Abstract:Autophagy
is a catabolic process to eliminate defective cellular molecules via lysosome-mediated degradation. Dysfunctional autophagy is associated with accelerated aging, whereas stimulation of autophagy could have potent anti-aging effects. We report that cannabidiol (CBD), a natural compound from Cannabis sativa, extends lifespan and rescues age-associated physiological declines in C. elegans. CBD promoted autophagic flux in nerve-ring neurons visualized by a tandem-tagged LGG-1 reporter during aging in C.… Show more
“…Thus, early-life induction of TLs might help to attenuate the autophagic load at older ages by providing robust autophagic turnover throughout life. Accordingly, continuous autophagy stimulation by other approaches has been shown to extend lifespan and healthspan in various species (Carmona-Gutierrez et al, 2019; Ogasawara et al, 2020; Wang et al, 2022). Remarkably, even short-term rapamycin administration in young individuals results in prolonged autophagy activation that suppresses age-related pathologies in the gut (Juricic et al, 2022).…”
Although life expectancy has increased, longer lifespans do not always align with prolonged healthspans and, as a result, the occurrence of age-related degenerative diseases continues to increase. Thus, biomedical research has been shifting focus to strategies that enhance both lifespan and healthspan concurrently. Two major transcription factors that have been heavily studied in the context of aging and longevity are DAF-16/FOXO and HLH-30/TFEB; however, how these two factors coordinate to promote longevity is still not fully understood. In this study, we reveal a new facet of their cooperation that supports healthier aging in C. elegans. Namely, we demonstrate that the combinatorial effect of daf-16 and hlh-30 is required to trigger robust lysosomal tubulation, which contributes to systemic health benefits in late age by enhancing cross-tissue proteostasis mechanisms. Remarkably, this change in lysosomal morphology can be artificially induced via overexpression of SVIP, a previously characterized tubular lysosome stimulator, even when one of the key transcription factors, DAF-16, is absent. This adds to growing evidence that SVIP could be utilized to employ tubular lysosome activity in adverse conditions or disease states. Mechanistically, intestinal overexpression of SVIP leads to nuclear accumulation of HLH-30 in gut and non-gut tissues and triggers global gene expression changes that promotes systemic health benefits. Collectively, our work reveals a new cellular process that is under the control of DAF-16 and HLH-30 and provides further insight into how these two transcription factors may be exerting their pro-health effects.
“…Thus, early-life induction of TLs might help to attenuate the autophagic load at older ages by providing robust autophagic turnover throughout life. Accordingly, continuous autophagy stimulation by other approaches has been shown to extend lifespan and healthspan in various species (Carmona-Gutierrez et al, 2019; Ogasawara et al, 2020; Wang et al, 2022). Remarkably, even short-term rapamycin administration in young individuals results in prolonged autophagy activation that suppresses age-related pathologies in the gut (Juricic et al, 2022).…”
Although life expectancy has increased, longer lifespans do not always align with prolonged healthspans and, as a result, the occurrence of age-related degenerative diseases continues to increase. Thus, biomedical research has been shifting focus to strategies that enhance both lifespan and healthspan concurrently. Two major transcription factors that have been heavily studied in the context of aging and longevity are DAF-16/FOXO and HLH-30/TFEB; however, how these two factors coordinate to promote longevity is still not fully understood. In this study, we reveal a new facet of their cooperation that supports healthier aging in C. elegans. Namely, we demonstrate that the combinatorial effect of daf-16 and hlh-30 is required to trigger robust lysosomal tubulation, which contributes to systemic health benefits in late age by enhancing cross-tissue proteostasis mechanisms. Remarkably, this change in lysosomal morphology can be artificially induced via overexpression of SVIP, a previously characterized tubular lysosome stimulator, even when one of the key transcription factors, DAF-16, is absent. This adds to growing evidence that SVIP could be utilized to employ tubular lysosome activity in adverse conditions or disease states. Mechanistically, intestinal overexpression of SVIP leads to nuclear accumulation of HLH-30 in gut and non-gut tissues and triggers global gene expression changes that promotes systemic health benefits. Collectively, our work reveals a new cellular process that is under the control of DAF-16 and HLH-30 and provides further insight into how these two transcription factors may be exerting their pro-health effects.
“…In the present study, we demonstrated that DMSO-induced oxidative stress is accompanied by the inhibition of SIRT3 and SOD2 and that LnHS prevented the downregulation of both enzymes induced by DMSO. Previously, a modulation of SIRT proteins had been highlighted but only by phytocannabinoids and never by the lignamide fraction ( Gerasymchuck et al, 2022 ; Wang et al, 2022 ). Similarly, the effects of hemp extracts on the modulation of IL-8 have been found for phytocannabinoids but not considering different extracts and cellular models such as lung epithelial cells, macrophages, and human keratinocytes ( Anil et al, 2021 ; Suryavanshi et al, 2022 ; Tortolani et al, 2023 ).…”
Section: Discussionmentioning
confidence: 99%
“…In addition to oxidative stress, mitochondrial malfunction seems also to be implicated in DMSO detrimental effects; sirtuins are the main regulators of mitochondrial stress response ( Yuan et al, 2014 ). The sirtuin family comprises a group of highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases, consisting of seven species in mammals, known as sirtuin 1–7 (SIRT1-7) ( Wang et al, 2022 ).…”
Introduction: Dimethyl sulfoxide (DMSO) is widely used as a diluent and/or solvent for pharmacological compounds. Furthermore, DMSO crosses the blood-brain barrier acting on the nervous system. The natural compounds phenylamides and lignanamides (LnHS) have protective effects on neuronal health, being promising neuroprotective candidates. In this scenario, we evaluated the impact of DMSO and/or LnHS on SH-SY5Y and U-87 cells, taken as in vitro model of neurons and glia.Methods: Cells were treated with DMSO and/or LnHS at different doses and proliferation (MTT and trypan blue counting, colony forming ability, autophagy, oxidative stress (NO, ROS determination) and inflammatory (IL8, IL6, TNFα mRNA expression) response was evaluated.Results: We found that DMSO reduces both neuronal and glial cell viability, while LnHS does not affect viability of SH-SY5Y cells but reduces that of U-87 cells. Therefore, we focused on SHSY5Y cells and investigated whether LnHS could counteract DMSO toxicity. LnHS partially attenuates the inhibitory effects of DMSO on cell viability and restores the colony-forming ability of SH-SY5Y cells exposed to DMSO. Furthermore, we found that co-administration of LnHS modulates the expression of SIRT3 and SOD2 enzymes, reduces nitrite release and ROS generation increasing IL-8 levels. Interestingly, co-administration of LnHS counteracts the DMSO-induced production of IL-6, while no modification in TNF-α was found.Discussion: Our study indicates LnHS as a potential feasible compound to support neuronal health as it counteracts DMSO induced cytotoxic effects by improving SH-SY5Y cells survival. Further studies are needed to clarify the molecular mechanisms underlying the LnHS biological activities.
“…Cannabidiol, a natural compound from Cannabis sativa L. (Cannabaceae) extended lifespan and improved neuronal health in C. elegans by induction of autophagy (Ref. 226). Figure 5.Autophagy-related pathways regulated by natural compounds in neurological aging (Figure created with Biorender.com).…”
Section: Natural Active Compounds In Longevity Interventionmentioning
The term ‘autophagy’ literally translates to ‘self-eating’ and alterations to autophagy have been identified as one of the several molecular changes that occur with aging in a variety of species. Autophagy and aging, have a complicated and multifaceted relationship that has recently come to light thanks to breakthroughs in our understanding of the various substrates of autophagy on tissue homoeostasis. Several studies have been conducted to reveal the relationship between autophagy and age-related diseases. The present review looks at a few new aspects of autophagy and speculates on how they might be connected to both aging and the onset and progression of disease. Additionally, we go over the most recent preclinical data supporting the use of autophagy modulators as age-related illnesses including cancer, cardiovascular and neurodegenerative diseases, and metabolic dysfunction. It is crucial to discover important targets in the autophagy pathway in order to create innovative therapies that effectively target autophagy. Natural products have pharmacological properties that can be therapeutically advantageous for the treatment of several diseases and they also serve as valuable sources of inspiration for the development of possible new small-molecule drugs. Indeed, recent scientific studies have shown that several natural products including alkaloids, terpenoids, steroids, and phenolics, have the ability to alter a number of important autophagic signalling pathways and exert therapeutic effects, thus, a wide range of potential targets in various stages of autophagy have been discovered. In this review, we summarised the naturally occurring active compounds that may control the autophagic signalling pathways.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
