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Aging by autodigestion.

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Aging tissue breakdown may stem from digestive enzymes leaking from the gut. Blocking pancreatic trypsin in older rats reduced enzyme buildup, collagen damage, and hyperglycemia.

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Area of Science:

  • Biogerontology
  • Digestive Physiology
  • Molecular Biology

Background:

  • The mechanisms driving age-related cellular dysfunction, inflammation, and tissue degradation remain largely unknown.
  • Digestive enzymes, synthesized in the pancreas, are typically confined to the small intestine lumen by a mucin/epithelial barrier.

Purpose of the Study:

  • To investigate a novel hypothesis that aging-related tissue breakdown is caused by autodigestion from digestive enzymes leaking from the gastrointestinal tract.
  • To examine the role of pancreatic enzymes in age-associated tissue damage and metabolic dysfunction.

Main Methods:

  • Immune-histochemistry was used to detect pancreatic enzymes (trypsin, elastase, lipase, amylase) in peripheral organs of young and old rats.
  • Analysis of the small intestine mucin layer density and enzyme leakage from villi.
  • Assessment of collagen damage and insulin receptor cleavage in aged tissues.
  • Treatment of old rats with tranexamic acid, a serine protease inhibitor, to block pancreatic trypsin.

Main Results:

  • Significant accumulation of pancreatic enzymes was observed in peripheral organs of old rats compared to young rats.
  • Old rats exhibited attenuated mucin layer density and trypsin leakage from intestinal villi.
  • Collagen damage and proteolytic cleavage of the insulin receptor's extracellular domain were prevalent in old rats.
  • Tranexamic acid treatment reduced enzyme accumulation, collagen damage, hyperglycemia, and insulin receptor cleavage in old rats.

Conclusions:

  • Tissue breakdown during aging may result from autodigestion by prematurely activated digestive enzymes.
  • The integrity of the intestinal barrier is crucial for preventing systemic enzyme leakage and age-related damage.
  • Targeting pancreatic enzyme activity, such as with serine protease inhibitors, shows potential for mitigating aging-related pathologies.