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Review
. 2021 Aug;1(8):634-650.
doi: 10.1038/s43587-021-00098-4. Epub 2021 Aug 12.

Autophagy in healthy aging and disease

Yahyah Aman  1   2   3 , Tomas Schmauck-Medina  1   3 , Malene Hansen  4 , Richard I Morimoto  5 , Anna Katharina Simon  6 , Ivana Bjedov  2   7 , Konstantinos Palikaras  8 , Anne Simonsen  9   10 , Terje Johansen  11 , Nektarios Tavernarakis  12   13 , David C Rubinsztein  14   15 , Linda Partridge  2   16 , Guido Kroemer  17   18   19   20   21 , John Labbadia  2 , Evandro F Fang  1   22
Affiliations
Review

Autophagy in healthy aging and disease

Yahyah Aman et al. Nat Aging. 2021 Aug.

Abstract

Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease. In addition, we discuss current preclinical evidence arguing for the use of autophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases. Finally, we highlight key questions and propose novel research avenues that will likely reveal new links between autophagy and the hallmarks of aging. Understanding the precise interplay between autophagy and the risk of age-related pathologies across organisms will eventually facilitate the development of clinical applications that promote long-term health.

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Conflict of interest statement

Competing interests E.F.F. has a CRADA arrangement with ChromaDex and is a consultant to Aladdin Healthcare Technologies, the Vancouver Dementia Prevention Centre and Intellectual Labs. A.K.S. is a consultant to Oxford Healthspan. D.C.R. is a consultant for Aladdin Healthcare Technologies, Drishti Discoveries and Nido Biosciences. G.K. is a scientific co-founder of everImmune, Samsara Therapeutics and Therafast Bio. All other authors declare no competing interests.

Figures

Fig. 1 |
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.
Fig. 2 |
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.
Fig. 3 |
Fig. 3 |. Autophagy in health and disease.
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. These diseases include AD, Parkinson’s disease (PD), Huntington’s disease, ALS and frontotemporal dementia (FTD). We emphasize that these are not the only drivers of the diseases and other processes may have roles leading to pathology and symptomatology.
Fig. 4 |
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.
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