Foods 2020 , 9 , 1147
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is the fact that chronic low-grade inflammation is characteristically experienced during ageing, in a phenomenon known as “inflammaging” [7,8]. Inflammaging increases the risk of pathologic conditions and age-related diseases, and it has also been associated with increased skeletal muscle wasting, strength loss, and functional impairments [9,10]. Inflammaging is characterized by typically a 2 − 4-fold increase in levels of pro-inflammatory cytokines such as TNF- α [11] with values in healthy young populations averaging 3.21 ( ± 4.04) pg / mL [12]. TNF- α is a pleiotropic cytokine, which has been identified as a central mediator of chronic inflammatory responses in many diseases [13]. Signaling through two distinct, membrane expressed receptors, TNFR1 and TNFR2, TNF- α modulates important cellular functions such as proliferation, di ff erentiation, and apoptosis [14,15]. Crucially, TNF- α is not only responsible for mediating inflammatory e ff ects directly, but also through the induction of a pro- inflammatory cytokine cascade [16], earning it the reputation as a “master regulator” of inflammation [14]. Accordingly, targeting TNF- α has emerged as an important strategy for the treatment of chronic inflammatory diseases [17,18]. While undoubtedly a landmark development in terms of patient health, anti-TNF drugs present known limitations in terms of safety, potentially leading to increased bacterial infections [18]. Due to the functional diversity associated with endogenous peptides, many are investigating the potential of exogenous bioactive peptides from food and plant sources for the prevention and treatment of various conditions [19], including inflammation [20,21]. Distinct advantages of peptide-based approaches include pleiotropic functionality, high selectivity and e ffi cacy, as well as favorable safety and tolerability profiles [22]. However, the functional food-based approach has benefitted from the recent advancements of various “omics” techniques. The use of bioinformatics has proven influential in the discovery of bioactive peptides from natural sources [23–25], with health benefits being associated with the presence of multiple bioactive peptides in a single natural peptide network (NPN) / hydrolysate discovered through artificial intelligence (AI) [26]. While there is an opportunity for functional food in immunomodulatory preventative strategies [27,28], there has been limited clinical data to suggest that functional foods can promote good health [29]. Accordingly, there is a need for a characterized and scientifically validated functional ingredient which can attenuate overproduction of pro-inflammatory cytokines and an AI approach is increasingly seen as an opportunity to overcome these issues by deciphering large, complex datasets, such as functional food proteomes [26,30,31]. In order to functionally assess the e ff ects of interventions designed to counteract the development of frailty and its associated state of inflammation, standardized, relevant testing methods are required. These standardized tests include the short physical performance battery (SPPB) which comprise of walking speed of a person over a distance of 4 meters, the ability to stand unassisted (standing balance), the strength of hand grip in both arms, and the ability to stand up from a chair five times without using their arms (repeated chair raise test). All tests have been extensively validated [32]. In subjects > 65 years of age, the SPPB is an e ff ective and inexpensive protocol that can be carried out with minimal equipment. It has been shown to consistently score high for reliability, validity, and responsiveness [33]. It is important to note that hand grip strength does not provide a valid means to evaluate the e ffi cacy of invention therapies to increase muscle function in an older population and as such, is likely to be less sensitive to interventions than lower limb tests, such as the chair sit test. These tests can be useful as predictors of the likelihood of events such as falling. For example, the most strongly associated with falling in woman was gait speed whereas in men, it was the chair test [34]. It may be possible to a ff ect these readouts with daily exercise and a significant increase in protein intake. However, in this study, we did not alter daily activity nor protein intake, indicating that the NPN is acting independent of any lifestyle changes. Apart from its role in the development of frailty [35], TNF- α changes have been linked to key physiological processes that are associated with the development of diseases. Insulin signal transduction can be disrupted, resulting in insulin resistance [1], and subsequent development of Type 2 diabetes. This can also lead to thickening of blood vessels and compromised endothelial barrier strength and thus increases the risk of cardiovascular disease [8]. A state of chronic inflammation has also been associated with the development of atherosclerosis [36]. We thus incorporated measurements
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