or older found that consuming aloe vera gel improves skin elasticity, boosts collagen production, and significantly reduces wrinkles. Although the study was done with a small group, the author’s data clearly indicate that dietary aloe vera gel could exert various anti-aging benefits of the skin.

Disturbance in the gut microbiota is known to associate with development of many diseases. Various nutraceuticals including probiotics, prebiotics and aloe vera are known to enhance gut microbial homeostasis, thus reducing the deleterious effects of pathogenic organisms as well as the pro- inflammation potential. It was reported that the aloe vera gel leads to increased fermentation and promotes the bacterial growth as shown by Chiodelli et al[6]. The authors also reported the growth of lactic acid bacteria after fermentation of aloe vera gel, thus raising the opportunity of the probiotic effect of aloe vera. In our earlier paper, we identified butyrate, from in vitro fermentation by endophytic bacteria, Lactobacillus and Bacillus species, in aloe vera gel[7]. Fakhry et al[8] isolated a total of 25 spore-formers from feces and ileal biopsies of healthy human volunteers and identified various species. The authors characterized spore-former bacteria able to colonize the human gastrointestinal tract (GIT). Plant roots and GIT are similar in multiple ways including nutritional absorptive functions, and the site of diverse microbial colonization in an-aerobic conditions. These same authors found that sequence comparisons between GIT and plant root isolates using multiple genes, implying that human and plant isolates are closely related strains. Therefore, it is likely that much of the GIT microbes may be acquired by consumption of foods bearing microbes, Bacillus species, in plants. The presence of Bacillus species in human intestinal tract was evaluated through isolation of Bacillus from mucosa derived from intestinal resection from 20 males and females aged 18 to 88 years by Torrens et al[9]. Sequence comparisons of Bacillus strains between human and plant root isolates using multiple genes indicated that human and plant isolates are closely related strains. Bacillus species have adapted to life within the GIT and should be considered gut commensals rather than solely soil microorganisms, as consumption of microbes in plants may be one of the major routes by which human gut microbiome becomes established.

Wide benefits of aloe vera and its ingredients

Aloe vera gel is commercially used in cosmetics as well as food supplements because of its multiple efficacy. One of such effects is the inhibitory action on various enzymes. Sacan et al[10] tested it out on elastase, neuraminidase, α-amylase, and lipase. Their results showed that aloe vera extracts exhibit a high inhibitory action against elastin and α-amylase activities, and mild inhibition on neuraminidase and lipase activities. In addition, the antioxidant activities of aloe vera leaf skin and gel extract were detected with the help of the use of reducing agent, DMPO, and NO radical scavenging activity. Therefore, aloe vera gel could potentially be used as a source of natural elastase and α-amylase inhibitory activities and anti-oxidant activity in pharmaceutical, cosmetic and food industries. Regarding aloe’s antioxidant capability, Lim et al[11] showed that lifelong dietary aloe vera supplementation in aged rats had superior anti-oxidation action against lipid peroxidation, while boosting superoxide dismutase (SOD) and catalase activity.

Bala et al[12] evaluated the possible radio-protective potential of aloe vera extract against whole-body X-ray irradiation-induced testicular alterations in male balb/c mice. X-ray irradiation resulted in elevation of the levels of reactive oxygen species, lipid peroxidation, a reduction in glutathione concentration, but interestingly, enhanced activities of antioxidant enzymes such as glutathione reductase, glutathione peroxidase, catalase, SOD and glutathione-S-transferase. The protective action of aloe vera was documented as irradiated animals pre-treated with aloe vera extract revealed an improvement in antioxidant status, inhibition of lipid peroxides, apoptotic cell formation and enhanced testicular parameters compared to the X-ray-exposed group. Aloe vera extract could ameliorate X-ray-induced damage due to its free radical scavenging properties and its potential to boost cellular antioxidant defense machinery.

Recently the protective effect of aloe vera extract against bisphenol A (BPA) was reported. BPA is a potential endocrine-disrupting chemical because it has the capability to imitate the activity of natural estrogen and among numerous harmful effects it is considered as a potent risk factor for infertility because it induces testicular toxicity. Behmanesh et al[13] analyzed the protective effect of aloe vera on tissue and oxidative stress in male rats. BPA significantly decreased body weight as well as testis weights. Seminiferous tubule diameter and height of seminiferous epithelium were decreased significantly in groups receiving BPA compared to the control. Thus, it appears that aloe vera gel extract could be used as a protective agent against the harmful BPA and its toxicity, for example, in BPA-containing can lining materials for food-containers.

Protective effect of aloe vera gel polysaccharides (APs) on pancreatic β-cells in response to free fatty acids (FFA) was determined using hamster pancreatic β-cells line HIT-T15 by Kim et al[14]. It was found that the anti-apoptotic properties of APs were largely due to the relief of endoplasmic reticulum (ER) stress signaling. APs were effective in interfering with the FFA-induced activation of the PERK and IRE-mediated pathways as well as ROS generation, thereby protecting pancreatic β-cells from lipotoxicity. After oral administration of APs, markedly lowering fasting blood glucose levels were observed in db/db mice, providing evidence of the potential of APs as an alternative insulin sensitizer. Therefore, it seems that APs have a protective effect against type 2 diabetes by modulating obesity-induced ER stress in pancreatic β-cells.

Prevention of cardiovascular disorders by aloe vera

Coronary heart disease causally associated with the accumulation of blood lipids in the lining of the arteries is one of the major causes of death. The ingestion of aloe vera gel may have beneficial effects by lowering blood cholesterol, triglycerides, and phospholipids that accumulate in the large and medium-sized arteries, including the coronary arteries. In our previous papers, prevention of cardiovascular and cerebro-vascular disorders by aloe species were reviewed[3]. Agarwal[15] conducted the prevention of heart disease study with 5,000 atheromatous patients over a period of five years. Addition of husk of isabogol (Plantago ovata seeds) and aloe vera to diet markedly reduced total serum cholesterol, serum triglycerides, fasting- and postprandial blood sugar levels in diabetic patients with concomitantly increased HDL. The clinical profiles of these individuals showed a reduction in the frequency of angina attacks and the intake of drugs, like verapamil, β-blocker and nitrites, were gradually tapered off. One notable outcome of the study was that no untoward side effect of the dietary supplements was detected. Aloe vera beverage intake was found to affect lipid metabolism by decreasing total cholesterol, and triglycerides as important biomarkers of cardiovascular disease, and increasing HDL cholesterol. Interestingly, aloe vera juice intake also was reported to decrease angina pectoris frequency and relaxed chest pain caused by cardiac oxygen deficiency[10, 16].

Zheng et al[17] systematically assessed the effects of external application of aloe vera for the prevention and treatment of infusion phlebitis. Twenty-two trials with 5,546 participants were involved in prevention studies of aloe vera for phlebitis, and an additional 21 trials with 1,919 participants were involved in the treatment of phlebitis. However, there is no clear-cut evidence obtained, requiring further systemic investigation. Chemotherapy-induced phlebitis (CIP) not only causes new health hazards to the patients, but also affects the implementation of chemotherapy. Aloe vera has been frequently used for the prevention and treatment of CIP in clinical practice. Gao et al[18] evaluated the clinical value of aloe vera for the prevention and treatment of CIP. The results show that aloe vera significantly reduced the occurrence of second and third-degree phlebitis compared with the control group.

The putative microbiota modification by health-promoting calorie restriction

Calorie restriction (CR) without malnutrition is epigenetically most powerful anti-aging intervention with the increased not only median, more importantly, also maximum lifespan in all experimental organisms tested to date. The beneficial CR was observed also in monkeys and humans. One unique aspect of CR is its most potent and diversified anti-oxidative defense system, thereby suppressing oxidative stress-induced chronic inflammation that underlies many chronic diseases. If aging is caused by increased free radical damage and weakened defense system, as happen under oxidative stress, elimination of free radicals and/or boosting defense against oxidative stress should exert beneficial effects against organism’s aging process[19]. One such attempt was launched by Mathur et al[20], who examined the effect of larval diet supplementation on longevity with five different concentrations of aloe vera gel on short-lived adult Drosophila melanogaster populations. Aloe vera gel supplement of larval diet extended adult longevity in both male and female flies without reducing fecundity. In addition, the authors found the efficient reactive oxygen species scavenging through increased antioxidant enzymes activity and better neuroprotection as indicated by increased locomotor activity in adult male flies.

For human study of CR, Redman et al[21] with 53 non-obese adults (34 CR and 19 control), reported that energy expenditure and several endocrine mediators are reduced with CR regimen. Findings from this 2-year CR trial in healthy, non-obese human subjects provided evidence of metabolic slow-down accompanied with reduced oxidative stress, which is in line with the oxidative stress hypothesis of aging. CR elicits benefits for healthspan extension with decreased risk of cardio-metabolic disease (CVD). Most et al[22] investigated whether CR can reduce risk factors for CVD and insulin resistance in non-obese humans, and assessed whether improvements are exclusive to a period of weight loss or continue during weight maintenance. They concluded that sustained CR in healthy, non-obese individuals is beneficial for reducing risk factors of cardiovascular and metabolic diseases, ectopic lipid accumulation, blood pressure, and lipid profile, while improving insulin sensitivity. Das et al[23] evaluated the effect of a 2-year CR regimen on body composition of human subjects including the influence of gender and human body mass index (BMI) of participants enrolled in Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)-2, a multicenter, randomized controlled trial. It was found that two years of CR produced the positive impacts on both whole-body and regional adiposity. Data on fat-free mass (FFM) were commensurated with the reduced body mass, although men in the CR group lost more FFM than the women did, the percentage of FFM in the men in the CR group was higher than at baseline. CALERIE was registered at clinicaltrials.gov as NCT00427193.

Environmental stresses experienced during development exert many long-lasting effects on health and disease status. In some cases, the beneficial effects of low-dose oxidants are attributed to adaptive protective mechanisms of mitochondria called mitohormesis, with increased anti-oxidative defense enzymes through the enhanced expression of stress response genes. For instance, Obata et al[24] showed that the transient exposure to low concentrations of oxidants during development in Drosophila leads to an extension of adult lifespan, which is a typical hormetic response. This phenomenon depends upon oxidants acting in an antibiotic-like manner to deplete selectively the microbiome of Acetobacter proteobacteria. These authors were able to show that the presence of A.species, such as A. aceti, in the indigenous microbiota increases age-related gut dysfunction and shortens lifespan. Their study demonstrates that low-dose oxidant exposure during early life can extend lifespan more likely due to microbiota modification rather than mitohormesis.

Microbiota involved in reducing adiposity by butyrate and short chain fatty acids

Currently obesity from an excessive calorie intake is one of the major public health threats because of its underlying cause for many chronic diseases. Obesity is recognized globally as a major mortality risk factor due to its involvement in other metabolic complications like chronic inflammation, insulin resistance and type2 diabetes. Although there is no simple solution for the complex obesity-related problems, more basic approaches could lead to physiological clues on the solution for the obesity problem. As turned out, recent emerging microbiota data pose clearly as one of the major contributors in the development of obesity.

Tsai et al[25] who investigated gastrointestinal tract microbiota’s critical role in the development of obesity, identified lactic acid bacteria as the likely candidate responsible for the anti-obesity effect. In our previous report, we described the innovative approach on the symbiotic effect by blending Lactobacillus fermentum into aloe vera juice to yield lactic acid, acetic acid, and propionic acid in the fermentation extract[26]. Mollica et al[27] demonstrated that hepatic mitochondria were identified as the main target of the beneficial effect of butyrate in attenuating insulin resistance and fat accumulation in diet-induced obese mice. Butyrate activated the AMPK-acetyl-CoA carboxylase pathway, boosting metabolism. Butyrate that modulates mitochondrial efficiency can be a new therapeutic strategy for counteracting obesity and insulin resistance. Butyrate may prevent diet-induced obesity through increasing energy expenditure. However, it is unclear whether ß3-adrenergic receptors (ARß3) mediate butyrate-induced adipose lipolysis or not. For instance, Jia et al[28] reported that butyrate treatment stimulates adipose lipolysis and mitochondrial oxidative phosphorylation through histone hyper-acetylation-associated ARß3 activation. A short-term oral administration of butyrate is effective in alleviating diet-induced obesity through activation of the ARß3-mediated lipolysis in the epididymal white adipose tissue, and is beneficial for anti-obesity in mice, revealing a possibility of butyrate and its derivatives for the treatment and prevention of obesity-related metabolic disorders in humans. Aquilar et al[29] demonstrated the action of orally administered butyrate on adipose tissue expansion and insulin resistance using diet-induced obese Apo E -/- mice. The obese mice fed with butyrate presented a modest reduction of weight gain associated with reduction of adipocyte expansion, induction of adipogenesis and angiogenesis, and adiponectin production. Butyrate also improved insulin sensitivity by increasing insulin receptor expression associated with activation of Akt signaling pathway. These results strongly suggest that oral supplementation of butyrate reduces obesity-associated inflammation and insulin resistance in in vitro and in vivo models. In animal model of metabolic syndrome with non-alcoholic fatty liver disease, researchers have recently demonstrated that the administration of butyrate is able to reduce insulin resistance, liver damage, dyslipidaemia through modulation of the inflammatory process. Pharmacokinetic and pharmacodynamic studies in human show that oral administration of butyrate is safe and well tolerated, thus suggesting a reasonable approach for the attenuation of insulin resistance in the obese child. Most recently, Berni Canani R.[30] initiated obesity clinical trials of butyrate on children with obesity on 2018.

Goswami et al[31] explored the possible role of vagal afferents in the anorexigenic effect of short chain fatty acids (SCFAs). Intraperitoneal injection (IP) of SCFA molecules (6 mM/kg body wt) suppressed food intake in fasted mice with the rank order of butyrate>propionate>acetate. Butyrate IP induced significant phosphorylation of extracellular-signal- regulated kinase1/2, cellular activation markers, in nodose ganglia and their projection site, media nucleus tractus solitaries. Moreover, butyrate directly interacted with isolated neurons from nodose ganglia and induced intracellular Ca2+ signaling. These results identified the vagal afferent as the novel pathway through which exogenous SCFAs execute the remote control of feeding behavior and possible other brain functions. Vagal afferents might participate in suppression of feeding by intestinal-born SCFAs. Whitt et al[32] investigated whether histone deacetylase 3 (HDAC3) in intestinal epithelial cells (IECs) regulates metabolism and the development of obesity in mice. Butyrate significantly reduced the activity of HDAC3 in IECs of mice to prevent diet-induced obesity. The importance of HDAC3 in obesity was also seen in human subjects. The authors evaluated HDAC3 levels in 43 pediatric patient ileal biopsies relative to age-normalized patient weight, and found that HDAC3 levels in the intestine positively correlated with patient weight, which suggests dysregulation by intestinal HDAC3 may lead to alterations in body weight. Rastelli et al[33] analyzed various specific complex pathways and their key interactions. For instance, the nervous routes, endocrine routes by which gut microbes communicate with host, and the key metabolites involved in such specific interactions (e.g. SCFAs) as well as their targets. Their review, focusing on the mechanisms linking microbes, obesity, and related disorders, highlighted the role of metabolic endotoxemia in the onset of metabolic disorders and the implications for alterations in gut microbiota-host interactions and ultimately the onset of diseases.

Effects of aloe-emodin related components on cellular signaling involved in diabetes and obesity

Subash-Babu et al[34] examined the effects of aloe-emodin (AE) on the inhibition of adipocyte differentiation during 3-isobutyl-1-methylxanthine- induced adipocytes differentiation in human mesenchymal stem cells (hMSCs). Using quantitative reverse transcription polymerase chain reaction, the authors studied the mRNA expression levels of resistin, adiponectin, aP2, lipoprotein lipase, PPARγ, and TNF-α in hMSCs undergoing adipocyte differentiation; treatment with AE decreased the expression of these adipogenic genes and decreased adipocyte differentiation. AE significantly inhibited hMSCs proliferation and pre-adipocyte differentiation within the first 2 days of treatment, indicating the anti-adipogenic effect. Sangeetha et al[35] obtained evidence showing AE’s significant insulin mimic effect favoring glucose uptake in L6 myotubes (an in vitro model mimicking skeletal muscle cells). AE modulates glucose uptake through activation of PI3K, an important insulin signaling intermediate. The authors discussed bioactive compounds from medicinal plants offering enhanced therapeutic potential for the combined pathophysiology of diabetes and obesity. Alshatwl et al[36] determined the protective effect of AE from high glucose induced toxicity in RIN-5F (pancreatic ß-cell) and analyzed the restoration of its function. RIN-5F cells have been cultured in high glucose condition, with and without AE. RIN-5F treated with both high glucose and AE suppressed ROS generation and prevent RIN-5F cell from glucotoxicity. In addition, AE treated cells cultured in high glucose were transferred to standard medium, normal responsiveness to glucose was restored within 8 h and normal basal insulin release within 24 h was achieved when compared to high glucose. AE appears to possess a putative therapeutic property to overcome ß-cell failure that occurs most of type2 diabetic patients.

Youn et al[37] examined the anti-obesity effect of aloe vera barbaloin by using 3T3-L1 adipocytes. Barbaloin suppressed lipid accumulation in the process of differentiation of 3T3-L1 adipocytes. During the differentiation of 3T3-L1 adipocytes, barbaloin treatment significantly down regulated the mRNA expression of PPAR-γ and C/EBP-α. It also significantly up-regulated the phosphorylation of AMPK-α, when examined by a western blot assay. These results indicate that barbaloin has a potent antiadipogenic effect in 3T3-L1 cells via the inhibition of adipocyte differentiation and adipogenesis. Effects of AE on hyperlipidemia rats were investigated by Ji et al[38] using UPLC-ESI-QTOF-MS based urinary metabolomics. After oral administration of AE for 6 week by rats, the total cholesterol and low-density lipoprotein-cholesterol levels in 50 and 100 mg/kg of AE groups were both decreased significantly. The results indicate that AE has an efficacious effect on HFD-induced hyperlipidemia.

Anand et al[39] reported the efficacy of aloe-emodin-8-O-glucoside (AEG) on alleviating insulin resistance and augmenting glycogen synthesis in L6 myotubes and 3T3L1 adipocytes. AEG was found to enhance glycogen synthesis through the inhibition of glycogen synthase kinase 3β. AEG enhances glucose transport by modulating the proximal and distal markers involved in glucose uptake and its transformation into glycogen.

Prophylactic roles of aloe vera in various physiological functions

It is well known that obesity raises the risk of numerous health problems, including cardiovascular disease, type 2 diabetes, and some form of cancer. Lately, researchers are increasingly finding out that overweight may also have negative impacts on the brain structure, as suggested by some studies that obesity accelerates the onset and progression of brain shrinkage: the volume reduction in white and gray matter as occurring with aging.

Ronan et al[40] conducted a cross-sectional analysis of magnetic resonance image-based brain structure on a population-based cohort of healthy adults. Study participants included 527 individuals aged 20-87 years. Cortical reconstruction techniques were used to generate measures of whole-brain cerebral white-matter volume, cortical thickness, and surface area. Results indicated that cerebral white-matter volume in overweight and obese individuals was associated with a greater degree of atrophy, with maximal effects in middle-age corresponding to an estimated increase of brain age of 10 years. These findings implied the possibility of adiposity as a significant risk factor underlying neurodegeneration and cognitive decline.

Obesity is implicated with many other health problems including sleep disorders. While sleep apnea and neuropathy resulting from diabetes may drastically decrease the quality of sleep, insomnia is a common side effect of medications taken for obesity-related disorders like high blood pressure and cholesterol. Abdollahneijad et al[41] investigated the sedative and hypnotic effects of the aqueous extract of aloe vera on rats. Analysis of the electroencephalography showed that there is concomitant change in rapid- eye and none rapid-eye movement sleep in parallel with the prolonged total sleeping time. Results show that the aloe extract has sedative-hypnotic effects on both functional and electrical activities of the brain, thus revealing the efficacious effects of aloe vera extract on the brain activity. The effect of aloe vera in animal models of learning and memory, depression, and locomotion was investigated by Halder et al[42]. To assess learning and memory, the passive avoidance task and elevated plus-maze were used. For assessment of depression, forced swim and tail suspension tests were performed, and to assess locomotor activity, the rota rod test and photoactometer were used. Results show that aloe vera (0.2 and 0.4g/kg, per oral) was found to significantly increase the acquisition and retention step-down latency as compared to control in the passive avoidance task. These findings substantiate that aloe vera ingestion enhances learning and memory, and also alleviates depression in mice.

A pilot study of Lewis et al[43] investigated the effect of an aloe vera polymannose multinutrient complex (APMC) formula on cognitive and immune functions of adults with Alzheimer’s disease (AD). Subjects participated in an open-label trial, females (n=28) and males (n=6), and consumed 4 teaspoons per day of APMC. The APMC formula used in the study was well-tolerated among all subjects. The product showed a significant improvement in the ADAS-cognition score and demonstrated sound immune-modulator activity with noteworthy responses in cytokines and several lymphocytes and monocytes subsets. Several correlates were also found between the cognitive assessments and physiological outcomes at baseline and 12 months follow-up. The results show that a high-quality, concentrated dietary supplement may offer an alternative option for persons with AD. The APMC formula may not only facilitate cognitive improvement, but may also improve the inflammatory status and immune functioning profile as well, thereby enhancing host’s recovery and improving overall quality of life.

Effects of aloe supplementation on skin photo-aging

Collagen is the most abundant protein in our bodies, disturbing throughout in skin, bones, muscles, and organs, just about everywhere in the body. It provides skin’s elasticity and also replaces dead skin cells. With aging, our bodies produce less collagen, which is one of the reasons why the elderly have sagging and wrinkled skin. Aloe vera gel can lessen the unavoidable problem because it stimulates collagen production in the skin. The increased collagen produced by aloe vera gel can significantly improve the skin’s elasticity, and thereby remove and reverse wrinkles of the old appearance[5]. Aloe vera gel was shown to help rebuilding the skin collagen more quickly and can even prevent collagen breaking down through regeneration of the skin fibroblasts.

Chithra et al[44] reported the influence of aloe vera on the collagen content and its characteristics in healing dermal wounds. Aloe vera increased the collagen content of the granulation tissue as well as its degree of crosslinking as seen by increased aldehyde content and decreased acid solubility. Tanaka et al[45] confirmed that daily oral aloe sterol-containing aloe vera gel powder significantly reduced facial wrinkles in women aged ≥ 40 years, and aloe-sterol stimulated collagen and hyaluronic acid production by human dermal fibroblasts. The question on whether aloe sterol intake affected skin conditions following sunlight exposure was investigated by Tanaka et al[46] with Japanese healthy 48 men, aged 30-59 years. The subjects were instructed to expose the measurement position of the arms to the sunlight outdoors every day for 12 weeks. The skin parameters were measured at 0 (baseline), 4, 8, and 12 weeks. Depending on the time for the revelation of the sunlight, the b* value and melanin index increased and the skin moisture decreased. After taking an aloe sterol tablet daily for 12 weeks, the skin elasticity index levels were significantly higher than the baseline value. Aloe sterol ingestion increased skin elasticity in the photo-damaged skin of men aged < 46 years. Furthermore, the same research group evaluated the effects of oral aloe sterol supplementation on skin elasticity, hydration, and the collagen score in 64 healthy Japanese women aged 30-59 years. It was concluded that continued aloe sterol ingestion contributes to maintain healthy skin and prevents the skin photo-aging[47]. Saito et al[48] investigated the effects of oral aloe vera gel powder (AVGP) containing aloe sterols on skin elasticity and the extracellular matrix in UVB-irradiated hairless mice. The results suggested that AVGP has the ability to prevent the skin photo-aging. Furthermore, Misawa et al[49] investigated the protective effects of aloe sterols without polysaccharides, against UVB-induced skin photo-aging in mice, using aloe vera gel extract obtained by supercritical fluid extraction. The results indicated aloe sterols can prevent skin photo-aging through the suppression of inflammation and proinflammatory matrix metalloproteinase activity.

Role of butyrate as an epigenetic modifier

Alterations in the gut microbiota have been associated with age-related phenotypes, and proper maintenance of microbiota with epigenetic modifiers, like probiotics has shown to be effective in managing chronic disease progression. Histone acetylation which is one of the key epigenetic modification processes controlling gene expression is known to be involved in lifespan determination. There is substantial evidence that indicate the geroprotective potential of histone deacetylase (HDAC) inhibitors. Vaiserman et al[50] reported the effects of HDAC inhibitor, butyrate on the parameters of viability and lifespan of Drosophila melanogaster. The flies fed butyrate at concentration of 10 and 20 mM through both pre-adult and adult stages demonstrated significant increases in mean lifespan in both males and females compared with controls. However, treatment with 20 and 40 mM butyrate during the adult stage only resulted in a statistically significant increase in male lifespan. Since butyrate is a known inducer of epigenetic changes, it raises the possibility of its use as a life-extending agent. These authors[51] proposed HDAC inhibitor as a promising therapeutics potential that is able to combat aging and its manifestations. 


Becker et al[52] demonstrated that treatment of whole living D. melanogaster heads with HDAC/KDAC inhibitors, butyrate, and trichostatin A (TSA), induces a rapid transient increase of oxygen consumption rate. The authors suggested that these HDAC/KDAC inhibitors induce enhanced mitochondrial activity in a rapid manner and may be beneficial to treat various maladies. Investigation on novel probiotic and symbiotic formulations by Westfall et al[53] showed the extended longevity in male D. melanogaster through mechanisms of gut-brain-axis communication with implications in chronic disease management. Both the probiotic and symbiotic formulations restored markers of metabolic stress by modulating insulin resistance and energy regulatory pathways. The concomitant action of the gut microbiota on the key risk factors of aging makes it a powerful therapeutic tool against neurodegeneration, diabetes, obesity, cardiovascular disease and other age-related chronic diseases. Storelli et al[54] demonstrated that Drosophila microbiota promotes larval growth upon nutrient scarcity, and revealed that Lactobacillus plantarum, a commensal bacterium of the Drosophila intestine, is sufficient on its own to recapitulate the natural microbiota growth-promoting effect. The authors showed that L. plantarum exerts its beneficial effect on larval growth through the host nutrient sensing system. The study of Clark et al[55] indicated a distinct shift in microbiota composition following intestinal barrier dysfunction, leading to systemic immune activation and organismal death in D. melanogaster. Alterations in microbiota dynamics could contribute to and also predict varying rates of health decline during aging.

The heat shock proteins (Hsps) also play a positive role in lifespan determination, and histone acetylation has been shown to be involved in transcription of Hsp genes in Drosophila. Zhao et al[56] investigated the roles of HDAC in expression of Hsp genes during aging, and longevity determination in D. melanogaster. The results showed that the increase in acetylation level of histone H3 enhances the basal and inducible expression of Hsp 22 and Hsp 70 during aging, and extents both mean and maximum lifespan, to variable extents, in different lines of D. melanogaster. Moreover, the authors revealed the influences of histone acetylation modification on longevity and Hsp gene expression by using HDAC inhibitors, TSA and butyrate in Drosophila. These HDAC inhibitors caused the hyperacetylation of core histone H3, implicating the involvement of chromatin modulation in Hsp gene transcription. These data suggested a close correlation among histone acetylation, Hsp gene expression and longevity in D. melanogaster. Furthermore, the authors[57] showed that HDAC inhibitors caused the hyperacetylation of core histone H3, implicating the involvement of chromatin modulation in Hsp gene transcription. Greer et al[58] found that HDAC inhibitor-mediated repression requires Hsp 90 activity. HDAC inhibitors promote the association of RNA polymerase II and negative elongation factor, a complex stabilized by Hsp 90 activity, at the same genomic sites. The activity of Hsps can be regulated by HDACs, and HDAC inhibitors block transcription elongation. The authors demonstrated that HDACs positively regulate transcription through the elongation machinery. A number of HDAC inhibitors are used in clinical trials for anti-cancer therapy. Jafary[59] described that histone deacetylation, similar to the induction of Hsps, is an essential process in the cellular defense against stress.


In the previous paper, we discussed the health-promoting potential of the balanced gut microbiota and health maintenance with long-term intake of aloe vera gel[60]. In the present review, we described the influence of lifelong aloe vera ingestion with microbiota on anti-obesity, healthy aging and longevity. Further mechanistic insights into how the microbiota modulates metabolic disease certainly pave the way for identification of innovative metabolic-based diagnostics and/or probiotic-based therapeutics.

It seems clear that the gut microbiota that produces butyrate from aloe vera gel ingestion plays an important role for maintaining our body’s homeostasis by suppressing gastrointestinal tract-derived diseases and improving our general health status,


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