Plant-derived products used in traditional medicine have provided a veritable cornucopia of effective therapeutic compounds for drug discovery in modern medicine . Several drugs used in the clinic are originally phytochemicals that have been discovered from plant extracts, that is, aspirin from willow bark, taxol from Pacific yew and metformin from French lilac. The term phytochemicals refers to a multitude of small-molecule compounds that have functions in chemical defense against environmental stress and can support the repair of wounds in the plant. Phenolic compounds, for example, flavonoids, stilbenoids and terpenoids that contain a variable number of isoprene units, are the major ingredients in fruits, vegetables and different spices. We have recently reviewed the structures of different terpenoid compounds and their therapeutic indications related to their anti-inflammatory and anticancer potential . There is a plethora of articles on the beneficial medicinal effects of phytochemicals and specific herbal diets, although very few of them have been confirmed in clinical studies. This may be due to several reasons, for example, the low concentrations of specific ingredients in plants, their transformation by gut microbiota, their limited bioavailability and sometimes their toxic side-effects. However, recently the molecular targets of many natural compounds have been identified and they can be viewed as lead molecules for drug design in specific diseases. We will review shortly the current knowledge on the major molecular targets of phytochemicals and furthermore assess their therapeutic potential in age-related diseases and possible effects on the aging process itself that could explain their beneficial effects on health span.
Franceschi et al. were the first authors who postulated that increased proinflammatory status is a driving force in the aging process. They named this state inflamm-aging. During recent years, this theory has received substantial evidence at both the systemic level and the tissue level, for example, in vasculature, brain and liver [4,5,6▪▪]. The aging process is also associated with the activation of the NF-κB system, a major regulator of immune responses [7,8▪]. Adler et al. demonstrated that the NF-κB transactivation motif was the most strongly associated regulatory unit with aging in several human and mouse tissues. Moreover, the upstream inhibitors of NF-κB signaling, AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1), are well known anti-inflammatory factors with beneficial effects on health span and longevity [10–12]. De Magalhaes et al. conducted a meta-analysis of expression profiles and demonstrated that inflammatory and immune response genes become overexpressed during aging. Currently, it is not known whether the age-related increase in cellular NF-κB signaling is the trigger for inflammatory changes in tissues or whether inflammation induces the activation of NF-κB system.
Interestingly, recent studies into cellular senescence have revealed that senescent cells secrete large amounts of proinflammatory factors, a state called senescence-associated secretory phenotype (SASP) [14,15▪]. The secreted inflammatory factors can remodel the extracellular matrix and recruit macrophages to help in the cleansing of possible apoptotic and necrotic cellular corpses. Two recent studies have indicated that NF-κB signaling is required for the SASP in the genotoxic stress  and sustained activation of NF-κB signaling promotes cellular senescence . These observations highlight the role of NF-κB signaling in the appearance of senescent cells. Currently, it is known that senescent cells accumulate in tissues during aging, but their role in the induction of inflammation and in the functional decline of tissues still needs to be clarified. It seems that the aging process itself may involve a low-grade inflammation that could promote the onset of age-related disorders and subsequently this could accelerate the progress of diseases explaining why aging is such a strong risk factor for many degenerative diseases.
MAJOR SIGNALING PATHWAYS TARGETED BY PHYTOCHEMICALS
Polyphenolic phytochemicals are potent antioxidants and in that way they can reduce oxidative stress and subsequently relieve many age-related disorders . Oxidative stress affects also several redox-sensitive signaling pathways, particularly the NF-κB system, which is a crucial participant in inflammatory responses associated with both aging process and age-related diseases, for example, cancer, obesity and diabetes [19▪▪,20▪▪]. Interestingly, two major molecular targets of phytochemicals, that is, nuclear factor-erythroid 2-related factor 2 (NRF2) and AMPK signaling pathways, can also inhibit oxidative stress but, in addition, they can directly repress NF-κB signaling (Fig. 1). These signaling effects highlight the role of phytochemicals in the prevention of diseases linked to the activation of NF-κB signaling.
NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2
NRF2 is a redox-sensitive transcription factor that can induce a large set of cytoprotective genes in the cellular defense against intrinsic and environmental stress [20▪▪]. In the unstressed condition, NRF2 is sequestered in cytoplasm by binding to an inhibitory protein called Kelch-like ECH-associated protein (Keap1), but if there are electrophilic and oxidative stresses, NRF2 translocates into nucleus and generates protective stress response. Phytochemicals can activate NRF2 signaling either by oxidizing cysteine thiols of Keap1 protein or stimulating upstream kinases that subsequently phosphorylate NRF2 protein; both of these modifications release NRF2 protein from the Keap1 inhibitor and induce a cellular defense response [20▪▪,21]. Surh et al. have reviewed in detail several phytochemicals that can activate NRF2 signaling, for example, curcumin, epigallocatechin gallate, resveratrol and sulphoraphane. Many studies have indicated that the activation of NRF2 signaling can combat against oxidative injuries in age-related diseases, particularly in chronic inflammatory states, and thus enhance health span [21,22]. Recent studies have demonstrated that in addition to antioxidant effects, NRF2/Keap1 signaling can also suppress NF-κB signaling via autophagic degradation of the inhibitor of κB kinase (IKKβ)  and in that way repress inflammatory responses and cancer growth (Fig. 1).
AMP-ACTIVATED PROTEIN KINASE
Mammalian AMPK is a serine/threonine kinase that is a member of the evolutionarily conserved family of sucrose nonfermenting-1 kinase (Snf1)/AMPK kinases [24,25]. In plants, Snf1 controls the signaling network that links the maintenance of metabolic homeostasis with stress signaling triggering protection against environmental insults . In mammals, AMPK is a crucial survival factor combating several metabolic stresses, stimulating energy production via glucose and lipid metabolism and reducing energy consuming functions. Moreover, emerging studies have demonstrated that AMPK signaling in hypothalamic neurons controls the food intake and whole-body energy balance, for example, lipid metabolism, under the regulation of several hormones [26▪]. Metformin, an oral antidiabetic drug, is a potent activator of AMPK and effectively lowers blood glucose and lipid levels . Several studies have demonstrated that the activation of AMPK, including conformational changes in its structure and phosphorylation of α subunit (Thr172), can inhibit NF-κB system and suppress inflammatory responses and oxidative stress . We have recently reviewed the signaling pathways through which AMPK can repress NF-κB signaling, for example, by activating SIRT1, Forkhead box O members (FoxO) and peroxisome proliferator-activated receptor-γ co-activator-1α, which can subsequently repress the expression of inflammatory factors .
Many natural compounds are able to activate AMPK, either via upstream kinases or increasing local AMP concentration . For instance, berberine, curcumin, quercetin, theaflavin and ginsenoside Rh2 are potent activators of AMPK signaling. Jeong et al. observed that the traditional Chinese medicine berberine, a plant alkaloid, suppressed proinflammatory responses by activating AMPK signaling in macrophages. Berberine treatment also reduced the expression of inflammatory genes in the adipose tissue of obese db/db mice. It is known that the activation of AMPK has diverse functional responses in different tissues  and by this means phytochemicals could have distinct effects, for example, in gut microbiota, adipose tissue, skeletal muscle and hypothalamus.
NUCLEAR FACTOR-κB: CONVERGING PATHWAYS
The NF-κB system is an ancient, redox-sensitive transcription mechanism. Its activation is linked to several upstream signaling pathways, particularly those recognizing immune attacks and several internal and external danger signals and some growth factors [19▪▪,20▪▪]. The components of NF-κB/Rel complex are arrested in cytoplasm by inhibitory κB (IκB) proteins in nonstimulated cells, but after stimulation IκB proteins are ubiquitinated and break down via proteasomes. Subsequently, the NF-κB complex translocates into nucleus and triggers the expression of a large set of genes, mostly inflammatory genes. Currently, it seems that oxidative stress does not directly activate NF-κB complex, but reactive oxygen species can target redox-sensitive protein phosphatases and kinases that consequently activate NF-κB signaling [20▪▪]. Interestingly, the activation of NRF2 and AMPK inhibits NF-κB signaling and accordingly stimulation of NRF2 and AMPK by phytochemicals can suppress NF-κB-dependent inflammatory responses (Fig. 1). Moreover, SIRT1, a downstream target of AMPK, can directly deacetylate the p65 component of NF-κB complex and inhibit the transactivation capacity of NF-κB complex . It is known that several polyphenols, for example, resveratrol and many other stilbenes, can activate SIRT1 and subsequently inhibit NF-κB signaling .
There is an extensive literature that indicates different phytochemicals, particularly flavonoids and terpenoids, can inhibit NF-κB signaling and prevent several age-related diseases, most of which are associated with inflammatory responses [2,30,31▪▪]. Gupta et al.[31▪▪] have discussed the mechanisms through which different phytochemicals can inhibit NF-κB signaling, including inhibition of upstream kinases, for example, IKKβ; inhibition of IKKβ degradation via proteasomes; blocking of NF-κB nuclear translocation and DNA binding; and inhibition of NF-κB transactivation capacity (Fig. 1). There are plenty of specific effects of terpenoids, for example, artemisinin, celastrol, kahweol, lutein and parthenolide, at inhibiting NF-κB signaling and subsequent prevention against inflammatory disorders and cancers . Commonly, phytochemicals can have a number of targets in different tissues, for example, celastrol targets the Cys-179 in the activation loop of IKKβ and thus inhibiting NF-κB signaling . In addition, celastrol is a potent heat shock protein 90 (HSP90) inhibitor by binding to the cochaperone Cdc37 and also activates heat shock factor 1, which triggers the expression of HSP70. Subsequently, both processes inhibit IKKβ and NF-κB signaling . The diversity of molecular targets for the same phytochemical complicates the understanding of the cellular mechanism of action as well as clarifying their use in therapy.
SIGNIFICANCE OF THE NUCLEAR FACTOR-κB INHIBITION
The NF-κB signaling system is ubiquitously expressed and regulates the expression of over 500 genes that not only control mostly immune responses but also cell proliferation, cancer transformation and some survival mechanisms, particularly against apoptosis [8▪,19▪▪,20▪▪]. NF-κB system is a pleiotropic factor that has not only distinct functions over the lifespan but can also have opposite functional effects, for example, in acute and chronic inflammation. The role of NF-κB signaling is crucially beneficial in acute inflammation, but this can become detrimental in chronic inflammation by increasing oxidative stress and secretion of cytokines, metalloproteinases and other toxins. Moreover, chronic inflammation along with sustained activation of NF-κB signaling can trigger cancer transformation . Recent studies have revealed that the aging process is also associated with a whole-body chronic, low-level inflammation [3,4]. Activation of innate immunity might expose the body to age-related diseases and by this means we could explain many beneficial effects of anti-inflammatory phytochemicals [34–36].
The activation of NF-κB system is associated with many common age-related diseases including cancer, cardiovascular diseases, type 2 diabetes, obesity and neurodegenerative diseases [6▪▪,19▪▪,33]. Inflammation is involved in all of these diseases and currently it is believed that inflammation has an important causal role in the pathogenesis of these diseases [19▪▪,37,38]. For example, obesity is a major risk factor for type 2 diabetes and atherosclerosis. Obesity, especially the lipid deposition into tissues, is associated with the infiltration of macrophages, which then become activated and trigger the secretion of pro-inflammatory cytokines, for example, interleukin-6 and tumor necrosis factor-α (TNFα). Consequently, this local inflammation can induce insulin resistance and lead to systemic symptoms, such as endothelial dysfunction, which then promotes the appearance of cardiovascular diseases. Recent studies have indicated that the activation of NF-κB in macrophages is the crucial inducer of many of the pathological cascades present in age-related metabolic diseases [19▪▪]. The reason why macrophages infiltrate into jeopardized tissues is still unknown, but NF-κB signaling is probably activated, which could trigger the secretion of molecules such as monocyte chemoattractant protein-1 and encourage their infiltration. In metabolic diseases, hyperglycemia is also a potent stimulator of NF-κB signaling and the trigger for inflammatory responses . Interestingly, Gareus et al. demonstrated that endothelial cell-specific inhibition of NF-κB signaling protected apolipoprotein E-deficient mice from atherosclerosis induced by a high cholesterol diet. This observation emphasizes the critical role of NF-κB signaling in age-related metabolic diseases.
Chronic inflammation with the accompanying secretion of TNFα is a well known inducer of cancer-induced cachexia in muscle tissues . TNFα-stimulated NF-κB signaling leads to catabolic reactions in several tissues, not only in skeletal and cardiac muscles. Gupta et al. have discussed the possible role of curcumin, resveratrol and lycopene in the inhibition of NF-κB activation and subsequent prevention of systemic inflammation as a possible treatment for cachexia. Recently, Shadfar et al. demonstrated that oral therapy with resveratrol clearly inhibited the cachexia-induced skeletal and cardiac muscle atrophy in a mouse model.
As discussed above, there is substantial evidence that phytochemicals, particularly flavonoids and terpenoids, can repress the inflammation induced by NF-κB signaling. Moreover, many epidemiological studies indicate that plant-derived, polyphenol-rich diets, for example, the so-called Mediterranean diet , can inhibit inflammatory responses and prevent many chronic age-associated diseases. In summary, it seems that phytochemicals can increase health span, but their role in lifespan regulation still needs to be clarified.
Plant-derived phytochemicals, for example, flavonoids and terpenoids, have anti-inflammatory and anticancer properties. These compounds are ingredients in many remedies of traditional medicine. Recent studies have revealed that phytochemicals can inhibit NF-κB signaling, a major inducer of inflammatory responses. Chronic, low-level inflammation plays a crucial role in the aging process and in the pathogenesis of many age-related degenerative diseases and accordingly phytochemicals are promising compounds for the development of novel drugs for age-related inflammatory disorders. However, the safety and potency of these compounds will need to be tested in clinical trials.
The authors thank Dr Ewen MacDonald for checking the language of the manuscript.
This study was financially supported by grants from the Academy of Finland and the University of Eastern Finland, Kuopio, Finland.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 93).
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