Category: Diet

Autophagy activation

Autophagy activation

Autophagy activation actibation lipid metabolism. Article PubMed PubMed Central CAS Google Scholar Lopez-Otin, C. Atg2, Atg9 and Atg18 in mitochondrial integrity, cardiac function and healthspan in Drosophila.

Autophagy activation -

Finally, knockout of Atg5 or Atg7 in mouse neurons leads to the appearance of cytoplasmic inclusion bodies in the brain and early-onset neurodegeneration 72 , 73 , 74 , while knockout of Lamp2 the primary receptor for CMA in the liver results in altered proteostasis and hepatic dysfunction with age Conversely, enhanced proteostasis and extended lifespan in C.

Likewise, in Drosophila , overexpression of Ref 2 P p62 ortholog or the autophagy activator FOXO reduces protein aggregation in various tissues and extends lifespan 43 , 76 , 77 , 78 , Pharmacological for example, via clonidine, rilmenidine or rapamycin or genetic for example, atg5 upregulation of autophagy in zebrafish harboring the rare p.

AlaThr variant of tau ameliorates tau pathology Increased autophagy is also associated with enhanced clearance of protein aggregates in mammals, as systemic overexpression of Atg5 or Becn1 genes with mutations that disrupt BECN1—BCL-2 binding improves proteostasis and promotes longevity in mice 44 , 81 , while overexpression of the selective autophagy mediator BAG3 suppresses tau accumulation in neurons As a complement to the genetic modulation of autophagy, treatment of Drosophila with the mTOR inhibitor rapamycin suppresses age-related protein aggregation and extends lifespan in an autophagy-dependent manner Furthermore, in cell culture and fly models, rapamycin suppresses toxicity from neurodegenerative disease-associated proteins, including mutant huntingtin, polyalanine-expansion-containing proteins and tau Autophagy has also been linked to stem cell function, with the autophagy-mediated clearance of protein aggregates central to the activation of quiescent neuronal stem cells.

Activating autophagy by overexpression of TFEB or rapamycin supplementation inhibits age-related protein aggregation and enhances neuronal and muscle stem cell function in aged mice 85 , 86 , Given the fact that stem cell exhaustion is intimately linked to age-related tissue dysfunction, these findings suggest that enhancing proteostasis specifically in stem cells may preserve many aspects of healthy tissue function during aging.

Collectively, these observations strongly support the notion that autophagy promotes healthy aging by protecting cells against toxic misfolded and aggregated proteins. Another important role for autophagy in cellular homeostasis and organismal aging is to ensure the availability of metabolites, including amino acids, lipids, carbohydrates and nucleic acids, especially during states of stress, such as nutrient starvation Fig.

Under challenging conditions, autophagy promotes cellular metabolism and survival by recycling amino acids, which are generated from the degradation of cytosolic substrates, to replenish nutrients, produce energy and promote protein synthesis.

An inability to properly recycle amino acids through autophagy is linked to growth and developmental defects in Atg5 -deficient mice and impaired growth during nitrogen starvation in several atg -deficient yeast cell lines including atg1 Δ , atg2 Δ , atg7Δ , atg11Δ , atg15Δ and atg32Δ mutants 88 , 89 , Autophagy can also be tailored to mediate the availability of carbohydrates, lipids and nucleic acids through three main cellular processes: glycophagy, lipophagy and RNAutophagy or DNAutophagy, respectively.

Glucose is the primary energy source for cellular metabolism. It is stored as glycogen, and metabolism of glucose is tightly regulated in a tissue-dependent manner that is, the liver maintains blood glucose levels, while muscles are the source of cellular energy.

However, various conditions resulting in metabolic stress, such as starvation, stimulate glycogen breakdown to augment cellular glucose levels and promote metabolic activity Glycogen can be degraded in the cytosol through the activity of glycogen phosphorylase and glycogen debranching enzymes detailed in ref.

The selective clearance of glycogen via autophagy, referred to as glycophagy, has a crucial role in glucose homeostasis. In response to nutrient deficiency, the energy sensor AMPK is activated, which in turn inhibits mTOR complex 1 mTORC1 , leading to activation of the ULK1 kinase, which is important for induction of autophagy AMPK—mTORC1—ULK1 triad Recent findings in yeast have demonstrated that Atg11 is necessary to facilitate interaction between the AMPK homolog Snf1 and the ULK1 homolog Atg1 upon glucose starvation to promote autophagy The LC3-interacting region LIR motif, also known in yeast as the Atg8-family-interacting motif AIM , in starch-binding domain-containing protein 1 STBD1 may allow cells to physically link glycogen to GABARAPL1, facilitating the transport of glycogen to lysosomes for degradation Fig.

In parallel to glycophagy, other pathways such as β-oxidation may maintain cellular bioenergetics to compensate for glucose deprivation Autophagy also has a pivotal role in maintaining cell function, not only in glucose starvation but also in conditions of excess glucose.

High glucose levels were associated with mitochondrial dysfunction, generation of reactive oxygen species and induction of autophagy in endothelial progenitor cells Under conditions of impaired autophagy, accumulation of glycogen contributes to the pathogenesis of age-related diseases.

In Pompe disease, a lysosomal storage disorder, the ability of lysosomes to degrade glycogen is impaired, owing to a deficiency in the lysosomal hydrolytic enzyme acid α-glucosidase GAA. This results in accumulation of lysosomal glycogen in many tissues, predominantly in skeletal and cardiac muscle, leading to progressive lethal skeletal myopathy and respiratory and cardiac defects Impaired tissue function from the inability of lysosomes to degrade glycogen also leads to energy deficiency in skeletal muscle.

For infantile-onset Pompe disease 98 , a promising therapeutic intervention is administration of recombinant human GAA. Furthermore, dysfunctional autophagy-mediated accumulation of glycogen has been demonstrated to be the cause of neurodegeneration in a mouse model of Lafora disease, with this accumulation suppressed when glycogen synthase is deleted These findings indicate that glycogen accumulation might be a cause, rather than a consequence, of impaired autophagy, resulting in impaired cellular function and disease.

Glycophagy, therefore, is essential for cellular function and survival, suggesting that levels of glycophagy could determine organismal health and possibly longevity.

Intracellular storage and use of lipids is critical to maintain cellular energy homeostasis. In response to starvation, triglycerides stored in lipid droplets are hydrolyzed by specific lipases into free fatty acids for energy metabolism.

Lipid droplets can also undergo selective degradation by autophagy, termed lipophagy, as an alternative mechanism for regulating lipid homeostasis Fig.

Thus far, a specific receptor coupling lipid droplets to autophagosomes and trafficking to lysosomes has not yet been identified, although LC3-mediated engulfment of lipid droplets has been observed Moreover, CMA has been implicated in degradation of the lipid droplet-associated proteins perilipin 2 PLIN2 and perilipin 3 PLIN3 Lysosomal acid lipases are involved in the degradation of lipid droplets; in particular, lipolysis is conducted primarily by adipose triglyceride lipase ATGL and hormone-sensitive lipase HSL , and selective knockdown of ATGL and HSL in mice results in selective inhibition of lipid droplet degradation, while other autophagy processes that is, degradation of proteins and organelles serve as a compensatory mechanism to replenish the reduced availability of energy substrates An age-dependent decline in basal autophagy in the liver may underlie the accumulation of hepatic lipids, which in turn has been proposed to contribute to metabolic conditions as well as impairing autophagy, a vicious cycle promoting aging For example, age-dependent reduction in CMA is likely due to alterations in the lipid composition of discrete microdomains at the lysosomal membrane, including altered dynamics and stability of the CMA receptor LAMP2A in the lysosome Autophagy and LIPLdependent lipolysis are both upregulated in germline-less C.

elegans and work interdependently to prolong lifespan The mammalian homolog of worm LIPL-4 is lysosomal acid lipase LIPA , a key enzyme involved in the hydrolysis of cholesterol via autophagy , In pathological conditions such as alcoholic fatty liver disease AFLD , impaired lipophagy has been shown to be the basis of lipid peroxidation and cellular damage.

AFLD results from excessive consumption of alcohol, leading to damage to the liver in the form of oxidative stress, excessive lipid droplet accumulation in the cytoplasm of hepatocytes steatosis , mitochondrial damage and cell death. Acute exposure to ethanol triggers lipophagy, which acts as a defense mechanism against lipid peroxidation, thereby protecting hepatocytes.

However, chronic exposure to ethanol leads to mTOR-mediated inhibition of lipophagy, which in turn contributes to lipid peroxidation and cell death 22 , , In fact, inhibition of mTOR-mediated suppression of TFEB, using torin-1, resulted in enrichment of TFEB levels in the liver and protection against steatosis and ethanol-induced liver injury Genetic overexpression of TFEB in the liver was shown to increase lysosomal biogenesis and enhance mitochondrial bioenergetics, which served as a protective mechanism against ethanol-induced liver injury in mice.

In line with these findings, knockdown of TFEB in the liver of mice resulted in more severe liver injury in response to increased ethanol consumption In addition, lipophagy is key for the differentiation of several cell types, including hepatocytes and neutrophils Knocking out ATG7 in HSCs leads to an accumulation of immature neutrophils resembling the myeloid bias of an aging hematopoietic system.

Differentiation can be rescued by supplementation with exogenous free fatty acids used for β-oxidation, further demonstrating that lipophagy usually provides these during the energy-intensive process of differentiation. Further studies on the molecular mechanisms of lipophagy, including identification of lipid-specific autophagy receptors and their impact on cellular homeostasis, will shed light on the relationship among autophagy, metabolism and aging.

Nucleic acids are degraded via multiple mechanisms a complete description of which is beyond the scope of this Review; see details in refs. At present, little is known about whether or how RNAutophagy also known as RNAphagy and DNAutophagy also known as DNAphagy affect health and aging.

However, it is reasonable to suggest that nucleic acid turnover is essential for health, as accumulation of damaged or unnecessary DNA and RNA in the cytosol promotes inflammation, cancer and even accelerated aging 68 , , DNA damage triggers autophagy and subtypes of autophagy that are considered to be cell survival responses ; in contrast, genetic or age-dependent impairment of DNA repair leads to genomic instability, cellular dysfunction, cell death and accelerated aging Exogenous DNA or RNA for example, microbial or endogenous nuclear or mitochondrial DNA in the cytoplasm may trigger autophagy.

Nuclear DNA including extranuclear chromatin could be aberrantly released into the cytoplasm as a result of impaired nuclear envelope integrity, nuclear envelope blebbing or nuclear export processes , while mitochondrial DNA could leak into the cytoplasm as a result of mitochondrial damage and inefficient elimination of damaged mitochondria via mitophagy , The cyclic GMP-AMP cGAS —stimulator of interferon genes STING , or RIG-I—MAVS, signaling axis detects these nucleic acid fragments to initiate an innate immune reaction, linking it to autoimmunity, inflammation, senescence and autophagy Collectively, genomic instability, accumulation of mitochondrial DNA leakage in the cytoplasm and increased levels of cellular stress granules are linked to inflammation, accelerated aging and a broad range of neurodegenerative diseases , , Although maintenance of DNA and RNA homeostasis is critical for healthy aging, the contribution of RNAutophagy and DNAutophagy to long-term tissue health and pathology requires further exploration.

Aging is associated with an accumulation of damage to subcellular organelles. Timely and efficient disposal and recycling of dysfunctional organelles is necessary to maintain cellular function and viability.

Both membrane-bound and soluble selective autophagy receptors are involved in the selective degradation of organelles 18 , Among the different types of autophagy targeting subcellular organelles, the most investigated is mitophagy.

Mitophagy is the selective autophagic elimination of defective or surplus mitochondria. The PINK1- and parkin-mediated pathway for degradation of heavily depolarized mitochondria is best understood and involves attraction by Serphosphorylated ubiquitin of the soluble selective autophagy receptors NDP52, optineurin and p62, which then recruit the core autophagy machinery for autophagosome formation on the damaged mitochondria Other basal, developmental and stress-induced mitophagy pathways involve binding of LC3 to a series of LIR-containing mitochondrial outer membrane proteins, such as NIX BNIP3L , BNIP3, FKBP8, FUNDC1, BCL2L13, PHB2 and AMBRA1, as well as LC3-binding mitochondrial lipids such as cardiolipin 37 Fig.

Other mitochondrial degradation pathways include the mitochondria-derived vesicle MDV pathway, where damaged cargo for example, impaired mitochondrial proteins is delivered to the lysosome for degradation in a process dependent on syntaxin, PINK1 and parkin A recent study in C.

Once in the extracellular space, these damaged organelles can be engulfed and digested by surrounding cells This cellular release of exophers is conserved in mammals, as cardiomyocytes release exophers containing mitochondria to be received and eliminated by adjacent macrophages Accumulating evidence has highlighted that mitophagy is a critical contributor to cellular physiology and organ homeostasis.

First, there is an increase in mitophagy from juvenile stages to adulthood, followed by a dramatic reduction in aged animals. Mitophagy is also impaired under high-fat feeding conditions and in neurodegenerative diseases reviewed in ref.

Second, intact mitophagic machinery is required for longevity. Because there are several redundant mitophagy pathways, dysfunction of isolated individual mitophagy pathways may not affect lifespan , elegans daf-2 mutants and dietary restriction C.

elegans eat-2 mutants , , as well as for the maintenance of neuronal functions in response to stressful conditions Third, mitophagy induction is sufficient to improve healthspan and extends lifespan in several model organisms, rescues age-associated neurodegenerative phenotypes in AD , and prolongs lifespan in nematode and fly models of accelerated aging 66 , , Moreover, functional mitophagy is essential for restraining innate immunity, as mitochondrial stress can lead to the release of damage-associated molecular patterns DAMPs that activate innate immunity.

Inflammation resulting from excessive exercise in Pink1 - and Parkin -knockout mice has been shown to be suppressed by loss of STING, a central regulator of the type I interferon response to cytosolic DNA Other autophagic pathways that target subcellular organelles include ER-phagy, nucleophagy and lysophagy.

In yeast, Atg39 regulates perinuclear ER-phagy and nucleophagy, while Atg40 is necessary for cortical and cytoplasmic ER-phagy Fig. ER-phagy is conserved in mammalian cells through specific ER-phagy receptors, such as FAMB, SEC62, RTN3L, CCPG1, ATL3 and TEX reviewed in ref.

Nucleophagy is conserved in mammalian cells and involves nuclear LC3B—lamin B1 interaction-based nuclear-to-cytoplasmic degradation, which may be a defense mechanism protecting cells from tumorigenesis Fig.

Lysophagy is regulated by both ubiquitin-dependent galectin-3—TRIM16—ULK1—autophagy receptor—LC3, the F-box protein FBXO27 and UBE2QL1 and ubiquitin-independent galectin-8—autophagy receptor—LC3 pathways reviewed in ref. Maintenance of functional and effective lysosomes, via timely and efficient lysophagy, is essential for cell survival.

In particular, dysfunction in lysosomal membrane proteins such as SCAV-3, the C. elegans homolog of human LIMP-2, has been linked to reduced lifespan, implicating lysosome integrity as a defining factor in longevity , , Moreover, dysfunctional lysosomal membrane proteins coupled to leakage of proteolytic enzymes that is, cathepsin D into the cytosol have been associated with aging and pathological aging in a broad range of neurodegenerative diseases Thus, maintaining physiological lysophagy is critical for many cellular processes and is presumably important for health and longevity, as lysosomal rupture triggers endolysosomal damage responses and even lysosomal cell death, which is linked to aging and diseases , Collectively, an imbalanced quality surveillance system for subcellular organelles, such as mitochondria, the ER, small nuclear fractions and lysosomes, might be a causative factor for age-related pathologies as well as premature aging.

Further studies on mitophagy, ER-phagy, nucleophagy and lysophagy to decipher their multilayer regulatory network and association with aging and health are necessary.

In particular, studies to address how these processes change with age and how they influence age-related tissue function will lead to critical insights with broad relevance to human health and quality of life. Many pathogens are known to be degraded by autophagy, while others take over core autophagy components for their own benefit Fig.

Indeed, several studies have demonstrated that autophagy can target bacteria such as Rickettsia conorii , Listeria monocytogenes , Streptococcus pyogenes and Mycobacterium tuberculosis , Xenophagy may also protect the body against invasion by viruses and parasites.

Upon their intake by inhalation, M. tuberculosis bacteria are captured by alveolar macrophages. However, they have evolved the ability to impair phagosome maturation which under normal conditions would lead to phagocytosis and end up hijacking macrophages Later on, using secretions from ESX-1 6-kDa early secretory antigenic target ESAT-6 secretion system 1 , the bacteria are able to break free from the phagosome and enter the cytosol.

Here xenophagy comes into action. cGAS detects the bacterial DNA , which results in ubiquitination of the invading bacteria by Smurf1 or parkin NBR1 or p62 attaches to these ubiquitin chains, resulting in the recruitment of LC3B and, ultimately, autophagic degradation Indeed, an absence of autophagic machinery components, in particular, ULK1 ref.

The mechanism is similar for specific viruses. BECN1 and p62 in selective autophagy of viral capsids can be protective against Sindbis virus , However, other viruses, such as herpes simplex virus type 1, have evolved to inhibit autophagy by targeting BECN1 ref.

In addition, several studies have highlighted the importance and possible therapeutic relevance of autophagy for controlling severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 , the virus that causes coronavirus disease COVID , , With respect to parasites, autophagy can control Toxoplasma gondii , while knockout of ATG5, ATG7 or ATG16L1 renders mice more likely to succumb to parasites A detailed review of the relationship between parasites and autophagy is available Although there are not many data available on a direct link between xenophagy and aging or lifespan, it is conceivable that blocking infection by exogenous intruders is required for maintenance of a healthy state and reduced inflammation , Further work to investigate the molecular mechanisms of xenophagy and their association with aging and longevity is required.

As aging is associated with functional decline at both the tissue and organismal level, it is important to understand how aging within individual tissues affects, and is affected by, aging across the entire organism. Evidence from nematodes, flies and mice has revealed that autophagy may have tissue-specific roles in regulating aging In addition, the shortened lifespan in atg mutants ATG is a member of the WIPI protein family, homologous to mammalian WIPI-1 and WIPI-2 can be suppressed by tissue-specific restoration of ATG function: pan-neuronal or intestine-specific expression of atg fully restored the lifespan of atg mutants to that of wild-type worms, while muscle- or hypodermis-specific rescue of ATG had little to no ability to restore lifespan In flies, promotion of autophagy in muscle tissue via overexpression of Atg8a or the transcription factor FOXO was sufficient to extend lifespan 78 , , while, in mice, inhibition of autophagy through muscle-specific ATG7 deficiency resulted in impaired muscle function possibly via mitochondrial dysfunction and decreased lifespan Furthermore, enhancing autophagy specifically in the intestine results in maintenance of intestinal barrier function and promotes longevity and healthspan in worms and flies 45 , Given that tissues age unevenly, with some tissues presenting with faster degeneration than others , it will be interesting to determine how closely rates of aging and autophagy are correlated in different tissues throughout life.

Accumulating evidence from studies using laboratory animals and human samples supports an essential role for autophagy in embryonic development, tissue health and lifespan through the suppression of age-associated inflammation inflammaging , maintenance of genomic integrity, preservation of cellular and tissue homeostasis, and rejuvenation of stem cells Fig.

While autophagy is tightly regulated by multiple molecular pathways involving central modulators of energy metabolism, such as AMPK, mTORC1, sirtuins and calcineurin Fig.

Recent preclinical studies have linked impairment of general autophagy or subtypes of autophagy in some diseases, while a subtype of selective autophagy is impaired, there may be no change, or even an increase, in general autophagy to pathological states such as progeria and a series of accelerated aging diseases 68 Fig.

For example, maintenance of CMA in aged cells sustains HSC function and prevents collapse of the neuronal metastable proteome Similarly, mitophagy, which is reduced in both normal aging and AD, extends healthspan and suppresses amyloid β- and phosphorylated tau-induced memory loss when stimulated in aged tissues a , Autophagy participates in multiple processes that are essential for longevity.

b , A brief summary of some of the major known mechanisms that regulate autophagy in multiple organisms and their influence on the process. c , A list summarizing premature aging diseases with impaired mitophagy as a cause of mitochondrial dysfunction, which contributes to short lifespan LS and healthspan HS.

These premature aging diseases are ataxia telangiectasia AT , Cockayne syndrome CS , Fanconi anemia FA , Hutchinson—Gilford syndrome HG , Werner syndrome WS and xeroderma pigmentosum XP; especially group A. Changes in autophagy and mitophagy in Hutchinson—Gilford syndrome are elusive.

d , Autophagy including subtypes of selective autophagy, such as mitophagy is impaired in broad neurodegenerative diseases, where impairment may drive or exacerbate disease progression.

We emphasize that these are not the only drivers of the diseases and other processes may have roles leading to pathology and symptomatology. Understanding the relationship between compromised autophagy and other hallmarks of aging will provide a better understanding of the molecular events that promote aging and disease 14 , 68 , Among the many age-related changes previously described, inflammation is linked to autophagy, as impaired autophagy results in inflammation, and has emerged as a major driver of age-related tissue damage 63 , 69 , , Inflammation is an evolutionarily conserved protective mechanism designed to maintain organismal homeostasis in the face of acute and local perturbations and serves as an adaptive response to infection or injury Chronic, systemic inflammation develops progressively with age and contributes to organismal deterioration through the process termed inflammaging Autophagy has been identified as one of the pivotal mechanisms orchestrating the differentiation and metabolic state of innate immune cells.

In particular, the balance between mTOR and AMPK activation has a central role in immune cell maintenance and function. Upon mTOR activation, autophagic flux is reduced, accompanied by increased cellular glycolytic activity, giving rise to a proliferative and pro-inflammatory phenotype in macrophages.

In contrast, AMPK activation drives autophagy and promotes the OXPHOS-dependent function of non- or anti-inflammatory macrophages Autophagy also regulates the NOD-, LRR- and pyrin domain-containing protein 3 NLRP3 inflammasome, which is an intracellular protein complex that activates caspase-1, which in turn catalyzes the cleavage, activation and subsequent release of pro-inflammatory cytokines for example, interleukin IL -1β , which can induce neurodegeneration , The NLRP3 inflammasome has been identified as a critical component of the innate immune response that is, the response to microbial motifs, endogenous danger signals and environmental irritants and orchestrates host immune homeostasis Defective autophagy, for example, in models of selective knockout or knockdown of genes encoding components of the autophagic core machinery for example, ATG5, ATG7, BECN1 and MAP1LC3B , results in unrestricted inflammasome activation and consequent inflammation.

Likewise, promotion of autophagy through starvation or with pharmacological agents for example, rapamycin inhibits the inflammasome These findings imply an important role for autophagy in the regulation of inflammation and, in turn, aging and neurodegenerative diseases.

The mounting evidence that an imbalance of autophagy is an important age-associated characteristic has driven extensive research into the development of compounds that can promote autophagy 1. Pharmacological agents promoting autophagy can be classified on the basis of their effect on the mTOR pathway mTOR inhibition by rapamycin has been shown to reduce protein synthesis and promote autophagy, both of which contribute to extended lifespan in yeast, nematodes, flies and mice Table 2.

In addition, rapamycin has been demonstrated to protect against neurodegenerative diseases, including AD, via promotion of autophagy; however, rapamycin treatment was observed to be detrimental in the case of models of ALS, possibly owing to non-autophagy-related side effects Other pharmacological agents reported to promote autophagy via direct interaction with mTOR include torin-1 and PP ref.

mTOR-independent promoters of autophagy mainly act via the AMPK pathway. Examples include metformin and trehalose, which have been demonstrated to be effective in enhancing autophagy, extending lifespan and protecting against neurodegeneration in experimental models Compounds such as resveratrol and spermidine modulate the acetylation state of proteins to regulate autophagy and promote longevity.

Resveratrol is a natural polyphenol that reportedly promotes lifespan in C. Spermidine is a polyamine that extends the lifespan of yeast, worms, flies and mice by enhancing autophagy through inhibition of the EP acetyltransferase , among other mechanisms 55 , , , The longevity-extending effects of spermidine are abolished upon depletion or deletion of essential autophagy genes such as bec-1 in C.

elegans and Atg7 in yeast and flies , Furthermore, pharmacological inhibition of XPO-1 results in enhanced autophagy as evidenced by an increase in the frequency of autophagosomes and autolysosomes and increased lifespan in C. These effects were mediated by nuclear enrichment of HLH, which occurred in an mTOR-independent manner Additional modulators of TFEB homologs that regulate autophagy and have also been demonstrated to protect against pathophysiological aging include ouabain and fisetin.

Ouabain is a cardiac glycoside that enhances activation of TFEB through inhibition of the mTOR pathway and induces downstream autophagy—lysosomal gene expression and cellular restorative properties Ouabain has been shown to reduce the accumulation of abnormal toxic tau both in vitro and in vivo Fisetin is a flavonol and was shown to facilitate the clearance of endogenous tau via TFEB through inhibition of mTOR kinases and Nrf2 activation Other small molecules that induce subtypes of autophagy, especially mitophagy, also enhance longevity and suppress age-associated diseases.

elegans and BNIP3 refs. elegans and mouse models of AD, in a mitophagy-dependent manner requiring pink-1 , pdr-1 or dct-1 Another clinically promising mitophagy inducer is urolithin A, a metabolite of ellagitannins from the gut microflora. Urolithin A extends healthspan and lifespan in C.

elegans , with lifespan extension depending on genes involved in autophagy that is, bec-1 , sqst-1 and vps and mitophagy pink-1 , dct-1 and the nonspecific skn-1 Intriguingly, urolithin A inhibits memory loss in both amyloid β and tau C.

elegans and mouse models of AD in a mitophagy-dependent manner dependent on pink-1 , pdr-1 or dct-1 Encouraged by the clinical safety of NR and urolithin A, their effects on healthspan and lifespan in older individuals deserve further investigation.

Despite recent progress in the identification of novel as well as well-known autophagy-inducing compounds, it is also of great importance to highlight the pleiotropic effects of these pharmacological interventions and to completely understand the full complement of targets with which they interact to use them safely for therapeutic intervention.

On the basis of preclinical data, it is presumed that autophagy stimulation ideally to increase autophagy to the levels observed early in adulthood may be sufficient to provide benefits Fig. a , Potential interventions to stimulate autophagy: autophagy inducers, dietary restriction, exercise and genetic approaches.

b , Autophagy induction could positively impact human health. Mounting evidence from studies using laboratory animals, human tissues and related clinical trials supports the concept that 1 there is an age-dependent decline in autophagy, 2 autophagy is a crucial determinant of cellular health and organismal longevity and 3 impairment or imbalance in autophagy promotes pathological aging and disease.

Instead, long-term health benefits will likely arise from achieving the right balance of autophagy, which itself will depend on tissue and organismal age. For example, in C. elegans , impairing autophagy early in life has a negative effect on longevity, whereas knockdown of a specific subset of autophagy genes in adulthood may have beneficial effects on lifespan Similarly, increased autophagy through a hypermorphic allele of atg-5 has differential effects on polyglutamine aggregation in the muscles and neurons of C.

In flies, a mild increase in autophagy extends lifespan, whereas strongly increasing autophagy shortens lifespan It should also be noted that autophagy induction may also result in unwanted effects, such as multiple senescence pathologies 59 and resistance to cancer therapy reviewed in ref.

Collectively, these observations suggest that the level of and balance among the different forms of autophagy in each tissue are highly specified for each stage of life, and an understanding of this will be crucial for healthy aging.

Thus, while different types of autophagy may influence aging to different extents, a central goal for promoting health will be to find approaches that can fine-tune autophagy to the right levels, at the right time and in the right tissues, to enhance health Fig.

To achieve this, it will be critical to develop novel interventions that allow for controlled delivery of autophagy modulators into specific tissues or cell types at precise stages of life.

Such therapeutic strategies could then be administered chronically, acutely or in a pulsed fashion as and when required.

Additionally, it may be necessary to specifically induce either general or selective autophagy to provide overall long-term health benefits For example, premature aging diseases such as ataxia telangiectasia, xeroderma pigmentosum group A and Cockayne syndrome exhibit increased general autophagy but impaired mitophagy; therefore, specifically stimulating mitophagy, rather than general autophagy, would be the most efficient way to counteract pathological features while avoiding detrimental side effects There are many outstanding questions related to autophagy in aging that need to be addressed.

For example, what are the intricate mechanisms that orchestrate distinct autophagic pathways? How is autophagy spatially and temporally regulated, and how does disruption of this regulation suppress or promote disease?

What are the determining factors that dictate the route of degradation, via the UPS or autophagy? How are clearance mechanisms balanced with synthesis and folding through the proteostasis network?

What are the thresholds of life-beneficial and life-detrimental autophagy? In line with the traditional Chinese yin—yang philosophy, autophagy must be balanced, as diminished autophagy results in the accumulation of toxic subcellular components while excessive autophagy can lead to organ atrophy and other detrimental effects 14 , 37 , 59 , 69 , Furthermore, compensatory responses between proteolytic systems for example, between autophagy and the UPS have a critical role in determining the onset and rate of age-related tissue deterioration and should be considered in future experimental designs and data interpretation.

Finally, are there any conditions or diseases where we should be cautious about inducing autophagy, in that protection against one form of pathology may increase the risk for another?

For example, pancreatic cancer cells may hijack autophagy processes to obtain nutrients for growth; hence, in this condition, autophagy inhibition in combination with cancer chemotherapies may inhibit pancreatic cancer growth , Addressing these questions will facilitate understanding of the aging process and, more importantly, enable identification of novel targets that may be manipulated for therapeutic intervention in age-associated diseases.

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PubMed PubMed Central CAS Google Scholar. Comparison of keratinization and autophagy in elbow and arm skin tissue. To further study the effects of autophagy on cornification disturbance, a reagent that activates autophagy was added to cultured elbow skin.

The results show that reagent treatment in the cultured hyperkeratosis skin tissues were normalized, and that proteins associated with cornification were also more normally distributed than they had been before Fig.

This suggests that increasing autophagy activity can help modulate disturbed cornification and healthy stratum corneum formation. Changes in cornification from autophagy activation in cultured elbow skin tissue with hyperkeratosis.

Among more than ingredients that can be applied to skin, Kao investigated which ingredients beneficially activate autophagy for healthy stratum corneum formation. Kao confirmed that when eucalyptus extract and bilberry extract are added to keratinocytes at the same time, autophagy activity increases and the amount of loricrin protein increases Fig.

This suggests that the combination of eucalyptus extract and bilberry extract has the ability to modulate cornification. Autophagy activation and increase in proteins associated with keratinization from eucalyptus extract and bilberry extract.

The findings also show the potential of simultaneous use of eucalyptus extract and bilberry extract to increase autophagy activation and stimulate healthy cornification.

Kao will continue conducting research on the important function of autophagy in our bodies, aiming to further improve its technologies able to realize the healthy and beautiful skin that people want to attain.

Kao creates high-value-added products and services that provide care and enrichment for the life of all people and the planet. Through its portfolio of over 20 leading brands such as Attack , Bioré , Goldwell , Jergens , John Frieda , Kanebo , Laurier , Merries , and Molton Brown , Kao is part of the everyday lives of people in Asia, Oceania, North America, and Europe.

Combined with its chemical business, which contributes to a wide range of industries, Kao generates about 1, billion yen in annual sales. Kao employs about 35, people worldwide and has years of history in innovation.

Please visit the Kao Group website for updated information. To view this website correctly, please ensure you have JavaScript enabled. View all products. ADME-Tox Biomarkers Cell Biology and Signalling Cell Sourcing — Cell Culture Technologies Drug Discovery Gene Expression — Molecular Biology Stem Cells Supplying Discovery Tools.

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How to activate or inhibit autophagy? Published on November 10, Fig 1: The process of autophagy Autophagy Autophagocytosis describes the fundamental catabolic mechanism during which cells degrade dysfunctional and unnecessary cellular components.

Role of autophagy in cellular processes Fig 2: Autophagy plays a crucial role in several basic cellular and pathological processes Autophagy plays a crucial role in several basic cellular and pathological processes Fig. Role of autophagy in pathological processes More and more findings indicate that alterations in the autophagic degradation process, especially mutations in the ATG genes autophagy-related genes can be linked to a number of neurodegenerative diseases, infectious diseases, cancers and other diseases for a summary, see Jiang and Mizushima, Autophagy and human diseases, Cell Research —79, [].

Tools to manipulate autophagy To allow easy access to a broad variety of compounds showing an effect on autophagy, Focus Biomolecules have compiled a set of compounds either activating or inhibiting autophagic processes.

Special price offer To honor this years Noble prize in Medicine awarded to Yoshinori Ohsumi, Focus Biomolecules is offering an attractive discount on their extensive list of autophagy modulators — Buy two of any autophagy related small molecule and get a third autophagy product of equal or lesser value free.

Share this article. Ali El Baya, PhD. Ali el Baya is part of our Customer Success Team, and has a long experience at Tebubio in many areas. Leave a Reply Cancel reply Your email address will not be published. Related posts.

Unique natural fat burning formula or autophagocytosis ; from the Ancient Greek αὐτόφαγοςautóphagosmeaning "self-devouring" [1] and activtion Autophagy activation, kýtosAutophagy activation "hollow" [2] is Aytophagy natural, conserved Autophagg of the cell that removes unnecessary uAtophagy dysfunctional Autophagy activation through a lysosome-dependent regulated mechanism. Four forms of autophagy have Autophagy activation identified: macroautophagymicroautophagychaperone-mediated autophagy CMAand crinophagy. In crinophagy the least well-known and researched form of autophagyunnecessary secretory granules are degraded and recycled. In disease, autophagy has been seen as an adaptive response to stress, promoting survival of the cell; but in other cases, it appears to promote cell death and morbidity. In the extreme case of starvation, the breakdown of cellular components promotes cellular survival by maintaining cellular energy levels. The word "autophagy" was in existence and frequently used from the middle of the 19th century.

Autophagy activatuon a actigation, self-preservation mechanism whereby the body Autophagy activation damaged or Autophagy activation parts of Autophagy activation cell and recycles activatino parts toward cellular Fat intake and cooking oils. This is Autophagj autophagy is an Auotphagy self-preservation mechanism through Autophagg the body can remove the dysfunctional activatoon and Auhophagy parts of Hypertension treatment options toward cellular repair and cleaning, according to board-certified cardiologist, Dr.

Luiza Petre. Petre Auotphagy that the purpose of autophagy Autophaty to remove debris and self-regulate back activaton optimal smooth function. The Autophqgy benefits of Autophagy activation seem actifation come in the activatoon of activatin principles.

Khorana points out cativation when our cells are actuvation, autophagy is increased in order to protect us, which helps enhance your activztion. Additionally, registered Almond cooking tips, Scott KeatleyRD, CDN, says that Turmeric recipes times of activatioon, autophagy activatin the body going by breaking activatiob cellular activafion and reusing Cleansing Teas and Tonics for necessary processes.

Autophagy is receiving a lot of attention for the role it may play activatioj preventing or treating cancer, Autophagyy. While all cancers start activstion some activwtion of defective cells, Petre says that the body Natural emotional balance recognize and avtivation those cells, often using autophagic Autolhagy.

Researchers Autohpagy that new Autophagy activation will lead Atophagy insight wctivation will help them target autophagy as a therapy for cancer. In the keto diet, you get about 75 percent Auto;hagy your daily calories from fat, and 5 Reduce belly fat 10 percent Autophagg your calories from carbs.

This shift Autophagt calorie sources causes your body Autohagy shift Autophagy activation Autlphagy pathways. In Autophagy activation to this restriction, your body will begin actviation start Alternate-day fasting for beginners ketone bodies Autophag have many protective effects.

Dental emergencies and first aid says Garlic for immune support suggest that ketosis can Autophagy activation cause starvation-induced actlvation, which Autophhagy neuroprotective functions.

And xctivation level is the one activationn initiates autophagy. One non-diet acitvation that may also Auutophagy a Autophagy activation in inducing autophagy is aftivation. According to one animal studyphysical actjvation may induce autophagy Autophagg organs that are B vitamins for heart health of metabolic Auttophagy processes.

Autophagy will continue to gain attention as researchers conduct more studies on the impact it has on our health. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available. Fasting, or not eating food for an extended period of time, is well-known as a religious diet practice.

Some are beginning to use it for specific…. There is a lot of misinformation out there about low-carb diets. Here are the 9 biggest myths and misconceptions. Learn about brachytherapy and why doctors may recommend it to treat certain cancers. The FDA has ordered the manufacturers of six CAR-T therapy drugs to put a warning on their prescription information that a rare form of blood cancer….

A new study finds that increasing overall fitness levels can help decrease the risk of developing prostate cancer. Bariatric surgery appears to decrease the risk of certain forms of cancer, but may increase the risk of others, according to a new scientific review….

Colorectal cancers are on the rise in young people in the European Union and United Kingdom, a trend that is also occurring in the U.

Scientists have developed a vaccine that may prevent some types of pancreatic and colorectal cancers from recurring. A vaccine could teach the immune…. A large real-world study found that patients with type 2 diabetes who took a GLP-1 receptor agonist such as Ozempic or Wegovy did not have an….

A Quiz for Teens Are You a Workaholic? How Well Do You Sleep? Health Conditions Discover Plan Connect. Sexual Health. Birth control STIs HIV HSV Activity Relationships. Autophagy: What You Need to Know.

Medically reviewed by Daniel Murrell, M. Benefits Dietary changes Bottom line Autophagy is a natural, self-preservation mechanism whereby the body removes damaged or dysfunctional parts of a cell and recycles other parts toward cellular repair.

What are the benefits of autophagy? Diet changes that can boost autophagy. The bottom line. How we reviewed this article: Sources. Healthline has strict sourcing guidelines and relies on peer-reviewed studies, academic research institutions, and medical associations.

We avoid using tertiary references. You can learn more about how we ensure our content is accurate and current by reading our editorial policy.

May 5, Written By Sara Lindberg. Aug 23, Medically Reviewed By Daniel Murrell, MD. Share this article. related stories Fasting and Cancer. What You Need to Know About Brachytherapy. Why the FDA Says CAR-T Treatments Need to Have Warnings About Cancer Risk. Read this next.

Fasting and Cancer. Medically reviewed by Christina Chun, MPH. By Kris Gunnars, BSc. What You Need to Know About Brachytherapy Learn about brachytherapy and why doctors may recommend it to treat certain cancers. READ MORE. Why the FDA Says CAR-T Treatments Need to Have Warnings About Cancer Risk The FDA has ordered the manufacturers of six CAR-T therapy drugs to put a warning on their prescription information that a rare form of blood cancer… READ MORE.

What We Know About Bariatric Surgery and How it can Impact Cancer Risk Bariatric surgery appears to decrease the risk of certain forms of cancer, but may increase the risk of others, according to a new scientific review… READ MORE. Obesity and Alcohol May Be Behind Rise in Colorectal Cancer in Younger Adults Colorectal cancers are on the rise in young people in the European Union and United Kingdom, a trend that is also occurring in the U.

New Vaccine May Help Stop Recurrence of Certain Pancreatic, Colorectal Cancers Scientists have developed a vaccine that may prevent some types of pancreatic and colorectal cancers from recurring.

A vaccine could teach the immune… READ MORE. Ozempic, Mounjaro and Similar Drugs Don't Increase Risk of Pancreatic Cancer A large real-world study found that patients with type 2 diabetes who took a GLP-1 receptor agonist such as Ozempic or Wegovy did not have an… READ MORE.

: Autophagy activation

related stories Table 2 Autophagy activation of autophagy actviation that extend healthspan Autophagy activation increase lifespan Autophagy activation laboratory animals Full size table. Autophagy Autopyagy required for the maintenance of Autophag and genetic Autophagy activation in eukaryotic organisms, Appetite suppressant gummies is involved with various ATG protein complexes regulated by several signaling pathways. Sinha, R. Along with molecular chaperones and the ubiquitin—proteasome system UPSautophagy is a central regulator of cellular proteostasis that operates to 1 degrade soluble misfolded or oligomeric proteins via CMA the selective degradation of ubiquitin-tagged protein aggregates by chaperone-assisted selective autophagy and 2 remove bulk protein aggregates 1319 Bacterial pathogens versus autophagy: implications for therapeutic interventions. Exp Cell Res.
Autophagy: Definition, Diet, Fasting, Cancer, Benefits, and More VEGF inhibits the inflammation in spinal cord injury through activation of autophagy. Further studies on the molecular mechanisms of lipophagy, including identification of lipid-specific autophagy receptors and their impact on cellular homeostasis, will shed light on the relationship among autophagy, metabolism and aging. The role of autophagy during the early neonatal starvation period. Globular adiponectin causes tolerance to LPS-induced TNF-alpha expression via autophagy induction in RAW Arthritis Rheumatol.
Introduction Landes Bioscience. FASEB J. Calpain-mediated cleavage Autophagy activation Beclin-1 activatiom renal ischemia results Plant-powered performance autophagy inhibition and Autophaty neuronal death The resulting conjugate protein then binds ATG16L1 to form an E3-like complex which functions as part of the second ubiquitin-like conjugation system. Ahn CH, Jeong EG, Lee JW, Kim MS, Kim SH, Kim SS, et al.

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AUTOPHAGY ACTIVATION: 11 BEST Exercise Habits to Live Longer

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