Numerous natural products/nutraceuticals derived from food, plants, and other organisms have been evaluated for their beneficial effects for health.

Polyphenols, organic compounds found copiously in plants, have become an incipient field of interest in nutrition in latest decades. A growing body of research shows that polyphenol consumption may play a vital part in health through the setting of metabolism, weight, chronic syndromes, and cell proliferation, and minor risks of chronic and age-related degenerative syndromes. Animal, human, and epidemiologic searches demonstrate that several polyphenols have antioxidant and anti-inflammatory capabilities that could have preventive and/or therapeutic effects for non-communicable diseases, such as cardiovascular disease, neurodegenerative syndromes, cancer, and obesity [31,32,33].

Natural biophenols are a wide group of phytochemicals (over 8000 described so far) found only in the plant kingdom; they are synthesized as secondary metabolites by the plant for defense against the attack by fungi, bacteria, and insects (phytoalexins). They are essential for a diversity of functions in plants, and they are accountable for organoleptic (flavor, color, astringency) and nutritional properties of plant-derived foods [34,35]. Chemically phenolic molecules consist of aromatic ring to which one or more OH− substituents are attached [36]. Despite of their chemical variety, the phenolic complexes are mainly separated into two subgroups: (1) flavonoids and (2) non-flavonoids. The first one is comprised of heterocyclic oxygen which are bonded with two aromatic rings and depends on the quantity of hydrogenation. They can be further divided into six subgroups, i.e., flavanols, flavanones, flavonols, isoflavones, flavones, and other, for example anthocyanins. Meanwhile, the second one contains aromatic rings which are attached to organic acids, like cinnamic and benzoic compounds. Lignans, tannins, stilbenes, and coumarin are also the subgroups of non-flavonoid molecules [37,38] (Figure 1).

Polyphenolic compounds have fascinated scientists internationally for their peculiar activities, such as anti-inflammatory, antioxidant power, and anti-carcinogenic properties [39]. Polyphenolic compounds have been acknowledged for a long time to nutritionists and the numerous scientists, and they are reputed the most potent natural antioxidants [40]. Since ancient times, humans ingest enormous amounts of polyphenolic compounds within vegetable source. These phytochemicals are present in abundance among fresh fruit and vegetables, especially leafy vegetables with a dark green color and in fruit with shades inclining to red (Acai berries), in cocoa, tea, and wine. Polyphenol-rich dietary foods are fruits (grapes, apples, berries, pears, and cherries), cereals, tea, red wine, dry beans, coffee, and chocolate, and can behave as active antioxidants [41,42]. Several fruits are very abundant in polyphenolic molecules, which are responsible for their taste, aroma, and color [43]. Apples, blueberries, grapes, raspberries, blackberries, plums, and strawberries are the most abundant in polyphenolic compounds [31,44]. Anthocyanins are the most frequently occurring polyphenolic compounds in fruit (especially abundant in colored fruit); then hydroxybenzoic and hydroxycinnamic and acids along with their products, tannins, flavonols, and catechins [45,46].

Several natural polyphenols studied for their healthy abilities are curcumin, detected in the tuber of Curcuma longa Linn (family Zingiberaceae) and an element of the curry; epigallocathechins, markedly epigallocatechin-3-gallate (EGCG), the flavanol discovered in green tea; quercetin and myricetin, flavonols found in tea, onions, cocoa, red wine, and in Ginkgo biloba. Other polyphenolic compounds have also been examined, with different results; these comprise tannic, ferulic, ellagic, caffeic acid, rutin, kaempferol, apigenin, fisetin, baicalein, luteolin, piceatannol, rottlerin, silibinin, and malvidin [47].

Most of the natural polyphenols are pigments, typically yellow, red, or purple, and can absorb UV radiation. This ability of natural polyphenols to act as sunscreens can reduce inflammation, oxidative stress, and DNA damaging effects of UV radiation in the skin [48,49]. Marine algae-derived polyphenols have been investigated for their photo protective activities. Phlorotannins, as dieckol, phloroglucinol, fucofuroeckol-A, and triphlorethol-A, isolated from marine brown algae, exhibited prominent protective effect against photo damage, induced by UVB radiation [50,51]. Thring et al. determined anti-collagenase, anti-elastase, and antioxidant activities of 21 plant extracts and correlated them with the total phenolic content. The white tea extract showed the highest inhibitory activity against enzymes as well as the highest antioxidant activity and phenolic content [52]. Strawberry extract containing mainly flavonoids and anthocyanins, protected dermal fibroblasts from oxidative stress induced through H₂O₂ [53]. Studies suggest that polyphenolic extracts can be useful ingredients for both sunscreens and after sun cosmetic products.

In recent decades, special attention has been paid to the anti-proliferative [54,55] or anti-oxidative effect of phenolic compounds [56,57,58,59,60,61,62] with suggestion supporting the probable involvement of polyphenols in the inhibition of various diseases [63,64,65,66,67,68].

Flavonoids are the main antioxidants in the food, and are recognized to preserve against cardiovascular diseases by reducing the oxidation of low-density lipoproteins. Luteolin, apigenin, chrysin, quercetin, datiscetin, morin, myricetin, and kaempferol are some of the most commonly found flavonoids [69]. Numerous studies, both in vitro and in vivo, have revealed that polyphenols have a brilliant capacity to interfere with our cellular signals, and stimulate a bio-regenerating response. This allows the production of other endogenous antioxidants: oxidative stress advances and this turns into an anti-inflammatory and anti-radical actions [32].

The properties of polyphenols are also being assessed in terms of communications with the gut microbiota [70]. Food components are characterized by a two-way communication with microbiota: (i) they can directly control their conformation and (ii) they are catabolized by the intestinal microbes to release metabolites that are more efficient and more easily absorbed than the native molecules [71]. It is valued that only 5–10% of the total polyphenols intake is absorbed in the small intestine and that 90–95% accumulates in the large intestine, where they undergo enzymatic alteration by the gut microbiota [72,73,74]. Since accumulative evidence supports the hypothesis that the gut microbiota are involved in the progress of human syndromes such as obesity, diabetes, metabolic syndrome, cancer, cardiovascular syndrome, and neurodegenerative diseases, it is conceivable that the defense against age-related syndrome development and progression, hypothesized for some anti-senescence mixtures, is related to the properties of such molecules on the microbiota [75]. In turn, the gut microbiota can prompt epigenetic variations, as validated in DNA methylation and histone variation of immune system cells.

The gastrointestinal microbiota of healthy human adults involves primarily bacteria belonging to the phyla Firmicutes and Bacteroidetes and, to a lesser extent, to Actinobacteria and Proteobacteria [71]. Inflammation may product in a higher level of aerobiosis and making of ROS, which deactivate the strictly anaerobic Firmicutes and encourage blooms of facultative aerobes, commonly named “pathobionts,” a condition that is habitually observed in the elderly [76]. The capacity of particular flavonoids, like quercetin, resveratrol, and catechin, to control the gut microbiota has been known in animal models [77]. Interestingly, apples, which are rich in flavonoids, have been related to a reduction in certain inflammation markers and variations in the gut microbiota of healthy mice [78].

Natural polyphenols have been identified as essential plant compounds with anti-aging properties, such as blueberry polyphenols [79], black tea theaflavins [80], and procyanidins from apples [81], resveratrol [82], curcumin [83], and epigallocatechin gallate [84]. Current studies have revealed that polyphenols may modulate a number of phenomena that play a central role in the aging process. These phytochemicals possess a various and interesting pharmacological profile marked by connections with a broad range of biological targets.

Polyphenolic complexes have been revealed to modulate the redox status of cells, to alter cellular signaling, and to help avert the accumulation of injury in long-lived biological molecules such as nucleic acids, lipids, and proteins. This is accomplished both directly, through scavenging of reactive oxygen species, and secondarily, via interaction with transcription factors which coordinate the antioxidant reply. In fact, polyphenols have been revealed to prompt the overexpression of antioxidant enzymes such as superoxide dismutase and catalase [85]. Polyphenol-rich diets are strong antioxidants that function in vitro and in vivo. Polyphenol compounds such as resveratrol, quercetin, and curcumin have a defensive role against oxidative stress injuries [86,87].

Polyphenols can damp down inflammatory signaling, modulate nutrient sensing pathways, and induce the selective apoptosis of senescent cells. Significantly, these biological processes become dysfunctional with age and are relevant in the pathogenesis of age-related syndrome [88,89] (Figure 2). Deciphering the accurate molecular mechanisms of capability of polyphenols in altering biological phenotypes of age-related syndrome is challenging due to the complexity of biological systems, where multiple diverse biochemical pathways can all contribute to a specific phenotypic outcome such as aging [90].

Over the past numerous decades, research in the biology of aging has attempted to discover “biomarkers” of aging. For example, telomere length has been a highly considered a biomarker of aging, as they shorten as individuals grow older. As proposed by Horvath’s efforts to use methylation markers as a biological clock [91,92], high-dimensional protein and/or metabolite profiles might emerge as ideal biomarkers of aging. Several studies suggest polyphenols as modulators of several of these aging indicators.

There is evidence that the accumulation of oxidative mitochondrial DNA damage during normal aging is a risk factor for the development of age-associated neurodegenerative disorders [93]. It has been revealed that the frequency of point mtDNA mutations augmented about 5-fold during an 80-year lifespan [94,95]. The efficiency of mitochondria in producing ATP significantly decreases when humans start aging thereby, allowing the increase of free radicals in these organelles as well as allowing the transit of free radicals through their membranes, in this way damaging other cellular elements [96]. These changes have facilitated to control the increase in oxidative stress and a reduction in energy production [11,97]. Senescence therefore encourages extensive metabolic and bioenergetics modifications [98]. The removal of dysfunctional mitochondria called mitophagy is critical for cell survival and health, particularly for neurons, as impairments might generally happen with aging [99,100].

In fact, two theories of aging regard telomere shortening and exactly mitochondrial DNA (mtDNA) variations and dysfunction. The modern evidence displays the presence of a strong linkage between these two theories suggesting common molecular mechanisms and a complicated telomere-mitochondria interplay during the humans’ aging [101].

As for the mitochondria, several information prove that polyphenols as resveratrol, curcumin, oleuropein, and hydroxytyrosol exert their positive abilities via the improved incentive of mitophagy intermediaries. The molecules stimulate the up-regulation of mitophagy and so increase the degradation of damaged mitochondria as well as the synthesis of new ones. Resveratrol encouraged peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (mtTFA) expression to augment mitochondrial biogenesis and stimulus proteins expression to control the balance of mitochondrial fission/fusion, thus preserving mitochondrial homeostasis [102,103].

Furthermore, all of the mentioned bioactive food molecules also own anti-oxidative abilities, which have a very important biological role in that since oxidative stress is deemed as one of the principal mediators of mitochondrial damage and decay in mitophagy occurring during aging [104]. The efficient elimination of not functional organelles and aggregated proteins is therefore basic to avert raised cellular stress and degeneration. The defensive action of antioxidants, ROS scavengers, and stimulators of mitophagy appears to be the focal mechanism of longevity and of reducing the risk for degenerative syndromes [99,101].

Additional of the most critical elements in aging is the accumulation of genetic damages throughout life. DNA solidity is compromised invariably by exogenous factors such as physical, biological, and chemical injuries. Further, DNA integrity is at risk by endogenous factors such as unrepaired defects in replication (point mutations, translocations, chromosomal gains, and losses), and telomere shortening. Oxidative DNA damage seems to be serious for aging, age-related syndromes and cancer. ROS and products of lipid peroxidation can have an effect on both genomic and mitochondrial DNA, leading to several types of DNA damage: double- and single-strand breaks, intra- and interstrand DNA crosslinks, DNA-adduct formation, DNA base and deoxyribose changes [105]. If the DNA mutations caused by free radicals are not corrected by particular repair mechanisms, these alterations remain even after numerous consecutive replication, transcription, and translation cycles [106].

Shortening of telomeres is a well-known theory linked to aging. As a consequence of the problem of final replication, telomeres shrink in each generation of the cell until they reach a considerable length in the crisis phase of aging [107]. At this phase, cell division reduces speed noticeably, determining slow cell death. This phenomenon is called “replicative mortality.” The cells involved in growth, development, and reproduction (stem cells, eggs, and spermatozoa) synthesize large quantities of the enzyme telomerase, an enzyme involved in preserving the length of telomeric DNA [108]. Instead, most adult cells express little or none of this enzyme, producing these cells to age and ultimately die [101].

Levels of oxidative stress, antioxidants, mitochondrial alteration, inflammation, shortening of telomeres, and gene mutations all have a critical role in defining cellular aging. Studies propose that oxidative stress and the free radicals formed by it play an indispensable role in telomere shortening through reducing the action of telomerase or telomeric repeat-binding factor 2 (TRF-2) levels [87]. Shortening the telomere length harms health and leads to genomic variability and consequently jeopardizes the function of the cell cycle, and the cells enter the aging and apoptotic phases [87,109].

Nowadays, investigators are trying to increase telomerase activity and stabilize telomere length and prolong life by using antioxidant supplements such as polyphenols [110]. Studies and indication propose that polyphenols, with their antioxidant and anti-inflammatory capabilities, can affect telomere length and prevent shortening as far as possible. The antioxidant effects of diet on telomere function show that diet is a significant factor in determining telomere length status. A research indicated that leukocyte telomere length is considerably improved in subjects who take Mediterranean diet (MedDiet), rich in olive oil [111]. Proanthocyanidins and procyanidins are polyphenols found in grape seed extract. These polyphenols are powerful free radical scavengers, own anti-inflammatory capabilities decrease apoptosis, and impede hydrogen peroxide induced chromosomal injury in human lymphoblastic cells. Their free radical scavenging ability is 20 times more actual than vitamin E and 50 times more effective than vitamin C [112]. EGCG, and quercetin with strong antioxidant effect, may impede cardiac myocyte apoptosis by averting telomere shortening and TRF-2 loss [113]. Tea is rich in polyphenols, and other phytochemicals; a cross-sectional study of Chinese men and women found that elderly Chinese men had a helpful association with telomere length [114].

Therefore, studies propose that polyphenols, with their antioxidant and anti-inflammatory abilities, can affect telomere length and prevent shortening as far as probable and thus have powerful anti-aging capabilities [87].

Genetics is clearly significant in determining cellular aging in vitro and in vivo, and part of organismal aging may be dependent on cell division, with total cellular lifespan measured by the number of cell divisions (i.e., generations), not essentially by chronological time. This means that there is an intrinsic process occurring during cell growth which culminates in the interruption of cell division. If cellular age is controlled by a genetically determined counting programmer that controls the number of cell divisions, then it is central to define and understand the molecular pathways and regulation of this mechanism [109]. The studies have recognized the genes that can extend life expectancy and decrease age-related syndromes, including the Klotho gene. Polyphenols can influence intracellular function through activation of the Klotho gene, which induces the transcription factors, insulin-like growth factor 1 (IGF-1), and transforming growth factor (TGF-1β) [115].

Several reports highlighted that dietary supplementation of polyphenols may defend against neurodegenerative, cardiovascular, metabolic syndromes, inflammatory, and cancer by enhancing Sirt-1 deacetylase action. Sirtuins are a class of nutrient-sensitive epigenetic information regulators, including in promoting mammalian health, modulating cellular senescence and lifespan, and Sirt1 is called the longevity gene. Sirt1 is a (NAD⁺)-dependent deacetylase that targets a number of transcription factors, such as fork head box transcription factor (FOXO) 1, 3, and 4, p53, nuclear factor NF-κB, and peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1), moderating in turn a number of cellular stress adaptive responses. Sirt1 can deacetylase p53 in a NAD+-dependent manner to impede p53 transcription, modulating pathways involved in cellular and organismal aging [116]. Significantly, sirtuins are themselves controlled by diet and environmental stress [117,118,119]. Sirtuins impact multiple cellular pathways responsible for regulating gene expression, metabolism, DNA repair, apoptosis, and aging. Activating this pathway can increase life expectancy.

Resveratrol, curcumin, quercetin, tannins, and catechins may also be cited as molecules that increment sirtuins’ actions [120,121,122]. Resveratrol has been found to ameliorate brain health through numerous signaling pathways mechanisms through Sirt-1. The regulatory mechanisms include anti-inflammatory, anti-oxidative, anti-apoptotic processes and autophagy regulation, as well as increases in cerebral blood flow and enhancements in the plasticity of synaptic pathways [123]. Administration of polyphenols quercetin, silymarin, and naringeninin determined restorative actions on cognition and motor coordination in rats. These polyphenols inverted the age-induced insufficiencies in mono-aminergic neurotransmitters and amplified Sirt-1 levels and reduced NF-κB levels in hippocampus [124].

Chronic treatments with catechins, polyphenols present in many dietary foods, as gooseberries, apples, grape seeds, blueberries, strawberries, kiwi, red wine, green tea, cocoa, beer, cacao liquor, and chocolate, increase hippocampal Sirt-1 levels improving cognition in aged rats [125]. Therefore, polyphenols may defend Sirt-1 due to their antioxidant abilities and, in turn, moderate proteins affected by Sirt-1 action [122].

Aging has an important impact on male fertility, but the mechanisms diminishing fertility rate in elderly subjects are still poorly understood. The well-known endocrine route that sustains the progression of spermatogenesis and spermatozoa differentiation [126,127] declines due to steroid genesis defects. In addition, during the aging process morphological and functional alternations affect the testis, semen quality declines with changes in sperm morphology and concentration, and this causes defects in the acquisition of sperm motility [128]. At molecular level, sperm DNA damage, alteration in chromatin architecture mainly due to defective protamination, occurs. In parallel, the deregulation of epigenetic marks (i.e., non-coding RNA profile) in both spermatozoa and seminal plasma may affect the subsequent embryonic development and offspring health [129,130]. Oxidative stress, together with the decrease in antioxidant activity and mitochondria dysfunctions, is the main cause of testicular and sperm damage being ROS notably responsible for spermatogenesis failure, apoptotic loss of both germ and somatic cells, oxidative DNA damage, failure in gene expression and post-transcriptional gene regulation, APT depletion leading to insufficient axonemal phosphorylation in sperm tail, lipid peroxidation, and loss of sperm motility and viability, among the others [131,132].

Therefore, controlled antioxidant supplementation may be useful to preserve sperm quality along the life-span [132,133]. Furthermore, in animal models and humans antioxidants resulted to be useful to preserve semen quality before cryopreservation and after thawing [133] for in vitro fertilization (IVF) [134]. In this respect, several studies reported the effects of polyphenols supplementation on sperm quality parameters. For example, tea polyphenols, known as catechins, decreased the apoptosis rate of spermatogenic cells in rats with experimental varicocele [135]. Consistently, the ad libitum administration of 2% and 5% aqueous extract of green tea for 52 days increased sperm concentration and viability in rats, [136]. In the same study, the authors revealed spontaneous acrosome reaction and morphological changes in testis and epidydimis, with increased cauda epididymis epithelial height and decreased diameter and epithelial height of seminiferous tubules [136]. Similar effects on sperm vitality, motility, acrosome reaction, and morphological parameters in the seminiferous tubules and epididymis were observed following black tea administration [137]. Both green tea and black tea decreased serum levels of alanine transaminase and aspartate transaminase but black tea only increased creatinine levels [137]

Aqueous leaf extract of Moringa oleifera, the “miracle tree” containing a great number of bioactive compounds including polyphenols [138], reduced intracellular ROS production, DNA fragmentation and acrosome reaction without any effect on sperm motility, vitality, mitochondrial membrane potential and capacitation in human spermatozoa in vitro [139]. Quercetin improves the quality of cryopreserved human, dog and bull semen [140,141,142] and exerts protective effects against heavy metals induced oxidative injury in goat sperm and zygotes [143]. In vitro, resveratrol has protective effect on the sperm functions affecting motility, plasma zinc concentration, and acrosin activity in male infertility induced by body weight excess and obesity [144]. It also counteracts the detrimental effects of the polycyclic aromatic hydrocarbon benzo-α-pyrene on human sperm [145], and significantly improves the fertilization capacity in humans and animal models [146,147,148]. A comparative analysis of resveratrol and EGCG has been carried out on thawed boar spermatozoa revealing an increase in the total efficiency of fertilization, for both molecules [146]. Then, polyphenols may be useful to preserve spermatozoa quality parameter with potential application in IVF.