Chaperone-mediated autophagy prevents loss of brown adipose tissue activity during aging

#1

As the body ages, brown adipose tissue activity decreases, fewer calories are burned, and this can contribute to obesity and certain chronic cardiovascular diseases that worsen with age.

A study led by the University of Barcelona has identified a key molecular mechanism in the loss of brown fat activity during aging. The study opens up new perspectives for designing strategies to boost the activity of this tissue and prevent chronic metabolic and cardiovascular diseases as the population ages.

The paper, published in the journal Science Advances, was led by Professor Joan Villarroya, from the Faculty of Biology and the Institute of Biomedicine of the UB (IBUB)—based at the Barcelona Science Park-UB—and the CIBER Area for Physiopathology of Obesity and Nutrition (CIBEROBN). Teams from the Albert Einstein College of Medicine in New York (United States) also collaborated.

Brown adipose tissue: How to prevent its inactivation during aging?

Brown adipose tissue is the main organ capable of producing body heat from fat (thermogenesis). It has a protective function against obesity, type 2 diabetes and cardiovascular disease, and is activated in response to certain factors, such as cold or dietary stimuli, in which the body reacts by increasing the metabolism of excess calories consumed. However, the molecular mechanisms that cause its activity to decrease during aging are still unknown.

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#2

Checking on CGPT5:

Prompt:

Does any of the autophagy that rapamycin (sirolimus) provides invivo considered to be “Chaperone mediated autophagy”?

CGPT5 Response:

Good question — and very sharp distinction.

Short answer:

No, the autophagy induced by rapamycin (sirolimus) in vivo is primarily macroautophagy, not chaperone-mediated autophagy (CMA).

1.Type of Autophagy Rapamycin Triggers

Rapamycin inhibits mTORC1, the master nutrient and growth regulator. Inhibition of mTORC1:

  • Activates ULK1 (ATG1) and the ATG complex ,
  • Promotes autophagosome formation ,
  • Enhances macroautophagic flux (bulk degradation of cytoplasmic material inside double-membrane vesicles).

This is classic macroautophagy — the “canonical” form most associated with rapamycin.

2. What Chaperone-Mediated Autophagy Is

CMA is a selective autophagy pathway:

  • It recognizes KFERQ-like motifs in proteins,
  • Uses Hsc70 chaperones and the LAMP-2A receptor on the lysosomal membrane,
  • Directly translocates substrate proteins across the lysosomal membrane (no autophagosome formation).

CMA is not controlled directly by mTORC1. Instead, it’s regulated by:

  • mTORC2-AKT signaling ,
  • Lysosomal LAMP-2A levels and membrane stability,
  • Cellular stress states (e.g., oxidative or proteotoxic stress).

3. Relationship Between Rapamycin and CMA

  • Indirect Effects: Some studies (mostly in vitro) show that long-term mTOR inhibition can secondarily upregulate CMA, possibly through improved lysosomal function or suppression of mTORC2 over time.
  • Direct Evidence: In vivo, CMA activation by rapamycin is weak or inconsistent. LAMP-2A upregulation and Hsc70 recruitment are typically not observed after rapamycin treatment unless other CMA-specific triggers are present (e.g., nutrient deprivation, oxidative stress).

4. Summary Table

Autophagy Type Triggered by Rapamycin? Key Pathway Main Targets
Macroautophagy :white_check_mark: Strongly activated mTORC1 → ULK1 → ATG5/7 Bulk cytoplasmic turnover, damaged organelles
Microautophagy :white_circle: Possibly mild/secondary Endosomal–lysosomal engulfment Small cytosolic portions
Chaperone-Mediated Autophagy (CMA) :x: Not directly LAMP-2A, Hsc70, KFERQ motifs Soluble cytosolic proteins, oxidized enzymes

Bottom line:

Rapamycin’s autophagy is overwhelmingly macroautophagy. Any CMA modulation is indirect and context-dependent, not a primary or reliable in vivo effect.