Therapeutic Potential and Recent Advances of Curcumin in the Treatment of Aging-Associated Diseases

Curcumin, a low molecular weight, lipophilic, major yellow natural polyphenolic, and the most well-known plant-derived compound, is extracted from the rhizomes of the turmeric (Curcuma longa) plant. Curcumin has been demonstrated as an effective therapeutic agent in traditional medicine for the treatment and prevention of different diseases. It has also shown a wide range of biological and pharmacological effects in drug delivery, and has actively been used for the treatment of aging-associated diseases, including cardiovascular diseases, atherosclerosis, neurodegenerative diseases, cancer, rheumatoid arthritis, ocular diseases, osteoporosis, diabetes, hypertension, chronic kidney diseases, chronic inflammation and infection. The functional application and therapeutic potential of curcumin in the treatment of aging-associated diseases is well documented in the literature. This review article focuses mainly on the potential role of plant-derived natural compounds such as curcumin, their mechanism of action and recent advances in the treatment of aging-associated diseases. Moreover, the review briefly recaps on the recent progress made in the preparation of nanocurcumins and their therapeutic potential in clinical research for the treatment of aging-associated diseases.


Introduction
Aging is an inevitable process for all organisms. It creates numerous cellular and molecular malfunctions which lead to the development of various chronic diseases, also generally referred to as aging-associated diseases. The occurrence of aging-associated diseases is increasing worldwide and becoming the leading causes of disability and increased risk of mortality [1][2][3]. Some of the most common aging-associated diseases are atherosclerosis, cancer, cardiovascular diseases, chronic inflammation, chronic kidney diseases, diabetes, neurodegenerative diseases, hypertension, rheumatoid arthritis, ocular diseases, osteoporosis, and infections [4,5]. Aging-associated diseases usually develop in middle age after the prolonged exposure to an unhealthy early-life environment involving the excessive usage of tobacco and alcohol, anxiety, lack of physical activity and the consumption of a high-fat diet [1]. Clinical trials and epidemiological data has suggested that healthy lifestyle interventions help to prevent many aging-associated chronic diseases, and many can even be reversed [6].
Plant-derived natural products play a vital role in the prevention and treatment of aging-associated diseases [7]. Natural products extracted from plants has been used as an active ingredient in traditional medicine for many centuries [8]. Some plant-derived natural products possess a wide range of biological and pharmacological properties that have become indispensable in modern pharmacotherapy, e.g., paclitaxel (an anticancer drug) from Taxus brevifolia, vincristine and vinblastine (anticancer drugs) from Catharanthus roseus, camptothecin (anticancer drug) from Camptotheca acuminata and quercetin (anticancer drug), a polyphenol found in various vegetables and fruits [9][10][11]. Curcumin, which has the chemical structure 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, is a natural yellow, polyphenolic pigment compound extracted from the rhizomes of turmeric (Curcuma longa), is among these plant-derived natural products [12,13]. It is used as a food ingredient in all forms of Indian cuisine, and it shows a wide range of pharmacological activities. It is used for the treatment of neurodegenerative [14], atherosclerosis [15], cardiovascular [16], cancer [17], pulmonary, autoimmune and neoplastic diseases [18], biliary and hepatic disorders [19], diabetes [20], wound healing [21], rheumatoid arthritis [22], chronic inflammation [23], chronic kidney diseases [24], hypertension [25], ocular diseases [26], osteoporosis [27], and skin diseases [28]. Although curcumin possesses good therapeutic efficacy in the treatment of different diseases, the clinical administration of curcumin is difficult due to its poor oral bioavailability, low solubility in aqueous solution, and degradation under physiological conditions [13].
Nanocarrier-mediated delivery aids in overcoming the problems associated with curcumin and facilitates successful delivery without affecting its therapeutic efficacy. Several carrier molecules are used to enhance the bioavailability of curcumin such as polymeric nanoparticles (natural and synthetic polymers), liposomes, dendrimers, solid lipid nanoparticles, and gold nanoparticles [29]. Recent research has suggested that nanoformulated curcumin has a better therapeutic index than the native form of curcumin [30]. In this review article we primarily emphasize the therapeutic potential of curcumin and the possible advantages of using nanocurcumin, which possesses higher stability and increased bioavailability than free curcumin, in the prevention and treatment of aging-associated diseases.

Curcumin
Turmeric, the golden spice also known as "Indian saffron" is used as a traditional medicine in Southeast Asia [31]. The most important bioactive chemical constituents of turmeric are curcuminoids, which include curcumin, demethoxycurcumin and bisdemethoxycurcumin [32]. Curcumin, a hydrophobic polyphenol, is extracted from the rhizome of the herb Curcuma longa, which belongs to the Zingiberaceae family [33]. It has a wide spectrum of biological and pharmacological activities [34]. Curcumin is less soluble in water and highly soluble in organic solvents including methanol, ethanol, acetone and dimethyl sulfoxide [35]. Curcumin is commonly called diferuloylmethane, and it gives a yellow color to turmeric powder. The chemical structure is shown in Figure 1a. The ultraviolet-visible surface plasmon resonance spectrum of curcumin exhibits a strong absorption peak between 420-430 nm. In the last 10 years, over 15,000 scientific papers have been published on curcumin, and these numbers have been increasing annually. Scopus results for the period 2008-2017 are shown in Figure 1b. An extensive literature survey was conducted over the last 10 years on aging-associated diseases and their treatment strategies using the drug curcumin. Atherosclerosis-curcumin, cancer-curcumin, cardiovascular diseases-curcumin, chronic inflammation-curcumin, chronic kidney diseases-curcumin, diabetes-curcumin, hypertension-curcumin, neurodegenerative diseases-curcumin, ocular diseases-curcumin, osteoporosis-curcumin, and rheumatoid arthritis-curcumin were used as keywords to search the "Scopus" database for the period 2008-2017, and the results are represented in Figure 2. The literature study describes the annual publication history and the recent research progress of curcumin in relation to the above-mentioned aging-associated diseases.

Biological and Pharmacological Properties of Curcumin
Currently, curcumin is being investigated as an active therapeutic agent for several types of diseases including cardiovascular, pulmonary, skin disorders, liver disorders, fatigue, neuropathic pain, bone and muscle loss, and anxiety, due to its well reported biological activities which include anti-inflammatory, anti-proliferative, anti-angiogenic, pro-apoptotic, anti-oxidant, wound healing, anti-cancer, anti-viral, and anti-diabetic effects [36][37][38]. It is a well-recognized plant-based drug for the treatment of most chronic diseases. Curcumin has exhibited excellent anti-bacterial activity against both methicillin resistant and sensitive Staphylococcus aureus [39]. It is also one of the most frequently prescribed drugs for the treatment of different skin diseases and skin cancer [28].
Extensive investigation has indicated that curcumin resulted in a reduction in total cholesterol and low-density lipoprotein (LDL) levels in patients suffering from acute coronary syndrome [40], and that it effectively reduced platelet aggregation and hyperlipidemia [41]. Curcumin possesses anti-thrombotic activities and daily consumption helps to maintain anticoagulant status [42]. It can promote cardiac repair and restore cardiac dysfunction [43], molecular understanding in diabetic nephropathy [44], modulate cell cycle regulatory proteins in central nervous system-related disorders including multiple sclerosis [45], and it can be potentially used for the treatment of hepatic diseases [46], and different types of cancers [47]. The beneficial effects of curcumin have also been studied in detail in ocular diseases, which include corneal diseases, eye dryness, conjunctivitis, anterior uveitis, pterygium, regulating calcium hemostasis, cataracts and glaucoma [48].
Various in vitro and in vivo preclinical studies have demonstrated that curcumin has effective biological pharmacological and potential clinical applications by interacting with numerous cellular and molecular targets via a diverse range of mechanisms of action [49], which are presented in Table 1. Table 1. Diverse range of mechanisms of action of curcumin in aging-associated diseases.

Atherosclerosis
Reduces cholesterol accumulation; downregulates SR-A and upregulates ABCA1 by a proteasome and LXRα dependent pathway; inhibition of low density lipoprotein oxidation; stabilization of cell membrane cholesterol.

Therapeutic Potential of Curcumin in Aging-Associated Diseases
The aging process is related to a wide range of disorders. Aging-associated diseases are threatening the elderly population worldwide. Research over the last few decades has studied the therapeutic potential of curcumin and showed the beneficial aspects of curcumin in the prevention and treatment of aging-associated diseases. The therapeutic potential of curcumin used in the treatment of aging-associated diseases is discussed in Table 2. Table 2. Therapeutic potential of curcumin used in the treatment of aging-associated diseases.

Aging-Associated Diseases
Therapeutic Potential of Curcumin Outcomes References

Atherosclerosis
Anti-atherogenic effect of curcumin via different mechanisms.
The effect of curcumin was studied and compared with the drug lovastatin, and the long-term treatment with curcumin lowered plasma and hepatic cholesterol, and suppressed early atherosclerotic lesions. [59]

Cancer
Curcumin interferes with multiple cell signaling pathways which include cell cycle, apoptosis, proliferation, angiogenesis, invasion, metastasis and inflammation.
The anticancer activity of curcumin was reported against different cancers, and it plays a significant role in different cell signaling pathway and numerous molecular targets. The in vitro, in vivo and clinical studies revealed the therapeutic value of curcumin for the treatment of "old-age" diseases like cancer. [60]

Cardiovascular diseases
The inflammatory effects of curcumin may play a key role in the prevention of cardiovascular diseases.
Curcumin showed the possibility of preventing atrial arrhythmias and some ventricular arrhythmias. [16] Chronic inflammation Curcumin can suppress both acute and chronic inflammation by scavenging reactive oxygen species and enhancing antioxidant defences.
Curcumin shows very good antioxidant properties, and it plays a key role in the prevention and treatment of chronic inflammation. [23,61] Chronic kidney diseases Curcumin increases the expression of intestinal alkaline phosphatase and tight junction proteins.
The study shows the potential anti-inflammatory effects of curcumin and their positive effects for the treatment of chronic kidney diseases. [24] Diabetes Curcumin reduces glycemia and hyperlipidemia in rodent models, and favourably affects some leading aspects of diabetes which include insulin resistance, hyperglycemia and islet apoptosis and necrosis.
Curcumin is actively involved in the prevention and treatment of diabetes. The study showed that curcumin and their complexes can successfully be used for the treatment of various disorders associated with diabetes such as liver disorders, adipose tissue dysfunction, diabetic neuropathy, diabetic nephropathy, diabetic vascular disease, and other complications associated with diabetes. [20] Hypertension Curcumin shows beneficial effects on hypertension; it prevents the development of hypertension by regulating AT 1 receptor expression.
The study was performed using curcumin in an Ang II-induced hypertensive model, and it showed that curcumin aids in the downregulation of the AT 1 receptor in A10 cells and it subsequently prevents hypertension. [25] Neurodegenerative diseases Curcumin has reported to be an effective neuroprotective agent and it may prevent aging associated changes in cellular proteins.
Protein homeostasis plays an important role in aging-associated diseases. The study performed in an invertebrate model (Caenorhabditis elegans) showed that the drug curcumin aids to maintain protein homeostasis and increases the life span of the model organism. Several animal model studies showed that curcumin prevents or delays various neurodegenerative diseases. [14] Ocular diseases Curcumin exhibits potential therapeutic activity against several ocular diseases.
Curcumin showed beneficial effects in the prevention and treatment of several ocular diseases. The dosage of curcumin, up to 8g/day for three months, does not produce any dose-limiting toxicity in pharmacological studies. Clinical data proved that the few weeks of curcumin treatment reduced the signs and symptoms of eye discomfort and is safe in the treatment of humans. [26] Osteoporosis Curcumin may be a potential candidate for the treatment of osteoporosis.
The protective effects of curcumin were studied against dexamethasone induced osteoporosis in a rat model. The results proved that curcumin effectively prevented glucocorticoid-induced osteoporosis. [27]

Rheumatoid arthritis
Curcumin possess various pharmacological activities including antiarthritic effects.
The effect of curcumin was studied in an adjuvant-induced arthritis rat model, and it showed similar therapeutic effects for the treatment of rheumatoid arthritis compared with the drug methotrexate. [22]

Recent Advances of Nanocurcumin in Aging-Associated Diseases
In recent years, nanotechnology-based drug delivery systems have received considerable attention in drug delivery and pharmaceutical research due to their capability to deliver drugs and other substances (such as targeting ligands, fluorescent dyes) to the targeted region. Nanoformulation offers distinct advantages in drug delivery which include lack of toxicity, high drug loading capacity, controlled drug release, extended shelf life period, higher stability, functionalization with specific targets, intracellular release and targeted delivery [62]. Various nano-based formulations are successfully studied for imaging, diagnostic and therapeutic applications [63]. Recent advances in nanotechnology have facilitated the formulation of nanocurcumin and it significantly improved the therapeutic efficacy and bioavailability of its native counterpart [64] and provides the opportunity for disease specific targeting [65].
Curcumin-loaded spherical polymeric nanoconstructs with lipid chains was assessed in vitro using RAW 264.7 cells. The nanoconstructs significantly modulated the production of pro-inflammatory cytokines without any cytotoxic effect [66]. Curcumin-conjugated magnetic nanoparticles bind with amyloid plaques in mouse brains, which was confirmed through immunohistochemical studies and magnetic resonance images. This study revealed the potential application of curcumin magnetic nanoparticles to visualize amyloid plaques in Alzheimer's disease [67]. Curcumin loaded zinc oxide nanoparticles encapsulated with a co-polymer were successfully synthesized, and their anticancer activity showed excellent cytotoxicity effects in AGS gastric cancer cells [68]. In vitro and in vivo studies showed that curcumin encapsulated PLGA nanoparticles showed effective targeting and growth inhibition of prostate cancer cells [69]. Meena et al. synthesized small positively charged curcumin nanoparticles using PLGA as a carrier, and tested these nanoparticles in triple-negative breast cancer cells. Nanocurcumin showed higher cellular incorporation and produced more cytotoxic effects than free curcumin, and further apoptosis induction occurred due to DNA damage [70]. Fan et al. fabricated curcumin loaded nanoparticles using bovine serum albumin and dextran as a carrier molecule, and showed improved cellular antioxidant activity in Caco-2 cells [71]. Curcumin loaded solid lipid nanoparticles were synthesized and were revealed as a safe and effective therapeutic agent for the treatment of lipopolysaccharide-induced sepsis in IL-1b transgenic mice [72]. Curcumin nanoparticles possessed cardio protection against palmitate induced cardiomyocyte apoptosis in H9C2 embryonic rat heart-derived cells, and may be an alternative treatment for lipid toxicity and myocardial injury [73]. Dewangan et al. prepared curcumin-carboxymethyl cellulose acetate butyrate nanoparticles in the size range of 166.5 ± 4.2 nm with higher loading efficiency. This study demonstrated superior anti-inflammatory effects without any specific side effects for the successful treatment on adjuvant induced arthritis in rats [74]. The curcumin encapsulated PLGA nanoparticle approach enhanced the effect of curcumin against bone loss. It showed significant beneficial effects on osteoporotic bone loss treatment with an improved therapeutic index [75]. Curcumin encapsulation was performed using a novel nanomicelle formulation which significantly improved in vitro cellular uptake and in vivo corneal permeation as compared to free curcumin [76]. Some to the recent advances in the preparation of nanocurcumin for the treatment of aging-associated diseases are well studied and are listed in Table 3. Table 3.
Recent advances in the preparation of nanocurcumin for the treatment of aging-associated diseases.

Aging-Associated Diseases Detail of Nanoparticles Size (nm) Outcomes References
Cancer Curcumin loaded cationic liposome-polyethylene glycol (PEG) and poly (ethylene imine) complex

nm
Curcumin liposomes showed five-fold cytotoxic activity on curcumin-sensitive cells and twenty-fold against curcumin-resistant cells compared to native curcumin, and achieved 45 ± 0.2% curcumin encapsulation efficiency in the liposome complex. In vivo studies showed that the administration of curcumin liposomes inhibited 60-90% of tumor growth. [77] Cancer Curcumin loaded silk fibroin nanoparticles 155-170 nm Curcumin loaded silk fibroin nanoparticles were synthesized using both physical adsorption (drug loading content of 6.63 ± 0.09% and encapsulation efficiency of 53.75 ± 0.81%) and co-precipitation (drug loading content of 2.47 ± 0.11% and encapsulation efficiency of 48.84 ± 2.67%). The synthesized material showed excellent antitumor activity against both Hep3B and Kelly cells.

Cardiovascular diseases
Colloidal nanoparticles (Curcumin with gum ghatti solution) 190 nm A small amount of synthesized colloidal curcumin nanoparticles could be more therapeutically effective for heart failure than native curcumin. [79] Chronic inflammation Nano-emulsified curcumin (NEC) -NEC was orally supplied to NZM2410 mice (lupus nephritis model) and kidney function was monitored by testing blood urea nitrogen. Results suggested that NEC has a good therapeutic potential in the treatment of chronic inflammation and other autoimmune diseases. [80] Chronic kidney diseases Curcumin nanoparticles 80-100 nm The in vitro and in vivo study suggested that the curcumin nanoparticles enhanced the treatment efficacy of Rhabdomyolysis induced acute kidney injury than free curcumin. The release study was performed using dialysis. The initial 20 h of dialysis showed that upto 40% of curcumin nanoparticles were released and 80% of free curcumin was released. Nanoparticulate curcumin achieved prolonged release profile than free curcumin. [81] Neurodegenerative diseases Nanocurcumin (Curcumin loaded p(PEG-poly-lactic acid) micelles

nm
There was improved bioavailability of nanocurcumin in the brains of Tg2576 mice as compared to free curcumin, and nanocurcumin showed positive effects in the treatment of Alzheimer's disease. The entrapment efficiency of curcumin was almost 100% and the loading efficiency of curcumin was 37.6%. [82] Ocular diseases Curcumin encapsulated PLGA nanoparticles 282.50 ± 5.72 nm The study demonstrated the potential of curcumin encapsulated nanoparticles in managing diabetic cataracts in a streptozotocin induced diabetic rat cataract model. The enhanced performance of nanocurcumin was observed in different biochemical pathways than free curcumin. It may be due to the improved oral bioavailability of curcumin. [83] Osteoporosis Gold nanoparticles functionalized with cyclodextrin curcumin complexes

nm
Loading efficiency of curcumin was around 38.95% and the curcumin loaded nanoparticle complex showed an effective intracellular uptake and acts as a potential therapeutic agent in the treatment of bone diseases associated with excessive bone resorption. [84]

nm
In vivo rat study showed that the synthesized curcumin nanoemulsion acts as an effective antiarthritic agent. The oral route of curcumin nanoemulsion showed threefold increase of AUC (area under the curve) and Cmax value than the suspension (intravenous (iv) route) and it significantly enhanced the drug absorption than free curcumin. Overall, the in vivo rat study suggested that the nanoform of curcumin aids to convert the therapy route from iv to oral administration for the effective treatment of RA therapy [22]

Clinical Application of Curcumin in Aging-Associated Diseases
Curcumin has been extensively used in clinical trials and is showing positive outcomes for the treatment of aging-associated diseases. The global market is predominantly focused on curcumin as a health supplement due to its effective antioxidant and anti-inflammatory properties [39]. The different aging-associated diseases along with curcumin were used as a keyword to search the "https://clinicaltrials.gov" database. The number of clinical trials are listed in Table 4 and some of the major global clinical trial status of curcumin in aging-associated diseases are listed in Table 5. Table 4. Number of clinical trials generated from the "https://clinicaltrials.gov" database using the keywords (curcumin and the different aging-associated diseases).

Future Perspectives and Conclusions
In this review, we discussed in some detail the therapeutic potential of curcumin for the prevention and treatment of aging-associated diseases. Curcumin is a well-known plant-derived compound that exhibits a wide range of biological and pharmacological effects in modern medicine. It is well documented in the literature and shows positive effects on the treatment of aging-associated diseases. However, despite the fact that the native form of curcumin possesses good therapeutic efficacy, the clinical administration is problematic due to their poor oral bioavailability and stability. Recent advances in nanotechnology have helped to overcome these difficulties and efficiently deliver curcumin to the targeted region thereby improving curcumin bioavailability. An extensive literature study strongly suggests that the nanocarrier-mediated delivery of curcumin will become a successful treatment strategy for aging-associated diseases. Moreover, future perspectives should include additional clinical trial investigations on the formulation of nanocurcumin with improved stability and oral bioavailability, and focus more on targeted drug delivery of curcumin for the treatment of aging-associated diseases.
Author Contributions: S.S.D.K. conceptualized the idea and prepared the review article. N.N.H. was involved in drafting the manuscript, revising it critically for intellectual content, provided professional guidance and is the supervisor of lead author. H.A. organized this study, supplied editorial input and is a co-supervisor of the lead author. All authors read and approved the final manuscript.

Conflicts of Interest:
The authors confirm that this article content has no conflict of interest.