Spermidine is essential for fasting-mediated autophagy and longevity.

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.

A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.

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.

Inhibition of CERS1 in skeletal muscle exacerbates age-related muscle dysfunction.

Age-related muscle wasting and dysfunction render the elderly population vulnerable and incapacitated, while underlying mechanisms are poorly understood. Here, we implicate the CERS1 enzyme of the de novo sphingolipid synthesis pathway in the pathogenesis of age-related skeletal muscle impairment. In humans, CERS1 abundance declines with aging in skeletal muscle cells and, correlates with biological pathways involved in muscle function and myogenesis. Furthermore, CERS1 is upregulated during myogenic differentiation. Pharmacological or genetic inhibition of CERS1 in aged mice blunts myogenesis and deteriorates aged skeletal muscle mass and function, which is associated with the occurrence of morphological features typical of inflammation and fibrosis. Ablation of the CERS1 orthologue lagr-1 in Caenorhabditis elegans similarly exacerbates the age-associated decline in muscle function and integrity. We discover genetic variants reducing CERS1 expression in human skeletal muscle and Mendelian randomization analysis in the UK biobank cohort shows that these variants reduce muscle grip strength and overall health. In summary, our findings link age-related impairments in muscle function to a reduction in CERS1, thereby underlining the importance of the sphingolipid biosynthesis pathway in age-related muscle homeostasis.

Local coordination of mRNA storage and degradation near mitochondria modulates C. elegans ageing.

Mitochondria are central regulators of healthspan and lifespan, yet the intricate choreography of multiple, tightly controlled steps regulating mitochondrial biogenesis remains poorly understood. Here, we uncover a pivotal role for specific elements of the 5'-3' mRNA degradation pathway in the regulation of mitochondrial abundance and function. We find that the mRNA degradation and the poly-A tail deadenylase CCR4-NOT complexes form distinct foci in somatic Caenorhabditis elegans cells that physically and functionally associate with mitochondria. Components of these two multi-subunit complexes bind transcripts of nuclear-encoded mitochondria-targeted proteins to regulate mitochondrial biogenesis during ageing in an opposite manner. In addition, we show that balanced degradation and storage of mitochondria-targeted protein mRNAs are critical for mitochondrial homeostasis, stress resistance and longevity. Our findings reveal a multifaceted role of mRNA metabolism in mitochondrial biogenesis and show that fine-tuning of mRNA turnover and local translation control mitochondrial abundance and promote longevity in response to stress and during ageing.

MitoSNARE Assembly and Disassembly Factors Regulate Basal Autophagy and Aging in C. elegans.

SNARE proteins reside between opposing membranes and facilitate vesicle fusion, a physiological process ubiquitously required for secretion, endocytosis and autophagy. With age, neurosecretory SNARE activity drops and is pertinent to age-associated neurological disorders. Despite the importance of SNARE complex assembly and disassembly in membrane fusion, their diverse localization hinders the complete understanding of their function. Here, we revealed a subset of SNARE proteins, the syntaxin SYX-17, the synaptobrevins VAMP-7, SNB-6 and the tethering factor USO-1, to be either localized or in close proximity to mitochondria, in vivo. We term them mitoSNAREs and show that animals deficient in mitoSNAREs exhibit increased mitochondria mass and accumulation of autophagosomes. The SNARE disassembly factor NSF-1 seems to be required for the effects of mitoSNARE depletion. Moreover, we find mitoSNAREs to be indispensable for normal aging in both neuronal and non-neuronal tissues. Overall, we uncover a previously unrecognized subset of SNAREs that localize to mitochondria and propose a role of mitoSNARE assembly and disassembly factors in basal autophagy regulation and aging.

Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.

Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.

Mitochondrial biogenesis in organismal senescence and neurodegeneration.

Mitochondrial biogenesis is indispensable for organismal homeostasis. The semi-autonomous nature of mitochondria renders their biogenesis rather complex, as it requires the contribution of the nucleus, the cytoplasm and the organelle itself. Recently, several transcription regulators, RNA binding proteins and outer mitochondrial membrane (OMM) components have been implicated in the coordination of the process. Both the expression and the abundance of several of these factors are altered during ageing, and their impairment can have diverse, yet principally detrimental, effects on lifespan. These findings converge on the notion that mitochondrial biogenesis is an age-modulated process that, when perturbed, compromises survival. Notably, core brain functions are dependent on mitochondrial metabolite availability. Indeed, emerging evidence indicates that mitochondrial biogenesis regulators play important roles in the onset and progression of severe neurodegenerative syndromes such as AD, PD and HD. These devastating human pathologies remain incurable to date. A better understanding of the mechanisms that govern mitochondrial biogenesis could facilitate the development of effective pharmaceutical interventions against these diseases.

Hypoxia and Selective Autophagy in Cancer Development and Therapy.

Low oxygen availability, a condition known as hypoxia, is a common feature of various pathologies including stroke, ischemic heart disease, and cancer. Hypoxia adaptation requires coordination of intricate pathways and mechanisms such as hypoxia-inducible factors (HIFs), the unfolded protein response (UPR), mTOR, and autophagy. Recently, great effort has been invested toward elucidating the interplay between hypoxia-induced autophagy and cancer cell metabolism. Although novel types of selective autophagy have been identified, including mitophagy, pexophagy, lipophagy, ERphagy and nucleophagy among others, their potential interface with hypoxia response mechanisms remains poorly understood. Autophagy activation facilitates the removal of damaged cellular compartments and recycles components, thus promoting cell survival. Importantly, tumor cells rely on autophagy to support self-proliferation and metastasis; characteristics related to poor disease prognosis. Therefore, a deeper understanding of the molecular crosstalk between hypoxia response mechanisms and autophagy could provide important insights with relevance to cancer and hypoxia-related pathologies. Here, we survey recent findings implicating selective autophagy in hypoxic responses, and discuss emerging links between these pathways and cancer pathophysiology.

Mitophagy and age-related pathologies: Development of new therapeutics by targeting mitochondrial turnover.

Mitochondria are highly dynamic and semi-autonomous organelles, essential for many fundamental cellular processes, including energy production, metabolite synthesis, ion homeostasis, lipid metabolism and initiation of apoptotic cell death. Proper mitochondrial physiology is a prerequisite for health and survival. Generation of new and removal of damaged or unwanted mitochondria are tightly controlled processes that need to be accurately coordinated for the maintenance of mitochondrial and cellular homeostasis. Mitophagy is a conserved, mitochondria-specific autophagic clearance process. An intricate regulatory network balances mitophagy with mitochondrial biogenesis. Proper coordination of these opposing processes is important for stress resistance and longevity. Age-dependent decline of mitophagy both inhibits removal of dysfunctional or superfluous mitochondria and impairs mitochondrial biogenesis resulting in progressive mitochondrial accretion and consequently, deterioration of cell function. Nodal regulatory factors that contribute to mitochondrial homeostasis have been implicated in the pathogenesis of several age-associated pathologies, such as neurodegenerative and cardiovascular disorders and cancer, among others. Thus, mitophagy is emerging as a potential target for therapeutic interventions against diseases associated with ageing. In this review, we survey the molecular mechanisms that govern and interface mitophagy with mitochondrial biogenesis, focusing on key elements that hold promise for the development of pharmacological approaches towards enhancing healthspan and quality of life in the elderly.

Mitochondrial biogenesis and clearance: a balancing act.

Mitochondria are semi-autonomous organelles of prokaryotic origin that are postulated to have been acquired by eukaryotic cells through an early endosymbiotic event. Except for their main role in energy production, they are also implicated in fundamental cellular processes, including ion homeostasis, lipid metabolism, and initiation of apoptotic cell death. Perturbed mitochondrial function has been correlated with severe human pathologies such as type-2 diabetes, cardiovascular, and neurodegenerative diseases. Thus, proper mitochondrial physiology is a prerequisite for health and survival. Cells have developed sophisticated and elaborate mechanisms to adapt to stress conditions and alterations in metabolic demands, by regulating mitochondrial number and function. Hence, the generation of new and the removal of damaged or unwanted mitochondria are highly regulated processes that need to be accurately coordinated for the maintenance of mitochondrial and cellular homeostasis. Here, we survey recent research findings that advance our understanding and highlight the importance of the underlying molecular mechanisms.

Protein synthesis as an integral quality control mechanism during ageing.

Ageing is manifested as functional and structural deterioration that affects cell and tissue physiology. mRNA translation is a central cellular process, supplying cells with newly synthesized proteins. Accumulating evidence suggests that alterations in protein synthesis are not merely a corollary but rather a critical factor for the progression of ageing. Here, we survey protein synthesis regulatory mechanisms and focus on the pre-translational regulation of the process exerted by non-coding RNA species, RNA binding proteins and alterations of intrinsic RNA properties. In addition, we discuss the tight relationship between mRNA translation and two central pathways that modulate ageing, namely the insulin/IGF-1 and TOR signalling cascades. A thorough understanding of the complex interplay between protein synthesis regulation and ageing will provide critical insights into the pathogenesis of age-related disorders, associated with impaired proteostasis and protein quality control.