To Extend Lifespan, Scientists Are Forcing Cells to "Eat Themselves"...

You’ve probably heard of "cannibalism," but what about "self-cannibalism"?
Believe it or not, such strange phenomena exist in nature.

Some snake species are infamously known for self-cannibalism, and the reason is somewhat worthy: Snakes hunt using heat sensing, with poor hearing and vision. When extremely hungry, they may mistake their wriggling tails for heat-emitting prey.

Another lesser-known marine creature, the sea squirt, likes to "taste" itself starting from its brain. Juvenile sea squirts have complex nervous systems, but once they settle in a habitat, they no longer need the energy-intensive brain and nervous system. Adult sea squirts then eat their own brains to provide nutrients for new organ growth.

Some mammals also eat their placentas after giving birth—no pictures here, but you’ve likely heard of this.

I’m not switching to biology. While natural self-eating seems gross, similar phenomena occur in our bodies every second. Even in the field of longevity research, scientists are going to great lengths to force cells to better "eat themselves"...

The scientific term for cells eating themselves is "autophagy," and research on it is no trivial matter.

In 1955, Belgian scientist Christian de Duve first discovered lysosomes in mouse liver cells[1] and proposed the concept of "autophagy" in 1963[2]. In 1997, Japanese scientist Yoshinori Ohsumi identified 15 autophagy-related genes (ATGs)[3].

The two won the Nobel Prize in Physiology or Medicine in 1974 and 2016, respectively, for these contributions.

Cells don’t decide to "eat themselves" casually. In fact, most known longevity-promoting measures—whether dietary/behavioral controls, pharmacological interventions, or genetic modifications—ultimately activate autophagy.

We’ve covered the outcomes of autophagy in our previous article on spermidine: From preventing hair loss to anti-aging, autophagy even has unclear connections with telomerase... It’s high time to let autophagy take center stage; otherwise, our anti-aging 科普 landscape would be incomplete! Let’s dive in: 👇👇

Autophagy is a pathway for intracellular degradation widely present in eukaryotic cells. Simply put, it’s the cell’s natural recycling system, aimed at breaking down metabolic "waste" for reuse.

The process of cells "eating themselves" is a bit like snakes: swallowing prey whole and digesting it slowly. In this process, lysosomes act as the digestive organs, while the "food" includes misfolded proteins, lipids, nucleic acids, damaged organelles, and invading pathogens.

Based on how degraded substances enter lysosomes, scientists classify autophagy into three types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA)[4]. 👇👇

Autophagy in normal cells is generally maintained at a low level, known as basal autophagy. However, when cells are under stress due to pathological or physiological stimuli, autophagy levels increase significantly (induced autophagy). At this time, cells clear excess or damaged organelles through autophagy, degrade cytoplasmic lipids and misfolded/damaged proteins, thereby providing nutrients and maintaining survival.

Stress conditions that activate autophagy include starvation, hypoxia, oxidative stress, protein aggregation, endoplasmic reticulum (ER) stress, and increased intracellular demand.

Take starvation as an example: Macroautophagy, the first line of defense against adverse conditions, peaks after 4–6 hours of starvation and then gradually weakens. After 8–10 hours of starvation, chaperone-mediated autophagy is gradually activated, peaking at 16–18 hours and persisting for 36 hours, ensuring cellular homeostasis by selectively clearing damaged proteins.

Among all signaling pathways regulating autophagy, mTOR is the most important. mTOR exists in two protein complexes (mTORC1 and mTORC2), but only mTORC1 directly regulates autophagy. Under nutrient-rich conditions, mTOR phosphorylates the autophagy-activating kinase ULK1, inactivating it by binding to Atg13 and FIP200, thereby inhibiting autophagy. Under nutrient deficiency, mTORC1 is inhibited by upstream signaling pathways, and the phosphorylation site on ULK1 is dephosphorylated and dissociated, activating the autophagy initiation pathway[6].

Upstream of mTOR, there are multiple signaling pathways such as PI3K-AKT-mTOR and AMPK. These pathways form a complex network that jointly regulates mTOR levels, thereby affecting the activation of downstream autophagy signaling[7].

Additionally, there are autophagy signaling pathways independent of mTOR, such as the Beclin1 pathway, type I PI3K pathway, and Gai3 protein pathway, all of which can initiate autophagy[8].

(Optional reading)
Macroautophagy is the main and most widely studied form of autophagy. Taking macroautophagy as an example, we briefly introduce its molecular mechanisms.

Macroautophagy is a complex, step-by-step process involving initiation, elongation, encapsulation, and fusion.

✨ Initiation: When autophagy initiation signals are activated, autophagy-related proteins localize to specific subcellular sites, initiating and mediating the assembly of a cup-shaped single-membrane structure called the phagophore assembly site (PAS).
— The common target of signaling pathways is the ULK1 complex (composed of ULK1, ATG13, FIP200, and ATG101). The core protein structure of the ULK1 complex contains Thr226 and Ser230 sites; when phosphorylated and activated, it initiates autophagy and induces PAS formation on the endoplasmic reticulum.
The PI3K complex (composed of class III PI3K, VPS34, Beclin 1, ATG14, AMBRA1, and p115) then localizes to PAS, phosphorylating membrane PI to phosphatidylinositol 3-phosphate (PI3P). PI3P recruits multiple effectors involved in autophagosome formation.
PAS is then modified by the Beclin-1, ATG14, and VPS34 complex to form an isolation membrane[9].

✨ Elongation: Subsequently, under the action of multiple signaling molecules, PAS continuously elongates and expands, eventually forming a sphere.
— PAS elongation is related to ubiquitin-like conjugation reactions involving Atg8, Atg5, Atg12, Atg16, and Atg3. WIPI2 directly binds to ATG16L1, thereby recruiting the ATG12-ATG5-ATG16L1 complex[10]. This complex enhances the activity of the ATG3 enzyme, which mediates the coupling of ATG8 to membrane-associated phosphatidylethanolamine (PE), converting it from a freely diffusing form (LC3-I) to a membrane-bound lipidated form (LC3-II), promoting PAS elongation[11].

✨ Encapsulation: The isolation membrane finally seals to form a double-membraned vesicle called an autophagosome. Inside the vesicle is the engulfed autophagic content.
— PAS gradually elongates and seals to form double-membraned autophagosomes, which mature after steps such as ATG protein stripping and kinesin binding.

✨ Fusion: The outer membrane of the autophagosome can fuse with lysosomal membranes in the cytoplasm to form an autolysosome. After fusion, the autophagosome and its contents are degraded by various acid hydrolases in lysosomes.
— After autophagosome formation, it further fuses with intracellular lysosomes to form autolysosomes. This process includes autolysosome formation, vesicle breakdown, and lysosome reconstruction.

In the formed autolysosome, the content to be degraded and the inner membrane system are degraded by acid hydrolases in lysosomes. The degraded biomacromolecules are transported out of the autophagosome by transporters and released into the cytoplasm for reuse by the cell.

At the final stage of intracellular autophagy, autolysosomes can generate primary lysosomes through a budding-like process, ensuring the smooth progress of autophagy and ultimately maintaining cellular homeostasis. This complete biological process is called autophagic flux[12,13].

As we age, cellular autophagy capacity gradually declines. Therefore, in the familiar field of longevity research, scientists focus not only on "how cells eat" but also on "how to make them eat faster and better." We’ll discuss this in our next article.

▼附Key Autophagy Factors and Their Regulation [14]▼

References
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[7] Di Malta C, Siciliano D, Calcagni A, et al. Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth[J]. Science, 2017,356(6343):1188-1192.
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[10] Romanov J, Walczak M, Ibiricu I, et al. Mechanism and functions of membrane binding by the Atg5-Atg12/Atg16 complex during autophagosome formation[J]. EMBO J, 2012,31(22):4304-4317.
[11] Noda N N, Fujioka Y, Hanada T, et al. Structure of the Atg12–Atg5 conjugate reveals a platform for stimulating Atg8–PE conjugation[J]. EMBO reports, 2013,14(2):206-211.
[12] Diao J, Liu R, Rong Y, et al. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes[J]. Nature, 2015,520(7548):563-566.
[13] Koyama-Honda I, Itakura E, Fujiwara T K, et al. Temporal analysis of recruitment of mammalian ATG proteins to the autophagosome formation site[J]. Autophagy, 2013,9(10):1491-1499.
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