Mitochondrial Aging and Natural Products with Protective Potential: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Andrea Deledda.
It was found that mitochondrial activity decreases with aging and that degeneration is linked to the reductions in mitochondria, mRNA transcripts, protein expression, and mtDNA and increased oxidative stress. In particular, reduced protein synthesis hinders protein turnover. The inability to replace damaged proteins may explain why aging is related to reduced mitochondrial function. Mitochondria, the cellular organelles that produce most of the ATP, become dysfunctional during aging. This condition is coupled with inflammation, oxidative stress, and reduced cellular functionalities in every organ. Numerous genes have been linked to aging, with some favoring it (gerontogenes) and others blocking it (genes of longevity pathways). The desire for eternal youth is a constant in the history of humanity. The increased life expectancy in industrialized countries has unfortunately also led to a significant increase in the incidence of age-related diseases (ARDs) such as neurodegenerative diseases, diabetes, cardiovascular diseases, and cancers.
  • phytonutrients
  • epigallo-catechin-gallate
  • curcumin
  • oleuropein ,
  • antioxidants,

1. Senolytic Effects of Oleuropeine and Hydroxytyrosol

Oleuropein (OLE) is one of the most abundant phenolic compounds extracted from olive oil and leaves, and it exerts anti-inflammatory and antioxidant effects related to more general cardio- and neuroprotective actions [83][1]. In vitro studies have shown anti-senescence effects that are mainly mediated by the induction of autophagy [84][2]. Oleuropein and its metabolite hydroxytyrosol (HT) have a powerful antioxidant activity, which could be responsible for the main antioxidant and anti-inflammatory activities associated with the use of olive oil [85][3]. The antioxidant activity of the phenolic compounds of olive oil has been studied through many experimental models. These compounds, including oleuropein, mainly tend to release hydrogen, forming intramolecular hydrogen ionic bonds between the free hydrogen compounds of the hydroxyl group and their radicals [108][4]. Moreover, they contribute to the regeneration of vitamin E and chelate iron ions, which in turn are able to initiate and propagate lipid pre-oxidation [109][5].
The consumption of extra-virgin olive oil is associated with reduced risks for most age-related diseases, including cardiovascular and neurodegenerative diseases (CVD and NDD) as well as some types of cancer [110][6]. Some of these effects are related to epigenetic mechanisms, especially histone modifications that modulate gene expression [110][6]. OLE has antioxidant, anti-inflammatory, antiatherogenic, hypoglycemic, lipid-lowering, and antiviral properties [83,84,85,108,109,110,111][1][2][3][4][5][6][7]. OLE also activates AMPK, a cellular sensor of the energy state that is linked to CR and is an activator of autophagy [86][8]. A portion of OLE is metabolized in humans as tyrosol and HT [87][9], substances with potential antiobesity effects [112][10]. There is extensive literature on HT on its multiple anti-aging and mitochondrial-function-enhancing effects [113,114][11][12]. Furthermore, OLE activates the proteasome system. This system is involved in many essential cellular functions, such as cell cycle regulation, cell differentiation, signal transduction pathways, antigen processing for appropriate immune responses, stress signaling, inflammatory responses, and apoptosis. Thanks to the proteasome, the cell periodically removes aberrant and defective proteins while avoiding the unfolded protein response (UPR), a cellular response related to the inability to degrade defective proteins, which leads to diseases typical of aging, such as neurodegenerative diseases [115,116][13][14]. The UPR and an altered proteasome characterize aging cells and chronic diseases [88,117][15][16].

2. Quercetin

Quercetin (QUE) is a natural flavonoid found in various vegetables. The foods richest in QUE are onions, apples, capers, blueberries, kale, chili peppers, tea, and broccoli. QUE from foods and supplements is bioavailable, in particular if consumed with fatty foods. The most absorbable form is the glucoside found in onions [118][17]. QUE is able to exert many actions on molecular signaling pathways by increasing the transcription of PGC-1α [89][18]. PGC-1α is a transcription coactivator of longevity-related genes that improve cellular antioxidant defenses by promoting mitochondrial activity and simultaneously lowering oxidative stress. In such a way, PGC-1α activation reduces inflammation and insulin resistance [119][19]. The reductions in inflammation and oxidative stress are able to lower senescence in experimental models [90][20]. QUE can modulate pathways associated with mitochondrial biogenesis, the mitochondrial membrane potential, oxidative respiration and ATP anabolism, and the intramitochondrial redox state; moreover, the apoptosis is correctly modulated [91][21]. Mitochondrial biogenesis is fundamental for healthy aging. Healthy immunosenescence allows the repair of cellular structures. Mitochondrial biogenesis can optimize cell function and survival in vitro and in vivo and determines cellular recovery from injuries caused by damaging environmental, pathophysiological, and/or infectious factors [120,121][22][23]. Moreover, QUE has other numerous beneficial effects on human health, acting as an anticarcinogen [92][24], an anti-infective [122][25], and a psychostimulant [123][26]. It also inhibits lipid peroxidation and platelet aggregation as well as the production of enzymes that produce inflammatory mediators such as cyclooxygenase (COX) and lipoxygenase (LOX) [124,125][27][28]. QUE also has a modulating and regulatory action on inflammation and immunity [126][29] and has shown protective effects against dexamethasone-induced skeletal muscle atrophy by regulating the Protein-Βx/Bcl-2 ratio and abnormal ΔΨm, leading to the suppression of apoptosis [127][30]. Moreover, QUE exerts positive metabolic effects on blood pressure, HDL cholesterol, and triglycerides [93][31] and pleiotropic effects on senescent cells [94][32]. Furthermore, QUE can have an inhibitory effect on adipogenesis [128][33]. In clinical trials, QUE is often combined with dasatinib, a tyrosine kinase inhibitor. This combination induces apoptosis in adipocytes [76][34] and increases the senolytic effect [90][20]. QUE, like other CR mimetics such as curcumin and EGCG, can protect the heart from aging and failure [95][35].

3. Epigallo-Catechin-Gallate

Epigallo-catechin-gallate (or EGCG) is a natural compound of plant origin belonging to the group of catechins, i.e., flavonoids from the family of polyphenols. Various types of tea contain ECGC, and the richest varieties are green tea and cocoa products [129][36]. Studies have reported that EGCG has many bioactivities, such as anti-inflammatory [96][37], anti-oxidant [97][38], antiviral [130][39], antimicrobial [131][40], antidiabetic [98][41], antiapoptotic, and anticarcinogenic properties [99][42], activities that underlie its role in cardiovascular and neurodegenerative diseases and metabolic syndromes. EGCG has anti-inflammatory effects by blocking proteins and factors that promote inflammation, in particular NF-kB, MAPKs, STAT, AP-1, and COX-2 [132][43]. In vitro and in vivo studies have shown that EGCG is able to decrease cytokine production, endothelial activation, and neutrophil migration in inflammatory disorders. Tea and ECGC may also reduce cardiovascular risk by improving endothelial function. Moreover, due to its chemical structure, it acts as a scavenger of free radicals and therefore has strong antioxidant properties, preventing the formation of reactive oxygen species and providing protection against oxidative damage [100][44].
EGCG can inhibit the progression of various types of tumors. It is claimed that EGCG, combined with other anticancer drugs (e.g., doxorubicin, cisplatin, and sunitinib) or other natural compounds (e.g., curcumin, ascorbic acid, quercetin, genestein, and caffeine) [133][45], has a synergistic effect for the treatment of hepatocellular carcinoma, breast cancer, and colon cancer [132][43].
It is also known as an important catechin with a neuroprotective effect due to its ability to maintain cellular homeostasis by modulating crucial intracellular signaling pathways implicated in the regulation of cell survival and apoptosis. Due to its ability to suppress the active oligomers of α-synuclein and amyloid aggregation, EGCG has been shown to be potentially prophylactic/therapeutic for Parkinson’s [134][46] and Alzheimer’s diseases, respectively [135][47]. In experimental models, EGCG increased the healthy lifespan in the worm Caenorhabditis elegans. The mechanism of the extension of life appears to work by stimulating the EGCG-induced production of ROS. In addition, EGCG activated mitochondrial biogenesis by restoring mitochondrial function. The increase in lifespan induced by EGCG depends on energy sensors such as AMPK/AAK-2, SIRT1/SIR-2.1, and FOXO/DAF-16 [136][48]. It is assumed that it is possible through the mechanism of para-hormesis, whereby a small dose of a substance stimulates the antioxidant defense mechanisms [137][49]. EGCG as well as curcumin and hydroxytyrosol activate the antioxidant response after being oxidized. This is due to their strong electrophilic nature, which is highly prone to oxidation [138][50]. After their oxidation, EGCGs activate the transcription of genes controlled by the ligands of an antioxidant response element (ARE). This, later renamed the “electrophile response element”, is triggered by a nuclear factor (Nrf2). Activated Nrf2 translocates from the cytosol to the nucleus. The stimulus translator is a protein named Keap1. Keap1 can induce degradation or translocation, depending on the electrophilic nature of the ligand via cysteine residues [139][51].
Many studies have fully demonstrated that EGCG has anti-inflammatory and antioxidant properties and improves lipid metabolism in animal experiments and human studies. EGCG increases longevity-related Sirt1 and FOXO1 protein expression by reducing oxidative stress and ROS generation. EGCG also influences the metabolism of fatty acids by inhibiting the activity of free fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC1) and the catalysis of palmite synthesis from acetyl-CoA and malonyl-CoA and by suppressing the synthesis of free fatty acid (FFA). Thus, the lifespan prolongation mechanism of EGCG-fed rats is related to metabolic effects [140,141][52][53]. The consumption of green tea is associated with a reduced risk of death from all causes. Tang et al. (2015) performed a meta-analysis of five studies including 200,884 subjects, concluding that drinking 2–3 cups (16–24 ounces) of green tea per day is associated with a maximum reduction in the risk of all-cause mortality of approximately 10% [142][54].

4. Fisetin

Fisetin (FIS) is a 3,7,3′,4′-tetrahydroxyflavone bioactive flavonol found in fruits and vegetables such as strawberries, apples, persimmons, grapes, onions, and cucumbers at concentrations between 2 and 160 μg/g. The average human daily intake is estimated to be around 0.4 mg [143][55]. FIS is considered to be an anti-inflammatory, hypolipidemic, hypoglycemic, antioxidant, neuroprotective, anti-angiogenic, and chemopreventive/chemotherapeutic agent [104][56]. Moreover, mitochondrial membrane depolarization and apoptotic cell death were reduced in aging rat brains treated with FIS through increases in the expression of autophagy genes and decreases in the expression of inflammatory genes [105][57]. Interestingly, it was shown that treatment with FIS diminished brain edema and deficit by decreasing the levels of proinflammatory cytokines. Moreover, a reduction in proinflammatory NF-κB signaling was evidenced after FIS treatment [144,145][58][59]. Intriguingly, an in vivo study on aging senescence-accelerated prone 8 (SAMP8) mice proved that FIS prevents cognitive and locomotor deficits. Additionally, three proteins linked to synaptic function were reduced in aged mice compared to young mice, and FIS treatment blocked their reduction almost completely [146][60]. Moreover, FIS significantly reduced ROS generation induced in mouse brains by D-galactose (a senescence accelerator), along with neuroinflammation-related pathways and pro-apoptotic markers [147][61]. Furthermore, FIS is considered an inducer of apoptosis, has a protective effect on the skin and the extracellular matrix, and increases the synthesis of collagen and the availability of glutathione, the main intracellular antioxidant in the human body [148,149][62][63]. FIS can protect LDL from oxidation and modulates SIRT-2, supporting cell repair after radical damage [150][64]. Recently, FIS has been recognized to have a senolytic activity, as it can eliminate senescent cells. A comparison between flavonoids revealed that fisetin was more effective than quercetin as a senolytic agent. FIS, unlike many others, can work as a single senolytic agent to counteract senescence, influencing lifespan and health [106][65]. FIS supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuroinflammation, and neurodegeneration in the rat brain. These physiological effects have been related to its ability to maintain the redox balance, ameliorated mitochondrial membrane depolarization, apoptotic cell death, and impairments in the activities of synaptosomal-membrane-bound ion transporters in the aging rat brain. FIS also acts by upregulating the expression of sirtuin-1 genes and autophagy genes (Atg-3 and Beclin-1) and downregulating the expression of inflammatory genes (IL-1β and TNF-α) and Sirt-2 in the aging brain [105][57]. In a rat model of accelerated senescence induced by D-galactose and in naturally aged rat erythrocytes, FIS supplementation significantly increases antioxidant levels and activates the plasma membrane redox system by suppressing aging-induced increases in ROS levels, eryptosis, lipid peroxidation, and protein oxidation [107][66]. Collectively, these effects favor correct cell functioning and slow aging.

5. Curcumin

Turmeric (Curcuma longa), a rhizomatous herbaceous perennial herb, is a popular medicinal plant from Asia. Curcumin (CUR) is the main natural polyphenolic compound contained in turmeric, along with other secondary curcuminoids [151][67]. CUR is known for its effect against obesity and is particularly effective against ectopic fat. This is due to multiple mechanisms [152][68]. CUR’s effects on aging are progressively emerging. In Eastern populations with high consumptions of the spice curcuma, neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases have low incidences. As in the case of oleuropein and other molecules, this effect appears to be mediated by the action on the UPR, a mechanism that blocks the removal of aberrant proteins and is commonly found in diseases related to aging [101][69]. CUR modulates nutrient-sensing signaling pathways such as sirtuins and AMPK. Therefore, it is able to mimic caloric/diet restriction and increase the benefits linked to mild physical activity. CUR reduces the levels and activity of proteins involved in SASP and stimulates autophagy, favoring the renewal of cellular structures [153][70]. However, its role as a senolytic is not widely accepted [154][71]. Furthermore, curcumin can have an anti-aging effect via telomere protection; anti-inflammatory effects by the inhibition of NF-kB; and antitumor effects by modulating p53 [102][72]. The antioxidant effect of CUR is highlighted by the reduction in malondialdehyde, a marker of peroxidation, and the rise in the total antioxidant capacity, together with metal chelation and the augmented expression of enzymes related to ROS protection [103][73].

6. Senolytic Effect of Magnesium

In addition to the known effects of polyphenols, mineral salts also play a very important role in our health and in the prevention of cellular aging [155,156][74][75]. Magnesium, for example, plays an important role in many of the processes involved in regulating telomere structure, integrity, and cellular function. It is a divalent cation with a critical role in cellular metabolism [157][76] and is found in foods (whole grains, legumes, nuts, fruits, and vegetables) [158][77]. Water can also be a good source of magnesium [159][78]. The clinical relevance and biological significance of magnesium (Mg) has been documented in recent decades. Ferrè et al. demonstrated how Mg acts through the induction of the proinflammatory cytokine interleukin (IL)-1 alpha in cultured human endothelial cells. Indeed, the inhibition of IL-l alpha prevents the low-Mg-induced adhesion of monocytoid cells to the endothelium as well as the upregulation of the cdk inhibitor p21 [160][79]. Mg deficiency induces several characteristics typically associated with endothelial senescence. Mg deficiency, in addition to having a negative impact on the energy production pathway required by the mitochondria to generate ATP, also reduces the threshold antioxidant capacity of the aging organism and its resistance to free radical damage [161][80]. In fact, Mg also acts as an antioxidant against the damage of free radicals in the mitochondria [162][81]. Chronic inflammation and oxidative stress have both been identified as pathogenic factors in aging and various age-related diseases [81][82]. Mg deficiency over time causes the excessive production of oxygen free radicals and low-grade inflammation [162,163][81][83]. Despite the abundant distribution of magnesium in foods, several studies have indicated deficient intake, so much so that in American adults dietary magnesium intake is ∼70% lower than the reference dietary intake (DRI). As an essential mineral, the amount of magnesium within an organism must be continuously regulated, and distribution to individual cells must be ensured [164][84]. In the 1950s, the pathological focus of magnesium for various conditions in humans was introduced, and thereafter the importance of magnesium in physiological processes and in medicine was widely established [165][85]. The magnesium content in adult humans is about 0.4 g/kg, of which more than half is associated with bone connective tissue, while 38% is intracellular, mainly in plasma. Magnesium is mainly stored in bones but is also stored in striated muscle tissues, where it is associated with adenosine triphosphate, phospholipids, and proteins. In addition to carrying out structural functions, magnesium acts as a cofactor in about 300 enzymatic reactions, some of which are fundamental in glycolysis and the beta oxidation of fatty acids [164,166][84][86]. Magnesium in its ionic form (Mg2+) regulates various processes, including antioxidant and anti-inflammatory responses, and plays an important role in the proper functioning of other micronutrients, such as vitamin D [167][87]. Mg2+ participates as a second signaling messenger in the activation of T lymphocytes. Mg2+ deficiency can cause immunodeficiency, an exaggerated acute inflammatory response, a loss of antioxidant capacity, and an anti-inflammatory response by reducing the levels of nuclear factor kappa B (NF-κB), interleukin (IL)-6, and tumor necrosis factor alpha. Furthermore, supplementing Mg2+ improves mitochondrial function and increases the antioxidant glutathione (GSH) content, reducing OS [166,168][86][88]. Therefore, supplementing with Mg2+ is a potential way to reduce inflammation and OS while strengthening the immune system to manage COVID-19 [165,167][85][87]. These narrative reviews address the Mg2+ deficiency associated with worse disease prognosis, the supplementation of Mg2+ as a potent antioxidant, and anti-inflammatory therapy during and after COVID-19 and suggest that randomized controlled trials are needed. Studies show that chronic Mg deficiency can lead to increased oxidative stress and low-grade inflammation, which can be linked to various age-related diseases, including a greater predisposition to infectious disease. Hypomagnesemia is strongly related to oxidative stress markers, contributing to reductions in the expression and activity of antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase) and decreased concentrations of cellular and tissue antioxidants, in addition to increases in the production of hydrogen peroxide and superoxide anions by inflammatory cells [162][81]. Furthermore, an inadequate daily intake of magnesium can make an individual susceptible to infectious diseases. Alzheimer’s disease is one of the leading causes of dementia. This disease is the sixth leading cause of death in the United States, with over 79,000 deaths annually [169,170][89][90]. Some researchers have studied the magnesium balance in patients with mild to moderate Alzheimer’s disease. The study group included 101 older patients (73.4 ± 0.8 years of age; 42 men and 59 women) who were evaluated for total serum magnesium and ionized serum magnesium concentrations and underwent a Mini-Mental State Examination. This study showed that ionized magnesium concentrations were significantly related to cognitive function and not physical function, and individuals with Alzheimer’s disease had significantly lower Mini-Mental State Examination scores (20.5 ± 0.7 versus 27, 9 ± 0.2; p < 0.001) and significantly lower scores for physical function tests. This indicates that there is a correlation between the ionized magnesium concentrations and individuals with mild to moderate Alzheimer’s disease [171][91]. This knowledge shows us how magnesium can be considered a senolytic element, which is worth investigating in order to understand how it can be used to prevent or delay the processes of aging, an activity that magnesium could activate through a possible modulation of the SASP phenotype [172][92]. This could lead to new therapeutic strategies in humans towards related aging pathologies.

7. Selenium

Selenium (Se) is an essential trace element that was identified by Berzelius in 1817 and is involved in a multitude of cellular processes. Selenium was originally identified as a toxic element. However, in 1957, studies showed that selenium (along with vitamin E) was essential for the prevention of liver necrosis [178][93]. This led to the awareness that selenium deficiency was responsible for cell death in skeletal muscle cells, vascular smooth muscle cells, human uterine smooth muscle cells, and cardiomyocytes and was a contributing factor to Keshan disease in humans [179,180][94][95]. Although toxicity at higher levels is still a serious problem, appropriate amounts of this element are required for optimal human health [181][96]. Inorganic selenium is mostly stored in plants via the sulfur assimilation pathway, whereas animals and humans utilize these sources later as vegetables, meats, and dietary supplements [182][97].
In recent years, there has been an increasing interest in compounds containing selenium for their environmental, biological, and toxicological properties and especially for their various activities in the prevention and treatment of diseases, including cancer and infections [183][98]. Small amounts of selenium are protective against liver necrosis in vitamin-E-deficient rats [184][99]. Selenium deficiency has been associated with reduced immunity and chronic inflammation [185][100].
A significant amount of research conducted on cell cultures and animal models indicates that Se plays essential roles in regulating the migration, proliferation, differentiation, activation, and optimal functioning of immune cells, thus influencing innate immunity, the production of B-cell-dependent antibodies, and cell-mediated immunity [173][101]. Recent evidence on the roles of selenium and selenoproteins in the production of eicosanoids, derivatives of PUFAs with 20 atoms of carbon, which are involved in inflammatory responses, suggest that selenium supplementation could mitigate the dysfunctional inflammatory responses that contribute to the pathogenesis of many chronic health conditions [174,186][102][103]. Se has been shown to exert antioxidant and neuroprotective effects by modulating mitochondrial function and activating mitochondrial biogenesis [187][104]. Its biological function is achieved through the insertion of this trace element into a family of proteins known as selenoproteins. Among these, the glutathione peroxidase (GSH-Px) family, which includes six isoforms (GPX 1–6) that have selenocysteine on each subunit, is a family of selenium-dependent enzymes [182][97]. GPX is a component of the antioxidant glutathione pathways that detoxify lipid peroxides and provide protection to cellular and subcellular membranes against the reactive oxygen species (ROS) damage responsible for many diseases such as inflammation, anemia, cardiovascular disorders, and atherosclerosis [175][105]. Mammalian selenoproteins also include thioredoxin reductase (TR 1–3), iodothyronine deiodinases (D 1–3), selenophosphate synthetase (SPS2), methionine-R-sulfoxide reductase 1 (MsrB1), and several thioredoxin-like selenoproteins, some of which may act as safeguards against oxidant-induced toxicity in cells [176][106]. Normal cellular oxygen metabolism in aerobic organisms results in the production of ROS. The impairment of intracellular redox homeostasis leads to the condition of oxidative stress, which can damage biological macromolecules, with consequent alteration of the cellular functions and molecular mechanisms controlling cellular senescence [188][107]. In this context, cellular senescence represents the risk factor for several age-related diseases, including neurodegenerative, oncological, and cardiovascular diseases [189][108]. Therefore, the reduction in ROS and the related cellular damage is the primary objective of the prevention of age-related diseases. Aging leads to reduced cellular functioning and therefore reduced fitness as well as other effects. The protein, lipid, magnesium, phosphorus, selenium, and niacin intakes seem to promote a better quality of life [177][109]. 

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