Autophagy is a conserved process that catabolizes intracellular components to maintain energy homeostasis and to protect cells against stress. Autophagy has crucial roles during development and disease, and evidence accumulated over the past decade indicates that autophagy also has a direct role in modulating ageing. In particular, elegant studies using yeasts, worms, flies and mice have demonstrated a broad requirement for autophagy-related genes in the lifespan extension observed in a number of conserved longevity paradigms. Moreover, several new and interesting concepts relevant to autophagy and its role in modulating longevity have emerged. First, select tissues may require or benefit from autophagy activation in longevity paradigms, as tissue-specific overexpression of single autophagy genes is sufficient to extend lifespan. Second, selective types of autophagy may be crucial for longevity by specifically targeting dysfunctional cellular components and preventing their accumulation. And third, autophagy can influence organismal health and ageing even non-cell autonomously, and thus, autophagy stimulation in select tissues can have beneficial, systemic effects on lifespan. Understanding these mechanisms will be important for the development of approaches to improve human healthspan that are based on the modulation of autophagy.
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The authors apologize to the colleagues whose work they were unable to discuss owing to space limitations. The authors are grateful to the assistance of C. Karabiyc with the figures. Work in M.H.’s laboratory is funded by the National Institute on Aging (R01AG038664) and National Institute of General Medical Sciences (R01GM117466). Work in D.W.W.’s laboratory is funded by the National Institute on Aging (R01AG037514, R01AG049157 and R01AG040288). M.H. and D.W.W. are both Julie Martin Mid-Career Awardees in Aging Research supported by The Ellison Medical Foundation and the American Federation for Aging Research. Work in D.C.R.’s laboratory is funded by the UK Dementia Research Institute (funded by the Medical Research Council, Alzheimer Disease Research UK and the Alzheimer Disease Society), the Wellcome Trust (Principal Research Fellowship to D.C.R. (095317/Z/11/Z)), the Rosetrees Trust, Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z), Alzheimer Disease Research UK, the Tau Consortium and the Biomedical Research Centre at Addenbrooke’s Hospital.
D.C.R. is a consultant for E3Bio and has consulted for GlaxoSmithKline and AstraZeneca. D.C.R. has grant support from AstraZeneca and AbbVie.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Cytosolic double-membrane-bound vesicles capable of sequestering cytoplasmic inclusions and organelles destined for degradation in the autolysosome.
A cytosolic vesicle resulting from fusion between an autophagosome and acidic lysosomes in which degradation of the inner membrane and sequestered autophagosomal material takes place.
An evolutionarily conserved protein kinase that negatively regulates autophagy.
- Autophagy receptors
Proteins that facilitate recruitment of cargo to the phagophore for subsequent lysosomal degradation.
A region of forebrain that coordinates the autonomic nervous system and the activity of the pituitary, which controls various homeostatic systems, including body temperature.
- Lysosomal-associated membrane glycoprotein 2a
(LAMP2A). A lysosomal protein with a key role in chaperone-mediated autophagy.
- Insulin/IGF1 signalling
A multi-component signalling pathway that regulates metabolism and longevity in a conserved fashion.
- Spastic paraplegia
An inherited disorder characterized by spasticity of the legs.
Loss of control over bodily movements.
- Mitochondrial fission
The separation of a single mitochondrion into two or more daughter organelles.
- Urolithin A
A metabolite produced by gut microorganisms from ellagic acid. Urolithin A induces mitophagy.
- Lipid droplet
A cellular organelle that regulates the storage and hydrolysis of neutral lipids.
- Lipid chaperone
A fatty acid-binding protein important in the transport of lipids inside and between cells.
- Hormetic heat shock
An aspect of hormesis, meaning beneficial effects of a treatment for which higher intensity is harmful. During hormetic heat shock, non-lethal exposure to elevated temperature induces a response that results in increased stress resistance and longevity.
- Proximal tubules
The segment of the kidney that is responsible for reabsorption of nearly two-thirds of all filtered water, sodium and chloride.
Highly specialized cells of the kidney glomerulus that wrap around capillaries.
A key structure of a nephron, the functional unit of the kidney.
- Microbial dysbiosis
The condition of having imbalances in the microbial communities either in or on the body.
- Septate junction
An intercellular occluding junction found in invertebrate epithelia.
- Crohn’s disease
A chronic inflammatory bowel disease.
- Insulin-like peptide
A type of peptide with homology to insulin, a hormone produced in the pancreas that regulates glucose levels in the blood.
- Chemosensory neurons
Sensory neurons responsive to chemical stimuli.
- Presynaptic active zone
The part of the nerve terminal from which neurotransmitters are released by synaptic vesicle exocytosis.
The degenerative loss of muscle mass, quality and strength associated with ageing.
Loss of the ability of a cell to divide, differentiate and grow.
- Beclin 1
Mammalian orthologue of yeast autophagy-related 6 (Atg6), which forms part of the class III phosphatidylinositol 3-kinase complex involved in activating autophagy.
The selective degradation of the endoplasmic reticulum by autophagy.
The selective degradation of ribosomes by autophagy.
The selective degradation of intracellular pathogens by autophagy; xenophagy is part of the cell-autonomous innate immunity defence.
The selective removal of nuclear material from a cell by autophagy.
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Hansen, M., Rubinsztein, D.C. & Walker, D.W. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol 19, 579–593 (2018). https://doi.org/10.1038/s41580-018-0033-y
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