Fatty acids are the most efficient substrates for energy production in vertebrates and are essential components of the lipids that form biological membranes. Synthesis of triacylglycerols from ...non-esterified free fatty acids (FFAs) combined with triacylglycerol storage represents a highly efficient strategy to stockpile FFAs in cells and prevent FFA-induced lipotoxicity. Although essentially all vertebrate cells have some capacity to store and utilize triacylglycerols, white adipose tissue is by far the largest triacylglycerol depot and is uniquely able to supply FFAs to other tissues. The release of FFAs from triacylglycerols requires their enzymatic hydrolysis by a process called lipolysis. Recent discoveries thoroughly altered and extended our understanding of lipolysis. This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid' lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases. Answers to these questions will likely uncover novel strategies for the treatment of prevalent metabolic diseases.
Spermidine in health and disease Madeo, Frank; Eisenberg, Tobias; Pietrocola, Federico ...
Science,
01/2018, Volume:
359, Issue:
6374
Journal Article
Peer reviewed
Open access
Interventions that delay aging and protect from age-associated disease are slowly approaching clinical implementation. Such interventions include caloric restriction mimetics, which are defined as ...agents that mimic the beneficial effects of dietary restriction while limiting its detrimental effects. One such agent, the natural polyamine spermidine, has prominent cardioprotective and neuroprotective effects and stimulates anticancer immunosurveillance in rodent models. Moreover, dietary polyamine uptake correlates with reduced cardiovascular and cancer-related mortality in human epidemiological studies. Spermidine preserves mitochondrial function, exhibits anti-inflammatory properties, and prevents stem cell senescence. Mechanistically, it shares the molecular pathways engaged by other caloric restriction mimetics: It induces protein deacetylation and depends on functional autophagy. Because spermidine is already present in daily human nutrition, clinical trials aiming at increasing the uptake of this polyamine appear feasible.
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.
Madeo et al. summarize the current knowledge on the health-promoting potential of caloric restriction mimetics as a pharmacological option to ignite anti-aging effects. The authors thereby provide mechanistic details for each compound and evaluate the most recent literature on diverse models and clinical trials.
Caloric restriction, be it constant or intermittent, is reputed to have health-promoting and lifespan-extending effects. Caloric restriction mimetics (CRMs) are compounds that mimic the biochemical ...and functional effects of caloric restriction. In this Opinion article, we propose a unifying definition of CRMs as compounds that stimulate autophagy by favouring the deacetylation of cellular proteins. This deacetylation process can be achieved by three classes of compounds that deplete acetyl coenzyme A (AcCoA; the sole donor of acetyl groups), that inhibit acetyl transferases (a group of enzymes that acetylate lysine residues in an array of proteins) or that stimulate the activity of deacetylases and hence reverse the action of acetyl transferases. A unifying definition of CRMs will be important for the continued development of this class of therapeutic agents.
Cardiovascular diseases are the most prominent maladies in aging societies. Indeed, aging promotes the structural and functional declines of both the heart and the blood circulation system. In this ...review, we revise the contribution of known longevity pathways to cardiovascular health and delineate the possibilities to interfere with them. In particular, we evaluate autophagy, the intracellular catabolic recycling system associated with life- and health-span extension. We present genetic models, pharmacological interventions, and dietary strategies that block, reduce, or enhance autophagy upon age-related cardiovascular deterioration. Caloric restriction or caloric restriction mimetics like metformin, spermidine, and rapamycin (all of which trigger autophagy) are among the most promising cardioprotective interventions during aging. We conclude that autophagy is a fundamental process to ensure cardiac and vascular health during aging and outline its putative therapeutic importance.
Spermidine is a natural polyamine that stimulates cytoprotective macroautophagy/autophagy. External supplementation of spermidine extends lifespan and health span across species, including in yeast, ...nematodes, flies and mice. In humans, spermidine levels decline with aging, and a possible connection between reduced endogenous spermidine concentrations and age-related deterioration has been suggested. Recent epidemiological data support this notion, showing that an increased uptake of this polyamine with spermidine-rich food diminishes overall mortality associated with cardiovascular diseases and cancer. Here, we discuss nutritional and other possible routes to counteract the age-mediated decline of spermidine levels.
Highlights • Lysosomal processes associated with aging and longevity. • Executory and regulatory role of lysosomes for general and selective autophagy. • Lifespan control via lysosomal storage ...functions. • Lysosomal role in known anti-aging interventions.
Although autophagy has frequently been viewed as a cell death mechanism in the mammalian system, it is now considered as indispensable for the homeostasis of cells, tissues, and organisms. Basal or ...stress-induced autophagy plays essential and diverse roles in a variety of tissues, due to its cytoprotective properties. In this review, we briefly discuss the different homeostatic functions of autophagy that have been finely dissected in mammals through the generation and characterization of animal models with tissue-specific autophagic alterations. In addition, and given the importance of constitutive autophagy in neuronal tissues, we describe in more detail the specific roles of autophagy in the central nervous system (CNS). Finally, we discuss the contribution of autophagy malfunctions to the development of several common neurological disorders and the potential benefits of pharmacologically induced autophagy for the avoidance of neurodegeneration.
The phenomenon of aging is an intrinsic feature of life. Accordingly, the possibility to manipulate it has fascinated humans likely since time immemorial. Recent evidence is shaping a picture where ...low caloric regimes and exercise may improve healthy senescence, and several pharmacological strategies have been suggested to counteract aging. Surprisingly, the most effective interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy. Here, we critically examine drugs and behaviors to which life- or healthspan-extending properties have been ascribed and discuss the underlying molecular mechanisms.
The most effective antiaging interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy.
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.
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•For healthy, non-obese adults, ADF is safe to practice for several months•4-week ADF decreases the body weight by 4.5% and improves the fat-to-lean ratio•Cardiovascular parameters and the CVD risk are improved upon ADF•ADF reduces T3 and periodically depletes amino acids, while increasing PUFAs
Stekovic et al. show in the clinic that alternate day fasting (ADF) is a simple alternative to calorie restriction and provokes similar improvements on cardiovascular parameters and body composition. ADF was shown to be safe and beneficial in healthy, non-obese humans, not impairing immune function or bone health.
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