Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: We thank the reviewer for the opportunity to highlight the rationale for our original genetic screen in integration of growth and longevity outcomes. In our original study, we leveraged an RNAi library consisting of ~1000 genes annotated with a metabolic gene ontology to identify genetic elements required for metformin-mediated growth inhibition, to illuminate the physiologic mechanisms that regulate the drug’s known anti-neoplastic and anti-growth proliferative effects. We identified a pathway linking mitochondrial perturbation to improved nuclear pore complex (NPC) and nucleocytoplasmic trafficking function, resulting in reduced mTORC1 signaling and activation of biguanide response element CeACAD10 to induce growth inhibition10. We surprisingly found that improved NPC fidelity is not only required for the growth inhibitory properties of the drug, but were also necessary for the pro-longevity outcomes, suggesting a unified mechanism for both anti-cancer and lifespan extension10. Given our previous success in identifying genetic elements that bridge both the growth inhibitory and pro-longevity mechanisms of the drug, we were interested in identifying other hits from our genetic screen that may be required for both mechanisms, leading to our current study interrogating the role of ether lipid machinery in regulation of biguanide-mediated lifespan extension. We have amended the text in lines 135 to 153 to succinctly describe this transition. 4. Metformin is used in the clinic, phenformin is much less prescribed due to side effect complications. The authors do address reasons they chose to use phenformin in most studies, but the clinical differences between metformin and phenformin underscore how interesting it is to ask the question as to what the metabolic differences might be. A complete analysis is beyond this paper's scope, but simple testing for key findings, even simple lipid droplet impact and fat distribution using metformin (as in Figure 6) could define lipid distribution outcomes as a common feature; or possibly identify a difference. We agree with the reviewer that the potential link between clinical differences and metabolic outcomes of metformin and phenformin administration are alluring to investigate and of upmost importance to clarify. We are currently preparing a manuscript in which we thoroughly dissect the differential metabolic responses to metformin and phenformin in nematodes, and highlight their relationship to stress response, pro-longevity, and growth inhibitory outcomes. [SEP] Justify:

Output: The text contrasts the claim by discussing the mechanisms of metformin in promoting growth inhibition and pro-longevity outcomes without guaranteeing lifespan doubling. It highlights how improved nuclear pore complex fidelity is required for growth inhibition and pro-longevity outcomes, indicating that while there may be an association with longevity, there is no certainty or guarantee of doubling the average human lifespan as the claim suggests.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: We calibrated the setup by aligning the position of the stylus with the location of five projected dots. This calibration allowed us to accurately display a cursor that represented the location of the stylus above the graphic tablet. The projected background was black (depicted as gray in Fig 1A). The feedback had a systematic delay of approximately 40 ms with relation to the hand movement. This value was determined before the start of the study with an interception task (similar to the one described below), in which we compared the stylus position and the target location on trials in which participants indicated they had hit the target. The system delay will have been corrected for in all of the future display and analysis of the data. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 1. Set-up and procedure. A. Set-up of the task: The task image was projected onto a screen that was visible for the subject through a mirror. Recorded movements with a stylus were made on a graphic tablet. The hand and hand-held stylus were blocked from view by the mirror. B. Task procedure: (1) A white dot at the bottom of the screen (diameter = 6 mm) indicated the start location. A red cursor represented the movements made by the stylus (diameter = 6 mm). The trial initiated when the participant moved the cursor to the start location. The goal of the task was to intercept a ball (diameter = 10 mm) moving from left to right or vice versa with a straight ballistic movement. (2) During the adaptation phase there was a temporal perturbation (delay) of 100 ms between the hand and cursor. (3) (TE) was defined as the temporal lead or lag of the stylus (hand) crossing the target’s trajectory line in relation to the target. A lead was denoted by a positive TE, and a lag with a negative TE. (4) In the area within the dashed lines, vision of the cursor was obstructed from view. 1 shows the setup and the procedure for the experiment. The goal of the task was to intercept a target (white dot) on the screen with the cursor (red dot), that followed the movement of the hand. In order to start a trial, the participant had to move the cursor to the starting position (Fig 1B-1). A high-pitched sound marked the start of the trial. [SEP] Justify:

Output: The text does not address the claim regarding urban living and stress levels. Instead, it provides a detailed description of a calibration setup for a study involving stylus movements and a graphic tablet, which is unrelated to the effects of urban living on stress.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Due to their unpaired electron, free radicals are very reactive species and their overproduction can cause damage to all biological macromolecules (DNA, proteins, lipids), resulting in cell alteration. Polyphenols can also act as antioxidants through their capacity to chelate metal ions such as iron. Some of them have antioxidant activity stronger than the reference water soluble vitamin E analogue Trolox, (Fauconneau et al. , 1997). There are increasing evidences that polyphenols may protect cell constituents against oxidative damage and limit various disease associated with oxidative stress. Number of in vitro and in vivo studies have demonstrated that polyphenols intake limits the incidence of coronary heart diseases, in particular atherosclerosis in which low density lipoprotein (LDL) oxidation play a key mechanism in the development of this pathology. Likewise, studies provide evidence for a protective role of a diet rich in polyphenols against chronic diseases including cancers (Anantharaju et al. , 2016) and diabetes (Jung et al. , 2007). In more recent works, polyphenols may provide protection in neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD) (Figure 1). Figure 1: Classification of representative natural polyphenols reported in this 42. Moreover, these polyphenols dose-dependently destabilized preformed fAβs, with overall activity of the molecules examined in the order of: myricetin = morin = quercetin > kaempferol > (+)-catechin = (–)-epicatechin. The same authors demonstrated similar effects for tannic acid on the formation, extension and destabilization of fAβ (Ono et al. , 2004). Rivière et al. (2007) examined the effects of stilbenes on Aβ25–35 fibril formation, using UV-visible measurements and electron microscopy. The inhibitory properties of resveratrol, piceid, resveratrol diglucoside, piceatannol, astringin and viniferin were characterized and compared. Resveratrol and piceid were shown to be the most efficient to inhibit Aβ polymerization (Rivière et al. , 2007). [SEP] Justify:

Output: The text corroborates the claim by indicating that polyphenols may provide protection in neurodegenerative disorders, specifically mentioning Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, it references studies that examine the effects of various compounds on amyloid-beta fibril formation, which is related to protein misfolding, thus linking the study of protein folding directly to these diseases.


Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: We believe that the lipid distribution experiments as suggested by the reviewer will be of critical importance in our next manuscript but is beyond the scope of this manuscript, specifically highlighting the unified importance of ether lipid machinery in both metformin and phenformin-mediated lifespan extension. 5. One naturally wonders whether the over-expression of enzymes ads-1 and/or acl-7 would also be bioactive. I do not think these are essential studies to add, but if the authors have the information they should add it to the paper. We thank the reviewer for this insightful suggestion. We are currently working on developing these genetic reagents for future studies that will finely delineate the specific nodes during ether lipid biosynthesis that may confer pro-longevity and healthspan benefits in the nematode. 6. Figure 1-B-D; E-G seems to share the same WT control for all presented data, authors should indicate that all tests run in the same control experiment if this is the case, and should confirm in methods that same-day WT controls are run in the same experimental test of each study. We apologize for the oversight in clearly highlighting that the lifespan analyses shown in Figure 1B-D;E-G are representative of results from 1 replicate run in the same batch with same-day wildtype controls. We amend in the figure legends for Figure 1 and Materials and methods sections that this is the case (lines 179 to 180) and note that additional replicates with independent wild type controls and all appropriate statistics for comparisons are included as Supplementary file 1. 7. ads-1 and acl-7 mutants exhibit modest increases in longevity with metformin treatment; acl-7 + phen might be different at end stages. Authors do comment that the response is blunted but some note that not all impact of the drug is eliminated should be added. We thank the reviewer for their careful interpretation of our lifespan analyses. We have amended the text in lines 153 to 155 to note that ads-1 and acl-7 mutants may display a modest increase in lifespan with metformin administration, but with a percentage median lifespan increase significantly reduced in comparison to wildtype controls (Supplementary file 1). We also note that although these mutations result in a loss of function of the protein, they are missense mutations, and thus a small amount of residual ether lipid biosynthetic capacity cannot be completely ruled out (see the following comment in the response to point 8 below). [SEP] Justify:

Output: The text contrasts the claim by discussing the results of lipid distribution experiments and the effects of metformin and phenformin on longevity. It mentions that acl-7 and ads-1 mutants show 'modest increases in longevity' with metformin treatment but does not support the idea of biohacking doubling human lifespan as the increases noted are 'modest' and compared to 'wildtype controls.' This suggests that while there may be some positive effects on lifespan, the claim of guaranteeing longevity or doubling lifespan is not substantiated.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: Randomly across trials, the target would move from left to right or vice versa at one of 3 different speeds (17. 5, 22. 5 or 27. 5 cm/s). The three different speeds were used to prevent participants from learning were to intercept at what time, without taking the movement of the target into account. The target path was +20 cm in the y-direction from the starting position. Participants were instructed to intercept the target with a smooth straight movement, and to end their movement well beyond the target’s trajectory line. There were no points rewarded, only when the center of the cursor hit the target, an acoustic signal would sound. After the explanation of the task and a familiarization phase of 10 trials, the experiment started. The experiment consisted of a baseline phase followed by an adaptation phase. During the baseline phase of 80 trials, no additional delays were added to the system. During the adaptation phase, the cursor movement was delayed with an additional 100 ms compared to the hand movement (Fig 1B-2). As participants could not see their own hand, they were unaware of these additional delays. This was verified by verbal confirmation at the end of the experiment. To discourage online corrections we blocked the cursor’s path from view between 0. 5 and 16 cm (see Fig 1B-4) along the y-axis from the starting location. During the baseline this led to an average of 126 ms (95% bootstrapped CI [124-128 ms]) visibility of the cursor before it would reach the trajectory line. As a result, participants could see the cursor cross the target’s trajectory line, but online corrections were minimized. Analysis of responses The data was prepared for analysis with the aid of the R-program [41]. In order to account for any deficient recordings and missing data, the raw position data for the hand and cursor in the x and y direction were interpolated by steps of 0. 008 s and filtered with a bidirectional Butterworth filter (cut-off = 6Hz, sampling rate = 125 Hz). The velocity and acceleration of the hand were computed by calculating the first and second order derivatives of the filtered position data with respect to time. The derivatives were calculated for each time point by dividing the change in position by the change in time over the past two time points (average Δt = 0. 016s). [SEP] Justify:

Output: The text is irrelevant to the claim as it describes an experimental setup involving target interception tasks, cursor movement, and participant responses without providing any information about urban living or stress levels. There are no references to stress, living conditions, or the effects of urban environments, which makes it unrelated to the claim.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: The ability of multiple polyphenolic glycosides and their esterified derivative to interact with metal ions and metal-free/-associated Aβ, and further control both metal-free and metal-induced Aβ aggregation was investigated through western blot assay, transmission electron microscopy, ultraviolet (UV)-visible spectroscopy, fluorescence spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy by Korshavn et al. (2015) The cytotoxicity of the compounds and their ability to mitigate the toxicity induced by both metal-free and metal-bound Aβ were also examined. Thus, verbascoside, natural product present in olive tree and its esterified derivative was shown to regulate the aggregation and cytotoxicity of metal-free and/or metal-associated Aβ to different extents (Korshavn et al. , 2015). A recent study demonstrated that trans ε-viniferin disaggregated Aβ1–42 with better efficiency than resveratrol (Vion et al. , 2017). These effects can be partially explained by interaction of polyphenols with amyloid peptide. Thus, a non-covalent complex between ε-viniferin glucoside and Aβ was observed by electrospray ionization mass spectrometry (Richard et al. , 2011). Moreover, in a recent review, rosmarinic acid was described to also directly interact with Aβ1–42 (Taguchi et al. , 2017). These molecules interfere with β-sheet to exert their activity (Francioso et al. , 2015). But polyphenols effects on metal ions contribute also to their properties. An assay using 2-(5-Bromo-2-pyridylazo)-5-[N-propyl-N-(3-sulfopropyl)amino]phenol disodium salt dihydrate (5-Br-PAPS) allowing the examination of Zn(II) and Cu(II) complexation showed that gallic acid, EGCG, and curcumin are multifunctional agents (Chan et al. , 2016). Many in vivo studies demonstrated in different AD models that polyphenols inhibited amyloid deposits in brain mice. [SEP] Justify:

Output: The text corroborates the claim by discussing the impact of polyphenolic glycosides on Aβ aggregation, which is a critical factor in the pathology of Alzheimer's disease. It references multiple studies and compounds that interact with Aβ, underscoring the importance of understanding protein folding and aggregation in the context of neurological diseases. The mention of amyloid deposits being inhibited by polyphenols in various AD models further supports the relevance of protein folding research in understanding such diseases.


Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: The authors show that expression of ether lipid biosynthesis genes does not increase with biguanide treatment (Figure 2 —figure supplement 2; Results lines 305 – 313), and FARD-1::RFP levels decrease with phenformin treatment (Figure 2 —figure supplement 2M) and suggest that "post-translational negative feedback of ether lipids on the ether lipid biosynthetic pathway, as has been previously reported" (Results lines 311 – 313)--a citation for these results should be added. We apologize for this oversight and have included the citation for Honsho, et al. 2010 in lines 312 and 6481. 12. These data argue against phenformin and fard-1 overexpression triggering downstream pathways in the same way. Although fard-1 oe increases lifespan in a manner that is not additive with phenformin treatment (Figure 5 A and B), fard-1 overexpression evidently does not trigger the same negative feedback mechanism, as overexpressed FARD-1 levels shown in Figure 2 —figure supplement 2 M appear to be high in vehicle controls, and are lowered with phenformin treatment. If both fard-1 overexpression and phenformin treatment signal similarly to trigger a post-translational negative feedback mechanism (which would presumably be important for lifespan extension), one would expect similar FARD-1 levels in fard-1 oe animals with and without phenformin treatment. It is possible that fard-1 overexpression simply overwhelms – or is insufficient to trigger – negative feedback mechanisms. Data showing overexpressed fard-1 mRNA and FARD-1 protein levels vs. endogenously expressed fard-1 and FARD-1, with and without biguanide treatment, would help clarify these seemingly paradoxical results. We thank the reviewer for this important suggestion, and we have performed the experiment as suggested. We include in Figure 5G-H qRT-PCR analysis of wild type and fard-1(oe3) animals treated with phenformin, evaluating the RNA expression levels of endogenous fard-1 (using qRT-PCR primers probing for the native 3’ UTR of fard-1, Figure 5D). [SEP] Justify:

Output: The text contrasts the claim by discussing the effects of phenformin and fard-1 overexpression on lifespan. Specifically, it indicates that fard-1 overexpression does not trigger the same lifespan extension mechanisms as phenformin treatment, as overexpressed FARD-1 levels decrease with phenformin treatment. This suggests that the supposed biohacking methods do not guarantee longevity or doubling the average human lifespan, instead presenting a more complex interaction that does not support the claim.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: Of the 20 participants, one was excluded from the study due to recording issues with the graphic tablet. For the remaining 19 participants (3040 trials), we inspected the movement speed during the movement before the target’s trajectory line was reached. As we had instructed participants to move through the target’s trajectory line, we discarded trials in which subjects moved through it with very low speeds (v < 20 cm/s). Two other participants were removed from the study because the systematically failed to comply with these instructions of the task (in >25% of their trials). For the 17 included participants we removed the trials in which this was the case (2. 1% of the remaining trials discarded). We calculated the Error (TE) on each trial. TE was defined as the temporal difference between the hand and the target reaching the same point on the target’s trajectory line (Fig 1B-3). The TE was baseline-corrected by subtracting the average TE of the last 30 baseline trials for each participant in order to make sure any biases within subjects were removed. Positive values denoted the hand leading the target and negative values denoted the hand lagging behind the target. In order to hit the target when a temporal perturbation was applied, subjects would have to start leading the target with their hand. The TE was used to calculate the for each participant. Score was calculated by fitting a two-state line through the TE data points of the adaptation phase (see Fig 2), with intercept 0. The slope (a) and asymptote (b) that resulted in a minimum residuals were each first normalized across subjects and then summed. Score gave us the ability to reward both speed and final level of adaptation. High values of the score meant that participants were relatively fast and had more complete levels of adaptation. Low values meant that participants adapted slowly and incomplete. Although we had the possibility to analyze slope and asymptote separately (to see if speed or final level of adaptation was affected differently) we only had a few participants with higher slopes, which made this analysis more difficult (see Table 1). We therefore decided only to focus on the Adaptation Score. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 2. Adaptation score examples. The dots represent the moving averages (window = 4 trials) of two example participants. [SEP] Justify:

Output: The text is irrelevant to the claim as it discusses a study on movement speed and adaptation scores in a psychological or performance context, with no mention or implication regarding urban living or its effects on stress levels.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Thus, it was shown that curcumin, injected peripherally into aged APPsweTg2576 mice crossed the blood brain barrier (BBB) and bound to amyloid plaques, reducing amyloid levels and plaque formation decisively (Yang et al. , 2005). Another study, using in vivo multiphoton microscopy, demonstrated that curcumin crossed the BBB and labeled senile plaques and cerebrovascular amyloid angiopathy in another model of AD, APP(Swe)/PS1dE9 mice. Moreover, systemic treatment on these mice with curcumin for 7 days cleared and reduced existing plaques (Garcia-Alloza et al. , 2007). When these same mice were fed during 6 months, between 3 and 9 months of age, with polyphenol-rich grape seed extract, containing gallic acid, catechin, epicatechin and proanthocyanidins or with curcumin, a decrease of Aβ deposition was observed (Wang et al. , 2009). In the same way, when APPsweTg2576 were fed with myricetin, nordihydroguaiaretic acid (NDGA) or rosmarinic acid for 10 months from the age of 5 months, amyloid plaques in mice brains were significantly decreased (Hamaguchi et al. , 2009). Resveratrol administrated by food at AD Tg19959 mice during 45 days also diminished plaque formation in a region specific manner, in medial cortex, striatum and hypothalamus (Karuppagounder et al. , 2009). Polyphenols and tau Some polyphenols were also shown to inhibit phosphorylation and aggregation of tau. For example, EGCG was described to bind tau in this phosphorylation site with high affinity and to modify tridimensional structure of tau, leading to inhibition of its aggregation (Gueroux et al. , 2017). A recent study showed that, by direct interaction with tau, rosmarinic acid prevented β-sheet assembly (Cornejo et al. , 2017). Grape seed-derived polyphenol extract seems to potentially interfere with the assembly of tau peptides into neurotoxic aggregates (Wang et al. , 2010). [SEP] Justify:

Output: The text corroborates the claim by discussing the effects of various compounds on amyloid plaques and tau aggregation, which are crucial in the pathogenesis of Alzheimer's disease. It highlights how curcumin and other polyphenols can influence protein folding processes and potentially alleviate disease symptoms, thus supporting the importance of studying protein folding mechanisms in relation to Alzheimer's disease.


Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: These results indicate that FARD-1 overexpression indeed reduces native fard-1 expression by ~40%, and that biguanide treatment does not additively reduce fard-1 expression even further. Interestingly, biguanide treatment appears to reduce the expression of exogenously overexpressed fard-1 by about ~60%, consistent with the reduction in RFP-tagged protein levels shown in Figure 2 —figure supplement 2M. We speculate that the discrepancy in feedback mechanisms between the endogenous and exogenous fard-1 transcripts is likely due to the design of the overexpressor, as the fard-1(oe) strains in this manuscript all utilize a synthetic unc-54 3’ UTR to enhance permissive expression in all C. elegans somatic cells, and likely maintain expression as a multicopy integrant in the genome, thus overwhelming negative feedback mechanisms. Indeed, several studies have suggested that the 3’ UTR structure of several mRNAs mediate negative feedback loops to finely tune protein expression patterns12,13. Combined, these results suggest that FARD-1 overexpression and biguanide treatment regulate endogenous fard-1 levels through similar mechanisms, but the differential UTR utilization and potential for multicopy integration may explain their distinct lifespan promoting dependencies. We discuss the significance of these results in lines 650 through 655. 13. Figure 3D (D-H) RNAi of three fatty acid desaturases (D-F) two fatty acid elongases (G and H) …blunt phenformin-mediated lifespan extension in wild type worms. fat-1 RNAi extends lifespan, phen treatment brings this close to wt +phen, and there is no significant difference wt+phen vs. fat-1(RNAi) + phen; it might be technically reasonable to indicate the response is blunted (percent increase) but fat-1 does not appear to be all that impactful on longevity. These data do not impress regarding the importance of fat-1 in phenformin outcome; the discussion should be toned down or eliminated. We thank the reviewer for their careful interpretation of the lifespan results for fat-1 RNAi. We agree that there does not appear to be a meaningful or interpretable interaction between fat-1 and biguanide action in longevity, and so we have removed the fat-1 data and reference to it from this version of the text. [SEP] Justify:

Output: The text contrasts the claim by providing data that suggests no significant relationship between certain genetic factors and longevity enhancement. It states that 'fat-1 does not appear to be all that impactful on longevity,' indicating that the overexpression and treatments mentioned do not guarantee or substantially contribute to increasing lifespan, which goes against the idea of biohacking doubling the average human lifespan.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: In order to calculate the Adaptation Score, the slope (a) and asymptote (b) were normalized across subjects and then summed for each participant. For P1 we were able to fit an exponential function, while for P2 the adaptation an exponential could not be fit. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageTable 1. Pre-normalized slopes (a) and Asympotes (b) and adaptation scores for all the subjects. is often quantified by fitting the exponential function (exp(−τ ⋅ trial)) and calculating the time constant τ of this function. However, our pilot data showed we could not fit this function for each participant, as some participants adapted in a non-exponential way. There were 11 participants for which we were able to calculate the exponential function. In order to verify our method of quantifying adaptation, we compared τ of this exponential to our and confirmed our main finding (see below) using τ instead of the Adaptation Score. Movement onset was calculated according to algorithm A as proposed by [42] on the tangential velocity of the hand (tolerance range = 10%). The average movement speed (Mv) between the time of movement onset and the crossing of the target’s trajectory line was calculated. We also calculated the absolute movement angle (Ma) from the y-axis, calculated between movement onset and movement onset + 200 ms. In order to identify the relationship between different kinematic variables and Error, we analyzed the relationship between Mv, Ma, movement time (T), absolute target velocity (tv), (σMv)2- group (LOW = 0; HIGH = 1) and their interactions on TE. We did this with a for both the baseline and adaptation phase (lambda = 0. 6). can be used with multicollinear variables. We calculated bootstrapped confidence intervals (95%). LASSO regression includes a penalization. Confidence intervals can therefore only provide information about the variability regarding β for each predictor, but they should be interpreted with caution when it comes to the significance of the predictors. Additionally, we performed another analysis with this technique in order to verify the respective contributions of movement speed variability ((σMv)2) and movement angle ((σMa)2) and their interaction on the Adaptation Score. [SEP] Justify:

Output: The text is irrelevant to the claim as it discusses the details of a scientific study regarding adaptation scores, movement variables, and statistical analysis without any mention of urban living or stress levels. Thus, it does not provide any support or contradiction to the claim.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Same authors showed that oral administration of this extract significantly decreased the development of AD type tau neuropathology in the brain of Thy-1 mutated human tau (TMHT) mouse model of AD through mechanisms associated with attenuation of extracellular signal-receptor kinase 1/2 signaling in the brain (Wang et al. , 2010). Moreover, polyphenols induce disaggregation of aggregated tau (Duff et al. , 2010) and modify ultrastructure of paired helical filaments isolated from AD brains, decreasing enlargement of filaments (Ksiezak-Reding et al. , 2012). Both daily intraperitoneal injections between 12 and 14 months and oral treatment between 8 and 14 months by green tea EGCG induced decrease of insoluble hyperphosphorylated tau in brain of APPswe Tg2576 mice (Rezai-Zadeh et al. , 2005, 2008). Moreover, a systemic treatment with curcumin during 7 days, partially restored distorted neurites in APP(Swe)/PS1dE9 mice (Garcia-Alloza et al. , 2007). Polyphenols and PD Polyphenols and α-syn In vitro, α-syn has been shown to form amyloid fibrils and these fibrils have been detected in patient with PD in the form of plaques in the brain. However, autopsies have shown that there is no correlation between the amount of fibrils and the severity of PD (Goldberg and Lansbury, 2000). A prominent hypothesis is that the soluble β-oligomers which are formed prior to the formation of mature fibrils are the cause of cytotoxicity, probably by membrane pore formation (Sivanesam and Andersen, 2016). Therefore, the prevention of protein aggregation and oligomerization is an attractive strategy in combating the neurodegeneration because it acts on the very beginning of the proposed cellular pathway leading to cell death. In order to modulate amyloidogenesis pathways, common strategies are (i) to prevent α-syn from forming toxic oligomers, (ii) to increase the amyloidogenesis so that α-syn spends very little time in the presumably toxic oligomers state, and (iii) to direct α-syn to form off-pathway non¬toxic aggregates (Sivanesam and Andersen, 2016). [SEP] Justify:

Output: The text corroborates the claim by discussing various studies that highlight the role of protein aggregation and misfolding in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). It explains mechanisms associated with tau neuropathology in Alzheimer's and mentions that soluble β-oligomers may be cytotoxic, thereby emphasizing the importance of understanding protein folding and aggregation in relation to these diseases.


Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Compellingly, metabolically inactivating the bacterial food source does not impair the ability of the ether lipid machinery to abrogate biguanide-mediated lifespan extension (Figure 2 —figure supplement 4). Additionally, our previously published study interrogating the role of CeACAD10 in regulation of metformin action in growth and cancer highlights that UV-mediated inactivation of OP50-1 growth does not affect metformin-mediated growth inhibition, and that direct injection of metformin into the animal is sufficient to drive CeACAD10 biguanide response activation14. Combined, these data rigorously exclude the possibility that biguanides alter ether lipid levels or the activity of the machinery via indirect effects through bacterial metabolism. We include a new section in Results to highlight this important statement (lines 509 to 547) and include a brief description of these results in the Discussion (lines 577 to 580). 21. Finally, as the authors point out, identification of the specific lipids necessary for promoting healthy aging is not feasible here; with which I totally agree. The actual mechanism by which ether lipid synthesizing enzymes modulate extended survival for the isp-1, eat-2, and raga-1 backgrounds or +phenformin is not really defined by this work. Still, the highlight of a critical biosynthetic pathway in biguanide outcomes and the implication of SKN-1/NRF2 in the biology is of sufficient importance in the field to merit high-profile publication. We again thank the reviewer for their support of our work and for their excellent feedback, which greatly strengthened the mechanistic underpinnings of our work. Reviewer #2 (Recommendations for the authors): Key points to address: 1. Address the impact of biguanides on bacterial growth (OP50, HT115) experimentally e. g. bacterial growth, the impact of heat-killed bacteria on key biguanide phenotypes, and their relationship to ether lipids. The impact of biguanide concentration should also be considered in this regard. We thank the reviewer for this important suggestion, and we have performed the experiment as suggested. As indicated in 3 and 22, we have performedMS of adult day 1 nematodes treated with or without phenformin and grown on live or metabolically dead OP50-1 E. coli food sources using a rigorously established 1% PFA treatment protocol 3. [SEP] Justify:

Output: The text contrasts the claim by focusing on scientific findings related to biguanides, their mechanisms, and the limitations of current understanding regarding their role in longevity. It mentions that the actual mechanism by which ether lipid synthesizing enzymes may modulate extended survival is not defined and that identifying lipids necessary for promoting healthy aging is challenging. This implies that while there are pathways related to longevity, the assertion that biohacking, specifically through methods like biguanides, guarantees doubling human lifespan is not supported by the presented data.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: As expected with regards to our hypothesis, we found the only included predictor of the to be the (σMv)2 (see Results). The remainder of our analysis was therefore focused on the role of Mv on Adaptation. The correlation between Mv variability across baseline trials ((σMv)2) and the was calculated using the rcorr- function from the Hmisc-package [43]. We used Spearman, in addition to Pearson, because Spearman (based on ranks) captures monotonic relation better than Pearson (which requires linear relations). We also calculated this relationship for τ calculated for the 11 participants that showed exponential adaptation curves. We examined if the predictive capacity of (σMv)2 was due to the sequential effects of the TE on Mv by dividing the participants in a LOW (n = 9) and HIGH (n = 8) (σMv)2 group based on the size of their movement speed variability. In order to verify if there were group differences in variances for Mv and TE, we did F-tests on the results from the baseline phase (var. test-function for R). As we suspected that the benefit of (σMv)2 came from error correction rather than exploration, we expected sequential effects of TEt on Mvt+1. The sequential effects can show us if the error on one trial had an effect on the movement speed of consecutive trials. We verified this idea in two different ways: First, we fit a linear mixed model (lmer-function of the lme4-package [44] that examined the slopes of the HIGH and LOW (σMv)2 group, with subject as a nested random effect. We found significant effect for the HIGH (σMv)2 group, indicating that movement speed was used to account for previous encountered errors. In order to examine this effect in more detail, we calculated the cross correlation (ccf-function for R) between the TE and Mv for lag 0 through 3 for each subject individually to capture the corrective pattern. This way we could examine the effects of the movement speed on the error (lag 0) and the effect of the error on the movement speed over the next 3 trials (lag 1-3). [SEP] Justify:

Output: The text is irrelevant to the claim as it focuses on movement speed variability and adaptation analysis without mentioning urban living, stress levels, or any related themes. It discusses statistical methods and results of an experiment without connecting to the claim about stress in urban environments.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Effects of natural polyphenols on α-syn aggregation/disaggregation are studied and described (Figure 2B and 1). Using fluorescence spectroscopy with thioflavin S and electron microscopy, Ono and Yamada (2006) examined the effects of 13 antioxidants on the formation and destabilization of preformed α-syn fibrils. Their anti fibrillogenic and fibril-destabilizing activity was in the order: tannic acid = nordihydroguaiaretic acid = curcumin = rosmarinic acid = myricetin > kaempferol = ferulic acid > catechin = epi-catechin. Thus, they concluded that these antioxidants could prevent the development of α-synucleinopathies, not only through scavenging reactive oxygen species, but also through directly inhibiting the deposition of fibrils in the brain. Masuda et al. (2006) tested 39 polyphenols and 14 from them are strong inhibitors of α-syn filament assembly. Baicalein, delphinidin, gallocatechin gallate, and rosmarinic acid seem to be of particular interest for their properties to inhibit α-syn filament formation. They formed soluble, non cytotoxic (on human neurons SH-SY5Y cells), oligomeric α-syn, probably by binding to the C-terminal region, suggesting that this may be the mechanism by which filament formation is inhibited. 48 different flavonoids belonging to several classes were tested by Meng et al. (2010) for their ability to inhibit the aggregation of α-syn by stabilizing non-pathogenic protein conformation. Majority of the flavonoids inhibit α-syn polymerization either delaying or completely abolishing fibril formation and disaggregate the preformed fibrils into monomer and non¬pathogenic oligomers. Molecule such as baicalein tightly bind to the protein and greatly stabilize its native unfold conformation. The mechanism of the strong inhibition is mostly due to the formation of Schiff base (Meng et al. , 2009). Hong et al. (2008) specified that baicalein-stabilized oligomers are β-sheet-enriched according to analysis. They did not form fibrils even after very prolonged incubation. Oligomers were extremely stable. [SEP] Justify:

Output: The text corroborates the claim by discussing how antioxidants and polyphenols influence α-synuclein aggregation, a process closely related to neurodegenerative diseases such as Parkinson's. The mention of various studies, including those by Ono and Yamada (2006) and Masuda et al. (2006), highlights the importance of understanding protein conformations and their aggregation behaviors in developing potential therapeutic strategies for α-synucleinopathies, thereby supporting the role of protein folding studies in understanding these diseases.


Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: This PFA treatment protocol, as opposed to heat or UV killing protocols, both completely kill and metabolically inactivate the food source (Figure 6 —figure supplement 2A), making this a more reliable, uniformly consistent strategy to eliminate bacterial growth and metabolism as confounding variables in lipidomic and lifespan analyses 3. These analyses rigorously show that biguanides increase relative nematode ether lipid levels independent of any indirect effects on bacterial growth, proliferation, or metabolism (Figure 6 —figure supplement 2D-G). Compellingly, metabolic inactivation of the bacterial food source neither impairs the lifespan extending effects of biguanides nor impairs the ability of the ether lipid machinery to abrogate biguanide-mediated lifespan extension (Figure 6 —figure supplement 3A-F). Combined, these data rigorously exclude the possibility that biguanides alter ether lipid levels or the activity of the machinery via indirect effects through bacterial growth or metabolism. We performed experiments utilizing a final dosage of 4. 5 mM phenformin and 50 mM metformin, both of which are minimally required to robustly and reproducibly extend C. elegans lifespan, as corroborated and utilized by several independent laboratories7-10. Thus, these data strengthen the conclusion that phenformin and metformin prompt ether lipid-dependent increases in lifespan via direct effects on the worm, i. e. independently of biguanide effects on bacteria. Given that these results contrast with previously published work by others, and the importance to the field, we plan a whole separate manuscript about biguanide effects directly on nematode lifespan versus indirectly through the bacteria. As such we do not dwell extensively on the subject herein. 2. Address whether different amounts of biguanide cause the same effect on ether lipids. We thank the reviewer for this suggestion. We again wish to clarify to the reviewer that the intention of this study is to illuminate the requirements for ether lipid biosynthesis on the pro-longevity mechanism of biguanides. As such, we utilized doses of metformin and phenformin that minimally robustly extend C. elegans lifespan (4. 5 mM phenformin and 50 mM metformin) without resulting in negative pleiotropies, as utilized by multiple independent laboratories to identify genetic regulators of the drug7-10. [SEP] Justify:

Output: The text contrasts the claim by discussing research findings that indicate certain treatments (such as biguanides) can extend lifespan in model organisms (like C. elegans) but does not support the notion that biohacking can guarantee doubling the average human lifespan. Instead, it highlights the complexity and specificity of the effects observed and suggests that while biohacking might have some effects on lifespan, it does not guarantee such extreme outcomes as claimed.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: In order to decrease the effect of any auto-correlation or common trends within the time-series we prewhitened the TE and Mv for each participant with the prewhiten-function of the psd-package. Bootstrapped confidence intervals (95%) were calculated. The results were correlated with the individual results, in order to examine if sequential effects of TE on Mv could predict differences in adaptation. ResultsWe first analyzed the behavior or participants within a trial for both phase 1 and 2 (see Table 2). A negative TE denoted being late, and a positive TE denoted being early. Both phases included (σMv)2-group and movement time (T) as predictors of TE. Larger movement times led to a more negative TE. The HIGH (σMv)2 group had on average more positive TE. None of the other main effects were included as predictors, although there seemed to be some small interaction effects. As movement time was one of the main predictors of error, it is likely that participants use Mv to account for errors. However, another way to account for errors is by varying the movement angle (Ma). We found a significant correlation between Mv and Ma (R = 0. 62, p < 0. 001), and (σMv)2 and (σMa)2 (R = 0. 67, p < 0. 005). The results of the (λ = 0. 37) showed us that only (σMv)2 was a significant predictor of the (β = 0. 01; 95% CI[0. 008–0. 020]), while (σMa)2 and (σMa)2 ⋅ (σMv)2 were dropped. The remainder of the analysis will therefore only focus on Mv. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageTable 2. Predictors for temporal hand error within a trial for Phase 1 and 2. λ = 0. 6 for both models. regression includes a penalization, caution is required when interpreting Confidence Intervals. experiment was designed to study the relationship between (σMv)2 and the Adaptation score. Fig 2 shows two example subjects and their responses during the experiment. Participants showed various degrees of adaptation. Adaptation scores varied between -1. 49 and +1. 67 (Table 1). [SEP] Justify:

Output: The text provided does not address the claim regarding urban living and stress levels. It discusses a study on predicting differences in adaptation scores based on various factors, including movement time and temporal hand error in an experimental setup, without mentioning urban living or stress.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: These baicalein-stabilized oligomers, being added to the solution of the aggregating α-syn, were able to noticeably inhibit its fibrillation. Using confocal single-molecule fluorescence spectroscopy, Caruana et al. (2011) used the structural diversity of 14 polyphenols to define key molecular scaffolds most effective in inhibiting oligomer formation by α-syn and disaggregating pre-formed oligomers. They found that baicalein, EGCG, nordihydroguaiaretic acid, morin, myricetin, quercetin and tannic acid have strong effects. They conclude that the best candidate required: (1) aromatic recognition elements that would allow non-covalent binding to the α-syn monomer/oligomer and (2) hydroxyl groups (especially the presence of three > two > one –OH group on the same ring structure) that would hinder the progress of the self-assembly process and/or destabilize its structure. In another work, Caruana confirmed the ability of α-syn oligomers to permeabilise phospholipids membranes, potentially via pore-forming mechanism resembling the mechanism of neuronal toxicity in vivo (Caruana et al. , 2012). They found that a group of small-molecule polyphenols (Nordihydroguaiaretic acid, Morin, Baicalein and Apigenin) strongly protect against membrane perturbation induced by aggregated wild-type and mutant (A30P, A53T) α-syn. Some studies focused more specifically on one polyphenol and drew attention. Curcumin has been extensively studied on different models of neurodegenerative diseases and the results suggested that it could be of interest in the treatment of these pathologies. However, the potential efficacy of curcumin is limited owing to its poor potency and bioavailability. For this reason, Ahsan et al. (2015) screened different curcumin derivatives and they found that curcumin pyrazole derivatives inhibit α-syn aggregation and reduce α-syn associated neurotoxicity by employing several biophysical, imaging techniques, dot blot and cell based assays. EGCG bind to the natively unfolded polypeptides, forming complexes and preventing their conversion into toxic, on-pathway aggregation intermediates. [SEP] Justify:

Output: The text corroborates the claim by discussing various studies that focus on the aggregation and inhibition of α-synuclein, a protein associated with both Alzheimer's and Parkinson's diseases. The text references research on the effects of polyphenols like baicalein and curcumin derivatives on α-synuclein aggregation, highlighting the relevance of protein folding and aggregation processes in the context of neurodegenerative diseases. This supports the assertion that studying protein folding is vital for understanding diseases such as Alzheimer's and Parkinson's.


Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: The supraphysiological 160 mM dosage of metformin used in our prior genetic screens was only initially utilized to identify biguanide response elements. Given that the prior literature shows that higher doses of biguanides do not positively influence C. elegans lifespan5,7, even if additive effects on ether lipids were evident, we argue that they are not relevant to the major thrust of this manuscript on longevity-promoting effects of biguanides and ether lipids. 3. Address the direct genetic connections between skn-1 and fard-1 (etc) e. g. by creating a fard-1; skn-1 gof double and examining fat +/- Phenformin. Alternatively, could this be examined using fat measurements from aak-2 and daf-16 +/- fard-1? It would be interesting to see if the mechanism is the same for all of these longevity processes and make the study of even broader relevance. We thank the reviewer for this suggestion. To clarify, we believe that SKN-1 is the transcription factor operating downstream of the ether lipid machinery to induce somatic lipid depletion, metabolic stress defenses, and pro-longevity outcomes. We have multiple lines of evidence to support this conclusion: (1) A skn-1 RNAi targeting all isoforms of SKN-1 completely abrogates the pro-longevity effects of fard-1 (oe1) animals (Figure 5D), (2) a total SKN-1 loss-of-function mutant completely prevents both biguanide-mediated lifespan extension4 and somatic lipid depletion phenotypes (Figure 6D-E), and (3) skn-1gf animals displaying depleted somatic lipid content elevate 18:0 DMA levels (1), in contrast to changes in 16:0 DMA and 18:1 DMA in fard-1 (oe3) animals, suggesting that skn-1gf alone does not mirror FARD-1 overexpression mediated changes in ether lipid levels. As such, we do not believe that a fard-1lf,skn-1gf animal will suppress the skn-1gf Asdf phenotype. [SEP] Justify:

Output: The text contrasts the claim by discussing specific findings about the effects of biguanides and the skn-1 transcription factor on longevity. It mentions that higher doses of biguanides do not positively influence lifespan in C. elegans, which challenges the idea that biohacking or specific interventions can guarantee increased longevity. Furthermore, the conclusion drawn from the evidence presented indicates that merely relying on the effects of certain compounds (like biguanides) does not support the claim that biohacking can double average human lifespan.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: Fig 3A displays the moving average (window = 4 trials) of TE throughout the task. The blue line shows the mean of the nine participants with below-average (σMv)2, and the orange line depicts the mean of the eight participants with above-average (σMv)2. The spread around these lines represent the standard deviation of the data across subjects. When the temporal perturbation of 100 ms is introduced, subjects account for this delay by reaching the target’s trajectory earlier with their hand in relation to the target. This is depicted by a more positive TE in Fig 3. Upon visual inspection there seemed to be a slightly faster adaptation for the HIGH group than for the LOW group (see Fig 3B). In order to verify this notion, we calculated an adaptation score for each participant. We found a significant correlation between (σMv)2 and the adaptation score (Pearson r = 0. 51, p = 0. 037). We found an even higher Spearman correlation (r = 0. 61, p = 0. 009), indicating that the relationship might be better described by a logarithmic curve (dashed line in Fig 3B). These findings imply that there is a strong positive relationship between (σMv)2 and the adaptation. We confirmed this result by finding a negative correlation between (σMv)2 and τ (r = -0. 63, p = 0. 038) (Fig 4A). This was as expected, as the had a negative (albeit not significant) correlation with τ as calculated by the exponential (r = -0. 54, p = 0. 088) (Fig 4B). Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 3. The relationship between (σMv)2 and adaptation score. (A) The moving average data (+- SD) of the LOW (blue) and HIGH (orange) variability group. (B) The relationship between (σMv)2 and the Adaptation Score. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 4. Verification of the adaptation score. A. The relation between movement speed variability and τ of the exponential function. B. The relationship between the and τ of the exponential function. [SEP] Justify:

Output: The text does not address the claim about urban living and stress levels. Instead, it discusses data related to participant adaptation scores and movement speed variability, which is unrelated to the assertion that urban living causes increased stress.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: The stimulation of this off-pathway led to the reduced cytotoxicity (Ehrnhoefer et al. , 2008). It has also been suggested that EGCG is capable of binding to the oligomeric state of α-syn, destabilizing it and preventing it from interacting with membranes that would ultimately lead to cytotoxicity (Lorenzen et al. , 2014). In a recent study, Yang et al. (2017) showed that EGCG exhibited its protective effect against α-syn mediated cytotoxicity, not only by producing the off-pathway compact oligomers, but also by facilitating the conversion of “active” oligomers into fibrils, thus accelerating the removal of active oligomers which could exert the membrane disruption and subsequent cellular degeneration. Gallic acid potently inhibited the formation of fibrils of α-syn and reduced the rate of formation of oligomers (Liu et al. , 2014). It binds to soluble, non-toxic oligomers and stabilize their structure. Additionally, by using structure activity relationship, data obtained from 14 structurally similar benzoic acid derivatives showed that the inhibition of α-syn fibrillation was related to the number of hydroxyl moieties and their position on the phenyl ring (Ardah et al. , 2014). Piceatannol inhibited the formation of α-syn fibrils and was able to destabilize preformed filaments. Furthermore, it protected PC12 (neuron like) cells against α-syn-induced toxicity (Temsamani et al. , 2016). Albani et al. (2009) showed that resveratrol pre-treatment protect SK-N-BE cells from the toxicity arising from aggregation-prone protein (α-syn(A30P), mutated α-syn in familial Parkinsonism). In animal models of PD, several studies clearly demonstrated that various polyphenols possess neuroprotective effects, but no study provided information on interaction between polyphenols and α-syn and on fibrils formation. Polyphenols and synphilin-1 Few studies described the role of polyphenols in aggregation of synphilin-1. [SEP] Justify:

Output: The text corroborates the claim by discussing various factors related to α-synuclein (α-syn) and how proteins associated with diseases like Parkinson's Disease (PD) are affected by different compounds. It includes studies that show protective effects against α-syn-mediated cytotoxicity, thereby linking protein folding and aggregation processes to neurodegenerative diseases, specifically mentioning the importance of investigating the interactions of polyphenols with proteins involved in protein folding and aggregation.


Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Skip to Content eLife home page your research Search by keyword or author Reset form my search to Genetics and 10. 7554/eLife. 82210 Open access Copyright information Version of RecordAugust 22, 2023 Open annotations (there are currently 0 annotations on this page). 1,990 views 271 downloads 15 2210. Copy to clipboard Download BibTeX Download. RIS Full text Figures and data Peer review Side by side Abstract Editor's evaluation eLife digest and methods Data availability 10. 7554/eLife. 82210. sa0 Decision letter Reviews on Sciety eLife's review process eLife digest Metformin is the drug most prescribed to treat type 2 diabetes around the world and has been in clinical use since 1950. The drug belongs to a family of compounds known as biguanides which reduce blood sugar, making them an effective treatment against type 2 diabetes. More recently, biguanides have been found to have other health benefits, including limiting the growth of various cancer cells and improving the lifespan and long-term health of several model organisms. Epidemiologic studies also suggest that metformin may increase the lifespan of humans and reduce the incidence of age-related illnesses such as cardiovascular disease, cancer and dementia. Given the safety and effectiveness of metformin, understanding how it exerts these desirable effects may allow scientists to discover new mechanisms to promote healthy aging. The roundworm Caenorhabditis elegans is an ideal organism for studying the lifespan-extending effects of metformin. It has an average lifespan of two weeks, a genome that is relatively easy to manipulate, and a transparent body that enables scientists to observe cellular and molecular events in living worms. To discover the genes that enable metformin’s lifespan-extending properties, Cedillo, Ahsan et al. systematically switched off the expression of about 1,000 genes involved in C. elegans metabolism. They then screened for genes which impaired the action of biguanides when inactivated. This ultimately led to the identification of a set of genes involved in promoting a longer lifespan. Cedillo, Ahsan et al. then evaluated how these genes impacted other well-described pathways involved in longevity and stress responses. The analysis indicated that a biguanide drug called phenformin (which is similar to metformin) increases the synthesis of ether lipids, a class of fats that are critical components of cellular membranes. [SEP] Justify:

Output: The text contrasts the claim as it discusses the effects of metformin, a drug that has shown potential in extending lifespan, but it does not support the assertion that biohacking guarantees or doubles the average human lifespan. The mention of health benefits and findings regarding longevity does not equate to guarantees; rather, it indicates ongoing research and potential improvements in health, not absolute outcomes.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: expected, the F-test revealed a significant difference between the HIGH and LOW variability groups in baseline Mv (F(1, 1315) = 2. 5, p < 0. 001). However, no differences were found for TE (F(1,1315) = 1. 1, p = 0. 35). This is important because it ensures that differences in sequential effects that are found between groups are not the result of differences in errors that were made. We examined the relationship between the TE on a certain trial, and the change in Mv on the next trial for participants in the HIGH and in the LOW (σMv)2 group (see Fig 5). The mixed linear model revealed that, when the error was zero, neither of the groups significantly changed their Mv (p = 0. 69 (LOW); p = 0. 59 (HIGH)). The effect of TE on the next trial’s Mv was significant for the HIGH (σMv)2 group (slope = -15. 9 cm/s2; p = 0. 02). The LOW (σMv)2 group did not show a significant effect (slope = 6. 3 cm/s2; p = 0. 68). revealed a significant difference between groups (F(1, 1263) = 5. 2, p = 0. 02). This suggests that participants with a higher (σMv)2 increased their speed when encountering a negative error and vice versa, while the participants with lower (σMv)2 did not. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 5. The relationship between the baseline TE on trial t-1 and the subsequent change in Mvel. Dots represent individual trials for subjects within the HIGH (orange) and LOW (blue) (σMv)2 group. The lines indicate the predicted slope of the model. order to examine if this difference can predict adaptation on an individual level, we calculated the cross correlation (ccf) between Mv at different t+lag and TE (Fig 6). A negative ccf indicates that a negative error (arriving too late) leads to increased velocities, and a more positive error (earlier) leads to decreased velocities. Consequently, a positive ccf indicates the opposite (negative error → decreased velocities; positive error → increased velocities). [SEP] Justify:

Output: The text does not address the claim regarding urban living and stress levels. It discusses statistical results concerning variability groups and errors in a different context, without any mention of urban living or its relationship with stress.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: However, Pal et al demonstrated that a curcumin analogue, the 3,5-bis(2-flurobenzylidene)piperidin-4-one induced a marked decrease in synphilin-1 aggregation in the dopaminergic SHSY-5Y cells (Pal et al. , 2011). This curcumin analog prevents this aggregation by preventing covalent modifications and by maintaining the expression of the protein disulfide isomerase. paper reviews the significant papers that demonstrated beneficial effects of natural polyphenols against protein aggregates found in AD an PD. These properties can be explained by the capacity of polyphenols to inhibit aggregation of major components of pathological aggregates, i. e. , Aβ in amyloid plaques, tau in NTF, α-syn and synphilin-1 in LB and LNs and to partially disaggregate them. Many mechanisms are implicated, such as direct interaction of polyphenols with β-sheets of these proteins, leading to inhibition of abnormal conformational changes or hyperphosphorylation, but also by interaction with metal ions promoting aggregation. These effects are particularly interesting because polyphenols possess other beneficial properties, such as antioxidative, anti-inflammatory, pro-autophagic and neuroprotective activities. These properties, by themselves, may participate in the reduction in protein aggregation and deposition, without a direct effect of polyphenols on the process of protein aggregation and deposition. As multi-targeting drugs, polyphenols may lead to the development of therapeutic agents that could prove useful in combating AD and PD. However, it is difficult to predict nontoxic efficient doses for in vivo studies and clinical trials, because there is not necessarily a conversion relationship between in vitro and in vivo doses, notably because in vivo experiments are influenced by complex factors such as neuroendocrine system and immunity (Chen et al. , 2018). Moreover, the doses between humans and animals are usually converted by body surface area calculation method, but this result may be not reliable because of the differences in drug metabolism between these two species. To our knowledge, no clinical trial studied the role of polyphenols in the formation of protein aggregates in prion-like diseases. The only clinical studies investigating polyphenols effects in neurodegenerative diseases evaluated their role to prevent or treat cognitive impairment associated with neurodegeneration. [SEP] Justify:

Output: The text corroborates the claim by discussing the role of protein aggregates in Alzheimer's and Parkinson's diseases, specifically noting how polyphenols can inhibit the aggregation of proteins such as Aβ, tau, α-syn, and synphilin-1. It highlights the importance of understanding these aggregation mechanisms in the context of developing therapeutic agents for these diseases, aligning with the claim that studying protein folding is crucial for understanding such neurodegenerative conditions.


Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Indeed, genetically mutating the three major enzymes required for ether lipid production stopped the biguanide from extending the worms’ lifespans. Critically, inactivating these genes also prevented lifespan extension through other known strategies, such as dietary restriction and inhibiting the cellular organelle responsible for producing energy. Cedillo, Ahsan et al. also showed that increasing ether lipid production alters the activity of a well-known longevity and stress response factor called SKN-1, and this change alone is enough to extend the lifespan of worms. These findings suggest that promoting the production of ether lipids could lead to healthier aging. However, further studies, including clinical trials, will be required to determine whether this is a viable approach to promote longevity and health in humans. is the first line therapy for type 2 diabetes and the most frequently prescribed oral hypoglycemic medication worldwide (Inzucchi et al. , 2012). Human epidemiologic studies note an association between metformin use and decreased incidence of cancer (Evans et al. , 2005; Yuan et al. , 2013). In addition, metformin extends lifespan in invertebrate and vertebrate models (Cabreiro et al. , 2013; Martin-Montalvo et al. , 2013; Onken and Driscoll, 2010), and therefore may reduce aging-related diseases in humans (Barzilai et al. , 2016). Nonetheless, our understanding of the molecular pathways governing the health-promoting effects of metformin is only just beginning to emerge. Our previous work identified a conserved signaling axis connecting mitochondria, the nuclear pore complex, and mTORC1 inhibition that is required for metformin-mediated extension of lifespan in Caenorhabditis elegans and inhibition of growth in worms and human cancer cells (Wu et al. , 2016). The energy sensor AMP-activated protein kinase (AMPK) is not necessary for metformin-induced growth inhibition in C. elegans but is required for the drug’s pro-longevity effects (Cabreiro et al. , 2013; Onken and Driscoll, 2010; Chen et al. , 2017). [SEP] Justify:

Output: The text contrasts the claim by discussing various biological mechanisms and research related to promoting longevity but stops short of claiming that biohacking can guarantee longevity or specifically double the human lifespan. It indicates that while certain gene modifications and treatments like metformin have shown potential in extending lifespan in organisms, further studies are necessary before such methods can be deemed effective in humans. The statement that 'evidence suggests promoting the production of ether lipids could lead to healthier aging' implies that while there are possibilities for lifespan extension, it does not guarantee doubling lifespan, directly contradicting the claim.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: In congruence with Fig 6, participants with higher (σMv)2 scores seemed to have a trend towards more negative ccfs, while the participants with low (σMv)2 scores had ccfs near zero. The high (σMv)2 group showed a positive ccf(0) (i. e. the cross correlation between Mv and TE within a trial). Slower hand movements led to more negative TE and fast hand movement to positive TE. It shows that for this group there is some dependency of the TE on the Mv within a trial. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 6. Serial ccf for each (σMv)2 group. The serial ccf for lag 0-3 for the HIGH (orange) and LOW (blue) (σMv)2 groups. The error bars represent the 95% bootstrapped confidence intervals. see if this difference could explain the differences in adaptation, we calculated the correlation between the different lags and the (Fig 7). The correlation between Mv and TE within a trial (lag0), i. e. how the Mv affected the TE, seemed to not be able to explain differences in adaptation. Although there is also no correlation for ccf(1), the lag2 and lag3 ccf seem to predict the in this experiment. This suggests that errors might not be corrected right away, or only partially from trial to trial. Download: PPTPowerPoint slidePNGlarger imageTIFForiginal imageFig 7. The relationship between the ccf score and the adaptation score. The ccf is shown for lags 0-3 (A-D). The color of the data-points (blue-orange) indicates the size of the (σMv)2. The dotted line indicates a ccf of zero. DiscussionThis study found a positive relationship between variability of movement speed during the baseline phase, and the adaptation to a temporal perturbation. Our results indicate that this variability might be a result of error correction strategies, rather than exploration. Participants that corrected their movement velocity after encountering an error on average adapted more than participants who did not. To our knowledge, we are the first ones to reveal such a relationship in temporal adaptation. The role of noise in adaptation has recently received a lot of attention. A study by Wu et al. [SEP] Justify:

Output: The text does not address the claim regarding urban living and its effects on stress levels. Instead, it focuses on the relationship between movement variability and adaptation to temporal perturbation in a study. The contents are technical and relate to motor performance rather than living conditions and their impact on stress.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: 2017;32:945–953. The role of tau kinases in Alzheimer's disease Devel. 2010;13:595–603 Dong W, Wang R. Effects of resveratrol-induced cellular autophagy in control of neurodegenerative diseases Xue Bao. 2016;51:18–22. Disaggregation of tau as a therapeutic approach to tauopathies Res. 2010;7:235–240. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers Mol Biol. 2008;15:558–566 Fauconneau B, Waffo-. Comparative study of radical scavenger and antioxidant properties of phenolic compounds from Vitis vinifera cell cultures using in vitro tests Life Sci. 1997;61:2103–2110 ’Erme M, Mosca L. β-sheet interfering molecules acting against β-amyloid aggregation and fibrillogenesis Chem. 2015;23:1671–1683. Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice J Neuroinflammation. 2014;11:139. Targeting oligomers in neurodegenerative disorders: lessons from alpha-synuclein, tau, and amyloid-beta peptide J 24 Suppl. 2011;2:223–232 Garcia-. Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model J Neurochem. 2007;102:1095–1104. Is there a cause-and-effect relationship between alpha¬synuclein fibrillization and Parkinson's disease? Biol. 2000;2:E115–119 Greenwald J, Riek R. Biology of amyloid: structure, function, and regulation Structure. 2010;18:1244–1260 Greenwald J, Riek R. On the possible amyloid origin of protein folds J Mol Biol. 2012;421:417–426. Epigallocatechin 3-gallate as an inhibitor of tau phosphorylation and aggregation: a molecular and structural insight J Dis. 2017;4:218–225. [SEP] Justify:

Output: The text corroborates the claim by discussing various studies related to protein behavior in the context of neurodegenerative diseases, specifically Alzheimer's and Parkinson's. It references the role of tau kinases and tau aggregation in Alzheimer's disease, and mentions amyloid beta and alpha-synuclein in the context of protein misfolding and aggregation, which are crucial in understanding these diseases.


Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Consistently, mechanistic studies indicate that the longevity-promoting transcription factor SKN-1/nuclear factor erythroid 2-related factor (Nrf) is required for biguanide-mediated lifespan extension (Cabreiro et al. , 2013; Onken and Driscoll, 2010). The relationship of these metformin longevity response elements to each other and their hierarchy in the biological response to biguanides remains unknown. Thus, the mechanisms by which metformin exacts its beneficial effects on health are likely to be branching and complex. The importance of ether lipids, a major structural component of cell membranes, to aging and longevity is not fully established. Ether lipids are involved in the maintenance of general membrane fluidity and in the formation of lipid rafts within microdomains, which are important for promotion of membrane fusion and cellular signaling (Glaser and Gross, 1994; Komljenovic et al. , 2009; Marrink and Mark, 2004). Ether lipids have broad roles in the regulation of cell differentiation (Davies et al. , 2001; Facciotti et al. , 2012; Rodemer et al. , 2003; Teigler et al. , 2009), cellular signaling (Thukkani et al. , 2002; Albert et al. , 2003), and reduction of oxidative stress through their action as antioxidants (Morand et al. , 1988; Zoeller et al. , 1988; Reiss et al. , 1997; Maeba et al. , 2002). Humans deficient in ether lipid biogenesis suffer from rhizomelic chondrodysplasia punctata (RCDP), a rare genetic disorder, which results in skeletal and facial abnormalities, psychomotor retardation, and is uniformly fatal typically before patients reach their teenage years (White et al. , 2003). Thus, current evidence linking alterations in ether lipid levels to aging and longevity in humans is strictly correlative (Gonzalez-Covarrubias et al. , 2013; Pradas et al. , 2019). Ether lipids, which are structurally distinct from canonical phospholipids, have a unique biosynthetic pathway through which a fatty alcohol is conjugated to the glycerol backbone at the sn-1 position via an ether linkage. [SEP] Justify:

Output: The text contrasts the claim by indicating that while studies show mechanisms related to longevity, such as the role of ether lipids and the transcription factor SKN-1 in lifespan extension, it clarifies that the evidence for alterations in ether lipid levels being directly linked to aging and longevity is 'strictly correlative.' This suggests that biohacking does not guarantee a doubling of lifespan, as the text emphasizes the complexity and multifactored nature of longevity-related biological processes.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: [32] suggested that there might be a positive influence of variability on adaptation through reinforcement learning, revealed by an increased baseline variability for fast adapters. In line with these results, we found a benefit of increased baseline variability on the adaptation for temporal perturbations. However, our results suggest that participants with higher variability use their velocity more as a way to correct for errors. Our results are therefore more in line with the idea that motor noise from different types of processes can have either a positive, negative or neutral effect on adaptation [13]. Two types of noise that are relevant for adaptation are sensory noise and motor noise. Sensory noise can influence adaptation by influencing the uncertainty of the error [22, 45]. More sensory noise can lead to higher variability. However, error correction actually decreases with more uncertain sensory information. It is therefore unlikely that sensory noise was the source of the increased adaptation. Motor noise can roughly be divided into planning noise and execution noise [16]. A recent study by Vliet et al. [46] found that execution noise correlated negatively with adaptation rate, while planning noise revealed the opposite trend. Execution noise increases the uncertainty of the feedback that is received. Contrarily, more noise in the planning process can lead to more uncertain forward predictions, with a higher rate of error correction as a result. In the current study, we did not measure noise in the system directly. We therefore cannot determine the direct effect of planning noise and/or execution noise on the adaptation. However, it has been suggested that planning noise, in the form of stochastic resonance, could have a positive effect on signal detection by enhancing sub-threshold signals to supra-threshold [47–49]. Enhanced error-detection could lead to more error correction. Our results are in line with the idea that higher planning noise could increase the reliance on error feedback and lead to larger trial-to-trial corrections [46]. The question remains: why did we find a positive relationship between baseline variability and adaptation, while many other studies did not [13, 50–53]? It is likely that differences in design, such as variability measure or feedback provided, trigger variations in the accumulation of the different types of noise. In this study, we defined the average movement speed as an indicator of task-relevant variability, instead of the movement speed at the moment of interception, or the error at interception. [SEP] Justify:

Output: The text does not address the claim directly. It focuses on the concepts of adaptability, motor noise, and variability in error correction, without any mention of urban living or stress levels. Therefore, it is irrelevant to the claim that urban living leads to increased stress.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Recent advances in alpha¬synuclein functions, advanced glycation, and toxicity: implications for Parkinson's disease Mol Neurobiol. 2013;47:525–536. ATP13A2 regulates mitochondrial bioenergetics through macroautophagy Neurobiol Dis. 2012;45:962–972 Habtemariam S. Molecular pharmacology of rosmarinic and salvianolic acids: potential seeds for Alzheimer's and vascular dementia drugs Mol Sci. 2018;19:E458. Phenolic compounds prevent Alzheimer's pathology through different effects on the amyloid-beta aggregation pathway Pathol. 2009;175:2557–2565. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases Neuromolecular Med. 2003;4:21–36. Structural characteristics of alpha-synuclein oligomers stabilized by the flavonoid baicalein J Mol Biol. 2008;383:214–223. Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles Biochem Pharmacol. 2014;88:631–639 -. Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity J Neurol. 1998;57:334–337. Hypoglycemic effects of a phenolic acid fraction of rice bran and ferulic acid in C57BL/KsJ-db/db mice J Chem. 2007;55:9800–9804. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease Neurochem Int. 2009;54:111–118. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis Science. 2003;300:486–489. Reactivity of metal-free and metal-associated amyloid-beta with glycosylated polyphenols and their esterified derivatives Sci Rep. 2015;5:17842 Kroemer G, Levine B. Autophagic cell death: the story of a misnomer Biol. 2008;9:1004–1010 Ksiezak-Reding H, Ho L, Santa-Maria I, Diaz-. [SEP] Justify:

Output: The text corroborates the claim by explicitly mentioning 'the role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases' which indicates that protein folding and aggregation are significant factors in the pathology of these diseases. Furthermore, it discusses various advancements and therapeutic approaches related to Alzheimer's and Parkinson's, underscoring the importance of studying protein folding in understanding these conditions.


Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Interestingly, requirement for the ether lipid biosynthetic genes extends to multiple genetic longevity paradigms, including defective mitochondrial electron transport function (isp-1), defective pharyngeal pumping/caloric restriction (eat-2), and compromises in mTOR complex 1 activation (raga-1). We show that overexpressing fard-1, the enzyme that produces fatty alcohols for ether lipid biogenesis in C. elegans, extends lifespan, supportive of the idea that alterations in the ether lipid landscape alone is sufficient to promote healthy aging. Mechanistically, ether lipids promote longevity downstream of biguanide action through activation of metabolic stress defenses and somatic lipid redistribution driven by the transcription factor SKN-1/Nrf. These data suggest that a heretofore unappreciated role for ether lipids is to enable organismal-level, longevity-promoting stress defenses. responsible for ether lipid biosynthesis are necessary for biguanide-induced lifespan extension A prior screen of ~1000 metabolic genes for RNA interference (RNAi) knockdowns that interfere with the growth-inhibitory properties of a high, 160 mM dose of metformin in C. elegans (utilized to maximize the sensitivity and specificity of our assay to identify true epistatic candidates) (Wu et al. , 2016), yielded fard-1 and acl-7, which are required for ether lipid biosynthesis. Ether lipids are distinguished from canonical phospholipids as the latter contain exclusively fatty acids conjugated to glycerol, whereas ether lipids contain a fatty alcohol conjugated to the glycerol backbone at the sn-1 position via an ether linkage (Figure 1A). Confirming our screen results, granular, quantitative analysis following RNAi knockdown of fard-1 and acl-7 reveals significant resistance to biguanide-induced growth inhibition (Figure 1—figure supplement 1A). Our lab has previously demonstrated that biguanide effects on growth in C. elegans share significant overlap mechanistically with the machinery by which metformin extends lifespan in the worm, thus suggesting that modulation of ether lipid biosynthesis may also be responsible for the lifespan-extending properties of the drug (Wu et al. , 2016). [SEP] Justify:

Output: The text contrasts the claim by implying that while certain genetic and biochemical mechanisms related to longevity exist, there is no guarantee that biohacking alone can double the average human lifespan. The discussion on the role of ether lipids and metabolic pathways suggests that these are important for lifespan extension but does not assert that biohacking methods will necessarily lead to doubling lifespan as claimed.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: We theorized that movement velocity would provide the richest information about the temporal contingencies of the sensorimotor system, and therefore could be more beneficial for exploration. By averaging the movement speed on each trial we believe to have filtered out a large part of the execution noise. This could have highlighted the effect of planning noise on adaptation. Similarly, Wu et al. [32] calculated the variability of deflection of a rewarded hand path throughout the movement, while He et al. [13] looked at the endpoint error. It is likely that endpoint error is more susceptible to execution noise. On the other hand, Dhawale et al. [54] suggested in a recent review that differences in results between studies might be inherent to differences in feedback. et al. [32], feedback was absent during the baseline, which may have led to an accumulation of planning noise (drift) that could not be corrected trial-to-trial [55]. et al. [13], feedback was provided throughout the movement, which means the variability measure might be dominated by execution noise. In the current study, we did provide error feedback in the baseline, which might be taken as evidence against the latter idea. However, these ideas together support the hypothesis that experimental designs that promote planning noise over execution noise are more likely to reveal a positive relationship between variability and adaptation. Next, we need to consider the effect of generalization on the results. The term generalization refers to how the mapping between action and consequence generalizes to other tasks and target speeds. Research has shown that generalization of temporal perturbations is limited to tasks that are very similar to the learned task [39]. We used three different target speeds in two directions in this study. Some participants might had a better generalization from one speed to the other than others. It is possible that at the moment the perturbation was applied, some participants were able to generalize the changing consequences better for all target speeds and, as a result, adapt faster. For generalization to have an effect on our results there would need to be a relationship between movement speed variability and generalization. More variable people might develop broader tuning curves, and as a result adapt faster. We think this idea is captured well within the notion of exploration that is part of our original hypothesis: higher variability due to exploration might broaden the brain’s knowledge on the temporal contingencies over a broader range of target speeds and situations. [SEP] Justify:

Output: The text does not address the claim regarding the relationship between urban living and stress levels. Instead, it discusses concepts related to movement velocity, sensorimotor systems, and generalization in an experimental study, which is unrelated to urban living or stress.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Ultrastructural alterations of Alzheimer's disease paired helical filaments by grape seed-derived polyphenols Neurobiol Aging. 2012;33:1427–1439. EGCG-mediated autophagy flux has a neuroprotection effect via a class III histone deacetylase in primary neuron cells Oncotarget. 2015;6:9701–9717 -. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations Cell. 2010;141:1146–1158. Resveratrol partially prevents rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through induction of heme oxygenase-1 dependent autophagy Mol Sci. 2014;15:1625–1646 Liu F, Iqbal K, Grundke-. Dephosphorylation of tau by protein phosphatase 5: impairment in Alzheimer's disease J Biol Chem. 2005;280:1790–1796. Gallic acid interacts with alpha-synuclein to prevent the structural collapse necessary for its aggregation Acta. 2014;1844:1481–1485. How epigallocatechin gallate can inhibit alpha-synuclein oligomer toxicity in vitro J Biol Chem. 2014;289:21299–21310 Lynch-. The role of autophagy in Parkinson's disease Med. 2012;2:a009357. Understanding the broad-spectrum neuroprotective action profile of green tea polyphenols in aging and neurodegenerative diseases J Alzheimers Dis. 2011;25:187–208. Small molecule inhibitors of alpha-synuclein filament assembly Biochemistry. 2006;45:6085–6094 Mazzanti G, S. Curcumin and resveratrol in the management of cognitive disorders: What is the clinical evidence? Molecules. 2016;21:E1243. Molecular mechanisms underlying the flavonoid-induced inhibition of alpha-synuclein fibrillation Biochemistry. 2009;48:8206–8224. Effects of various flavonoids on the alpha-synuclein fibrillation process Parkinsons Dis. 2010;2010:650794 Mietelska-. Tau protein modifications and interactions: their role in function and dysfunction Mol Sci. 2014;15:4671–4713 -. [SEP] Justify:

Output: The text corroborates the claim by discussing various research findings related to Alzheimer's and Parkinson's diseases, indicating that protein-related mechanisms such as tau protein modifications and interactions, alpha-synuclein aggregation, and the role of autophagy are essential for understanding these neurodegenerative diseases. The mention of studies focusing on how different compounds prevent or manage these protein alterations highlights the importance of protein folding in the context of these diseases.


Input: Task: contrast the claim using the given text. Claim: Biohacking guarantees longevity by doubling the average human lifespan. [SEP] Text: Indeed, loss-of-function mutations in any of three genes encoding enzymes required for ether lipid biosynthesis, fard-1, acl-7, or ads-1, significantly abrogate lifespan extension induced by lifespan-extending doses of metformin (50 mM) and the related biguanide phenformin (4. 5 mM) (Figure 1B–G). Loss-of-function of ads-1 and acl-7 may display a modest increase in lifespan with metformin administration but display a percentage median lifespan increase significantly reduced in comparison to wild-type controls (Figure 1B–G, and throughout manuscript see Supplementary file 1 for all tabular survival statistics and biological replicates). Confirming that these mutations confer resistance to metformin by compromising ether lipid synthetic capacity, RNAi knockdowns of fard-1 and acl-7 in wild-type worms also partially impair lifespan extension promoted by phenformin (Figure 1—figure supplement 1B–C). This dependency is not confounded by chemical inhibition of reproduction, as lifespan analyses performed without the use of the thymidylate synthase inhibitor 5-fluoro-2′-deoxyuridine (FUdR) reveal similar abrogation of biguanide-mediated lifespan extension with inactivation of the ether lipid synthetic machinery (Figure 1—figure supplement 2A–F; and Hekimi, 2011). Studies from this point forward are presented predominantly with phenformin because phenformin is more readily absorbed without need for a specific transporter, unlike metformin (Wu et al. , 2016; Sogame et al. , 2009; Segal et al. , 2011), and our experience indicates more consistent lifespan extension with phenformin in C. elegans. Figure 1 with 2 supplements see all Download asset Open asset Genes responsible for ether lipid biosynthesis are necessary for biguanide-induced lifespan extension. (A) C. elegans ether lipid synthesis is catalyzed by three enzymes: fatty acyl reductase FARD-1, acyltransferase ACL-7, and alkylglycerone phosphate synthase ADS-1 (adapted from Figure 1 of Shi et al. , 2016 and Dean and Lodhi, 2018). The latter two are localized to the peroxisomal lumen. [SEP] Justify:

Output: The text contrasts the claim by discussing the specific biochemical mechanisms that limit lifespan extension despite interventions such as metformin and phenformin. It describes how loss-of-function mutations in certain genes can significantly hinder lifespan extension, indicating that biohacking methods do not reliably guarantee doubling of lifespan. The mention of specific enzymes essential for ether lipid biosynthesis and their role in lifespan extension further emphasizes that lifespan enhancement is complex and not guaranteed, directly opposing the claim that biohacking can guarantee longevity.


Input: Task: pass the claim using the given text. Claim: Urban living always leads to increased stress levels. [SEP] Text: Unfortunately our current dataset cannot give a definitive answer to the question of generalization. Throughout the study, we mainly focused on how participants change their movement speed from trial-to-trial. However, in this task subjects were free to change their interception location or movement angle and onset time in order to account for prediction errors. This leads to a variety of strategies that participants can use to perform the task and correct for errors. These strategies are not independent of the target speed, nor independent of each other. For example, faster targets can lead to faster movements, earlier onset times and/or to broader hitting positions [56–58]. Furthermore, we found a correlation between the movement angle and the movement speed. These interconnections between movement features make it challenging to examine the participants’ strategies. However, it has been proposed that, in order to successfully hit a target, people benefit more from estimating the time it takes to reach the target’s trajectory, followed by fine-tuning the point of interception throughout the movement (online correction), as opposed to estimating when the target will reach the interception location [2]. As a result, errors are likely attributed to incorrect estimations of the time it takes to reach the target’s trajectory, rather than an incorrect estimations of interception location. As online correction was discouraged in our experiment, the reliance on error correction through changing the predicted temporal features of the movement was enhanced even further. During this experiment, successful participants used their movement speed as a control agent for trial-to-trial error correction in interception, and to a lesser extend their interception location or movement angle. This does not mean that low adapters do not have useful strategies of error correction. However, if the source of an error is temporal, using movement speed as a corrective strategy can be beneficial. Vice versa, if an error is spatial, corrections in movement angle would be more favorable. It is therefore possible that the difference in adaptation is rooted in the interpretation of the error. Ccf(0) seemed to be slightly higher in the high variability group compared to the low variability group. This shows that participants with higher variability had a higher cross-correlation between the speed of movement and the temporal hand error in the same trial. This suggests that the temporal hand errors that participants with higher variability make are more dependent on the movement speed. This is not a surprising feature, given that more variability can more easily reveal a dependency of the temporal hand error on the movement speed. [SEP] Justify:

Output: The text discusses the complexities of participants' movement strategies and error correction in an experimental setting, without addressing the claim regarding urban living and stress levels. It does not provide any information about the relationship between urban living and stress, making it irrelevant to the claim.


Input: Task: corroborate the claim using the given text. Claim: The study of protein folding is essential in understanding diseases like Alzheimer's and Parkinson's. [SEP] Text: Regulation of autophagy by polyphenols: Paving the road for treatment of neurodegeneration Biotechnol Adv. 2017 doi: 10. 1016/j. biotechadv. 2017. 12. 001 Naczk M, Shahidi F. Phenolics in cereals, fruits and vegetables: occurrence, extraction and analysis J Anal. 2006;41:1523–1542 Ono K, Yamada M. Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro J Neurochem. 2006;97:105–115. Anti-amyloidogenic activity of tannic acid and its activity to destabilize Alzheimer's beta-amyloid fibrils in vitro Acta. 2004;1690:193–202. Potent anti¬amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer's disease J Neurochem. 2003;87:172–181. Nitrosative stress-induced Parkinsonian Lewy-like aggregates prevented through polyphenolic phytochemical analog intervention Res Commun. 2011;404:324–329. Plant polyphenols as dietary antioxidants in human health and disease Cell Longev. 2009;2:270–278 Rezai-. Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice Brain Res. 2008;1214:177–187 Rezai-. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice J Neurosci. 2005;25:8807–8814 -. Protective effect of epsilon-viniferin on beta-amyloid peptide aggregation investigated by electrospray ionization mass spectrometry Chem. 2011;19:3152–3155 Rivière. Inhibitory activity of stilbenes on Alzheimer's beta-amyloid fibrils in vitro Chem. 2007;15:1160–1167. [SEP] Justify:

Output: The text corroborates the claim by discussing various studies that examine the effects of polyphenols and antioxidants on protein aggregation, specifically mentioning anti-amyloidogenic activities and fibril destabilization related to Alzheimer's disease. These activities are crucial for understanding the mechanisms of protein folding and misfolding in diseases like Alzheimer's and Parkinson's, thus supporting the importance of this research area.