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Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine-hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity., (© 2024. The Author(s).)

Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies. This fasting-induced surge in spermidine constitutes the critical first step of a phylogenetically conserved biochemical cascade that leads to spermidine-dependent hypusination of EIF5A (eukaryotic translation initiation factor 5A), which favors the translation of the pro-macroautophagic/autophagic TFEB (transcription factor EB), and hence an increase in autophagic flux. We observed that genetic or pharmacological inhibition of the spermidine increase by inhibition of ODC1 (ornithine decarboxylase 1) prevents the pro-autophagic and antiaging effects of fasting in yeast, nematodes, flies and mice. Moreover, knockout or knockdown of the enzymes required for EIF5A hypusination abolish fasting-mediated autophagy enhancement and longevity extension in these organisms. Of note, autophagy and longevity induced by rapamycin obey the same rule, meaning that they are tied to an increase in spermidine synthesis. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin. Abbreviation : EIF5A: eukaryotic translation initiation factor 5A; IGF1: insulin like growth factor 1; MTOR: mechanistic target of rapamycin kinase; ODC1: ornithine decarboxylase 1; TFEB: transcription factor EB.

Aging and obesity are intertwined in a vicious circle that leads to declining general and brain-specific functions. Kapogiannis and colleagues demonstrate that implementing just 8 weeks of two distinct low-calorie regimes can enhance cognition and biochemical markers of aging in older people with obesity., Competing Interests: Declaration of interests F.M. has equity interests in The Longevity Labs (TLL) and Samsara Therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Optimizing food quantity and fasting time may improve health and lifespan. We summarize emerging knowledge on sex, age, and circadian timing as important determinants for the efficacy of dietary interventions and highlight results from Duregon et al. pointing to a favorable combination of caloric restriction (CR) and fasting in aged female mice., Competing Interests: Declaration of interests F.M. is a scientific cofounder of Samsara Therapeutics, a company that develops new pharmacological autophagy inducers. F.M. has equity interests in and is an advisor of The Longevity Labs (TLL)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood-brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis., (© 2023. The Author(s).)

Metabolic regulation of glucose can be altered by fasting periods. We examined glucose metabolism and metabolomics profiles after 12 h and 36 h fasting in non-obese and obese participants and people with type 2 diabetes using oral glucose tolerance (OGTT) and intravenous glucose tolerance testing (IVGTT). Insulin sensitivity was estimated by established indices and mass spectrometric metabolomics was performed on fasting serum samples. Participants had a mean age of 43 ± 16 years (62% women). Fasting levels of glucose, insulin and C-peptide were significantly lower in all cohorts after 36 h compared to 12 h fasting ( p < 0.05). In non-obese participants, glucose levels were significantly higher after 36 h compared to 12 h fasting at 120 min of OGTT (109 ± 31 mg/dL vs. 79 ± 18 mg/dL; p = 0.001) but insulin levels were lower after 36 h of fasting at 30 min of OGTT (41.2 ± 34.1 mU/L after 36 h vs. 56.1 ± 29.7 mU/L; p < 0.05). In contrast, no significant differences were observed in obese participants or people with diabetes. Insulin sensitivity improved in all cohorts after 36 h fasting. In line, metabolomics revealed subtle baseline differences and an attenuated metabolic response to fasting in obese participants and people with diabetes. Our data demonstrate an improved insulin sensitivity after 36 h of fasting with higher glucose variations and reduced early insulin response in non-obese people only.

Aging involves the systemic deterioration of all known cell types in most eukaryotes. Several recently discovered compounds that extend the healthspan and lifespan of model organisms decelerate pathways that govern the aging process. Among these geroprotectors, spermidine, a natural polyamine ubiquitously found in organisms from all kingdoms, prolongs the lifespan of fungi, nematodes, insects and rodents. In mice, it also postpones the manifestation of various age-associated disorders such as cardiovascular disease and neurodegeneration. The specific features of spermidine, including its presence in common food items, make it an interesting candidate for translational aging research. Here, we review novel insights into the geroprotective mode of action of spermidine at the molecular level, as we discuss strategies for elucidating its clinical potential., (© 2022. Springer Nature America, Inc.)

Fasting provokes fundamental changes in the activation of metabolic and signaling pathways leading to longer and healthier lifespans in animal models. Although the involvement of different metabolites in fueling human fasting metabolism is well known, the contribution of tissues and organs to their supply remains partly unclear. Also, changes in organ volume and composition remain relatively unexplored. Thus, processes involved in remodeling tissues during fasting and food reintroduction need to be better understood. Therefore, this study will apply state-of-the-art techniques to investigate the effects of long-term fasting (LF) and food reintroduction in humans by a multi-systemic approach focusing on changes in body composition, organ and tissue volume, lipid transport and storage, sources of protein utilization, blood metabolites, and gut microbiome profiles in a single cohort. This is a prospective, single-arm, monocentric trial. One hundred subjects will be recruited and undergo 9 ± 3 day-long fasting periods (250 kcal/day). We will assess changes in the composition of organs, bones and blood lipid profiles before and after fasting, as well as high-density lipoprotein (HDL) transport and storage, untargeted metabolomics of peripheral blood mononuclear cells (PBMCs), protein persulfidation and shotgun metagenomics of the gut microbiome. The first 32 subjects, fasting for 12 days, will be examined in more detail by magnetic resonance imaging (MRI) and spectroscopy to provide quantitative information on changes in organ volume and function, followed by an additional follow-up examination after 1 and 4 months. The study protocol was approved by the ethics board of the State Medical Chamber of Baden-Württemberg on 26.07.2021 and registered at ClinicalTrials.gov (NCT05031598). The results will be disseminated through peer-reviewed publications, international conferences and social media., Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT05031598]., Competing Interests: Authors FG, RM, and FWT are employees of the Buchinger Wilhelmi Development and Holding GmbH, Überlingen. Author CvS was employed by Omegametrix. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Grundler, Viallon, Mesnage, Ruscica, von Schacky, Madeo, Hofer, Mitchell, Croisille and Wilhelmi de Toledo.)

Background: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial., Methods: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well., Results: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity., Conclusions: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.

Amyloid beta 42 (Abeta42) is the principal trigger of neurodegeneration during Alzheimer's disease (AD). However, the etiology of its noxious cellular effects remains elusive. In a combinatory genetic and proteomic approach using a yeast model to study aspects of intracellular Abeta42 toxicity, we here identify the HSP40 family member Ydj1, the yeast orthologue of human DnaJA1, as a crucial factor in Abeta42-mediated cell death. We demonstrate that Ydj1/DnaJA1 physically interacts with Abeta42 (in yeast and mouse), stabilizes Abeta42 oligomers, and mediates their translocation to mitochondria. Consequently, deletion of YDJ1 strongly reduces co-purification of Abeta42 with mitochondria and prevents Abeta42-induced mitochondria-dependent cell death. Consistently, purified DnaJ chaperone delays Abeta42 fibrillization in vitro, and heterologous expression of human DnaJA1 induces formation of Abeta42 oligomers and their deleterious translocation to mitochondria in vivo. Finally, downregulation of the Ydj1 fly homologue, Droj2, improves stress resistance, mitochondrial morphology, and memory performance in a Drosophila melanogaster AD model. These data reveal an unexpected and detrimental role for specific HSP40s in promoting hallmarks of Abeta42 toxicity., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Importance: Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline., Objective: To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group., Design, Setting, and Participants: This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021., Interventions: One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (0.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention., Main Outcomes and Measures: Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed., Results: A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups., Conclusions and Relevance: In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage., Trial Registration: ClinicalTrials.gov Identifier: NCT03094546.

Age-associated diseases are rising to pandemic proportions, exposing the need for efficient and low-cost methods to tackle these maladies at symptomatic, behavioral, metabolic, and physiological levels. While nutrition and health are closely intertwined, our limited understanding of how diet precisely influences disease often precludes the medical use of specific dietary interventions. Caloric restriction (CR) has approached clinical application as a powerful, yet simple, dietary modulation that extends both life- and healthspan in model organisms and ameliorates various diseases. However, due to psychological and social-behavioral limitations, CR may be challenging to implement into real life. Thus, CR-mimicking interventions have been developed, including intermittent fasting, time-restricted eating, and macronutrient modulation. Nonetheless, possible side effects of CR and alternatives thereof must be carefully considered. We summarize key concepts and differences in these dietary interventions in humans, discuss their molecular effects, and shed light on advantages and disadvantages., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Numerous pro-autophagic dietary interventions are being investigated for their potential cancer-preventive or therapeutic effects. This applies to different fasting regimens, methionine restriction and ketogenic diets. In addition, the supplementation of specific micronutrients such as nicotinamide (vitamin B3) or spermidine induces autophagy. In humans, leanness, plant-based diets (that may lead to partial methionine restriction) and high dietary uptake of spermidine are associated with a low incidence of cancers. Moreover, clinical trials have demonstrated the capacity of nicotinamide to prevent non-melanoma skin carcinogenesis. Multiple interventional trials are evaluating the capacity of autophagy-inducing regimens to improve the outcome of chemotherapy and immunotherapy. Here, we discuss the mechanistic underpinnings of autophagy induction by nutritional interventions, as well as the mechanisms through which autophagy induction in malignant or immune cells improves anticancer immunosurveillance., Competing Interests: Conflicts of interest O.K. is a cofounder of Samsara Therapeutics. G.K. has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sotio, Tollys, Vascage and Vasculox/Tioma. G.K. has been consulting for Reithera. G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. G.K. is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. S.J.H. declares no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The human diet and dietary patterns are closely linked to the health status. High-calorie Western-style diets have increasingly come under scrutiny as their caloric load and composition contribute to the development of non-communicable diseases, such as diabetes, cancer, obesity, and cardiovascular disorders. On the other hand, calorie-reduced and health-promoting diets have shown promising results in maintaining health and reducing disease burden throughout aging. More recently, pharmacological Caloric Restriction Mimetics (CRMs) have gained interest of the public and scientific community as promising candidates that mimic some of the myriad of effects induced by caloric restriction. Importantly, many of the CRM candidates activate autophagy, prolong life- and healthspan in model organisms and ameliorate diverse disease symptoms without the need to cut calories. Among others, glycolytic inhibitors (e.g., D-allulose, D-glucosamine), hydroxycitric acid, NAD + precursors, polyamines (e.g., spermidine), polyphenols (e.g., resveratrol, dimethoxychalcones, curcumin, EGCG, quercetin) and salicylic acid qualify as CRM candidates, which are naturally available via foods and beverages. However, it is yet unclear how these bioactive substances contribute to the benefits of healthy diets. In this review, we thus discuss dietary sources, availability and intake levels of dietary CRMs. Finally, since translational research on CRMs has entered the clinical stage, we provide a summary of their effects in clinical trials., Competing Interests: FM has equity interest in and is advisor of TLL The Longevity Labs GmbH and Samsara Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hofer, Davinelli, Bergmann, Scapagnini and Madeo.)

Spermidine is a natural polyamine, central to cellular homeostasis and growth, that promotes macroautophagy/autophagy. The polyamine pathway is highly conserved from bacteria to mammals and spermidine (prominently found in some kinds of aged cheese, wheat germs, nuts, soybeans, and fermented products thereof, among others) is an intrinsic part of the human diet. Apart from nutrition, spermidine is available to mammalian organisms from intracellular biosynthesis and microbial production in the gut. Importantly, externally supplied spermidine (via drinking water or food) prolongs lifespan, activates autophagy, improves mitochondrial function, and refills polyamine pools that decline during aging in various tissues of model organisms, including mice. In two adjacent studies, we explored how dietary spermidine supplementation enhances eEF5/EIF5A hypusination, cerebral mitochondrial function and cognition in aging Drosophila melanogaster and mice.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans., Competing Interests: Declaration of interests F.M., S.J.S., and D.C.-G. have equity interests in The Longevity Labs (TLL), a company founded in 2016 that develops natural food extracts. T.E. has equity interests in and conducts paid consultancies for TLL. G.K. holds research contracts with Bayer Healthcare, Genentech, GlaxoSmithKline, Institut Mérieux, Kaleido Biosciences, Lytix Biopharma, NuCana, Oncolinx, PharmaMar, Samsara Therapeutics, SOTIO, and Tioma Therapeutics. G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific cofounder of everImmune, a biotech company that develops immunostimulatory bacteria, and Therafast Bio. F.M. and T.E. are inventors on a pending patent application related to this work., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Ageing provokes a plethora of molecular, cellular and physiological deteriorations, including heart failure, neurodegeneration, metabolic maladaptation, telomere attrition and hair loss. Interestingly, on the molecular level, the capacity to induce autophagy, a cellular recycling and cleaning process, declines with age across a large spectrum of model organisms and is thought to be responsible for a subset of age-induced changes. Here, we show that a 6-month administration of the natural autophagy inducer spermidine in the drinking water to aged mice is sufficient to significantly attenuate distinct age-associated phenotypes. These include modulation of brain glucose metabolism, suppression of distinct cardiac inflammation parameters, decreased number of pathological sights in kidney and liver and decrease of age-induced hair loss. Interestingly, spermidine-mediated age protection was associated with decreased telomere attrition, arguing in favour of a novel cellular mechanism behind the anti-ageing effects of spermidine administration.

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD + ). Elevating NAD + by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD + precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD + precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Natural polyamines (spermidine and spermine) are small, positively charged molecules that are ubiquitously found within organisms and cells. They exert numerous (intra)cellular functions and have been implicated to protect against several age-related diseases. Although polyamine levels decline in a complex age-dependent, tissue-, and cell type-specific manner, they are maintained in healthy nonagenarians and centenarians. Increased polyamine levels, including through enhanced dietary intake, have been consistently linked to improved health and reduced overall mortality. In preclinical models, dietary supplementation with spermidine prolongs life span and health span. In this review, we highlight salient aspects of nutritional polyamine intake and summarize the current knowledge of organismal and cellular uptake and distribution of dietary (and gastrointestinal) polyamines and their impact on human health. We further summarize clinical and epidemiological studies of dietary polyamines.

Autophagy is a catabolic pathway with multifaceted roles in cellular homeostasis. This process is also involved in the antiviral response at multiple levels, including the direct elimination of intruding viruses (virophagy), the presentation of viral antigens, the fitness of immune cells, and the inhibition of excessive inflammatory reactions. In line with its central role in immunity, viruses have evolved mechanisms to interfere with or to evade the autophagic process, and in some cases, even to harness autophagy or constituents of the autophagic machinery for their replication. Given the devastating consequences of the current COVID-19 pandemic, the question arises whether manipulating autophagy might be an expedient approach to fight the novel coronavirus SARS-CoV-2. In this piece, we provide a short overview of the evidence linking autophagy to coronaviruses and discuss whether such links may provide actionable targets for therapeutic interventions., Competing Interests: Conflict of interest: D.C-G., G.K. and F.M. are the scientific co-founders of Samsara Therapeutics, a company that develops novel pharmacological autophagy inducers. A.Z. has equity interests in Samsara Therapeutics. F.M. and D.C-G. have equity interests in TLL (The Longevity Labs), a company that develops natural food extracts., (Copyright: © 2020 Carmona-Gutierrez et al.)

Unicellular organisms like yeast can undergo controlled demise in a manner that is partly reminiscent of mammalian cell death. This is true at the levels of both mechanistic and functional conservation. Yeast offers the combination of unparalleled genetic amenability and a comparatively simple biology to understand both the regulation and evolution of cell death. In this minireview, we address the capacity of the nucleus as a regulatory hub during yeast regulated cell death (RCD), which is becoming an increasingly central question in yeast RCD research. In particular, we explore and critically discuss the available data on stressors and signals that specifically impinge on the nucleus. Moreover, we also analyze the current knowledge on nuclear factors as well as on transcriptional control and epigenetic events that orchestrate yeast RCD. Altogether we conclude that the functional significance of the nucleus for yeast RCD in undisputable, but that further exploration beyond correlative work is necessary to disentangle the role of nuclear events in the regulatory network., Competing Interests: Conflict of interest No competing financial interests exist., (© 2020 Elsevier Inc. All rights reserved.)

Aging is associated with functional alterations of synapses thought to contribute to age-dependent memory impairment (AMI). While therapeutic avenues to protect from AMI are largely elusive, supplementation of spermidine, a polyamine normally declining with age, has been shown to restore defective proteostasis and to protect from AMI in Drosophila. Here we demonstrate that dietary spermidine protects from age-related synaptic alterations at hippocampal mossy fiber (MF)-CA3 synapses and prevents the aging-induced loss of neuronal mitochondria. Dietary spermidine rescued age-dependent decreases in synaptic vesicle density and largely restored defective presynaptic MF-CA3 long-term potentiation (LTP) at MF-CA3 synapses (MF-CA3) in aged animals. In contrast, spermidine failed to protect CA3-CA1 hippocampal synapses characterized by postsynaptic LTP from age-related changes in function and morphology. Our data demonstrate that dietary spermidine attenuates age-associated deterioration of MF-CA3 synaptic transmission and plasticity. These findings provide a physiological and molecular basis for the future therapeutic usage of spermidine.

Caloric restriction mimetics (CRMs) are natural or synthetic compounds that mimic the health-promoting and longevity-extending effects of caloric restriction. CRMs provoke the deacetylation of cellular proteins coupled to an increase in autophagic flux in the absence of toxicity. Here, we report the identification of a novel candidate CRM, namely 3,4-dimethoxychalcone (3,4-DC), among a library of polyphenols. When added to several different human cell lines, 3,4-DC induced the deacetylation of cytoplasmic proteins and stimulated autophagic flux. At difference with other well-characterized CRMs, 3,4-DC, however, required transcription factor EB (TFEB)- and E3 (TFE3)-dependent gene transcription and mRNA translation to trigger autophagy. 3,4-DC stimulated the translocation of TFEB and TFE3 into nuclei both in vitro and in vivo, in hepatocytes and cardiomyocytes. 3,4-DC induced autophagy in vitro and in mouse organs, mediated autophagy-dependent cardioprotective effects, and improved the efficacy of anticancer chemotherapy in vivo. Altogether, our results suggest that 3,4-DC is a novel CRM with a previously unrecognized mode of action., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The age-induced deterioration of the organism results in detrimental and ultimately lethal pathologies. The process of aging itself involves a plethora of different mechanisms that should be subverted concurrently to delay and/or prevent age-related maladies. We have identified a natural compound, 4,4'-dimethoxychalcone (DMC), which promotes longevity in yeast, worms and flies, and protects mice from heart injury and liver toxicity. Interestingly, both the DMC-mediated lifespan extension and the cardioprotection depend on macroautophagy/autophagy whereas hepatoprotection does not. DMC induces autophagy by inhibiting specific GATA transcription factors (TFs), independently of the TORC1 kinase pathway. The autophagy-independent beneficial effects of DMC might involve its antioxidative properties. DMC treatment results in a phylogenetically conserved, systemic impact on the metabolome, which is most prominently characterized by changes in cellular amino acid composition. Altogether, DMC exerts multiple, geroprotective effects by igniting distinct pathways, and thus represents a potential pharmacological agent that delays aging through multipronged effects.

Autophagy, a membrane-dependent catabolic process, ensures survival of aging cells and depends on the cellular energetic status. Acetyl-CoA carboxylase 1 (Acc1) connects central energy metabolism to lipid biosynthesis and is rate-limiting for the de novo synthesis of lipids. However, it is unclear how de novo lipogenesis and its metabolic consequences affect autophagic activity. Here, we show that in aging yeast, autophagy levels highly depend on the activity of Acc1. Constitutively active Acc1 ( acc1 S/A ) or a deletion of the Acc1 negative regulator, Snf1 (yeast AMPK), shows elevated autophagy levels, which can be reversed by the Acc1 inhibitor soraphen A. Vice versa, pharmacological inhibition of Acc1 drastically reduces cell survival and results in the accumulation of Atg8-positive structures at the vacuolar membrane, suggesting late defects in the autophagic cascade. As expected, acc1 S/A cells exhibit a reduction in acetate/acetyl-CoA availability along with elevated cellular lipid content. However, concomitant administration of acetate fails to fully revert the increase in autophagy exerted by acc1 S/A Instead, administration of oleate, while mimicking constitutively active Acc1 in WT cells, alleviates the vacuolar fusion defects induced by Acc1 inhibition. Our results argue for a largely lipid-dependent process of autophagy regulation downstream of Acc1. We present a versatile genetic model to investigate the complex relationship between acetate metabolism, lipid homeostasis, and autophagy and propose Acc1-dependent lipogenesis as a fundamental metabolic path downstream of Snf1 to maintain autophagy and survival during cellular aging., (© 2019 Gross et al.)

GATA transcription factors (TFs) are a conserved family of zinc-finger TFs that fulfill diverse functions across eukaryotes. Accumulating evidence suggests that GATA TFs also play a role in lifespan regulation. In a recent study, we have identified a natural compound, 4,4' dimethoxychalcone (DMC) that extends lifespan depending on reduced activity of distinct GATA TFs. Prolonged lifespan by DMC treatment depends on autophagy, a protective cellular self-cleaning mechanism. In yeast, DMC reduces the activity of the GATA TF Gln3 and, at the same time, deletion of GLN3 increases autophagy levels during cellular aging per se. Here, we examine current data on the involvement of GATA TFs in the regulation of both autophagy and lifespan in different organisms and explore, if GATA TFs are suitable targets for anti-aging interventions., Competing Interests: Conflict of interest: O.K., G.K., D.C-G. and F.M. are the scientific co-founders of Samsara Therapeutics.

The increase in life expectancy has boosted the incidence of age-related pathologies beyond social and economic sustainability. Consequently, there is an urgent need for interventions that revert or at least prevent the pathogenic age-associated deterioration. The permanent or periodic reduction of calorie intake without malnutrition (caloric restriction and fasting) is the only strategy that reliably extends healthspan in mammals including non-human primates. However, the strict and life-long compliance with these regimens is difficult, which has promoted the emergence of caloric restriction mimetics (CRMs). We define CRMs as compounds that ignite the protective pathways of caloric restriction by promoting autophagy, a cytoplasmic recycling mechanism, via a reduction in protein acetylation. Here, we describe the current knowledge on molecular, cellular, and organismal effects of known and putative CRMs in mice and humans. We anticipate that CRMs will become part of the pharmacological armamentarium against aging and age-related cardiovascular, neurodegenerative, and malignant diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.