Reduced collagenolytic activity of matrix metalloproteinases and development of liver fibrosis in the aging rat.

Although moderate fibrosis is a histological hallmark of the aging liver, the molecular mechanisms underlying this phenomenon are little known. Here, we provide a comprehensive description of hepatic collagen expression and metabolism during natural aging in rats. Interstitial collagen accumulated significantly in the oldest animals, mainly in the periportal area (P<0.05, 19- vs. 2-month-old rats). This was ascribed to COL-III protein deposition (P<0.05 vs. 2-month-old rats), rather than COL-I. Conversely, the transcription activity of COL-III gene decreased (P<0.05) during the considered lifespan (2-19-months), whereas COL-I and transforming growth fator-beta1 (TGF-beta1) mRNA content was substantially unchanged. In the aged rats, hepatic matrix metalloproteinases (MMP) activity, (both MMP-1 and MMP-2) dropped significantly (P<0.05), with a concomitant increase of the inactive tissue inhibitor of MMP (TIMP-1)/MMP-1 complex (P<0.05). MMP-2 and TIMP-1 levels were weakly affected. All together, these results suggest that during natural aging, (i) COL III is the protein that accumulates preferentially in the liver; (ii) liver fibrosclerosis is mainly explained by a reduced proteolytic activity of matrix MMP, in which TIMP-1 seems to be a major regulating factor.