Autophagy: The recycling and repair process within cells has enormous potential to help fight aging-related diseases


The study of autophagy – the recycling and repair process within cells – has huge potential to aid in fighting the aging process, bacterial and viral infections and diseases including cancer, Alzheimer’s and Parkinson’s.

A team of researchers led by Professor Ioannis Nezis from the School of Life Sciences at the University of Warwick, has identified the molecular and cellular mechanisms that regulate selective autophagy in the fruit fly Drosophila melanogaster.

While the function of these processes is increasingly understood in mammals this is one of the first studies in insects.

The study opens new avenues in our understanding of the regulation of Golgi complex turnover by selective autophagy. The Golgi complex is a stack of flat sacs formed by membranes inside the cell. It prepares proteins and fat molecules for transportation and use in other places inside and outside the cell.

Professor Nezis and his team used gene editing, confocal and electron microscopy to identify a novel type of selective autophagy, termed Golgiphagy, meaning how cells degrade a cell organelle called Golgi complex by autophagy.

In the paper, ‘GMAP is an Atg8a-inteacting protein that regulates Golgi turnover in Drosophila’ published today in the journal Cell Reports, PhD students Ashrafur Rahman, Raksha Gohel and colleagues describe how gene editing was used to create fruit flies unable to process specific proteins by autophagy.

Comparison of the gene-edited flies with their wild type counterparts showed:-

  • That Atg8a’s LDS docking site is important in the execution of selective autophagy
  • That selective autophagy regulates the size and morphology of the Golgi apparatus
  • That the GMAP (Golgi microtubule-associated protein) protein interacts with Atg8a and the LIR motif at position 320-325 is important for this interaction 
  • That GMAP’s LIR motif is important Golgiphagy

Lead author of the research Professor Ioannis Nezis from the School of Life Sciences at the University of Warwick, said:

“Understanding the molecular mechanisms of selective autophagy of Golgi complex in cells will help open new avenues of research that will assist elucidating the underlying cellular mechanisms of diseases.”

Aging is a biological process that is characterized by time-dependent cellular and functional decline, resulting in reduced quality of life for the organism1. In line with this, aging is the primary risk factor for the development of many disorders, including cardiovascular disease (for example, stroke), cancer and neurodegenerative disease (for example, Alzheimer’s disease (AD)).

Collectively, age-related ailments represent a formidable global socioeconomic burden and a significant healthcare challenge2,3. Therefore, identifying therapeutic interventions that promote ‘healthy aging’ (that is, the maintenance of functional ability in old age, enabling older individuals to independently carry out daily tasks) and simultaneously halt the progression of multiple age-related pathological conditions is of paramount importance2.

Among the many molecular changes associated with old age, altered autophagy has emerged as a feature of aging across diverse species. However, recent advances in understanding the numerous substrates of autophagy and the temporal and spatial effects of impaired autophagy regulation on tissue homeostasis have revealed a complex and multifactorial relationship between autophagy and aging. Here we examine the relationship among autophagy, aging and disease and propose novel links between specific autophagic processes and long-term tissue health, as well as possible implications for anti-aging therapeutic interventions.

Compromised autophagy is a hallmark of aging
Research over the last decade has revealed that the process of autophagy can take many different forms. Autophagy (from the Greek words auto, meaning ‘self’, and phagein, meaning ‘to eat’) is a highly conserved pathway that degrades cellular components, such as defective organelles and aggregates of misfolded protein4, through lysosomes.

The process of autophagy was first described in the 1960s, but it was the identification of autophagy-related genes (ATG genes) in the 1990s that propelled major breakthroughs in unravelling the mechanistic complexities of autophagy5–12. There are three major types of autophagy: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA) (Fig. 1a–c), all of which involve delivery of substrates to the lysosome for degradation (see detailed reviews in refs.13,14).

Macroautophagy (hereafter referred to as autophagy) was originally thought of as a nonselective bulk degradation process (Fig. 1a, pathway (1)). However, the discovery of selective autophagy receptors, among which p62/SQSTM1 was the first, changed this notion15,16. Today, autophagy is recognized as a highly selective cellular clearance pathway that is associated with the maintenance of cellular and tissue homeostasis17,18.

Selective autophagy can be further divided into many subtypes on the basis of the specific cargos involved. These subtypes target various macromolecules (glycophagy and lipophagy) (Fig. 1a, pathways (2)–(5)), mitochondria (mitophagy) (Fig. 1a, pathway (6)), the endoplasmic reticulum (ER) (ER-phagy) (Fig. 1a, pathway (7)), parts of the nucleus (nucleophagy) (Fig. 1a, pathway (8)), pathogens (xenophagy) (Fig. 1a, pathway (9)) and lysosomes themselves (lysophagy) (Fig. 1a, pathway (10)).

Below we will discuss the links among these selective autophagy pathways, aging and disease. The core process of autophagy has been described in detail elsewhere14,19. However, in brief, the core process is initiated following inhibition of mechanistic target of rapamycin (mTOR) or activation of 5′ AMP-activated protein kinase (AMPK), both of which are canonical inducers of autophagy in response to stress (for example, starvation or elevated temperatures) and physical exercise.

In addition, transcription factor EB (TFEB) is an important positive regulator of autophagy and lysosomal biogenesis whose nuclear translocation is coupled to the activity of both mTOR (via phosphorylation) and AMPK (via folliculin (FLCN))20–23. Upon activation of autophagy, the process is initiated by membrane nucleation and phagophore formation followed by elongation and maturation before autophagosome fusion with the lysosome for cargo degradation and recycling. The key proteins involved in each step are presented in Fig. 2.

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Fig. 1 |
Different mechanisms of autophagy.
a, Macroautophagy (referred to herein as autophagy) (1) is a nonselective process that targets macromolecules or subcellular organelles in bulk. Cytoplasmic material is sequestered into an autophagosome and delivered to the lysosome (or endolysosome) for degradation). Selective autophagy involves recognition of specific cytoplasmic cargo via autophagy receptors that also interact with LC3 in the autophagic membrane, leading to cargo sequestration into autophagosomes that are delivered to a lysosome (or endolysosome) for degradation. This includes aggrephagy (2), where aggregated proteins are ubiquitinated and targeted by ubiquitin-binding autophagy receptors such as p62 (or NBR1); glycophagy (3), where STBD1 (genethonin-1) binds to glycogen and GABARAP, facilitating lysosomal glycogen breakdown into non-phosphorylated glucose by enzymes such as GAA; lipophagy (4), in which lysosomal lipids are degraded into free fatty acids, which are then converted into ATP; the identity of the receptor(s) (yellow) involved in sequestration of lipid droplets is unknown;; granulophagy (5), where sequestration of stress granules (RNA + protein) is mediated by Cdc48/VCP, allowing the stress granule to be delivered to the lysosome for degradation; mitophagy (6), where damaged mitochondria are bound by soluble or membrane-bound mitophagy receptors (mReceptors) that can also bind LC3, leading to engulfment of the mitochondrion into an autophagosome and subsequent delivery to a lysosome for degradation (left); in piecemeal mitophagy, degradation of parts of mitochondria occurs via binding of the outer mitochondrial membrane protein metaxin-1 (MTX1, in the extruded fraction) to LC3C, resulting in the recruitment of p62 and autophagosome formation (right); ER-phagy (7), which in mammals uses the specific receptors FAM134B, RTN3L, ATL3, SEC62, CCPG1 and TEX264, which are located in different parts of the ER; these receptors bind to LC3, leading to sequestration of the ER into an autophagosome and lysosomal degradation of the ER; nucleophagy (8), which, when triggered in mammals, results in nuclear LC3 binding to lamin B1, leading to formation of a bulge that is pinched off to the cytoplasm where degradation by autophagy occurs; xenophagy (type A, 9), where a bacterium’s DNA is detected by cGAS, a sensor that triggers a process of ubiquitination via Smurf1; this is followed by attachment of the NBR1 receptor to the ubiquitin chains and LC3 to continue the autophagy process for degradation of the bacterium; xenophagy (type B, 10), where a bacterium damages the membrane of the phagosome, exposing interior glycans that recruit galectin-8 (Gal-8), which is then recognized by NDP52 to recruit TBK1, LC3C, Nap and Sintbad; the optineurin, p62 and NDP52 receptors interact with ubiquitin on the pathogen and recruit the autophagic engulfment system, and the engulfed pathogen is then brought for degradation; and lysophagy (11), which occurs upon lysosomal membrane permeabilization and can be achieved with or without ubiquitination: recruitment of galectin-3 (Gal-3) to damaged lysosomes further recruits TRIM16 and autophagic proteins such as ULK1 and ATG16L1, and ubiquitination on the lysosome results in the recruitment of p62, which binds to LC3 to facilitate the autophagic process (left); in a parallel ubiquitin-independent process, galectin-8 is recruited to damaged lysosomes and is capable of directly binding to the NDP52 receptor that interacts with LC3 to continue the autophagic process (right). b, Microautophagy involves capture of cytoplasmic components through direct invagination of endolysosome membranes and can be nonspecific (bulk) (12) or highly specific (13,14). Examples of selective microautophagy in mammalian cells include micro-ER-phagy (13), which uses the SEC62 receptor and involves ER capture and degradation by invagination of the lysosome/endolysosome, and endosomal microautophagy of proteins with the KFERQ pentapeptide motif (14) in a process requiring the chaperone HSC70. c, CMA (15) also involves targeting of proteins containing a KFERQ pentapeptide-related motif by HSC70 and other co-chaperones such as HSP40. The substrate is then imported into the lysosome through the LAMP2A receptor for further degradation. The LAMP2A receptor is modulated by the glial fibrillary acidic protein (GFAP). Finally, in a CMA-like manner, DNAutophagy/RNAutophagy (16) can occur: nucleic acids (DNA or RNA) bind to the LAMP2C receptor (orange), which also binds to lysosomes. This process allows nucleic acids to be taken up by the lysosome. It has been proposed that a transporter called SIDT2 (green) might have a role in direct uptake of nucleic acids by the lysosome.
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Fig. 2 |
Core machinery of autophagy.Initiation of autophagy requires the ULK1 kinase complex, which is tightly regulated by AMPK and mTOR, which act as an activator and inhibitor, respectively. AMPK activates ULK1 through phosphorylation. The ULK1 complex, composed of FIP200, ATG13 and ATG101, stimulates the class III phosphatidylinositol 3-kinase (PIK3C3) complex, which is composed of BECN1 (which can be inhibited by BCL-2), AMBRA1, ATG14L, VPS15 and VPS34. This complex then produces a pool of phosphatidylinositol 3-phosphate (PtdIns3P), which leads to the recruitment of WIPI proteins, which recover ATG9-positive vesicles from previous membranes, as well as recruiting the ATG5–ATG12–ATG16L1 (E3) complex. LC3 is first cleaved by the ATG4 protease to form cytosolic LC3-I, which is further recognized by E1 (ATG7), E2 (ATG3) and E3 components, leading to its conjugation to phosphatidylethanolamine (PE). After this process, LC3-I is referred to as LC3-II. LC3-II binds to LIR-containing autophagy receptors (AR; such as p62) bound to cargo targeted for degradation. Fusion of autophagosomes with lysosomes is mainly mediated by the assistance of RAB proteins, SNARE proteins and a HOPS complex. After fusion, the cargo is degraded by lysosomal hydrolases and the degradation products can be reused by the cell. LC3-II bound to the outer membrane is cleaved by ATG4 to be reused for a new round of lipidation.

A growing body of evidence suggests that autophagic activity declines with age in diverse organisms1. Studies in Caenorhabditis elegans, rodents and human cells have demonstrated an age-dependent reduction in lysosomal proteolytic function that thereby impairs autophagic flux24–27, exacerbating cellular impairment and contributing to the development of age-related diseases1,28,29. Further evidence stemming from Drosophila has demonstrated that aging is associated with reduced expression of several Atg genes (Atg2, Atg8a and bchs (encoding blue cheese)), which are pivotal for both autophagy initiation and activity30.

In aged wild-type mice, autophagy is diminished in neuronal cells, as evidenced by decreased rates of autophagolysosomal fusion and impaired delivery of autophagy substrates to lysosomes in the hypothalamus31. Moreover, a decrease in autophagic processes was observed in brain tissue from 18- to 25-month-old mice, as demonstrated by a reduction in the levels of Atg5–Atg12 and Becn1, elevated mTOR activity and increased levels of ferritin H (ferritin H is mainly removed from cells by the autophagy–lysosome pathway)32.

In addition, emerging evidence in aged rats has highlighted an age-associated decline in expression of the autophagy-related protein beclin 1 (BECN1) in whole brain tissue, as well as in the hippocampus of naked mole rats and Wistar rats33,34. In line with observations in rodent models, findings in humans have suggested that the expression of autophagy-related genes, such as ATG5, ATG7 and BECN1, declines with age35.

Moreover, the development and progression of several human pathologies is highly associated with age-dependent autophagy deficits19,36,37. Collectively, these studies demonstrate that a gradual decline in the abundance of autophagy-related proteins and reduced delivery of cargo to lysosomes occur with age, implicating compromised autophagy as a cardinal feature of organismal aging.

In line with a causal role for autophagy in the aging process14, genetically impairing nonselective or selective autophagy results in accelerated tissue functional decline and disease in a range of experimental models. Transcriptomic profiling in Saccharomyces cerevisiae has provided evidence of defective autophagy among short-lived as compared to long-lived mutants38. In addition, selective mutation(s) and/or knockdown of genes encoding components of the autophagic machinery in C. elegans (lgg-1 (ortholog of ATG8), unc-51 (ortholog of ATG1), bec-1, atg-7, lgg-3 (also known as atg-12) and atg-18), Drosophila (Atg3 and Atg8a) and mice (Atg5, Atg7 and Becn1) shorten lifespan and healthspan1,14,30,39. In line with these observations, systemic genetic knockout of autophagy components (Becn1, Atg5, Atg9 and Atg13) is lethal in mice, highlighting the importance of autophagy in development40. Furthermore, knockdown of genes encoding transcription factors that regulate autophagy, such as TFEB (ortholog in C. elegans, hlh-30) and FOXO (encoding forkhead box O; ortholog in C. elegans, daf-16) shortened lifespan in both wild-type worms and long-lived daf-2 (insulin/insulin-like growth factor-1 (IGF-1) receptor) mutants41.

In contrast, studies in long-lived mutant animals have shown that increased autophagy is associated with delayed aging. In particular, the extended lifespan of C. elegans daf-2 loss-of-function mutants is dependent on autophagic genes, such as bec-1, lgg-1, atg-7 and atg-12 (refs.1,14,42). Furthermore, HLH-30 is required for the long lifespan of multiple longevity mutants, including not only daf-2 mutants with reduced insulin/insulin-like signaling, but also germline-less glp-1(e2141) mutants, dietary-restricted eat-2(ad1116) mutants, mitochondrial respiration-defective clk-1(e2519) mutants and mRNA translation-impaired rsks-1(sv31) mutants43. These findings coincide with impaired induction of autophagosome formation and lysosomal degradation upon loss of hlh-30, suggesting that HLH-30 promotes longevity by regulating the autophagy process downstream of multiple lifespan extension paradigms43. In addition, formation of long-lived dauer worms, corresponding to a larval hibernation stage, is also associated with increased autophagy and is dependent on the autophagy genes atg-1, atg-7, lgg-1 and atg-18, underlining the essential role of autophagy in organismal adaptation during challenging conditions42.

In line with observations from long-lived mutants, genetic or pharmacological upregulation of autophagy promotes longevity in animals. Autophagy induction by overexpression of Atg genes in Drosophila (Atg1 and Atg8a) and mice (Atg5) extends lifespan30,44,45. Similarly, Bcl2 mutations that disrupt the BECN1–BCL-2 complex increase basal autophagic flux, which results in long-lived male and female mice with improved healthspan46. Overexpression of autophagic regulators in C. elegans and Drosophila, such as AMPK, further facilitates autophagy in diverse tissues and in turn extends longevity14,45. Additionally, hlh-30 overexpression enhances autophagy and promotes lifespan extension in C. elegans43, and silencing of the nuclear export protein exportin-1 (XPO-1) enhances autophagy by enrichment of HLH-30 in the nucleus, which is accompanied by proteostatic benefits and improved longevity47. Moreover, rapamycin, an inhibitor of the mTOR pathway, has been shown to extend the median and maximum lifespan of both female and male mice when fed to them late in life48.

Accumulating evidence in aged mice, as well as in rodent models recapitulating characteristic features of human diseases, has shown that compromised autophagy is among the most common factors contributing to the collapse of tissue homeostasis. In particular, age-associated dysregulation of autophagy (demonstrated by the accumulation of autophagosomes), possibly due to impaired lysosomal fusion and/or degradation, is associated with cellular dysfunction and/or death, which contribute to neurodegeneration, as well as cardiac and skeletal muscle aging49–53. In hematopoietic stem cells (HSCs), autophagy has been shown to delay aging via activation of downstream sirtuin-3 (SIRT3), a key mitochondrial protein capable of rejuvenating blood and protecting against oxidative stress in mice and human HSC-enriched cells54.

Moreover, autophagy appears to be a critical mechanism to maintain immune memory in mice, and levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. In fact, supplementation of T cells from older donors with spermidine restores autophagy levels to those observed in younger donors via the eIF5A translation factor and TFEB transcription factor55. Furthermore, spermidine administration in a mouse model of mild cognitive impairment, a transitional phase between healthy aging and AD, led to an improvement in degradation of misfolded proteins and an accompanying delay in age-related memory deficits, thereby implicating autophagy as a pathophysiological mechanism of action56.

While dysregulation of autophagy underlies aging and disease phenotypes, excessive autophagy may also contribute to the deterioration of cellular function in some contexts. Recent evidence has demonstrated that an age-dependent decline in the levels of Rubicon, a negative regulator of autophagy, exacerbates metabolic disorders in adipocytes57. While strongly upregulated autophagy may exacerbate metabolic disorders, this finding may also be attributed to autophagy-independent changes in metabolism. Furthermore, elevated autophagy has been found to shorten lifespan in C. elegans mutants lacking sgk-1 (encoding serum/glucocorticoid-regulated kinase-1).

Loss of this kinase results in increased mitochondrial permeability, leading to excessive autophagy and reduced organismal fitness in worms and mice58. Conversely, reducing the levels of autophagy in sgk-1 mutants or suppressing the opening of the mitochondrial permeability transition pore restores normal lifespan58. Similarly, suppressing autophagy exclusively in the intestine of post-reproductive adults at higher temperatures has been proposed to prevent the emergence of age-related pathologies in C. elegans59. However, it should be noted that this is in direct contrast to findings in long-lived mutants, where intestinal autophagy is enhanced60,61.

Another study in C. elegans showed that short interfering RNA (siRNA)-based reduction in the abundance of the VPS-34–BEC-1–EPG-8 autophagic nucleation complex in aged post-reproductive worms extended lifespan and improved neuronal integrity29. However, detailed data on knockdown efficiency in aged worms, as well as an understanding of the remaining levels of neuronal autophagy, are necessary to ensure accurate in-depth data interpretation. Collectively, these observations suggest that maintenance of functional autophagy is essential for healthy cellular and organismal aging and that dysregulation of autophagy in either direction, whether insufficient or excessive, contributes to cellular deficits and functional organismal decline.

A summary of autophagy-related genes linked to longevity and disease is provided in Table 1 and Supplementary Table 1. In addition, several interventions known to promote lifespan, including dietary restriction and treatment with pharmacological agents, such as rapamycin, spermidine and NAD+ precursors, require intact autophagic machinery. In totality, these findings reinforce the notion that autophagy stimulation is necessary and sufficient to sustain organismal homeostasis and extend longevity in multiple model organisms (discussed in detail below)1. An overview of autophagy inducers linked to enhanced longevity and improved health is presented in Table 2.

Together, numerous studies have provided evidence that (1) autophagy is compromised during the process of aging; (2) dysfunction of autophagy shortens lifespan in various experimental animal models; and (3) promotion or restoration of autophagy contributes to lifespan and healthspan extension in diverse organisms. This suggests that autophagy is a central regulator of aging. However, an important and fundamental question remains unanswered: how does autophagy facilitate long-term cell and tissue health?

Anti-aging effects of autophagy modulators
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 autophagy1. Pharmacological agents promoting autophagy can be classified on the basis of their effect on the mTOR pathway191. 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 effects191. Other pharmacological agents reported to promote autophagy via direct interaction with mTOR include torin-1 and PP242 (ref.192). 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 models191.

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. elegans and healthspan in mice via activation of the NAD+-dependent deacetylase SIRT1 (refs.112,193,194). Spermidine is a polyamine that extends the lifespan of yeast, worms, flies and mice by enhancing autophagy through inhibition of the EP300 acetyltransferase195, among other mechanisms55,196–198. 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 flies197,199. 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. elegans. These effects were mediated by nuclear enrichment of HLH-30, which occurred in an mTOR-independent manner47. 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 properties200. Ouabain has been shown to reduce the accumulation of abnormal toxic tau both in vitro and in vivo200. Fisetin is a flavonol and was shown to facilitate the clearance of endogenous tau via TFEB (through inhibition of mTOR kinases) and Nrf2 activation20.

Other small molecules that induce subtypes of autophagy, especially mitophagy, also enhance longevity and suppress age-associated diseases. These include NAD+, a fundamental metabolite in energy metabolism, redox homeostasis, mitochondrial function, and the arbitration of cell survival and death185. NAD+-activated sirtuins stimulate autophagy via mTOR inhibition and deacetylation of several key autophagy proteins (ATG5, ATG7 and ATG8)201,202. In addition, the NAD+–SIRT axis activates mitophagy by increasing the activity of a series of mitophagy-related proteins, such as PINK1, parkin, NIX (DCT-1 in C. elegans) and BNIP3 (refs.66,203). Supplementation with NAD+ precursors, such as nicotinamide (NAM), nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), can increase lifespan and/or improve healthspan in worms, flies and mice111,204–206. NAD+ augmentation also prevents memory loss in both amyloid β and tau C. elegans and mouse models of AD, in a mitophagy-dependent manner (requiring pink-1, pdr-1 or dct-1)138. Over seven human clinical trials have shown the safety and bioavailability of NR (1–2 g per day for up to 3 months); there are more than 30 ongoing clinical trials on the use of NR to treat premature aging and other age-related diseases (see a review in ref.185). 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-34) and mitophagy (pink-1, dct-1 and the nonspecific skn-1)207. 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)138. Urolithin A (500 mg and 1,000 mg per day for 4 weeks) was also shown to be safe in a phase 1 clinical trial208. A summary of different lifespan/health-benefit mitophagy inducers can be found in Table 2. 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.

While experimental/empirical evidence indicates that autophagy is defective in older individuals, it is conceivable that exposing individuals to autophagy inducers, dietary restriction and exercise late in life could boost autophagy and result in benefits to tissue function209,210 (Fig. 4a). 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. 4b).

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Fig. 4 |
Maintaining autophagy through lifestyle and medical interventions prolongs longevity.a, Potential interventions to stimulate autophagy: autophagy inducers, dietary restriction, exercise and genetic approaches. b, Autophagy induction could positively impact human health.

reference link :

Original Research: Open access.
GMAP is an Atg8a-interacting protein that regulates Golgi turnover in Drosophila” by Ioannis Nezis  et al. Cell Reports


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