For readers who regularly follow cutting-edge anti-aging science, the term autophagy is probably no stranger. The word autophagy derives from the ancient Greek “αὐτόφαγος,” meaning self-devouring.
When journals feature academic papers on autophagy, the cover often depicts a mysterious symbol that appears in various ancient Eastern and Western civilizations: the Ouroboros (οὐροβόρος), a serpent eating its own tail. In Greek, it also means self-devouring. Beyond that, the Ouroboros symbolizes renewal, rebirth, and infinity【1】— perfectly aligning with the physiological role of cellular autophagy: by consuming itself, life is sustained.
Image caption: The Ouroboros (Dragon Eating Its Tail) in ancient Chinese civilization.
What is Autophagy?
Autophagy is a process in which cellular components are degraded within the cell’s own lysosomes. To date, three distinct types of autophagy have been observed, differing mainly in how they transport the material (cargo) to lysosomes for degradation:
Macroautophagy (often simply referred to as autophagy)【2】:
This is the primary, active, selective, and highly regulated form of autophagy, responsible for cellular responses to environmental and physiological signals.
Here, a portion of the cytoplasm is enclosed by a double-membrane structure called the isolation membrane or phagophore, forming a double-membraned vesicle known as an autophagosome. The autophagosome fuses with the lysosome, whose enzymes degrade the autophagosome and its cargo. Macroautophagy can engulf large molecules, organelles, and even microbes, clearing damaged mitochondria (mitophagy), fragments of endoplasmic reticulum (reticulophagy), ruptured lysosomes (lysophagy), and invading pathogens (xenophagy).
Two key types of signals can activate macroautophagy:
Nutrient and stress signals, often acting via mTORC1, particularly under starvation or metabolic stress.
Signals linked to the identification of specific cargo, such as damaged mitochondria binding to adaptor proteins that initiate autophagosome formatio
Microautophagy【3】: Here, the lysosomal membrane directly engulfs portions of the cytoplasm.
Chaperone-mediated autophagy (CMA)【4】: Target proteins (or sometimes DNA/RNA, known as DNA/RNA autophagy) bind to chaperones and are transported directly into lysosomes for degradation.
Can Autophagy Combat Aging?
Macroautophagy—the most prominent form of autophagy (referred to simply as “autophagy” below)—requires the coordinated action of multiple protein complexes encoded by evolutionarily conserved autophagy-related genes (ATGs), found from yeast to humans.
By studying the phenotypes of organisms lacking ATG genes and the non-canonical functions of these genes, scientists have gradually uncovered the physiological and pathological roles of autophagy【5】.
In essence, autophagy serves two key physiological functions: famine preparedness and homeostasis maintenance.
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“Famine preparedness” — adaptive metabolic response to starvation and exercise
The most fundamental and conserved function of autophagy is meeting metabolic demands. During starvation or aerobic exercise, autophagy is upregulated to break down macromolecules, maintain protein synthesis, and produce energy, helping the organism survive harsh environments and metabolic stress【6】.
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“Homeostasis maintenance”
Autophagy maintains cellular homeostasis by clearing misfolded proteins, aggregates, excess or damaged organelles, and regulating levels of certain proteins and lipids for normal cell function【5】.This role is especially critical in long-lived, non-dividing cells like neurons, which cannot dilute cellular waste via cell division. In neurons, deletion of ATG genes leads to neurodegeneration and accumulation of ubiquitin-positive protein aggregates. Mice lacking ATG genes die within 2–3 months from neurodegenerative diseases or infections【8】【9】.
Thus, activating autophagy could pave the way for treating aging-related neurodegenerative diseases【5】, making it one of the most promising therapeutic directions.
Aging and Declining Autophagy
As we age, autophagic activity declines【10】. Experimental studies have shown that enhancing autophagy extends lifespan and healthspan in mammals. In mice with enhanced autophagy (via F121A knock-in or Rubicon knock-out), age-related phenotypes like cardiac and renal fibrosis and spontaneous tumors are reduced, and lifespan is extended compared to normal mice【11】【12】.
Autophagy promotes healthy longevity by maintaining protein/organelle quality control, genomic stability, and stem cell properties【13】.
Classic longevity-promoting metabolic interventions such as dietary restriction (DR), reduced IGF-1 signaling, as well as “new anti-aging molecules” like resveratrol and urolithin A, all rely heavily on autophagy. Without this core component, their beneficial effects may be greatly diminished or even absent【10】.
Autophagy and Cancer: Friend or Foe?
In theory, autophagy’s robust homeostatic functions should suppress tumor formation by clearing “dangerous molecules.” So why are autophagy inhibitors being developed as novel anticancer drugs?
This paradox arises because autophagy can also have protumorigenic effects. For example, autophagy in non-tumor cells can provide nutrients to tumor cells【14】 and suppress CD8+ T cell-mediated antitumor immunity【15】, thereby supporting cancer cell survival and metastasis.
In animal studies, mice lacking ATG genes developed only benign tumors. Thus, autophagy’s cancer-suppressing or cancer-promoting effects likely depend on the stage and context:
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Before tumor formation, autophagy activation suppresses cancer.
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After tumor formation, autophagy activation may support tumor growth and metastasis【16】.
How to Activate Autophagy?
Current research has identified multiple ways to activate autophagy:
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Intermittent Fasting (IF)
IF is the most classic way to activate autophagy. Earlier studies suggested that autophagy occurs only when glucose and insulin levels drop significantly—requiring 2–4 days of fasting in humans based on metabolic rates.Some animal experiments show that even short-term fasting (1–2 days) induces neuronal autophagy with neuroprotective effects【17】. Ongoing clinical trials aim to determine the optimal fasting duration to induce autophagy in humans (e.g., NCT04842864).
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Exercise
Human studies suggest exercise activates autophagy in skeletal muscle【18】. -
Dietary Components
Certain foods may induce autophagy, including turmeric, ginger, garlic, cinnamon, green tea, coffee, pomegranates, peanuts, and dark chocolate. -
Anti-Aging Compounds
From a molecular perspective, mTORC1 inhibitors (e.g., rapamycin, idalopirdine, SB-742457) and AMPK activators (e.g., metformin) are well-established autophagy inducers【19】【20】.Additionally, some mTOR-independent agents such as spermidine【21】, lithium salts【22】, and trehalose【23】 can activate autophagy and show neuroprotective effects in experiments.
The Future of Autophagy
Some readers may wonder: “You didn’t mention X, which also activates autophagy!” True—many other compounds may induce autophagy. But their effects may lack strict specificity【24】【25】.
In other words, the challenge isn’t that autophagy is a bad target; it’s that our understanding of autophagy remains rudimentary. Autophagy is a dynamic process, yet we currently “cannot see” autophagy at the cellular level. We can’t fully answer: When does autophagy occur? Where does it occur? How much autophagy is happening?
With the development of monitoring techniques (e.g., molecular probes, biomarkers), it may soon be possible to directly visualize autophagy in different tissues via PET-CT after fasting, or measure autophagy levels precisely via a simple blood draw after taking supplements【26】.
At that point, autophagy could become a powerful strategy to combat aging, neurodegenerative diseases, and cancer.
So, What’s the Right Attitude Toward Autophagy Today?
The author believes we should treat autophagy as an intermediary mechanism. Existing anti-aging interventions—fasting, exercise, certain supplements—already activate autophagy, and their ultimate purpose is to promote longevity.
There’s little practical difference between saying:
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“Intermittent fasting may promote longevity by activating autophagy”
and -
“Intermittent fasting promotes longevity.”
Obsessing over whether “two days of fasting activates autophagy, but one day doesn’t” is like putting the cart before the horse.