ATF-4 and hydrogen sulfide signalling mediate longevity from inhibition of translation or mTORC1 [preprint]

Inhibition of mTORC1 (mechanistic target of rapamycin 1) slows ageing, but mTORC1 supports fundamental processes that include protein synthesis, making it critical to elucidate how mTORC1 inhibition increases lifespan. Under stress conditions, the integrated stress response (ISR) globally suppresses protein synthesis, resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that the ATF-4 transcription program promotes longevity and that ATF-4 upregulation mediates lifespan extension from mTORC1 inhibition. ATF-4 activates canonical anti-ageing mechanisms but also increases expression of transsulfuration enzymes to promote hydrogen sulfide (H2S) production. ATF-4-induced H2S production mediates longevity and stress resistance from C. elegans mTORC1 suppression, and ATF4 drives H2S production in mammalian dietary restriction. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. Increasing H2S levels, or enhancing mechanisms that H2S modulates through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR or mTORC1 inhibition

Sex differences in pharmacological interventions and their effects on lifespan and healthspan outcomes: a systematic review

With an increasing aging population, the burden of age-related diseases magnifies. To alleviate this burden, geroprotection has been an area of intense research focus with the development of pharmacological interventions that target lifespan and/or healthspan. However, there are often sex differences, with compounds mostly tested in male animals. Given the importance of considering both sexes in preclinical research, this neglects potential benefits for the female population, as interventions tested in both sexes often show clear sexual dimorphisms in their biological responses. To further understand the prevalence of sex differences in pharmacological geroprotective intervention studies, we performed a systematic review of the literature according to the PRISMA guidelines. Seventy-two studies met our inclusion criteria and were classified into one of five subclasses: FDA-repurposed drugs, novel small molecules, probiotics, traditional Chinese medicine, and antioxidants, vitamins, or other dietary supplements. Interventions were analyzed for their effects on median and maximal lifespan and healthspan markers, including frailty, muscle function and coordination, cognitive function and learning, metabolism, and cancer. With our systematic review, we found that twenty-two out of sixty-four compounds tested were able to prolong both lifespan and healthspan measures. Focusing on the use of female and male mice, and on comparing their outcomes, we found that 40% of studies only used male mice or did not clarify the sex. Notably, of the 36% of pharmacologic interventions that did use both male and female mice, 73% of these studies showed sex-specific outcomes on healthspan and/or lifespan. These data highlight the importance of studying both sexes in the search for geroprotectors, as the biology of aging is not the same in male and female mice.Systematic Review Registration: [website], identifier [registration number]

Timut Pepper Extract Slows Age-Dependent Decline of Mobility and Collagen Loss and Promotes Longevity.

Investigations into human longevity are increasingly focusing on healthspan enhancement, not just lifespan extension. Lifestyle modifications and nutritional choices, including food supplements, can significantly affect aging and general health. Phytochemicals in centenarians' diets, such as those found in Timut pepper, a Nepalese spice with various medicinal properties, may contribute to their longevity. Similarly, Sichuan pepper, a related species, has demonstrated anti-inflammatory and neuroprotective activities. With the broader purpose of uncovering a novel treatment to address aging and its comorbidities, this study aims to investigate the potential lifespan- and healthspan-promoting effects of Timut pepper using the model organism We show that Timut pepper extract extends lifespan at different maintenance temperatures and increases the proportion of active nematodes in their early adulthood. In addition, we show that Timut pepper extract enhances speed and distance moved as the nematodes age. Finally, Timut pepper extract assures extracellular matrix homeostasis by slowing the age-dependent decline of collagen expression

Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity

Summary Interventions that delay ageing mobilize mechanisms that protect and repair cellular components1–3, but it is unknown how these interventions might slow the functional decline of extracellular matrices4,5, which are also damaged during ageing6,7. Reduced Insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile C. elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions (Supplementary Discussion)1,2. It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood2,8,9, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits1,10,11. Here we show that rIIS can promote C. elegans longevity through an program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) ortholog SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity12–14, but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix (ECM) genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood ECM remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that ECM remodelling is a generally essential signature of longevity assurance, and that agents promoting ECM youthfulness may have systemic benefit

Meeting Report: Aging Research and Drug Discovery

Aging is the single largest risk factor for most chronic diseases, and thus possesses large socioeconomic interest to continuously aging societies. Consequently, the field of aging research is expanding alongside a growing focus from the industry and investors in aging research. This year's 8th Annual Aging Research and Drug Discovery ARDD) meeting was organized as a hybrid meeting from August 30th to September 3rd 2021 with more than 130 attendees participating on-site at the Ceremonial Hall at University of Copenhagen, Denmark, and 1800 engaging online. The conference comprised of presentations from 75 speakers focusing on new research in topics including mechanisms of aging and how these can be modulated as well as the use of AI and new standards of practices within aging research. This year, a longevity workshop was included to build stronger connections with the clinical community

ARDD 2020: from aging mechanisms to interventions

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA

Dataset: CRISPR-activated expression of collagen col-120 increases lifespan and heat tolerance

Extended Data Fil

Dataset: Estimation of C. elegans cell- and tissue volumes

Updated File: Cell- and Tissue Volumes, including Syncytia and Ploidy. This table provides all the primary data obtained from measuring cell and tissue volumes of the Virtual Worm and the information collected from the literature on ploidy and syncytia.Related Publication:</p&gt