Delayed and reduced cell replication and diminishing levels of DNA polymerase‐α in regenerating liver of aging mice

Abstract

Kinetics of cell replication was compared in regenerating livers of Mus musculus at ages ranging between 6 and 32 months. Incorporation of [3H]-thymidine into DNA and autoradiographic analysis showed that the maximal extent of DNA replication following partial hepatectomy became delayed with age. Furthermore, the total fraction of parenchymal and nonparenchymal cells in S phase at different intervals during regeneration diminished as mice aged. The specific activity of DNA polymerase-alpha, the putative replicative enzyme, declined progressively during aging. The specific activity of DNA polymerase-beta, the purported repair enzyme, declined to an appreciably lesser extent during the lifespan of the mouse. No evidence was found for the appearance of a specific inhibitor of polymerase-alpha in senescent mouse liver. Also, the bulk of the activities of both hepatic DNA polymerase-alpha and -beta remained localized in the cell nucleus throughout the lifetime of the animal and were mainly associated with chromatin.

Global gene expression profile of normal and regenerating liver in young and old mice

“…According to previous results (Bucher et al 1964;Fry et al 1984;Wang et al 2001), while a strong proliferative response, as detected by BrdU incorporation, was observed in young mice (Fig. 2a, b), (LI of 52.5 %±8.8), liver regeneration was severely impaired in old mice; indeed, virtually, no hepatocyte nuclei were BrdU-positive at the same time point (LI of 1.5 %±0.5).…”

“…Each lane represents a pool of three livers. CO controls and mice (Bucher et al 1964;Fry et al 1984;Wang et al 2001). Among the possible causes, an age-related switch from cyclin-dependent kinase inhibition to repression of E2F transcription (Iakova et al 2003) and/or a decrease in expression of a gene coding for a critical Forkhead Box has been correlated with reduced proliferation of regenerating hepatocytes from old mice (Wang et al 2001).…”

“…The most documented age-related changes in the liver consist in a decline in organ volume (in men liver, weight is reduced by about 6.5 % and in women 14.3 %), decrease in hepatic blood flow, increased dense bodies volume, reduced concentration of smoothsurfaced endoplasmic reticulum, and of hepatocyte number (Schmucker 2005;Sheedfar et al 2013). The most important functional effect of all these agingrelated changes is a decrease in the regenerative capacity of the hepatocytes in rodents and humans (Bucher et al 1964;Fry et al 1984;Zhu et al 2014). Adult liver is a quiescent organ with no basal hepatocyte proliferation; however, in response to injury, hepatocytes can be recruited into an active cell cycle (liver regeneration).…”

“…Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event (Grana and Reddy 1995). Several studies have demonstrated that in old rodents, the liver's ability to regenerate and to adjust its size after PH is reduced and delayed (Bucher et al 1964;Fry et al 1984). Indeed, while in young rats, DNA synthesis peaks at 24 h after PH, in old animals, the S phase peak is reached at 36 h. Different explanation has been proposed to justify this proliferation defect observed in aged rodents.…”

Potential utility of xenobiotic mitogens in the context of liver regeneration in the elderly and living-related transplantation

“…Indeed, several studies on the regenerative response that follows two-third partial hepatectomy (PH) have shown that the response to PH was both delayed and reduced with aging in rats and mice. 7,8 Although the mechanism(s) responsible for the agerelated decline in the post-hepatectomy proliferative response are not known, an age-related switch from cyclin-dependent kinase inhibition to repression of E2F transcription 9 and/or a decrease in expression of a gene coding for a critical Forkhead Box transcription factor have been correlated with reduced proliferation of regenerating hepatocytes from old rodents. 10 In recent years, an increasing number of agents capable of inducing hepatomegaly without causing liver injury (direct hyperplasia) have been identified.…”