1 Introduction

The quest for immortality has been a widespread endeavor from the beginning of human society. Human lifetime has expanded significantly during the past century as a result of better living conditions and ongoing medical technology advancement [1]. More than 2.1 billion people will be over 60 by 2050, according to United Nations research from 2015. This is because of increased birth rates and better living conditions [2]. Aging is an irreversible physiological process, mediated by numerous biochemical and genetic processes, which are directly correlated with longevity and are also the root cause of all age-related diseases [3]. The major hallmark of aging is cellular senescence. This cellular senescence has unavoidable effects on the body. First, tissue regeneration is invariably impacted by an excessive buildup of senescent cells. Furthermore, senescent cells release a multitude of inflammatory mediators which have a negative effect on the body in many ways [4]. It is necessary to first define the cellular and molecular markers for aging to shed light on the processes and effects of anti-aging therapy on aging-related disorders (ARDs). The major hallmarks of aging include genomic instability, decreased telomere length, loss of proteostasis, epigenetic alterations, malnutrition, exhaustion of stem cells, and mitochondrial dysfunctioning [5].

The conventional view of aging is evolving nowadays, and it is no longer just seen as a normal biological process but also as a sickness. Patients, their families, and society at large bear a significant financial and psychological burden because of these age-related illnesses. Numerous ARDs, such as cancer, cardiovascular disease, neurological afflictions, and musculoskeletal disorders are all influenced by aging [3]. Cardiovascular diseases (CVDs) have been the predominant cause of mortality for at least a century. No doubt, aging is the most common factor of CVDs, but still the in-depth comprehension of mechanisms behind the aging associated CVDs is required [6]. Human investigations repeatedly show that aging and neurodegenerative diseases have a strong link and result from bioenergetic maladaptation. Getting older is thought to be one of the main causes of dementia and Parkinson’s diseases [7, 8]. The bone is an organ in constant motion, preserved by well controlled systems. As we age, the delicate balance between bone creation and resorption that maintains bone homeostasis begins to unravel. Osteoporosis is a common co-morbidity that can impact one’s life, and physiological aging is frequently associated with multiple of them [9].

The date palm (Phoenix dactylifera) is a highly profitable crop, belonging to the Aceraceae family. There are over 2500 species in the family and 200 genera. Originating in Mesopotamia, the date palm is a significant fruit crop in Central America, North Africa, South Asia, and the Middle East. P. dactylifera is said to have more than 5000 varieties now in existence. Its growth requires five stages [10]. These are Hababouk (beginning stage), Kimri (immature stage), Khalal (mature stage), Rutab, and Tamer stage (ripening) [11]. Dates are a significant source of nutraceuticals with a variety of benefits, such as hepatoprotective, anti-inflammatory, anti-mutagenic, gastro-protective, antioxidant, and anti-microbial properties [12]. Dates are consumed raw, but they are also used as a replacement of sugar in sweets, dairy products, and other foods. The harvest stage, variety, and method of preparation all affect the nutritional and phytochemical characteristics of dates [13]. The primary bioactive elements in date fruit that have the ability to function as nutraceutical agents include vitamins, amino acids, proteins, carbohydrates, fatty acids, tannins, flavonoids, carotenoids, procyanidins, and phytosterols [14].

It has been investigated that date palm phytochemicals could ameliorate the above-mentioned ARDs. In Alzheimer’s disease (AD), date palm reduces caspase-3 activation, IL-6 release, and ROS production due to which Aβ plaques aggregation declines [15]. Date palm can also mitigate Parkinson’s disease (PD) by regulating MAPK, JNK pathways and by decreasing α-syn protein accumulation [2, 16].

Date palm by restricting the release of angiotensin converting enzyme (ACE-II) and by decreasing the production of endothelin-1 (ET-1) vasoconstrictor regulates blood pressure [17]. In atherosclerosis, dietary fiber like lignin and cellulose causes the activation of FXR receptor that leads to decreases bile acid synthesis and also decreases the level of LDL and VLDL [11]. In myocarditis, flavonoids like quercetin decreases the level of C-reactive protein (CRP) and also the production of COX-1 and COX-2 which decreases inflammation [18]. In myocardial infarction, polyphenols like gallic acid restores the level of CD13 and CD133 positive progenitor cells [19].

In osteoporosis, genistein upregulates the ER, p38MAPK-Runx2 pathways, and also improves the growth of osteoblasts [20]. EGCG reduces the activity of RANKL and level of TNF-α which decreases oxidative stress [2].

This article is focused on the preventive and therapeutic role of date palm in ARDs by its diverse nutraceutical and phytochemical composition. The study elucidates the common signaling pathways in ARDs and the impact of date palm on various targets in these age-related signaling pathways.

2 Methodology

2.1 Literature search strategy

To thoroughly investigate all the characteristics of P. dactylifera, a literature search was done using a variety of internet databases including PubMed and Google scholar. We conducted the search using pertinent keywords and combinations like date palm, nutraceutical, aging, phytochemicals, ARDs, cardio-protective, AD, PD, osteoporosis, role of date palm in cardiovascular diseases, role of date palm in neurodegenerative diseases, role of date palm in osteoporosis etc.

2.2 Inclusion and exclusion criteria

Inclusion criteria consists of research describing the phytochemistry, health advantages, and physiological processes behind the therapeutic qualities of date palm, as well as research emphasizing the pharmacological mechanisms behind ARDs. To incorporate investigations that particularly address the connection among neurodegenerative diseases, cardiovascular diseases, and osteoporosis were also a part of inclusion criteria. It also includes research that sheds light on the mechanisms by which date palm reduces the risk of AD, PD, CVDs, and osteoporosis.

Exclusion criteria comprises of all the articles that explore the industrial applications of date palm and duplicated studies. Excluded from this review were any papers that were not written in English, included insignificant or irrelevant data, or whose entire text could not be accessed. Furthermore, studies with no direct connection to date palm as well as those with little to no information on the advantages to health or the mechanisms of action were disregarded.

3 Crosstalk among aging associated diseases

The structural damage-based theory, which is the foundation of free radical theory of aging (also known as the oxidative stress theory of aging), explains that age-related physiological dysfunctioning result from the buildup of oxidative damage to lipids, proteins, and DNA. [21]. Basically, inflammation and oxidative stress are interlinked and play a major role in ARDs. Aging increases oxidative stress in multiple ways which may lead to atherosclerosis, osteoporosis, cardiac hypertrophy, AD, PD, and myocarditis.

IL-1 is the major inflammatory mediator which when releases beyond the normal limit causes upregulation of NFκB activity which furthers increases oxidative stress. Resveratrol restricts the release of IL-1, thus providing protection against IL-1 induced oxidative damage [22]. Cellular senescence causes inhibition of FOXO (Forkhead box) proteins which plays a major role in providing protection against oxidative damage by insulin like growth factor-1. Sirtuins also act as a barriers towards oxidative damage which are inhibited by cellular senescence [23]. Resveratrol has the ability to restore the level of sirtuins [24].

A connection between vitamin D levels and Parkinson’s disease has been proposed by a number of experts. In fact, research on animals has shown that vitamin D may offer defense against harmful aggressions that harm dopaminergic cells. Many phytosterols in date palm increase the level of vitamin D3 in bones, thus increasing bones mass. Low-concentration phytosterols can improved trabecular microstructure, reduce serum levels of cross-linked C-telopeptide of type I collagen (CTX-1), and elevated serum levels of 1,25-dihydroxyvitamin D3 [25]. This means that it will prevent the death of neurons and will also ameliorate PD induced osteoporosis. Oxidative stress causes activation of Jun amino-terminal kinase and p38 mitogen activated protein kinase, which may lead to accumulation of Aβ plaques leading to AD [26]. Moreover, these plaques may also trigger ROS production, and in this way, the cycle continues. It has been observed that people with PD are at greater risk of developing osteoporosis [27]. Oxidative damage causes lipid peroxidation, a major marker of AD.

NADPH oxidases gene (Nox1 and Nox2) play a major role in exacerbating oxidative stress in CVDs. COX-1 and COX-2 also stimulate ROS production causing hypertension, myocarditis, atherosclerosis etc. [28]. Quercetin and rutin restrict the release of COX enzymes, thus preventing oxidative damage as shown in Fig. 1 [29].

Fig. 1
figure 1

Common pathways linked with ARDs. Oxidative. stress is the major contributor towards ARDs. Resveratrol restricts NF-Kb pathway that leads to ROS production. Quercetin and rutin hinder COX enzymes. Caffeic acid downregulates NOX genes. EGCG downregulates NOX4. Luteolin targets MAPK, JNK pathways. All these steps decrease oxidative stress that causes ARDs

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Though the precise processes and important factors involved are unknown, reactive oxygen species have been connected to bone loss. According to current research, NADPH oxidase 4 (NOX4) stimulates osteoclastogenesis in mice [30]. EGCG predominant in dates causes inhibition of NOX4 as shown in Fig. 1 [31]. NOX1 by NF-Kb pathways also causes oxidative damage in bones. Caffeic acid causes inhibition of NOX1 and acts as a barrier towards ROS production. Therefore, inhibition of these enzymes may have the ability to lessen osteoporosis-related bone loss [32].

Nrf2, or nuclear factor-erythroid 2 p45-related factor 2, is a crucial transcription factor that controls the activity of the enzyme that causes metabolism of drugs. It plays a major role in activating genes that response to oxidative damage in the body. Downregulation of this factor results in diminished levels of antioxidant enzymes leading to ROS production [33]. Coumarin and its derivatives found in date palm causes upregulation of Nrf2 [34]. MAPK, JNK, and PIK3 pathways also lead to oxidative damage which leads to ARDs. Luteolin found in date palms can regulate these pathways as shown in Fig. 1, thus providing protection against oxidative stress.

4 Nutritional composition of date palm

Date fruits and their derivatives are becoming more and more popular because they are a cheap and abundant source of several macro- and micronutrients as well as secondary metabolites that are critical to human health [35]. The two components that make up date fruit are the pulp (85–95%) and the seed (5–15%). The energy value of date fruit is considerable (354 kcal/100 g) [36].

Dates are rich in carbs, with > 80% of their dry matter made up of sucrose, glucose, and fructose. Nutritional composition depends upon the types of date fruits, mode of cultivation, and maturation of fruit [37]. Compared to Allig dates fruits, the Deglet Noor type has greater amount of sucrose [38]. The carbohydrate content was also studied. It was observed that maximum amount of carbs (81.4%) were present in Bumi, and the minimum amount was present in Labanah dates [39]. The composition of presence of different categories of carbs was also studied. Al-Farsi et.al tries to evaluate the monosaccharide content and he found that the highest amount of glucose was present in Khalas Al Kharj (95.4%).

Additionally, date palm has been recognized to be an excellent source of important amino acids. Amino acid composition was evaluated in 10 varieties of dates. After amino-acid sequencing, 23 amino acids were found in different dates out of which arginine was found in the range of (37–93 mg/100 g), which plays a significant role in our body [40]. Some amino acids which are responsible for eliminating toxins from the body were found in Ajwa dates. These were 1-aminocyclopropane-1-carboxylic acid, g-amino-n-butyric acid, and L-pipecolic acid [11].

Date fruits have a low amount of protein (2.5–6.5 g/100 g) as shown in Table 1. Shalal dates have a protein content of 3.62–5.23 g/100 g [41]. Different minerals that have a crucial significance in normal physiology of body are also present on dates like selenium, magnesium (64.2 mg/100 g), sodium (18.9 mg/100 g) and iron (0.3–6.03 mg/100 g) [42]. The trace amount of minerals is important to human body as Iron helps combat physical exhaustion, zinc improves immune system function, and sodium is necessary for blood pressure regulation.

Table 1 Nutraceutical composition of date palm
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Composition analysis of vitamins has also been evaluated. Different vitamins like folic acid (2.54–50.5 mg/mL), riboflavin (1.563–20.01 mg/mL), and thiamine (1.85–20.8 mg/ml) are present in dates as shown in Table 1 [43].

The nutritional composition of date fruit seeds has also been investigated. Oil content in Deglet Noor is about 10.19% and its protein content is 5.56%. Chief minerals in seeds are potassium (255.4 mg/100g), magnesium (62.7 g/100 g), and calcium (48.56 mg/100 g) [44].

The composition of date seed oil has also been evaluated. The composition of saturated fatty acids like myristic and lauric acid is 50%. The concentration of unsaturated acids like oleic acid is 43%. Polyunsaturated fatty acids (linolenic acid) are found in the range of about 8% [45]. Oleic acid is required for lowering high amounts of cholesterol from the body and unsaturated fatty acids play a major role in cardio protection.

Date seed essential oil should be regarded as a valuable product with economic value in the oil industry due to its nutritional and functional makeup [46]. The essential oil of P. dactylifera pollen was rich in unsaturated fatty acid, oleic acid. The essential content present in date buds were analyzed by GC–MS analaysis. It was discovered that the oil content was 0.48% (w/w), and 38 compounds from which 98.61% of the total essential oil was identified. Trans-Caryophyllene was the most abundant component of the bud oil (44.20%) followed by palmitic acid (9.23%), caryophyllene oxide (7.58%), hexadecanal (6.00%) and oleic acid (5.65%). In the same way, essential oil content was detrermined in the pollens of date palm. The oil yield was 1.47% (w/w). In addition, only three compounds, namely trans-caryophyllene (19.95%), palmitic acid (12.01%) and oleic acid (68.04%), were identified in the pollen oil. The essential oil present in the buds possessed both the components of the pollen oil and those of the spathe oil but at different percentages. 3,4-Dimethoxytoluene, which is the main constituent of the spathe oil, was found at lower percentage in the oil of the buds, whereas it was not detected in the pollen oil. Oleic acid was identified in the three oils but at different percentages as follows: 68% in the pollen oil, 5.6% in the bud oil and less than 0.05% in the spathe oil [47]. Another research was conducted to analyze the composition of essential oils in 7 different varieties of date palm. The major components that were identified were h 3,4-dimethoxy toluene (55.2%), p-methyl anisol (28.5%), and 2,6-dimethoxy toluene, 3,4- dimethoxy toluene(61.6%), 2,6-dimethoxy toluene (19.9%), n-nonanal (8.8%) and p-methyl anisol (4.5%). The main components of essential oil from the date-palm spathe in Saudi Arabia were found to be 3,4-dimethoxy toluene (73.5%), 2,4-dimethoxy toluene (9.5%), β-caryophyllene (5.5%), p-cresyl methyl ether (3.8%) and caryo-phyllene oxide (2.4%) [48]. Different techniques can be utilized for the extraction of essential oils from date palm which include cold pressure; conventional solid–liquid extraction like maceration, Bligh-Dyer and Soxhlet extractions; and non-conventional extractions such as microwave, ultrasound and supercritical fluid extractions using either petroleum solvents like hexane and petroleum ether or MeTHF as green solvent for the first two techniques and CO2 for the last one. Cold pressure, supercritical fluid and green solvent extractions afforded the safer oils while Soxhlet extractions give the better yields [49].

Dietary fiber content in dates is about 1.9–20.2% which includes cellulose, pectin, and lignin. A considerable amount of β-glucan is also present. The amount of dietary fibers in date seeds is 67% to 74% as shown in Table 1 [35].

5 Phytochemical analysis of different varieties of date palm

One of the primary aromatic secondary plant metabolites are phenolic acids and plants develop resistance mostly through the induction of phenolic chemicals [51]. Date fruits are high in phenolic compounds, which have antimutagenic and antioxidant effects in vitro, in addition to their nutritional benefits [52]. Mrabat et. al examined the amount of phenolic acid in date fruit. The major phenolic acids were gallic acid, protocatechuic acid, tyrosol, caffeic acid, vanillic acid and syringic acid. The predominant phenolic acid was gallic acid having composition ranging from 1.35 and 1.53 g/kg of the sample [53].

The ingestion of flavonoids has been linked to several health advantages, such as a longer lifespan, a reduction in cardiovascular issues, and a lower incidence of metabolic illnesses [54]. Regarding flavonoid concentration, the pulp of date fruits contained mostly quercetin (0.17–1.27 mg/100 g), according to Hamad et al. Date fruit is enriched with other flavonoids like rutin, kaempferol, and epicatechin etc. [50].

Carotenoids are the precursors of vitamin A, which is essential for sharp eyesight and protects the cell from oxidative stress [55]. Lutein was the primary carotenoids identified in date pulp (1.08 g/100 g of the sample) [56]. Β-carotene is also a chief carotenoid in date pulp (0.22 g/100 g). Other carotenoids are β-cryptoxanthin, lycopene, and γ-carotene.

Phytosterols, known for their cholesterol lowering, antipyretic, and anti-inflammatory activities are another important phytochemical present in the date fruit’s [57]. Besbes et. al, tried to analyze the phytosterol content of date fruits. He found that the total phytosterol composition was in the range of 3500 and 3000 mg/kg of different date fruits [58]. The principal sterol was found to be β-sitosterol (83.31%). Other phytosterols that are found in dates are campesterol and avensterol [44]. Some other phytosterols include genistein, formononetin, and diadzein as shown in Fig. 2.

Fig. 2
figure 2

Major phytosterols, flavonoids, and polyphenols were identified in date palm

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Because of their lipoperoxyl radical scavenging activity as antioxidants, tocopherols constitute an essential family of chemicals for human health [59]. As a result, date seed oil may be regarded as a rich source of tocopherols [60]. Habib et al. analyzed the tocopherol content in date fruits. He found that α-tocopherol (1.86 mg/100 g) was the most abundant tocopherol in date fruits [61]. Some other tocopherols were also found like γ -tocopherol, δ-tocopherol, and β-tocopherol.

At the Khalal stage, if maturation, fresh date fruits are preferred and extensively devoured, particularly those of the Barhi variety. These dates are luscious, sweet, and oozing with flavor. These dates have a rich butterscotch flavor and are incredibly smooth, creamy, and soft [62].

A popular palm date cultivar in Saudi Arabia, the UAE, and the Persian Gulf is called Khalas as shown in Fig. 3 (Arabic: خلاص). Brown skinned; this is one of the priciest sorts of Emirati dates. One characteristic that sets Khalas dates apart is how well their flavor holds up over time in storage. It is regarded as one of the greatest varieties of dates because of its peach color and sweet flavor. Khalas dates are high in those phytochemicals and minerals that boost health and combat illness [63]. This date palm has predominant cars and minerals as shown in Table 2.

Fig. 3
figure 3

Major phenolic acids and organic acids identified in date palm

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Table 2 Phytochemical analysis of different varieties of date palm
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In the globe, Ajwa dates (Dates of Heaven) are the most common. These dates are available only in Madinah. Researchers have validated the significance of this highly nutritious fruit. With flavors of honey and cinnamon, Ajwa dates are sweet with a meaty appearance [64]. Dan Agadas, the most delicious of all foreign dates as shown in Fig. 4, hails from Nigeria. Its skin is a very dark brown color and a little rough. Being a perfect alternative of sugar, it is of great importance in Nigeria [65].

Fig. 4
figure 4

Schematic representation of different varieties of date palm based on the type of fruit

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Halawi dates are among the most popular kind of dates because of their creamy golden flesh and caramel flavor as shown in Fig. 3. Indeed, the Arabic word “Halwai” means “sweet.” The Halawi date has been compared to the buttery flavor of a pecan pie, but without the overbearing sweetness. It is the pinnacle of butter and caramel [66]. This date is rich in vitamins like vitamin A and C as shown in Table 2. Production of dates in Algeria has skyrocketed, with 400 distinct types produced, including “Deglet Nour.” Due to its exceptional quality and nutritional content, this cultivar is considered to be among the greatest fruits in the world and has a high market value [67].

5.1 Biogenesis of different nutraceuticals of date palm

Two major biogenetic mechanisms, the pyruvate-mevalonate and shikimate pathways, are responsible for producing essential oils in date palm. All these pathways originate from photosynthesis, a leading process for the building block of the simple sugar glucose.

The main terpenoidal essential oils, such as monoterpenes and sesquiterpenes, are biosynthesised via the pyruvate-mevalonate pathway [73].

The shikimate pathway is the second major avenue for the biogenesis of essential oils. It is through this pathway that the phenyl alkyl group of essential oils is produced. This process produces chorismic acid via the reaction of shikimic acid with phosphoenol pyruvate following a single stage of dehydration. After being rearranged, the latter product, chorismic acid, becomes prephenic acid, which is then transformed into phenylalanine by decarboxylation and the elimination of ring alcohol. After that, phenylalanine is converted to cinnamic acid which is then converted to benzoic acid. Benzoic acid after a series of steps leads to the production of essential oils [74].

The plastid, cytosol, mitochondria, and peroxisome are the four cell compartments involved in the production of benzoic acids. The biosynthesis of quinic acid, protocatechuic acid, and gallic acids occurs in the plastid directly from the intermediates of the shikimic acid pathway. The carrier utilized to export phenylalanine from the plastid to the cytosol is not yet known. Phenylalanine is utilized to biosynthesis of benzoic acids from the phenylpropanoid pathway [75].

Flavonoids such as kaempferol and quercetin are synthesized through the phenylpropanoid pathway, transforming phenylalanine into 4-coumaroyl-CoA, which finally enters the flavonoid biosynthesis pathway.The first enzyme specific for the flavonoid pathway, chalcone synthase, produces chalcone scaffolds from which all flavonoids derive [76].

The phytosterols such as genistein and diadzein are products of the isoprenoid pathway. The dedicated pathway to sterol synthesis in photosynthetic plants occurs at the squalene stage through the activity of squalene synthetase. Squalene undergoes a series of enzymatic reactions to produce cycloartenol. Different plant sterols are produced by other modifications that take place after the production of cycloartenol. The addition of methyl groups to the sterol nucleus is a critical step. Following the methylation step, further modifications take place to generate the diverse array of plant sterols found in nature [77].

6 Role of date palm in aging-associated diseases

6.1 Role of date palm in aging associated neurodegeneration

Alzheimer’s disease (AD) is a debilitating neurodegenerative condition marked by pathological hallmarks such as the buildup of neurofibrillary tangles within neurons, the deposition of β-amyloid protein (Aβ) outside of neurons, and the death of neurons, which impairs cognition. It is the most common type of dementia in the elderly, characterized by a progressive loss of mental capacity and everyday functioning, and it is characterized by a progressive deterioration of memory and behavior. The illness has been the sixth most common cause of mortality overall and the fifth most common cause of death for people 65 and older. Empirical data validates that amyloid deposition plays a major role in the development of AD. Deposition of these plaques leads to oxidative damage. The production of reactive oxygen species (ROS) has the potential to cause structural and functional impairment via lipid peroxidation (LPO) and protein carbonylation, both of which may play a role in the development of AD. One of the other distinctive changes associated with AD is the rise in acetyl cholinesterase (AChE) in the vicinity of amyloid plaques.

Different experiments were conducted in transgenic mice to determine the positive effects of date fruit in the amelioration of AD. About 2–4% of dates were added to the diet of mice. The effect on LPO and carnolnyl proteins were observed. It was found that lipid peroxidation was reduced to a significant level as shown in Fig. 4. The same concentration of dates also reduced protein carbonylation, thus preventing the development of AD [15]. This antioxidant effect is due to polyphenols present in date palm fruit and seeds like malic acid and gallic acid etc. (structure showin in Fig. 3 [78].

As mentioned above, oxidative stress is the major contributing factor in AD. The effect of the same concentration of dates was also observed on the antioxidant status in mice. It was found that glutathione levels were restored after dietary supplementation with dates [79]. Glutathione peroxidase levels were also replenished by the administration of dates to mice. The breakdown of superoxide anions into hydrogen peroxide, which then breaks down into water and oxygen, is catalyzed by SOD [80]. The activity of this enzyme is also enhanced by date fruit.

The effects of dates on membrane bounded enzymes like AChE were also investigated. The effects was studied for 15 months and it was found that date palm has the ability to regulate the level of this enzyme as shown in Table 3, thus can prevent the AChE mediated progression of AD [79, 81].

Table 3 Mechanism of action of different parts of date palm on the targets linked with aging associated AD
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It is well known that modifications in the membrane lipids cause Na+ and K+-ATPase to be extremely sensitive, which causes a progressive rise in the production of free radicals. It has been shown that oxidative stress-induced decreased Na+, K+-ATPase activity is insufficient to sustain neuronal depolarization, which may be fatal to neurons. The activity of this enzyme is enhanced by different phytochemicals in date palm (fruit and seeds) like ferulic acid, syringic acid, and protocatechuic acid (structures shown in Fig. 3[15, 82].

β-amyloid plaques lead to significant degenerative alterations as well as harm to the cell membrane. Reactive oxygen species production and elevated caspase-3 expression were the causes of these harmful consequences [83]. Subash and coworkers also determined the effect of date fruit supplementation in diet on the buildup of amyloid plaques and there was a notable decrease in the levels of human amyloid β (Aβ) in circulation as shown in Table 3 [15]. Various phytochemicals like myricetin and kaempferol present in the whole fruit are responsible for this effect [84].

The effect on inflammatory mediators was also studied as it is linked with the production of ROS and neuroinflammation. IL-6, and TNF-α speed up the formation of β-amyloid plaques [85]. Essa et al. found that inflammatory mediators were reduced to a noticeable level in transgenic mice (APPsw/Tg2576 to which date palm was administered [86]. This restriction of cytokines is due to the free radical scavenging potential of ferulic acid and protocatechuic acid present in date seeds as shown in Fig. 5.

Fig. 5
figure 5

Role of date palm in aging associated AD. Chlorogenic acid in date palm reduces ROS production by restricting protein carbonylation. Ferulic acid hinders inflammatory mediators and myrecetin reduces caspase-3 activation which reduces Aβ plaques aggregation. Protocatechuic acid improves depolarization by activating Na+ K+ Atpase. This leads to the prevention of AD

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Cerebral ischemia is one of the leading causes of neurodegenerative disorders. So, an effort was made in order to determine the effect of date fruit on cerebral ischemic condition [82]. A methanolic extract of date palm was prepared and administered to transgenic mice. The administration of MDFE for 15 days before surgery resulted in a considerable reduction in neural loss and all biochemical markers. After that, the neuroprotective impact of MDFE (Mtehanolic date flesh extract) was reported by Pujari et al. Considerable improvements in cognition and spatial learning, reduced restlessness, attenuated necrosis, and increased GSH, GST, CAT, and SOD were reported [87]. Majorly, cinnamic acid, caffeic acid which are found in date fruit and seeds and polyphenols have this potent anti-oxidant effect [88].

Parkinson’s disease (PD) is the subsequent prevalent age-related illness since aging causes a decline in dopamine-producing neurons. PD is primarily caused by an elevated production of free radicals, buildup of \(\alpha\)-synculein, an imbalanced quantity of metals, and neurotoxicity [89].

Oxidative damage is a primary cause of Parkinson’s disease (PD) since it triggers the death of dopaminergic neurons. Polyphenols found in dates play a major role in putting a stop to the development of PD. Numerous signaling mechanisms contribute to ROS generation and dopamine neuron death. The signaling pathways for MAPK, JNK, and PIK3 lead to oxidative stress and deregulation of mitochondrial membrane potential [16]. Besides regulating JNK pathway, luteolin scavenges hydrogen peroxide free radicals as shown in Table 4.

Table 4 Dietary phytochemicals of date palm and their exceptional mechanistic role in Parkinson’s disease
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Dopaminergic neurons die when the ERK1/2 and PKB signaling pathways are downregulated, and eNOS activity is unbalanced [90]. Luteolin regulates the ERK pathway, thus preventing the death of dopaminergic neurons as shown in Fig. 6. The SNCA gene encodes α-Syn, a soluble amphipathic protein rich in lysine. This protein can change its structure within plasma membranes, but when its gene undergoes mutations, it causes the protein to aggregate abnormally and produce Lewy bodies (LB) that are rich in α-synuclein protein [91]. EGCG restricts the buildup of α-syn protein as shown in Fig. 6, a major contributor in the progression of PD. Resveratrol also produces the same effect by amplifying the expression of miR-214 [2].

Fig. 6
figure 6

The role of date palm in aging associated PD. Luteolin jn date palm by causing downregulation of MAPK, JNK pathways minimize the oxidative stress. EGCG decreases aggregation of α-syn protein accumulation and prevents the accumulation of lewy bodies. Gallic acid prevents the death of neurons by activating ERK1/2 pathway in PD

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6.2 Role of date palm in aging associated cardiovascular diseases

Globally, CVDs have been the primary cause of death for many years. According to the World Heart Federation, 20.5 million deaths worldwide in 2021 were attributed to cardiovascular disease. In North Africa, the Middle East, Central Asia, and North America, age-standardized incidences of cardiovascular disease (CVD) per 100,000 people for both sexes range from around 7066 to more than 9266 [92]. The primary etiological and risk elements for the onset of heart disease encompass obesity, hypertension, raised low-density lipoprotein (LDL) cholesterol, enhanced low-density lipoprotein (HDL) cholesterol, smoking, and improper nutrition [93]. According to certain research, adopting a nutritious diet regularly is crucial for preventing cardiovascular illnesses. In particular, a diet rich in bioactive substances such dietary fiber, vitamins, sterols, and polyphenols is more advantageous. Apart from fruits, dates are regarded as especially cardio-protective because they have a stronger capacity to scavenge free radicals than other fruits. Dates’ effects on blood vessels have mostly been linked to lipid and cholesterol management, oxidant defense, and inflammatory reactions [94].

In order to evaluate cardio-protective effects of date palm, different researches were conducted in depth that how date palm regulates blood pressure, absorption of cholesterol and fats, and how it increases or decreases the level of lipids in the body [11].

One of the main factors contributing to the progression of CVD is hypertension. Blood pressure is controlled and regulated by several enzymes in the body. Angiotensin converting enzyme (ACE) plays a critical role in this regard. Angiotensinogen, after being converted to angiotensin I becomes a substrate for ACE [95]. ACE is responsible for converting angiotensin I to angiotensin II. Angiotensin II increases systemic vascular resistance by constriction blood vessels which ultimately leads to hypertension [96]. It also potentiates the effects of sympathetic nervous system and enhances the synthesis of another enzyme, aldosterone. All these steps are responsible for increasing blood pressure. Braga et al. found that the polysachharides present in date palm can restrict the binding of ACE enzyme to its receptors as shown in Table 5 (ART1 and ART2) [97, 98]. This leads to decreased systemic vascular resistance which causes relaxation of blood vessels and that’s how blood pressure becomes normal. The synthesis of nitric oxide (NO) also increases and the level of ET-1 vasoconstrictor declines. Moreover, date fruit has a high potassium level and a low sodium content, which may assist in maintaining the electrolyte balance and reduction of blood pressure [17, 99]. Polysaccharides like arabinoxylan and galactomannan which are predominant in date pulp can regulate blood pressure.

Table 5 Different phytochemicals of date palm and their mechanisms, evaluated in light of their outstanding performance on the targets associated with cardiovascular diseases
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Since hypercholesterolemia has a major influence on the development of cardiovascular and cerebrovascular illnesses, it is a substantial risk factor. By studying date palm’s phytochemistry in depth, is has been found that certain chemical constituents in it can also prevent hypercholesterolemia. Countless research conducted on rats and other animals has revealed that dates have positive effects on plasma lipids. Cholesterol level is increased in the blood when its absorption is increased beyond the normal level [100]. Moreover, enhanced reabsorption of bile components and upregulation of cholesterol synthesis are also the contributing factors towards hypercholesterolemia [101]. It is commonly recognized that dietary fibers like cellulose, pectin, and hemicellulose which are mostly present in dates, can bind to cholesterol and triacylglycerols in the colon to aid in their removal, hence reducing blood cholesterol levels [102, 103]. As a result, concentration of lipoproteins in the blood declines, which lowers the risk of atherogenesis [104]. This effect of lipoprotein was co-related with the normal flora of body which increases acetate level in the body, thus preventing the risk of fibrosis and ventricular hypertrophy [105]. Actually, acetate increases the action of 5ʹ AMP-activated protein kinase enzyme which plays a major role in regulating the level of lipids in the body. Date vinegar has acetic acid which increases the mRNA levels of sterol regulatory element-binding protein which ultimately leads to reduction in level of HMGCoA and acetyl-CoA) as shown in Fig. 7 [106]. Β-sitosterol found in date palm has the same effect [107]. The insoluble fibers also regulate the level of T cells and activity of peroxisome proliferator activated receptor (PPAR) which decreases the biosynthesis of lipids and fats, thus reducing the chances of hypercholesterolemia [108, 109]. Ahmed et al. investigated that the low density lipoprotein (LDL) and triacylglycerol lowering effects of date palm are comparable to atorvastatin [110]. A similar effect was seen when an experiment was conducted by El-Kashlan et al. Rats were used in which hypercholesterolemia was induced and then (300–600 mg/kg) of date palm suspension was added in their diet. It was found that cholesterol level was significantly reduced on rats [111]. The effects of date palm polyphenols on destructed cardiac cells were also studied by Alhaider et al. It was observed that these polyphenols have the ability to provoke repairing of damaged cardiac tissues [19].

Fig. 7
figure 7

Some major mechanism by which date palm controls CVDs. Arabinoxylan in date palm causes inhibition of ACE-II. It increases NO production which promotes vasodilation and also decreases the level of sodium in body which plays a crucial role in hypertension. Acetic acid prevents atherosclerosis by inhibiting HMG-CoA and by regulation of PPAR and FXR receptors. By inhibiting COX-1 and COX-II, quercetin prevents myocarditis. Ferulic acid levels of CC34 and CD133 in myocardial infarction

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Some researchers made an attempt to study in detail the role of specific receptors involved in increasing the level of cholesterol and triacylglycerols. A date palm extracts having predominant anthocyanins was used. It was observed that this extract was a highly potent agonist for Farnesoid X Receptor (FXR) as shown in Fig. 6, which plays a major role in restricting the function of cholesterol 7 alpha-hydroxylase (CYP7A1). This enzymes plays a mjor role in biosynthesis of bile acids, thus hypertriglyceridemia can be prevented [11].

The role of anthocyanins in preventing the risk of atherosclerosis has been reported by some researchers which brings light to the fact that date palm anthocyanins can play a major role in targeting certain pathways at molecular level which are involved in atherosclerosis. Basically, anthocyanins restrict the release of inflammatory mediators like IL-6 and vascular cell adhesion protein-I which are responsible for the development of atherosclerosis. This effect was studied in detail by Kraga et al. He found that anthocyanins inhibit the attachment of monocytes to endothelial cells of vessels, which is the major causative agent for atherosclerosis [112].

A study was conducted to investigate the role of date palm in myocarditis. An extract of P. dactylifera was administered to mice and the level of inflammatory biomarkers were determined. C Reactive Protein (CRP) has been shown to be a prognostic marker in lymphocytic myocarditis and also its level is significantly and positively correlated with the extent of myocardial damage. It is also a major biomarker for acute myocarditis [113]. The study revealed that the level of C- reactive protein (CRP) and homocysteine declined to a significant level as shown in Table 5. Date palm extract can prevent stimulation of immune system caused by these inflammatory mediators, ultimately preventing the risk of mycocarditis [18]. Flavonoids, present in the whole fruit like quercetin, rutin, and luteolin can be the phytochemicals responsible for these effects (structures shown in Fig. 2).

Despite the significant advancements in the treatment of myocardial infarctions (MIs), the rate of death keeps rising. The potential of cell-based regenerative medicine was raised by the finding that progenitor cells had the ability to develop into adult cardiac cells CD34 and CD133 play a major role in preventing the progression of myocardial infarction (MI). Their levels were returned to their normal concentration after the administration of date palm extract in mice in which MI was induced [19]. Polyphenols like gallic acid, ferulic acid, hydroxybenzoic acid, vanillic and isovanillic acid which are present in the fruit and seeds play a significant role in this regard as shown in Table 5.

Oxidative stress can play a major role in different cardiovascular diseases. Pathological alterations or physiological abnormalities can boost immune cell function, which results in systemic inflammation marked by elevated reactive oxygen species levels. Date palm phytochemicals, particularly polyphenols and flavonoids can play a major role in putting a stop to oxidative stress. A study showed that Ajwa date can inhibit the release of COX-1 and COX-2 which are accountable for ROS production [28]. Moreover, date palm can also enhance the production of antioxidants in the body like superoxide dismutase thus preventing the risk of inflammatory heart diseases [114].

Disturbances in prothrombin time can lead to various heart problems. Fortunately, date palm also provides a solution for this problem. A research was conducted by Hasson et al. to evaluate the effect of date palm on bleeding time It was found that date palm has the potential to reduce prothrombin time and platelet aggregation [115].

Cardiotoxicity is brought on by high doxorubin dosage, an antibiotic used in the management of cancer. It dysregulates the level of creatine kinase-MB and also minimizes the level of antioxidant glutathione peroxidase. It also causes an increase in the level of cardiac malondialdehyde. All these steps lead to cardiac tissue injury. After using date palm fruit extract, the Doxorubincin-induced damage to the heart tissue was healed [116].

6.3 Role of date palm in aging associated osteoporosis

Reduced bone mass, deterioration of the microstructure of the bone, and an increased risk of fractures are the hallmarks of osteoporosis. The prevalence of osteoporosis shows an increasing tendency in tandem with the ongoing population aging process. Osteoporosis is primarily caused by an imbalance between the production process and resorption of bone, and unrestricted resorption can lead to deterioration of bone quality [117]. One of the main areas of research for bone abnormalities resulting from traumas and osteoporosis is bone repair. These problems require clinical manipulations to restore tissue functions [118]. An experiment was conducted by Marian et. al to determine the effect of date palm fruit extract (1 g/kg) on rats. It was found that serum calcium level was increased as compared to the group to which date palm was not given. The effect on bone density was also investigated. It was found that date palm caused increased bone density in rats as compared to control group [119].

Another experiment was designed by Priyanka et. at to evaluate its effect on bone pain relief due to geriatric diseases. It was found that geriatric patients who were enrolled in the study experienced a notable alleviation of their bone pain because dates contain a lot of minerals that make the bones strong. Selenium, magnesium, and manganese are also present in dates (whole fruit), and these elements are crucial for the development of strong, healthy bones in individuals who are starting to age [120, 121]. This chain of experiments was extended by Reshma et al. who studied the effect of date seed incorporated with chitosan conjugates on the activity of osteoblasts. It was found that dates have the capacity to encourage the formation of osteoblast cells and stimulating the process of osteogenic differentiation [118].

More and more natural compounds, especially flavonoids, are being investigated for their potential as therapeutics to stop bone loss and preserve bone health [122]. An isoflavone found in large amounts in dates, genistein, has two separate effects on bone cells: it can prevent osteoclasts from resorbing bone and promotes differentiation of osteoblasts and bone marrow stromal progenitor cells (BMSCs). By upregulating the ER, p38MAPK-Runx2 pathways, genistein present in the pulp of dates improves the growth of osteoblasts and also promotes their activity as shown in Table 6. By restricting NF-κB pathways and by activating osteoclastogenic inhibitor osteoprotegerin (OPG), it hinders the process of resorption of bone [20]

Table 6 Phytoconstituents of date palm, their mode of action, and considerable effects on aging associated osteoporosis
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As naturally occurring bioactive substances, phytosterols may be able to reduce osteoporosis. Stigmasterol found in fresh pulp of dates can play a major role in this regard. It has been investigated that these phytosterols can enlarge bone mass and can increase the level of vitamin D3 in bones as shown in Fig. 8. They can also improve the healing process of microfractues in bones [25]. By decreasing the activity of TNF-α and RANKL, EGCG found in fruit and seeds of dates can reduce the oxidative stress which can damage bone health as shown in Table 6. It also stimulates alkaline phosphatase in bones, leading to mineralization of bones [2]. Coumarin, which is predominant in dates can escalate the process of differentiation of bones by activating insulin like growth factor-1 as shown in Fig. 8 (IGF-1) [2].

Fig. 8
figure 8

Role of date palm in aging associated osteoporosis. Genistein stimulates the growth of osteoblasts by regulating MAPK-Runx2 pathways. Stigmasterol causes accumulation of vitamin D3 in bones and increases the bone mass. Caffeic acid prevents the bones from oxidative damage by downregulating NOX1. Coumarin causes osteoblasts to differentiate by activating IGF-1. EGCG decreases the production of inflammatory mediators and reduces oxidative stress in bones

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The skeletal system may be shielded from the damaging effects of oxidative stress by the free radical scavenging properties of caffeic acid..By studying genetic of bones in depth, it was found by that caffeid acid can increase the expression of genes involved in osteoblastic activity like bone morphogenetic protein-2 and -7 (BMP-2 and BMP-7) as shown in Table 6. It also has the potential to increase the level of osteocalcin. It can also restric the TNF-α induced bone resorption. It also reduces ROS production by decreasing nicotinamide adenine dinucleotide phosphate oxidase 1 (Nox1) expression by attenuating NF-Kb pathways [123].

6.4 Experimental data showing efficacy of date palm in ARDs

An experiment was conducted to study the effects of date palm on paraquat triggered cortico-nigral neurotoxicity which is responsible for triggering PD. Paraquat is a herbicide which can cause deleterious effects on normal functioning of brain. Out of 25 rats, control group received only distilled water, another group received the herbicide, and two other groups received herbicide alongwith aqueous extract of date palm. Neurobehavioral assessment was conducted using beam walking apparatus (BWA). Lipid peroxidation was assessed by biochemical testing and it was found that the group that was given date palm extract showed a significant reduction in the level of malondialdehyde which is a major marker of oxidative stress. SOD level was also increased. GSH activity was decreased in the group having only paraquat as compared to the group having extract. The xtract group also showed normal cytoarchitecture when compared to the control. These findings confirm that date palm has the potential to ameliorate neurodegeneration and can be utilized in neurological disorders [124].

Selvaraju et.al found that diet rich in date palm fruits improves memory, learning and reduces beta amyloid in transgenic mouse model of Alzheimer’s disease. He took four group of rats. Group 1 and 2 were provided with standard chow diet. Group 3 was given 2% date fruit extract in acetone. Group 4 was given 4% date fruit diet. Results showed that impaired coordinated motor movement were improved in aged amyloid precursor protein sw/Tg2576 mice exposed to a date rich diet. It was also found that 2% and 4% date rich diet improved spatial memory in aged amyloid precursor protein sw/Tg2576 mice. Amyloid precursor protein sw/Tg2576 displayed severely increased anxiety which was attenuated with date supplementation. Learning ability was improved following date supplementation. Circulating levels of both Aβ1–40 and Aβ1–42 were significantly reduced in 2% or 4% dates diet-fed APPsw/Tg2576 mice after 14 months of dietary supplementation [125]. It is evident from this study that the life-threatening complications in AD can be reduced by date palm.

Tariq et. al conducted research for the in vivo evaluation of hypolipidemic and antioxidative effect of Ajwa date seed-extract in high-fat diet-induced hyperlipidemic rat model. As hyperlipidemia and oxidative stress are the major contributors towards CVDs, the study was conducted to investigate the cardioprotective effects of date palm. Out of 30 rats, control group received regular diet. 24 animals received high fat diet, and half of them received Ajwa seed extract. Results showed that the group that received ajwa date extract showed significant reduction in hyperlipidemia. The level of liver damage biomarkers was also assessed and showed a notable decrease in the levels of ALT and AST. The modulation of oxidatives stress related enzymes was also examined. The level of SOD and GSH was significantly elevated in the group having the extract [126]. This study confirms the cardioprotective potential of date palm.

Santhanaraj and cowokers studied the ameliorative potential of Saudi Arabian date fruit varieties against Freund’s complete adjuvant induced arthritis in rats. Out of 4 groups, the first experimental group received methanol extract of Sukkari date fruits. Another group received methanol extract of Ekhlass Almajmaah date fruits. The third group received methanol extract of Abu Minifee date fruits. The fourth group was treated with a methanol extract of Dawee date fruits. Results suggested that the administration of methanolic extracts of all date fruit extracts significantly suppressed the increase in the swelling of both right and left hind paws. These observations suggest that date fruits could suppress the inflammatory reaction in arthritis [127]. Administration of date fruit extracts significantly increased the levels of these antioxidant enzymes when compared to the control group. All these studies confirm the efficacy of date palm in ARDs.

7 Conclusion

Dates are becoming a more sustainable, affordable, and environmentally friendly source of nutrients and energy for our diets, as well as a potentially useful source of functional food components, as evidenced by the numerous scientific studies included in this review that show the interest in date fruit production. The extraction of these bioactive compounds have attracted more attention recently with the goal of using them as useful components in the creation of date-based meals. Various biological activities are linked to the health advantages of consuming the phytoconstituents found in date fruit like cardioprotective, neuroprotective, anti-inflammatory, and antioxidant properties. Because of their remarkable effects on various molecular pathways like regulation of MAPK, JNK, RANKL, NF-KB, restriction of ACE-II, HMG-CoA, and reducing ROS, IL-6, and TNF-α production, date palm has been found to be beneficial and efficient weapon in the battle against ARDs. An increasing number of studies (in vitro, in vivo) are being carried out to illustrate these effects and clarify the biological mechanisms involved, but it can occasionally be challenging to do so due to the large number of factors that are implicated. The lack of clinical data and poor apprehension of ARDs have restricted their use to some extent. Thus, further studies are required to understand the pathogenesis of ARDs as well as the phytochemical profile of date palm by using sophisticated analytical and biochemical techniques which can be helpful in the drug discovery and development against ARDs.