The heat shock response is regulated by the heat shock transcription factor HSF1, an ancient and highly conserved transcription factor that responds to phototoxic challenges impairing the cytosolic proteome. The current predominant model of HSF1 regulation is that during normal conditions, HSF1 is sequestered as a monomer in the cytosol by a multichaperone complex consisting of Hsp70, TRiC and Hsp90 (Abravaya et al., 1992; Duina et al., 1998; Zou et al., 1998; Guo et al., 2001; Anckar and Sistonen, 2011; Neef et al., 2014; Zheng et al., 2016; Masser et al., 2019). During heat stress and other phototoxic conditions the chaperones are titrated away by misfolded proteins, releasing HSF1 which is then able to trimerize, and translocate to the nucleus to induce expression of heat shock proteins and other factors required to re-establish cellular protein homeostasis (Anckar and Sistonen, 2011).

In multicellular organisms HSF1 regulates stress adaptation and lifespan, that is tightly linked with behavioral responses. C. elegans senses thermal changes via amphid finger (AFD) neurons that control and direct the thermotactic movement of the animal away from damaging and life threatening temperatures (Mori et al., 2007; Sugi et al., 2011). These same neurons are also involved in the activation of HSF-1 in non-neuronal tissues following heat shock, a process that was shown to be mediated via serotonergic signaling (Prahlad et al., 2008; Tatum et al., 2015) (Figure 1A). Optogenetic activation of AFD neurons is sufficient to activate HSR in the animal, despite the nematode not being exposed to any thermal challenges and led to reduction of aggregated proteins in responding muscle tissue (Figure 1A) (Tatum et al., 2015). This however does not function in isolation as neurons still receive feedback from other tissues, demonstrating that neuronal as well as non-neuronal cells influence behavioral plasticity to environmental challenges (Sugi et al., 2011). Moreover, neuronal control can be overruled by tissues expressing chronic accumulation of aggregated proteins, such that chaperones are still induced despite AFD neuronal dysfunction (Prahlad and Morimoto, 2011). However how this is regulated is currently not known, and may perhaps rely on steroid hormone signaling induced by HSF-1 in non-neuronal tissues (Sugi et al., 2011).

In addition to thermo-sensory neurons, chemosensory neurons are also crucial for organismal responses to thermal challenges: during heat stress conditions, chemosensory neurons activate the GPCR thermal receptor GTR-1 to induce heat shock proteins in non-neuronal tissues (Figure 1A) (Maman et al., 2013). In addition to heat stress, chemosensory neurons also control the activation of DAF-16 but not HSF-1 in remote tissues in response to oxidative stress and pathogenic bacteria (Volovik et al., 2014). Thus, the nervous system has the capability to activate different proteostasis transcription factors in remote tissues of the body with distinct effects on proteostasis. Further work demonstrated that thermal adaptation requires neural HSF-1 in the thermo-sensory circuit to regulate stress resilience, whereas neural HSF-1 through another signal activates DAF-16/FOXO in the intestine to regulate longevity and aging (Douglas et al., 2015). This response initiated by neural HSF-1 is tightly associated with lipid metabolism in the intestine that can modulate membrane fluidity and thermal adaptation of the organism (Chauve et al., 2021). This HSF-1 dependent function through the thermo-sensory circuit is however different from HSF-1’s function in lipid surveillance, where it modulates lipid metabolism and age determination through the nuclear hormone receptor NHR-49 (Watterson et al., 2022).

The unfolded protein response of the endoplasmic reticulum (UPR^ER) in both mammals and invertebrates is regulated by three signaling cascades initiated by ER sensor proteins IRE1, PERK and ATF6. IRE1 is a kinase and endoribonuclease that during phototoxic stress in the ER oligomerizes and autophosphorylates to facilitate excision of an intron from the mRNA encoding the XBP1 transcription factor (Walter and Ron, 2011; Karagöz et al., 2019). This leads to translation of an active transcription factor, known as XBP1s that promotes the upregulation of chaperone and endoplasmic reticulum associated degradation (ERAD) genes (Walter and Ron, 2011).

Many studies using C. elegans as a model system have now established that if the ability to induce the UPR is lost, lifespan is shortened. For example, C. elegans mutants of ire-1 or xbp-1 genes have a shortened lifespan (Henis-Korenblit et al., 2010). In yeast, XBP1 is required for enhanced longevity during dietary restriction and activation of the UPR extends the replicative lifespan (Cui et al., 2015). In C. elegans, activating the UPR pharmacologically increases lifespan in an IRE-1 dependent manner (Matai et al., 2019) and activating the UPR genetically by expression of the XBP-1 active form XBP-1s in the nervous system is sufficient to not only improve lifespan (Taylor and Dillin, 2013), but also increase proteostasis and stress resistance and protects against phototoxic aggregative disease proteins (Figure 1B) (Imanikia et al., 2019a).

As with the HSR, activation of the UPR can be transmitted from 1 cell type to another in C. elegans and mammalian cells (Taylor and Dillin, 2013; Rodvold et al., 2017). In C. elegans this inter-tissue regulation seems to concentrate specifically between neurons and the intestine (Taylor and Dillin, 2013). Transcellular activation from the nervous system to the gut is governed by small clear vesicle release of neurotransmitters including tyramine (Taylor and Dillin, 2013; Imanikia et al., 2019a; Özbey et al., 2020) which leads to increased lysosome activity in the gut and altered lipid metabolism (Imanikia et al., 2019a; 2019b). This increases clearance of amyloid disease proteins at a cell nonautonomous level, and clearly links UPR activation with metabolism.

Activation of the UPR in glial like cells in C. elegans also leads to UPR activation in the intestine of the worm, however operates through a different signaling pathways that relies on neuropeptide release rather than neurotransmitters (Frakes et al., 2020). This indicates that the glial induced UPR pathway signaling to the gut requires a different mechanism (Figure 1B).

Mitochondrial impairment is associated with cellular dysfunction and is considered one of the hallmarks of aging (López-Otín et al., 2023). Impaired mitochondrial integrity induces the mitochondrial unfolded protein response (UPR^mt) which stimulates mitochondrial biogenesis, metabolic adaptations and mitochondria specific survival genes including heat shock proteins (Münch and Harper, 2016; Shpilka and Haynes, 2018). Activation of the UPR^mt as a result of low or reduced amount of mitochondrial function such as through perturbations of the electron transport chain (ETC.) can be beneficial for lifespan extension in C. elegans (Dillin et al., 2002; Durieux et al., 2011; Ito et al., 2021). However, whether the activation of the UPR^mt results in lifespan extension is context-dependent: For example, deletion of the UPR^mt transcription factor ATFS-1 has no effect on C. elegans lifespan, while constitutively active ATFS-1 mutants even reduce longevity (Bennett et al., 2014; Haynes and Hekimi, 2022). Thus, such observations argue against a causal link between the UPR^mt and longevity that needs to be further investigated in the future.

As with the UPR^ER and the HSR, the UPR^mt can also function at a cell nonautonomous level in metazoans (Durieux et al., 2011). Regulation of the UPR^mt across tissues in C. elegans depends on the neuronal release of serotonin and can be triggered by genetically induced perturbations of the, ETC., in neurons (Berendzen et al., 2016; Zhang et al., 2018). Interestingly polyQ protein aggregates in the nervous system can induce the UPR^mt in the intestine, a cross-tissue process that relies on Wnt signaling (Zhang et al., 2018). Similarly, germline cells can also release long-range Wnt signal to induce overactivation of the UPR^mt in somatic tissues, which determines protein aggregation related to Huntington and ALS (Calculli et al., 2021). Within this same context, it was shown that UPR^mt overactivation can also exacerbate toxic protein aggregation (Calculli et al., 2021) indicating that stress response induction is not always associated with beneficial organismal outcomes.

Heat shock protein 90 is one of the major chaperones involved in the regulation of the heat shock response (Zou et al., 1998). It has a wide yet very specific set of client proteins such as transcription factors and signaling kinases (Pearl, 2016). For example, almost every serine/threonine kinase is a client–and hence Hsp90 is involved in many developmental pathways including the cell cycle, Notch, stress and immune signaling pathways (Vowels and Thomas, 1994; Murakami and Johnson, 1996; Tewari et al., 2004; Inoue et al., 2006; Lissemore et al., 2018). Hsp90’s involvement in a multitude of crucial cellular signaling events implicates it in almost every aspect of cellular function and adaptability to environmental challenges, making it an integrator of stress signaling pathways. Therefore, alteration of cellular expression levels (overexpression or knockdown) has impactful consequences for cellular health and survival. Overexpression at the cellular level can suppress protein aggregation, but is also thought to repress the HSF1 transcriptional activity. On the other hand, knockdown or pharmacological inhibition of Hsp90 induces the heat shock response (Zou et al., 1998; Janssens et al., 2019). In multicellular organisms such as C. elegans beneficial consequences of Hsp90 overexpression or knockdown however depends on tissue-context and developmental stage. If Hsp90 is knocked down in specific tissues such as the C. elegans gut, this is sufficient to induce a Hsp70 chaperone response in other tissues and leads to lifespan extension and stress resilience (Miles et al., 2023). The induction of chaperones relies however on different transcription factors in addition to HSF-1 to orchestrate the cross-tissue regulation of stress responses, which includes PHA-4 (van Oosten-Hawle et al., 2013), PQM-1 (O’Brien et al., 2018) and CEH-58 (Figure 2) (Miles et al., 2023). Surprisingly HSF-1 suppresses this cross-tissue activation of Hsp70 expression, which relies on the homeodomain transcription factor CEH-58. The interplay of both HSF-1 and CEH-58 regulating Hsp70 and other stress induced genes is crucial for organismal survival during thermal stress (Miles et al., 2023), albeit molecular details of a likely interaction between both transcription factors needs to be further elucidated. CEH-58 potentially keeps HSF-1 activity in check to prevent overactivation of the HSR at a cell nonautonomous level. Notably, when Hsp90 is knocked down in the neurons, this can result in dauer formation, early larval arrest and decreased lifespan (Somogyvári et al., 2018) rather than lifespan extension, highlighting the importance for tissue-context. Overexpression of Hsp90 in the neurons induces transcellular chaperone signaling (TCS) which upregulates protective chaperones and protein quality control mechanisms in other somatic tissues and reduces the burden of accumulating aggregates in the neurons itself as well as in other tissues. This is thought to be regulated via glutamatergic neurotransmission in the neurons and the intestine. This then induces secreted innate immune peptides and triggers Hsp90 induction in muscle cells (O’Brien et al., 2018), albeit the how this process is regulated in muscle cells requires further investigation (Figure 2). In summary, these observations indicate that Hsp90 acts as an integrator of stress responses that dependent on the level of expression and tissue context determines organismal aging.

The nervous system integrates several input cues that can originate from environmental challenges to intrinsic phototoxic stresses as a result of aggregation-prone disease proteins in different tissues. Depending on the type of phototoxic stimulus, C. elegans utilizes distinct neurons to activate specific stress responses in distal tissues of the body. As mentioned earlier, thermo-sensory AFD neurons activate HSF-1 in response to thermal challenges in somatic and germ cells via serotonergic neurotransmission, particularly leading to upregulation of Hsp70 and Hsp16 (Prahlad et al., 2008). On the other hand, GABA and cholinergic signaling from stimulatory motor neurons impact poly Q aggregation in muscle cells (Garcia et al., 2007). Dependent on where HSF-1 is overexpressed in the nervous system, leads to different outcomes: HSF-1 in neurons uses the thermo-sensory neural circuit to promote heat stress resistance and heat shock protein expression in the soma (Douglas et al., 2015). HSF-1 expression in glial-like cells regulates the organismal heat shock response via neuropeptide signaling (Gildea et al., 2022). Transcellular activation of the UPR^ER appears to use similar routes to induce the UPR^ER in remote tissues. The genetic activation of the UPR^ER via xbp-1s in neurons uses tyraminergic neurotransmission (Özbey et al., 2020), whereas activation of the UPR^ER in glial cells triggers ER resident Hsp70 expression (BiP) to induce ER stress resistance and longevity via neuropeptide signaling (Frakes et al., 2020). The UPR^ER can also be induced by mutating the octopamine receptor 1 (octr-1) in neurons (Figure 1B), however this results in the increased expression of UPR^ER genes IRE-1 and XBP-1 in the rest of the body but not BiP (Sun et al., 2012).

The HSR as well as innate immune response can be activated by olfactory chemosensation pre-emptively inducing the expression of molecular chaperones in the anticipation of an environmental challenge (Ooi and Prahlad, 2017) (Figure 1A). Similarly, chemosensory activation by a specific odorant molecule is sufficient to trigger the cell nonautonomous activation of the UPR ER via TGF-β signaling (De-Souza et al., 2022) (Figure 1B). Thus, stimulating organismal proteostasis via olfactory sensory inputs that lead to activation of specific stress responses and quality control networks may be a promising avenue for therapeutics.

The intestine plays a key role in cell nonautonomous proteostasis through its signaling actions induced by dietary or nutrient status, olfactory cues induced by the nervous system and environmental challenges that challenge protein quality control.

In C. elegans the intestine is employed as one of the central organs for fat storage (Mullaney and Ashrafi, 2009) and pathogenic infection (Kim and Ewbank, 2018), feeding back information to the nervous system and other tissues. As such the intestine is instrumental to communicate crosstalk among different tissues thereby contributing to lifespan regulation. One avenue it achieves this is through its function as a fat storage organ and lipids that when released can act as signaling molecules to mediate tissue interactions and longevity (Imanikia et al., 2019b; Savini et al., 2022). Intestinal expression of XBP-1s is associated with lipid metabolic alterations that increase mono-unsaturated fatty acids (MUFAs), such as oleic acid, promoting longevity and cell nonautonomous proteostasis enhancement (Figure 1B) (Imanikia et al., 2019b). It is thought that MUFAs enriched either through diet or altered fat metabolism contribute to lifespan extension through upregulating lipid droplets and peroxisomes in the intestine (Papsdorf et al., 2023). This results in a modification of the ratio of membrane lipids and ether lipids leading to decreased age-associated lipid oxidation and preserving membrane and cell integrity in the intestine in older worms (Papsdorf et al., 2023).

Lysosomes are key organelles that actively participate in lipid metabolism and lipid break down by lysosomal lipases to release free fatty acids from triacylglycerols stored in the intestine. XBP-1s expression in the gut also induces lysosome upregulation that improves protein quality control processes such as autophagy at an organismal level and reduced aggregation and proteotoxicity of age-associated disease proteins such as amyloid beta in the muscle (Figure 1B) (Imanikia et al., 2019a). Free fatty acids released from lysosomes and other catabolic mechanisms can act as signaling hubs inside cells as well as intercellular signals. For example, intestinal lysosome-derived fatty acids are crucial for tissue-coordination promoting pro-longevity effects and mediating transcriptional activity of hormone receptors in the neurons (Savini et al., 2022). A fat-to-neuron signaling pathway was shown explicitly in a recent study, where the lipase LIPL-4 induced lysosomal lipolysis in the intestine. This increased di-homo-γ-linoleic acid, which binds to the secreted lipid chaperone LBP-3 and induces NHR-49 (PPARα) in the neurons to promote longevity (Savini et al., 2022).

Other intestinal perturbations of proteostasis also contribute to signaling to other tissues, such as reducing Hsp90 levels specifically in the intestine via TCS (Figure 2) (Miles et al., 2023). This activates pro-longevity effects by signaling directly to muscle cells via a signaling cue depending on the membrane associated protein PDZ domain protein TXT-1 in muscle and the transcription factor CEH-58. Interestingly, secreted lipases (TXT-4/TXT-8) are also involved in this process, suggesting that lysosomal lipolysis may be a contributing factor (Miles et al., 2023).

Germline removal, either by genetic interventions or ablation extends the lifespan of C. elegans (Hsin and Kenyon, 1999; Wang et al., 2008). The increased longevity is not the result of sterility, because removal of the gonad in addition to the germline, i.e., the entire reproductive system, has no effect on lifespan (Hsin and Kenyon, 1999). Lifespan extension depends on genes required for germline cell proliferation which produce signals responsible for modulation of longevity, with the best studied gene being glp-1 that encodes for a N-glycosylated transmembrane protein homolog of Notch expressed in germline stem cells (Austin and Kimble, 1987). If glp-1 is mutated, germ cells undergo premature meiosis resulting in long-lived adults that lack a germline (Arantes-Oliveira et al., 2002). This germline removal activates a signaling network regulated by proteostasis transcription factors including DAF-16/FOXO, DAF-12, TCER-1, SKN-1 and PHA-4 (Gerisch et al., 2001; Berman and Kenyon, 2006; Panowski et al., 2007; Ghazi et al., 2009). Similar to ILS mutants, lifespan extension in germline-lacking nematodes depends on DAF-16 activation and its localization localizing to intestinal nuclei suggesting germline-to-intestine signaling (Panowski et al., 2007; Antebi, 2013a; Magner et al., 2013), whereas ILS signaling which originates from neurons, results in nuclear localization of DAF-16 in almost all cell types (Hsu et al., 2003; Antebi, 2013b). Signals from the germline that promote somatic proteostasis significantly decreases once reproduction starts (Shemesh et al., 2013) due to epigenetic changes at stress gene loci that are determined through the germline-controlled demethylase jmjd-3.1 (Figure 1A) (Labbadia and Morimoto, 2015). Reproductive maturity reduces jmjd-3.1 expression and hence demethylation on DNA binding sites required for stress transcription factors such as HSF-1. As a consequence, activation of literally all stress response pathways dramatically drop. Germline lacking worms where this signal from the germline to block jmjd-3.1 expression is absent are more stress resistant even during advanced age (Labbadia and Morimoto, 2015). Interestingly, the proteostasis network promoting pro-longevity genes initiated through germline signaling is significantly different from those induced by other means such as dietary restriction (Shpigel et al., 2019). Germline induced signaling activates a DAF-16 dependent transcriptional network targeted at enhancing the ability to withstand acute stresses, whereas dietary restriction activates the transcription factor PQM-1 that induces a protein quality control network aimed at alleviating chronic stresses related to disease associated protein misfolding (Shpigel et al., 2019). However the signaling cue regulating PQM-1 activation in response to dietary restriction has not yet been determined. Moreover, not all germline induced signals depend on DAF-16 activation. For example, DNA damage in the C. elegans germline evokes innate immune signals that independently of the ILS pathway and DAF-16 activate the ubiquitin proteasome system (UPS) in somatic tissues, enhancing systemic stress resistance and organismal protein quality control (Ermolaeva et al., 2013). Notably, germline-less mutants have increased autophagy activity (Lapierre et al., 2011), which is mediated via the mTOR signaling pathway and the PHA-4 transcription factor that regulates the expression of many autophagy genes (Lapierre et al., 2013).

In addition to DAF-16 receiving signals from the germline to enhance animals stress responses and extend lifespan, active DAF-16 in the soma can also send signals to the germline that determines HSF-1 activation in the germline (Edwards et al., 2021). Thus, the germline is instrumental for pro-longevity signals regulating somatic aging, but reciprocally also receives signals from the soma that have an impact on organismal protein quality control.