Autophagy: How Your Cells Self-Clean — and Why It Matters for Longevity
Autophagy is the cell's main system for delivering unwanted material to lysosomes, where it is broken down and recycled.2 Its genetic machinery was uncovered in yeast from the early 1990s, work recognised with the 2016 Nobel Prize.1 Here is what autophagy does, how it is regulated and what is actually known about boosting it in people.
- Autophagy delivers worn-out cell contents to lysosomes for breakdown, acting as a recycling system that supplies building blocks and energy as well as a form of quality control.2
- Its starter enzyme, ULK1, is switched on by AMPK when glucose is scarce and blocked by mTOR when nutrients are plentiful, linking autophagy to the cell's energy status.3
- More autophagy extends lifespan in model organisms, and mice engineered to have higher autophagy lived longer and stayed healthier, but this has not been shown in people.6
- In a first-in-human trial, the mitophagy activator urolithin A was safe and shifted markers of mitochondrial health in older adults over four weeks; mitophagy itself was not measured.5
- There is no routine test of autophagy in people, so claims that a particular fast or diet maximises it go beyond the evidence; rapamycin, which blocks mTOR, extended lifespan in mice.7
The term autophagy was coined by Christian de Duve in the 1960s, but progress at the molecular level was slow until the early 1990s, when autophagy was seen in starving yeast and a genetic search uncovered the genes that drive it.1 That work earned Yoshinori Ohsumi the 2016 Nobel Prize in Physiology or Medicine.
How Autophagy Works
Autophagy comes in several forms. In the main one, macroautophagy, material is wrapped in a membrane to form an autophagosome, which then fuses with a lysosome where the contents are degraded; other forms deliver material to lysosomes more directly.2
How autophagy changes with age in people is still being worked out; much of the evidence comes from animal and cell studies.
The Nutrient-Sensing Connection: mTOR and AMPK
Autophagy is tied to the cell's nutrient sensors. Under glucose starvation, the energy sensor AMPK switches on ULK1, the enzyme that starts autophagy, by adding phosphate groups at two sites. When nutrients are plentiful, high mTOR activity adds a phosphate at a different site that prevents ULK1 activation and disrupts its interaction with AMPK.3
This is why fasting and exercise, which lower nutrient signalling and raise AMPK activity, are thought to promote autophagy. Whether chronic overeating suppresses autophagy enough to speed ageing in people remains a hypothesis rather than an established fact.
Selective Autophagy: Mitophagy and Its Longevity Relevance
Autophagy can also be selective. Mitophagy removes malfunctioning mitochondria, which would otherwise cause oxidative damage to the cell.4
Two proteins linked to Parkinson's disease, PINK1 and Parkin, drive this process: in nerve fibres, Parkin was rapidly recruited to damaged mitochondria, which were then engulfed by autophagosomes, and without PINK1 or Parkin this mitophagy failed.4
Can You Boost Autophagy?
In mice, a genetic change that raises baseline autophagy extended lifespan in both sexes and reduced age-related kidney and heart damage and spontaneous tumours,6 and rapamycin, an mTOR inhibitor, extended median and maximum lifespan when started late in life, by 14% in females and 9% in males at the age of 90% mortality.7
In people, autophagy cannot be measured with a routine test, and no trial has shown that a particular fasting schedule, supplement or drug boosts autophagy enough to slow ageing. Urolithin A, the best-studied supplement, was safe in a first-in-human trial and changed markers of mitochondrial health, but mitophagy itself was not measured.5 Two four-month randomized trials have since tested it on muscle, and both missed their primary outcomes. In 66 adults aged 65 to 90, 1,000 mg a day did not significantly improve the 6-minute walk distance or maximal energy production in muscle, though muscle endurance, a secondary measure, improved.8 In middle-aged adults, it did not improve peak power output, the primary outcome, although muscle strength rose by about 12%.9 Exercise and avoiding chronic overeating are worth doing for their proven benefits regardless.
References
- 1Ohsumi Y. "Historical landmarks of autophagy research." Cell Res. 2014;24(1):9-23. PubMed · DOI
- 2Mizushima N, Komatsu M. "Autophagy: renovation of cells and tissues." Cell. 2011;147(4):728-41. PubMed · DOI
- 3Kim J, et al. "AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1." Nat Cell Biol. 2011;13(2):132-41. PubMed · DOI
- 4Ashrafi G, et al. "Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin." J Cell Biol. 2014;206(5):655-70. PubMed · DOI
- 5Andreux PA, et al. "The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans." Nat Metab. 2019;1(6):595-603. PubMed · DOI
- 6Fernández ÁF, et al. "Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice." Nature. 2018;558(7708):136-140. PubMed · DOI
- 7Harrison DE, et al. "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice." Nature. 2009;460(7253):392-5. PubMed · DOI
- 8Liu S, et al. "Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial." JAMA Netw Open. 2022;5(1):e2144279. PubMed · DOI
- 9Singh A, et al. "Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults." Cell Rep Med. 2022;3(5):100633. PubMed · DOI
