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Epidemiological role of plant pigment bixin in adipaging: In vivo pilot study

  • Leepica Kapoor
    Affiliations
    School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
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  • Siva Ramamoorthy
    Correspondence
    Corresponding author. Department of Biotechnology School of Bio Sciences and Technology Vellore Institute of Technology, Vellore, 632 014, Tamil Nadu, India.
    Affiliations
    School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
    Search for articles by this author
Open AccessPublished:November 22, 2022DOI:https://doi.org/10.1016/j.cegh.2022.101186

      Abstract

      Background

      Obesity and aging are linked in a cross talk, a phenomenon known as “Adipaging”. Here, we emphasize the similarity in the underlying mechanisms of obesity and aging and propose the probability of obesity being a risk factor for premature aging. In current times, several side effects of chemical usage in pharmaceuticals used for combatting adipaging have been reported. Thus, search for plant-based bioactive compounds as nutraceuticals against adipaging is the need of the hour.

      Methods

      Bixin, an FDA approved food additive and pigment derived from the plant Bixa orellana L. has been studied for its potential beyond a food colourant as a nutraceutical in targeting adipaging in vivo. Dual-energy X-ray absorptiometry (DXA) scan was used as a tool to study the impact of bixin supplementation on body composition of photoaged C57BL/6 mice.

      Results

      On comparing the DXA scans pre and post treatment with bixin in photoaged mice, statistically significant and dose dependent impact of bixin among various treatment groups of mice was observed with an increase in mean difference in lean mass ranging from 2.83g (B+ low dose (100 mg/kg of bixin)), to 2.86g (B++ medium dose (250 mg/kg of bixin)) and 3.73 g (B+++ high dose (500 mg/kg of bixin)). Also, a decline in mean difference in fat mass from −0.53g (B+), −0.33g (B++) and −1.033g (B+++) was observed with increasing bixin dosage.

      Conclusion

      DXA highlights the protective role of bixin on metabolic health and a probable target as an anti-adipaging nutraceutical.

      Keywords

      1. Introduction

      Recent developments in public health and medical research have made significant advancements leading to extended life expectancy. However, the incidence of chronic diseases such as diabetes, cardiovascular disease and neurological degeneration have become more frequent with advancing age and thus analysing the biochemical pathways involved in aging is critical. Obesity is one of the key regulatory switches which activates a cascade of metabolic disorders and has thus emerged as a major global health concern. Obesity is a complex phenomenon regulated by genetic, environmental, and socio-economic factors leading to energy imbalance. In current times, obesity spans over both genders, age groups and all racial groups.
      • Kapoor N.
      Endotext.
      • Kapoor N.
      • Furler J.
      • Paul T.V.
      • Thomas N.
      • Oldenburg B.
      Ethnicity-specific cut-offs that predict co-morbidities: the way forward for optimal utility of obesity indicators.
      • Verma M.
      • Das M.
      • Sharma P.
      • Kapoor N.
      • Kalra S.
      Epidemiology of overweight and obesity in Indian adults - a secondary data analysis of the National Family Health Surveys.
      • Verma M.
      • Kapoor N.
      • Chaudhary A.
      • et al.
      Prevalence and determinants of sarcopenic obesity in older adults: secondary data analysis of the longitudinal ageing study in India (LASI) wave 1 survey (2017-18).
      Obesity has been proposed as a premature aging phenotype
      • Nunan E.
      • Wright C.L.
      • Semola O.A.
      • et al.
      Obesity as a premature aging phenotype — implications for sarcopenic obesity.
      and thus a metabolic contributor to aging, while the age mediated alteration in function of adipose tissue could sow the seeds of obesity linked metabolic diseases.
      • Kapoor N.
      • Furler J.
      • Paul T.V.
      • Thomas N.
      • Oldenburg B.
      The BMI-adiposity conundrum in South Asian populations: need for further research.
      • Kapoor N.
      • Lotfaliany M.
      • Sathish T.
      • et al.
      Prevalence of normal weight obesity and its associated cardio-metabolic risk factors - results from the baseline data of the Kerala Diabetes Prevention Program (KDPP).
      • Kapoor N.
      • Lotfaliany M.
      • Sathish T.
      • et al.
      Obesity indicators that best predict type 2 diabetes in an Indian population: insights from the Kerala Diabetes Prevention Program.
      • Ramasamy S.
      • Joseph M.
      • Jiwanmall S.A.
      • et al.
      Obesity indicators and health-related quality of life - insights from a cohort of morbidly obese, middle-aged South Indian women.
      Thus, aging and obesity have been viewed as two sides of the same coin and the common grounds between them is termed as “adipaging”.
      Pharmaceutical research has suggested several chemical based drugs as anti-obesity and anti-aging agents.
      • Kalra S.
      • Kapoor N.
      Oral semaglutide: dosage in special situations.
      ,
      • Kalra S.
      • Bhattacharya S.
      • Kapoor N.
      Glucagon-Like Peptide 1 Receptor Agonists (GLP1RA) and Sodium-glucose co-transporter-2 inhibitors (SGLT2i): making a pragmatic choice in diabetes management.
      However, along with their therapeutic benefits, they are loaded with side effects. Therefore, natural plant-based alternative therapeutic agents with minimal side effects are the need of the hour. Several natural plant secondary metabolites such as alkaloids, polyphenols, terpenoids, flavonoids, saponins, glycosides and tannins have been reported to possess efficacy as anti-obesity agents via varied mechanisms of action. Among the nutraceuticals, plant pigments have not been much explored in comparison to other plant secondary metabolites. The biosynthesis of plant pigments such as chlorophyll, carotenoids, anthocyanins and betalain is regulated by ripening dynamics.
      • Kapoor L.
      • Simkin A.J.
      • George Priya Doss C.
      • Siva R.
      Fruit ripening: dynamics and integrated analysis of carotenoids and anthocyanins.
      Plant pigments not only aid in the photosynthetic machinery of the plant
      • Simkin A.J.
      • Kapoor L.
      • Doss C.
      • Hofmann T.A.
      • Lawson T.
      • Ramamoorthy S.
      The role of photosynthesis related pigments in light harvesting, photoprotection and enhancement of photosynthetic yield in planta.
      but are bioactive compounds with reported pharmaceutical and industrial applications as colorants in foods, textiles and pharmaceuticals.
      • Kapoor L.
      • Simkin A.J.
      • George Priya Doss C.
      • Siva R.
      Fruit ripening: dynamics and integrated analysis of carotenoids and anthocyanins.
      In this, view, we studied the efficacy of food pigment bixin, an apocarotenoid and FDA approved food additive, obtained from the plant Bixa orellana L. as an “anti-adipaging agent”. Bixin is a potent antioxidant
      • Kapoor L.
      • Ramamoorthy S.
      Strategies to meet the global demand for natural food colorant bixin: a multidisciplinary approach.
      and has been well documented for its wide range of therapeutic efficacy in several ailments in addition to its anti-aging properties
      • Kapoor L.
      • Ramamoorthy S.
      In Biology, Chemistry, and Applications of Apocarotenoids.
      making it a target drug for the phenomenon of adipaging. Here, we performed a pilot study to analyse the role of bixin vis-à-vis body composition parameters in vivo such as lean mass, fat mass and body weight. The study was performed on photoaged C57BL/6 female mice. Dual-energy X-ray absorptiometry (DXA) was used as a research tool for determining in vivo body composition in mice both prior to and after treatment with bixin as a measure of body fat, lean tissue mass and total body weight.

      1.1 Obesity and aging: Adipaging cross talk

      Obesity has been viewed to mirror aging with respect to the metabolic alterations accompanying the two phenomena. Current research on obesity has highlighted it as a condition involving premature metabolic dysfunction, thus resembling aging. Bixin's intervention in the metabolic relationship between obesity and aging could be revealed by analysing common biomarkers of obesity and aging (Fig. 3).

      1.1.1 Mechanistic links in Adipaging

      Since obesity and aging share common territories it is important to define the underlying mechanisms of action involved. Mechanistic similarities between aging and obesity are characterised by inflammation and oxidative stress owing to mitochondrial dysregulation, shortening of telomere and DNA damage. Similarities in alterations of physiological tissue in both obesity and aging is evident in diseases such as non-alcoholic fatty liver disease (NAFLD).
      • Sinton M.C.
      • Hay D.C.
      • Drake A.J.
      Metabolic control of gene transcription in non-alcoholic fatty liver disease: the role of the epigenome.
      Also, lack of metabolic stress sensing in aging and obesity is due to reduced activity of AMP-activated protein kinase (AMPK), a master regulator of energy supply and demand.
      • Wu L.
      • Zhang L.
      • Li B.
      • et al.
      AMP-activated protein kinase (AMPK) regulates energy metabolism through modulating thermogenesis in adipose tissue.
      In addition, both obesity and aging witness a diminished expression and activity of peroxisome proliferator-activated receptors (PPARs) reported as critical regulators of cellular metabolism and oxidative stress.
      • Xu L.
      • Ma X.
      • Verma N.K.
      • et al.
      Ablation of PPARγ in subcutaneous fat exacerbates age-associated obesity and metabolic decline.
      Furthermore, activation of mechanistic target of rapamycin (mTOR) signalling in both aging and obesity leads to metabolic distress.
      • Lamming D.W.
      • Ye L.
      • Katajisto P.
      • et al.
      Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity.
      Adipaging is characterised by cellular proliferation, and DNA damage due to reduced signalling by Forkhead Box O (FOXO) transcription factors,
      • Cheng Z.
      The FoxO–Autophagy Axis in health and disease.
      proteins such as sirtuins and reduced nuclear factor erythroid 2–related factor 2 (Nrf2) activity which is one of the master regulator of cellular response to oxidative stress as well as cellular senescence. Despite sharing common grounds obesity and aging differ in mechanisms associated with fat tissue dysfunction. Tissue inflammation in obesity is characterised by augmented fat cell size, leading to cellular exhaustion and macrophage infiltration while inflammation is a crucial originating factor for dysfunction of the fat tissue due to aging. Also, obesity and aging differ in the composition of the adipose tissue resulting in distinct transcriptional alterations.

      1.1.2 Immune paralysis

      Adipaging leads to a decline in the functioning of the immune system owing to repeated exposure to oxidative stress due to increased production of reactive oxygen species. This results in dysregulation of homeostatic networks associated with inflammation leading to the secretion of pro-inflammatory compounds, interlukin-6, and tumour necrosis factor α (IL-6 and TNFα) coupled with alterations in adipokine secretions. In addition, downregulation of the transcription factor peroxisome proliferator activated receptor gamma (PPARγ) critical for induction of adipogenesis is mediated by inflammation (Fig. 3). Moreover, an interplay of obesity and aging intensifies “inflammaging” (inflammation and aging), predisposing to insulin resistance, stroke, cancer, and heart attack. Inflammaging has been reported as a crucial factor for detrimental outcomes of COVID in the elderly obese population.
      • Sathish T.
      • Kapoor N.
      Normal weight obesity and COVID-19 severity: a poorly recognized link.
      ,
      • Kapoor N.
      • Kalra S.
      • Al Mahmeed W.
      • et al.
      The dual pandemics of COVID-19 and obesity: bidirectional impact.
      In addition to the decline in immune mechanisms, hypoxia also contributes to inflammatory response in both obesity and aging.

      1.1.3 Altered hormonal secretions

      One of the critical regulators of metabolic homeostasis are hormones. Among the hormones associated with obesity and aging, leptin, is one of the pro-inflammatory adipokine secretion that acts directly on the hypothalamus and initiates thermogenesis, augment oxidation of fatty acids, reduce glucose levels, downregulates appetite, and attenuates body fat. However, escalated levels of plasmatic leptin in obesity results in leptin resistance and thus fail to control satiety and body weight. Also, aging and leptin resistance are intertwined strongly, owing to aging-induced fat redistribution (from subcutaneous to visceral) coupled with age-related escalation in obesity and leptin levels. As a cross talk, metabolic stress (due to obesity) induced leptin resistance results in hypothalamic inflammation leading to systemic aging. Adipaging is also regulated by anti-inflammatory adipokine secretion, adiponectin. Adiponectin is a regulator of health span and life span by preserving the metabolic fitness during aging by inhibiting the pro-inflammatory cytokines and has been implicated by some of the genetics studies as the longevity gene. In aging, adipokine dysregulation is also mediated by frailty and thus high levels of adiponectin hormone are linked to poor nutritional status and sarcopenia in the elderly. However, obesity-mediated chronic inflammation and increase in size of adipocytes owing to unhealthy adipose tissue expansion results in lower levels of adiponectin. Adiponectin secretion is predominantly regulated by PPARγ, along with TNFα, IL-6, and FoxO1. The effect of adiponectin involves signalling by AMPK, mTOR, nuclear factor kappa B (NF-kB) and c-Jun N-terminal kinase (JNK).
      In addition, the phenomenon of aging is accompanied by attenuated levels of growth hormone (GH) which in turn has an impact on body composition. In obesity hormonal imbalances, are associated with low GH and high insulin levels, leading to fat accumulation. Also, insulin like growth factor1 (IGF-1) signalling in obesity mediates premature decline in GH levels thus accelerating aging.
      • AsghariHanjani N.
      • Vafa M.
      The role of IGF-1 in obesity, cardiovascular disease, and cancer.
      In adipaging, a decline in sensitivity of the hunger hormone, ghrelin is also observed thereby leading to weight gain and accompanied metabolic stress. The other hormonal alteration in obesity that are involved in metabolic dysfunction are an increase in insulin, renin, cortisol production rate, thyroid stimulating hormone (TSH), luteinizing hormone and follicle stimulating hormone LH/FSH (females).
      • Kalra S.
      • Kapoor N.
      • Bhattacharya S.
      • Aydin H.
      • Coetzee A.
      Barocrinology: the endocrinology of obesity from bench to bedside.

      1.1.4 Decline in BAT and lean mass

      The adipose tissue is classified into white adipose tissue (WAT; stores excess energy in single large droplet of lipid) and brown adipose tissue (BAT; possess multiple lipid droplets and mitochondria, generates heat by lipids). Reduced BAT activity (thermal dysregulation and energy imbalance) has been observed with advancing age and has been associated with reduced uncoupling protein-1 (UCP1) activity. Also, upregulation of fork head box protein A3 (FOXA3) transcription factor leads to loss of BAT, in both aging and obesity. In addition, accumulation of mutation induced mitochondrial impairment with advancing age activates the biochemical pathways of metabolic disorders resulting in loss of BAT
      • Zoico E.
      • Rubele S.
      • De Caro A.
      • et al.
      Brown and beige adipose tissue and aging.
      (Fig. 3). A limited adaptive strategy, to maintain metabolic health, allows adipose tissue to accommodate excess calorie without dislocating to other sites such as muscle and liver. Beyond the expandability capacity of adipose tissue, ectopic accumulation of lipids occurs resulting in metabolic complications. The decline of PPARγ function has been associated with reduced adipose tissue expansion capacity. Both obesity and aging have been associated with attenuated metabolic responsiveness associated with reduced expression of pro-adipogenic transcription factors such as PPARγ initiating ectopic fat deposition in muscle or bone marrow.
      One of the other critical biomarkers of aging is an irreversible decline in the lean mass. Obesity leads to increase in both fat mass and lean mass. However, the changes in lean mass linked to muscle and non-muscle, fat-free mass (liver, heart, kidney, intestine) need clarity. Chronic lipid overload exposure in obesity results in fat infiltration in the muscle which is also a hallmark of aging. Alteration in skeletal muscle is critical, being the site for insulin-facilitated glucose uptake. Therefore, diet induced weight loss in obese elderly is debated due to potential skeletal muscle loss. In addition, failure of muscle mass repair mechanisms with advancing age predisposes the cells to adipocytic status.

      2. Methods

      2.1 Treatments and Experimental model

      All experiments designed on animals were approved by the Institutional Animal Ethics Committee (IAEC), VIT, Vellore; VIT/IAEC/20/DEC2021/07, and the experimental outline was designed and performed with strict adherence to animal ethical guidelines. 15, five-week-old, C57BL/6 female mice were enrolled in the study at the animal house, VIT, Vellore. C57BL/6 mice have been widely used to study adipose tissue metabolism, obesity, and diseases related to protein and carbohydrate metabolism. Also, it has been suggested to use only one sex in these experimental trials to prevent complications as there are differences in magnitude and change of body components among young females and males.
      • Gargiulo S.
      • Gramanzini M.
      • Megna R.
      • et al.
      Evaluation of growth patterns and body composition in C57Bl/6J mice using dual energy X-ray absorptiometry.
      Moreover, female mice have been reported to exhibit less variance than male mice.
      • Smarr B.
      • Kriegsfeld L.J.
      Female mice exhibit less overall variance, with a higher proportion of structured variance, than males at multiple timescales of continuous body temperature and locomotive activity records.
      For a period of 7 days, before the initiation of experimental protocols, mice were caged in the animal house at 50% humidity, 24 ± 2 °C, and allowed to get accustomed to the animal house environment. Random sampling was used to divide the mice into five groups.
      Pre-Treatment: Body weight of all mice was recorded, and Dual energy X-Ray absorptiometry (DXA) scan was performed (Fig. 1). DXA scan was performed by the Hologic QDR 4500 with an internal collimator adapted for small animal measurements providing data on global and regional body composition of mice. The scan field was adjusted to 36 cm (length) x 18 cm (width) with a Spatial resolution of approximately 1 mm. The body composition results were calibrated by scanning with a specially designed small animal step phantom. The mice were anaesthetized before the DXA scan via the intra-peritoneal route by injecting ketamine hydrochloride (80 mg/kg body weight) and were positioned on a reference film.
      Fig. 1
      Fig. 1Experimental design and treatment in vivo. Pre-treatments include body weight and DXA scan for body composition. Treatment (A): Dividing the mice into five groups, (B): Shaving the hair on dorsal side, for UVA induced photoaging (C): UVA irradiation, (D) Intraperitoneal bixin administration.
      Treatment: A photoaging model based on mice dorsal skin exposure to UVA was established, to assess the role of bixin in adipaging. Group1 was not exposed to bixin and UVA treatment and was thus the negative control (NC). The other four groups of mice were treatment groups. Group 2 (V) was treated with UVA and 10% DMSO (vehicle for bixin), group 3 (B+) was treated with UVA and bixin (100 mg/kg), group 4 (B++) was treated with UVA and bixin (250 mg/kg), and group 5 (B+++) was treated with UVA and bixin (500 mg/kg). The hair on the dorsal skin (3 × 3 cm
      • Kapoor N.
      • Furler J.
      • Paul T.V.
      • Thomas N.
      • Oldenburg B.
      Ethnicity-specific cut-offs that predict co-morbidities: the way forward for optimal utility of obesity indicators.
      ) of all the mice was shaved and trimmed every 3 days. The treatment groups were exposed to a narrow spectrum UVA wavelength of 340–370 nm, with the peak at 365 nm, using the TL-D/18W Philips lamp. Mice were placed in a closed box where they could move around freely and the distance between the UV lamp and the bottom of the box was 25 cm with an exposure to UVA for a duration of 20 min (1 minimal erythemal dose, MED) five times in the first week and 2 MED three times per week during the following 3 weeks. After every UVA exposure the mice in the treatment group (V) were injected with 0.5 ml of 10% DMSO, while group3, group4 and group5 were injected with increasing dosage of bixin via the intraperitoneal route (Fig. 1).
      Post-Treatment: A Day after the last UVA exposure the body weight of mice was recorded and the impact of bixin was studied on the body composition of UVA treated mice using DXA (Fig. 1).

      2.2 Statistical analysis

      The graphical representation and analysis were performed with the GraphPad Prism Software Version 5. The results have been presented as the mean ± SD of three independent experiments. The difference between groups were considered significant at p < 0.05 by employing one-way analysis of variance (ANOVA).

      3. Results

      3.1 DXA highlights protective role of bixin on metabolic health in photoaged mice

      Body weight gain is a predisposing factor to the complications related to adipaging. Table 1 describes the body weight along with body composition parameters such as lean mass and fat mass both pre and post treatment to comprehend the impact of bixin supplementation on photoaged mice. The mean difference in body weight was highest in NC group, indicating weight gain and statistically significant in B++ and B+++ (least weight gain) groups (p < 0.01) in comparison to NC group (Fig. 2). Also, increasing bixin supplementation showed significant reduction in fat mass in B+, B++, B+++ groups (p < 0.01) vs. the NC group. Our results are in concurrence with data published earlier on the role of bixin in improving cardiac injury in rats,
      • Xu Z.
      • Kong X.-Q.
      Bixin ameliorates high fat diet-induced cardiac injury in mice through inflammation and oxidative stress suppression.
      anti-hyperlipidaemic effects in rabbits,
      • Somacal S.
      • Figueiredo C.G.
      • Quatrin A.
      • et al.
      The antiatherogenic effect of bixin in hypercholesterolemic rabbits is associated to the improvement of lipid profile and to its antioxidant and anti-inflammatory effects.
      and improvement in metabolic health of C57BL/6 mice
      • Pinzón-García A.D.
      • Orellano L.A.A.
      • de Lazari M.G.T.
      • Campos P.P.
      • Cortes M.E.
      • Sinisterra R.D.
      Evidence of hypoglycemic, lipid-lowering and hepatoprotective effects of the Bixin and Bixin: β-CD inclusion compound in high-fat-fed obese mice.
      owing to its antioxidant properties and inhibitory mechanism on enzymes involved in fat and carbohydrate digestion.
      • Perez Gutierrez R.M.
      • Valadez Romero R.
      Effects of bixin in high-fat diet-fed-induced fatty liver in C57BL/6J mice.
      However, statistically significant impact of bixin on increase in lean mass was observed only at high bixin dosage, such as in B++ (p < 0.05) and B+++ (p < 0.01) groups and not at lower dose of bixin in B+ group. Moreover, lean mass increase also requires strenuous exercise along with diet and lifestyle related modification. The findings of this pilot study may have future implications to study the role of bixin in adipaging related metabolic health.
      Table 1Mean body composition parameters in mice recorded both pre and post treatment with bixin on photoaged mice.
      GroupMEAN BODY WEIGHT (gm)MEAN FAT MASS (gm)MEAN LEAN MASS (gm)
      PrePostPPrePostPPrePostP
      NC22.66 ± 0.0626.766 ± 0.06<0.00012.033 ± 0.052.63 ± 0.060.000221.1 ± 0.123.7 ± 0.1<0.0001
      V22.36 ± 0.0524.8 ± 0.11<0.00012.166 ± 0.062.43 ± 0.110.021019.66 ± 0.0622.1 ± 0.1<0.0001
      B+21.13 ± 0.0523.83 ± 0.11<0.00012.3 ± 0.11.76 ± 0.05<0.000118.8 ± 0.121.63 ± 0.05<0.0001
      B++21.73 ± 0.0524.46 ± 0.15<0.00011.86 ± 0.061.53 ± 0.060.002319.6 ± 0.122.46 ± 0.15<0.0001
      B+++23.46 ± 0.0625.3 ± 0.1<0.00012.26 ± 0.061.26 ± 0.05<0.000119.63 ± 0.1523.3 ± 0.11<0.0001
      Fig. 2
      Fig. 2Mean difference between pre and post treatment with bixin on body composition of photoaged mice. (A): Mean difference in body weight. (B): Mean difference in fat mass. (C): Mean difference in lean mass. All Values are expressed as Mean ± SD (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001 vs. NC.
      Fig. 3
      Fig. 3Role of bixin in Adipaging. The crosstalk between obesity and aging has been depicted inside the black circle wherein the up arrows denote increased secretions/signalling and the down arrow denote decreased secretions/signalling. The red box showcases the role of bixin in adipaging. Red-down arrows denote bixin mediated inhibition and green-up arrows denote bixin mediated activation.

      4. Discussion

      The results of this pilot study showcase a statistically significant reduction in fat mass and augmented lean mass post treatment with bixin, specially at higher dosage in photoaged mice. Earlier, bixin has been studied beyond its role as a food pigment and has been reported to re-activate some of the silenced epigenetic signalling and regulatory mechanisms being a potent antioxidant, antimutagenic, anti-inflammatory, anticancerogenic agent. The findings of our study concur well with data reported on bixin's therapeutic role in, diabetes and obesity and aging and thus propose bixin as a pharmaceutical target as an anti-adipaging agent. Bixin has been reported for its several mechanistic links in regulation of adipaging. One of the key regulators of adipaging, PPARγ plays a crucial role in secretion of adiponectin and mediating adipose tissue expansion. Bixin has been reported to activate PPARγ (Fig. 3) and induce the expression of PPARγ target genes such as lipid chaperone (AP2), adiponectin and lipoprotein lipase (LPL) in 3T3-L1 adipocytes and thus attenuate abnormalities associated with carbohydrate and lipid metabolism induced by obesity. In a study on obese mice, bixin was found to suppress hyperlipidaemia and accumulation of hepatic lipids by increasing the expression of PPARγ target genes in the liver such as acyl-CoA oxidase (ACO), carnitine palmitoyl transferase I (CPT1), fatty acid translocase (FAT/CD36) and uncoupling protein 2 (UCP2). Moreover, bixin also helped to improve hyperglycaemia, and hypoadiponectinemia.
      • Goto T.
      • Takahashi N.
      • Kato S.
      • et al.
      Bixin activates PPARα and improves obesity-induced abnormalities of carbohydrate and lipid metabolism in mice.
      Bixin has also been found to be effective against the red flags of adipaging characterised by oxidative stress and reduced life span. In a recent study in Caenorhabditis elegans, bixin was found to be effective in stress resistance and longevity via the IGF-1 pathway
      • Gómez-Linton D.R.
      • Alavez S.
      • Navarro-Ocaña A.
      • Román-Guerrero A.
      • Pinzón-López L.
      • Pérez-Flores L.J.
      Achiote (Bixa orellana) lipophilic extract, bixin, and δ-tocotrienol effects on lifespan and stress resistance in Caenorhabditis elegans.
      (Fig. 1). Also, high fat induced secretion of proinflammatory cytokines, leading to “inflammaging” have been reported to be attenuated by bixin by blocking the NF-kB pathway and activation of Nrf2 signalling (Fig. 1). These findings support the underlying mechanistic action of bixin in progression of obesity and aging, thus indicate the effectiveness of bixin as a target for nutraceuticals in prevention of adipaging.

      5. Conclusion

      Obesity and aging share some common altered biochemical pathways which leads to the progression of metabolic syndrome. In current times, there is an increase in the prevalence of obesity and population above 60 years, with diminished life quality associated with obesity and age-related inflammation. Here we have presented the commonality in occurrence of red flags in aging and obesity and how these influence the phenomenon of adipaging. The role of food pigment bixin in metabolic health of photoaged mice has been performed as a pilot study highlighting its therapeutic efficacy in the mechanistic links of obesity and aging. This study emphasizes on bixin's potential as a target compound for future research work on plant-based, natural, drug target for the phenomenon of adipaging.

      Data availability

      All the data described are contained within the manuscript.

      Ethical considerations

      All experiments designed on animals were approved by the Institutional Animal Ethics Committee (IAEC), VIT, Vellore; VIT/IAEC/20/DEC2021/07, and the experimental outline was designed and performed with strict adherence to animal ethical guidelines.

      Funding statement

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      CRediT authorship contribution statement

      Leepica Kapoor: Methodology, Investigation, Writing – original draft, Editing, Conceptualization, Visualization, Supervision. Siva Ramamoorthy: Conceptualization, Visualization, Supervision.

      Declarations of competing interest

      None.

      Acknowledgements

      The authors are thankful to VIT Management for their support and encouragement.

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