*5.1. Polyphenols*

Plants are prime producers of secondary metabolites, especially polyphenolic compounds, and these are abundantly found in vegetables, fruits, cereals and beverages [112]. Polyphenols have intrigued researchers globally owing to their inherent properties, such as antioxidant potential, and their anticarcinogenic and anti-inflammatory action [113]. These characteristics enable polyphenolic compounds to be useful in the amelioration of various diseases, such as cancer, asthma, microbial infections, diabetes and cardiovascular diseases [114]. Studies have been conducted on numerous polyphenolic compounds, such as resveratrol, proanthocyanins and silymarin. They have been evaluated for their action on animal models subjected to DNA damage, oxidative stress and UV-induced skin irritation [115]. Moreover, these polyphenols, consolidated with sun protection cosmetic products, can effectively shield the skin from UV radiation-associated skin problems and aid in reducing the incidence of skin cancer [116]. Some polyphenols with therapeutic properties have been described below.

Resveratrol (Stilbenes) is a natural polyphenolic compound with antioxidant potential, and is present in the skin of peanuts and grapes [117]. In the last two decades, it has been a prime area of extensive research owing to its application as an anti-ageing ingredient [118]. Additionally, it exhibits anti-inflammatory action and radical scavenging properties, and can act as a chelating agen<sup>t</sup> [119]. Studies have found it to be effective in the treatment of various diseases, including Alzheimer's and cardiovascular disease [120]. Moreover, Bhat et al. stated that resveratrol possesses cancer chemo-preventive potential [121]. It also has a protective action against human skin, which was

confirmed via the study conducted on HaCat cells exposed to nitric oxide free radical donor sodium nitroprusside [122]. Giardina and colleagues conducted an in vitro study on skin fibroblast to assess the e fficacy of resveratrol on the proliferation and inhibition of collagen activity. The result obtained showed a dose-related increase in the proliferation rate of cells and substantial inhibition of collagenase activity [123]. Although it has been claimed that resveratrol has the potential to combat ageing at the cellular level and could be a breakthrough in anti-ageing and geriatric medicine, data supporting this claim in the human context are quite limited [124–126]. It has been well comprehended that resveratrol modulates mitochondrial biogenesis via stimulating Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α), which further slows down the process of ageing and circumvents the chronic diseases [127,128].

Flavonoids (Phlorizin): Few plants have been found to synthesize phlorizin, a type of flavonoid [129]. It has been immensely exploited by pharmaceutical industries for more than a century, while also serving as a platform to evaluate physiological functioning [115]. Several studies have been conducted on the nutritional benefits of phlorizin. In a recent study, the anti-aging effects of phlorizin and phloretin were tested on murine senile osteoporosis models. The study revealed that phlorizin helped in the managemen<sup>t</sup> of the ratio of receptor activator of nuclear factor kappa-B ligand (RANKL) to osteoprotegerin (OPG), which is a biochemical marker of osteoporosis. Phlorizin also reduced the population of osteoclast cells expressing tartrate-resistant acid phosphatase (TRAP) [130]. Phlorizin is found at high concentrations in unripe apples. A preliminary study on human volunteers revealed the beneficial e ffects of unripe apples containing phlorizin in mitigating post-prandial hyperglycemia. The study was carried out on six healthy individuals and revealed that the consumption of unripe apples caused statistically significant reductions in post-prandial glucose response, as well as increased urinary glucose [131]. Mela and colleagues conducted a study to evaluate the e ffects of eight plant extracts as well as their combinations (apple (AE, 2.0 g), mulberry fruit (MFE, 1.5 g), elderberry (EE, 2.0 g), mulberry leaf (MLE, 1.0 g), turmeric (TE, 0.18 g), white bean (WBE, 3.0 g), EE + TE and AE + TE) on post-prandial insulin (PPI) and glucose (PPG) response. The results obtained from the study revealed that extracts of AE, MLE and MFE were e ffective in reducing PPI and PPG response [132]. Hyperglycemia has been reported to accelerate the aging process, which describes the potential of phlorizin in mitigating the e ffects of ageing, thereby improving the quality of life [133]. Many other plant extracts have emerged as potent sources of compounds with antioxidant potential [134]. Metabolites such as silymarin, genistein and apigenin have been found to impact the symptoms of skin ageing positively [91]. Still, no clinical or human trials have been conducted to unveil the real anti-ageing potential of phlorizin.

Apple Polyphenols: Apple is enriched with phytochemicals, especially polyphenols that exhibit immense antioxidant potential [135]. A wide range of polyphenolic compounds is found in apples, such as rutin, chlorogenic acid, catechin phloretin, epicatechin and proanthocyanidin B2 [136]. The daily consumption of apples has been portrayed to reduce the incidence of the occurrence of hypercholesterolemia and cardiovascular diseases [137]. Research studies have suggested that consuming apples can considerably lower the risk of lung cancer, especially in females [138]. Di fferent studies have proven that apple is e ffective in impeding low-density lipoprotein (LDL) oxidation [137]. A study was conducted to evaluate the e ffects of apple polyphenols on the gene expression of CcO (cytochrome c oxidase) subunits III, CAT (catalase), Mth (methuselah), Rpn11, SOD and VIb. The result obtained from the study revealed that apple polyphenols increased the life span of fruit flies by 10%. Moreover, the downregulation of Mth, the upregulation of gene CAT, SOD1 and SOD2, and no significant change in the gene expression of CcO subunits, Rpn11 or VIb, were observed in the fruit flies [139]. Furthermore, concentrated apple juice has neuroprotective potential, confirmed via the studies conducted on normal aged mice and genetically compromised mice. Still, the anti-ageing potential of apple and its underlining mechanisms remain indefinable [51].

Blueberry Extract: Polyphenols are more abundantly found in blueberries than in other fruits and vegetables [140]. The high antioxidant potential of blueberry extracts has been associated with the amelioration of ageing symptoms [141]. Studies sugges<sup>t</sup> that the regular consumption of blueberries can potentially enhance memory-related issues in elderly populations [142]. It has been stated that the consumption of blueberry extract slows down age-related functional and physiological deficits [143]. Galli and colleagues have found that supplementation with blueberry extract reversed the age-linked decline in the heat shock protein (HSP) of the hippocampal in rats [144]. Additionally, blueberries have been found to be e ffective in improving motor and cognitive behavior in aged rat models [145]. The life-prolonging potential of blueberry extracts has also been studied in fruit flies to understand the underlying mechanism. The results obtained from the study revealed that the incorporation of 5 mg/mL of blueberry extract into the diet significantly increased the lifespan of fruit flies by 10% [146].

Tea Catechins and Theaflavins: Tea has emerged as the most preferred beverage in the Asian subcontinent [147]. The beneficial aspects associated with the consumption of tea can be attributed to its inherent compounds, namely theaflavins and catechins [148]. Studies have shown the reduced oxidation of DNA molecules via regular intake of green or black tea [149]. Otherin vivo studies on Drosophila have reported positive results concerning the increase in average life span by theaflavins and catechins [150]. Various published reports have stated that the consumption of oral tea polyphenols, as well as topical treatment with green tea, inhibits UV radiation- or chemical-induced skin tumorigenesis in various animal models [151]. Tea catechins and theaflavins possess both anti-inflammatory and anticarcinogenic properties [148]. Elmets and his team conducted a study to assess the e ffect of tea polyphenol extract on parameters linked with acute UV injury. For this, the skin of volunteers was first treated with green tea extract or its constituents, and treated sites were subjected to two minimal erythema doses of solar simulated radiation. Later, the skin was examined for the biochemical, clinical and histologic characteristics of UV-induced DNA damage. The results revealed that tea extract has a dose-dependent inhibitory e ffect on erythema response induced by UV irradiation. The histologic evaluation also showed a reduced number of Langerhans and sunburn cells [152].

Moreover, tea polyphenol extracts also reduced the DNA damage in the skin. Therefore, researchers stated that tea polyphenol extract could serve as a natural alternative for photoprotection [152]. Chiu and colleagues conducted a study to assess the e ffect of a combination therapy course of topical and oral green tea on the histological and clinical characteristics of photo-ageing. For this study, 40 women with rational photo-ageing were randomized either to a placebo regimen or a combination of 300 mg tea oral supplements (consumed twice daily) and 10% green tea cream for eight weeks. The results obtained from the study did not show any significant di fferences in the clinical characteristics of photo-ageing for the placebo or green tea-treated group. However, a histologic improvement in elastic tissue content was observed in the treated participants [153].

Black Rice Anthocyanins: Black rice is abundant in antioxidants, the supplementation of which has been proven to relieve symptoms in patients who have Alzheimer's [10]. It also has an anticarcinogenic and anti-inflammatory e ffect [154]. It is also rich in anthocyanins, namely peonidin-3-glucoside and cyanidin-3-o glucoside [155]. Zuo and colleagues conducted a study of the potential of black rice in extending the lifespan of fruit flies. For determination, the e ffects on the gene expressions of CAT, Mth, Rpn11, SOD1 and SOD2 were evaluated. The result obtained from the study revealed that the consumption of 30 mg/dL of black rice anthocyanins prolonged the lifespan by 14% of the fruit flies. Moreover, the downregulated gene expression of Mth and the upregulated gene expression of CAT, Rpn11, SOD1 and SOD2 was recorded [156]. Huang et al. also conducted a study on a subacute ageing mice model to assess the e ffect of black rice anthocyanins, and found that black rice anthocyanins exhibit anti-ageing, anti-fatigue and anti-hypoxic properties [157].

## *5.2. Carotenoids*

Carotenoids are vitamin A derivates, such as lycopene and β-carotene, which are known to possess high antioxidant potential as well as photoprotective characteristics [158]. β-carotene and lycopene can moderately improve skin texture [159].

β-Carotene is obtained from various plant sources, such as carrots, mangoes, papaya and pumpkins, among others [160]. It has emerged as a significant carotenoid owing to its characteristics, such as pro-vitamin-A activity, lipid radical scavenging activity and single oxygen quenching properties [161]. β-Carotene has been reported to avert erythema induced by UV rays and possess excellent photoprotection properties [162]. Reports have suggested the association of cellular ageing with low β-Carotene levels in plasma. A study conducted on 68 old-age subjects showed that β-carotene might modulate telomerase activity in older adults [163]. On the other hand, there are well-known ill e ffects of supplementary beta carotene for smokers, leading to the progression of lung cancer. A pioneering study in 1994 was published in the New England Journal of Medicine by the alpha tocopherol, beta carotene cancer prevention study group. This study reported that there was an unexpected observation of a greater incidence of lung cancer in men receiving supplementary beta-carotene, as opposed to those who did not [164].

Lycopene is a red carotene, carotenoid and phytochemical present in numerous fruits and vegetables such as papayas, watermelons, tomatoes, carrots and others [4]. It possesses a high single oxygen quenching potential, but lacks vitamin A activity [165]. Moreover, a study confirmed the role of lycopene in attenuating oxidative damage in tissues. Upon exposure to UV light, it was observed that more skin lycopene was destroyed in contrast to β-carotene [166]. Products of lycopene have also been reported to be e ffective against cancerous cells, in addition to their potential to significantly reduce MMP-1 activity, which is known to degrade collagen [167]. Both lycopene and β-carotene, dominant carotenoids found in human tissues and blood, are known to regulate skin properties [168]. In a very recently published paper, Cheng and co-workers reported that lycopene induces the base excision repair pathway in vitro in A549 cells. This study has opened a molecular pathway, which needs further investigation in vivo and in animal models [169].
