Organismal ageing is associated with increased chance of morbidity or mortality and it is driven by diverse molecular pathways that are affected by both environmental and genetic factors. The progression of ageing correlates with the gradual accumulation of stressors and damaged biomolecules due to the time-dependent decline of stress resistance and functional capacity, which eventually compromise cellular homeodynamics. As protein machines carry out the majority of cellular functions, proteome

more »

... quality control is critical for cellular functionality and is carried out through the curating activity of the proteostasis network (PN). Key components of the PN are the two main degradation machineries, namely the ubiquitin-proteasome and autophagy-lysosome pathways along with several stress-responsive pathways, such as that of nuclear factor erythroid 2-related factor 2 (Nrf2), which mobilises cytoprotective genomic responses against oxidative and/or xenobiotic damage. Reportedly, genetic or dietary interventions that activate components of the PN delay ageing in evolutionarily diverse organisms. Natural products (extracts or pure compounds) represent an extraordinary inventory of highly diverse structural scaffolds that offer promising activities towards meeting the challenge of increasing healthspan and/or delaying ageing (e.g., spermidine, quercetin or sulforaphane). Herein, we review those natural compounds that have been found to activate proteostatic and/or anti-stress cellular responses and hence have the potential to delay cellular senescence and/or in vivo ageing. Molecules 2018, 23, 1219 2 of 25 level, this process is largely achieved via the action of the highly integrated and modular proteostasis network (PN) [7] [8] [9] [10] . During the ageing process, cellular functions deteriorate and compromise these mechanisms, resulting in the impairment of signalling, repair and clearance pathways [11] . This promotes the gradual accumulation of stressors, which correlates with increased disability, morbidity and inevitably death [11, 12] . In accordance with this view, age is the major risk factor for several life-threatening diseases, including cancer, cardiovascular diseases, neurodegeneration and diabetes [13, 14] . Interestingly, ageing can be delayed by either dietary [e.g., caloric restriction (CR)] or genetic interventions, which modulate stress-responsive pathways and thus affect, either directly or indirectly, the impact of stressors and the rate that damaged biomolecules accumulate [15] . Herein, we summarise the most recent findings related to natural compounds that reportedly delay cellular senescence and/or prolong in vivo longevity by activating cytoprotective proteostatic mechanisms and/or the nuclear factor E2-related factor (Nrf2) anti-stress pathway. Overview of the Cellular Proteostatic Modules Downstream to genetic information, there is a world of immense complexity and plasticity, namely the proteome. The entry point in this world occurs via ribosome-mediated protein synthesis that takes place in both the cytosol and the endoplasmic reticulum (ER). As the average proteome size has increased during evolution [16] and the consequences of an unstable proteome can be catastrophic [17], cells have evolved a system that ensures proteome stability, namely the PN [6]. The PN machinery comprises numerous chaperones, folding enzymes, trafficking and degradation components [6]. During conditions of proteotoxic stress, the PN determines the fate of damaged polypeptides by either folding, holding, or degrading [18]. The PN is regulated at organismal, tissue-specific and cellular level [10] . The protein synthesis module along with the machineries involved in sorting and trafficking of newly synthesised polypeptides are key components of the PN and they are complemented by the unfolded protein response of the ER (UPR ER ) and mitochondria (UPR mt ), the intra-and extra-cellular molecular chaperones and a number of compartmentalised proteases, along with the two main degradation branches, i.e., the ubiquitin-proteasome system (UPS) and the autophagy-lysosome (ALP) pathway [9, 10, 19, 20] . A number of short-lived transcription factors are also considered to be part of the PN as they mobilise genomic cytoprotective responses [21] . These, among many others, include heat shock factor 1 (Hsf1), which regulates the levels of molecular chaperones [22] ; forkhead box O (FoxO), which promotes antioxidant and metabolic genomic responses [23] , and Nrf2, which responds to oxidative, electrophilic, and/or proteotoxic stress [24] . Deregulation of the PN functionality is associated with ageing and it is considered a major risk factor for a wide spectrum of age-related protein conformational diseases such as immunological and metabolic disorders, cardiovascular and neurodegenerative diseases and cancer [8, 25, 26] . Moreover, loss of proteostasis is recognised as a hallmark of ageing, indicating the great significance of the PN in cellular functionality and survival [27] . Additionally, several studies have revealed that the activation of proteostatic modules by genetic, dietary (e.g., CR), and/or pharmacological interventions increases organismal health-and/or life-span and delays cellular senescence [15] . For example, UPS activation is able to delay ageing in numerous cellular models [9] . Also, genetic activation of the 20S proteasome leads to lifespan extension and increases stress resistance in the nematodes Caenorhabditis elegans [28]. The Ubiquitin-Proteasome System (UPS) The UPS degrades short-lived, poly-ubiquitinated normal proteins and non-functional or misfolded polypeptides. Ubiquitinated polypeptides are degraded by the 26S proteasome, while non-native (e.g., oxidised) polypeptides are likely degraded by the 20S proteasome via chaperone-mediated targeting [29] . The ubiquitin-proteasome system is composed of ubiquitin-activating, conjugating and ligating enzymes and the 26S proteasome [9] . The 26S eukaryotic Molecules 2018, 23, 1219 3 of 25 proteasome is a protein machine of~2.5 MDa that is composed of a 20S core particle (CP) to which one or two 19S cap regulatory particles (RP) are bound [30, 31] . The 20S CP consists of four stacked heptameric rings (two α-type surrounding two β-type rings) that form a barrel-like structure; the caspase-(C-L; LLE/β1), trypsin-(T-L; LRR/β2), and chymotrypsin-(CT-L; LLVY/β5) like peptidase activities are located at the β1, β2, and β5 proteasomal subunits, respectively. The 19S RP is involved in substrate recognition, deubiquitination, unfolding and translocation of proteins into the 20S CP [9] . The catalytic activity of the proteasome is central to quality control of protein synthesis as non-functional newly synthesised polypeptides originating from cytosolic or ER-bound ribosomes are targeted for degradation to cytosolic or ER-bound proteasomes [ER associated protein degradation (ERAD)] respectively [32] . Proteasomes are also found in the nucleus, where they participate in DNA damage response (DDR) processes and in the outer membrane of the mitochondria, where they execute outer mitochondrial membrane-associated degradation (OMMAD) during the activation of the UPR mt [33] . UPS is also involved in the degradation of mitochondrial fusion/fission proteins [2] and, thus, apart from genome and proteome stability, UPS functionality is also critical for mitostasis maintenance.