CALORIC RESTRICTION - CONSERVATION OF IN-VIVO CELLULAR REPLICATIVE CAPACITY ACCOMPANIES LIFE-SPAN EXTENSION IN MICE

In male mice of a long-lived hybrid strain (B6D2F1), long-term 40% cal oric restriction (CR) extended both mean and maximum life spans by 36 and 20%, respectively, over that of ad libitum fed (AL) controls. Meas urements of entry into S-phase were made in vivo of six different cell types in five different organs using 2-week exposures to BrdU. The la beling index (L.I.) in all organs studied was lower in young CR mice t han in young AL fed mice. In most cases, the L.I. in AL mice fell to t he levels of that in the CR mice by 13 months of age, and the two grou ps then remained so through old age. However, when the L.I. was measur ed in old CR mice which had been placed on the AL diet for a period of 4 weeks (this was termed refeeding (RF)), it was found to be above th at of similar age AL or CR mice and almost at the level of young AL mi ce. This was still true, but to a lesser degree, in a repeat study usi ng an 8-week period of RF. In a separate but parallel in vitro study ( companion paper, this volume), the superiority of CR over AL for reten tion of cellular replication capacity was confirmed by clone size dist ribution measurements made in several cell types in mice of several ag e groups. These results indicate that: (1) the rate of cell replicatio n in AL diet mice diminishes greatly by early middle age in all organ sites studied and then plateaus or declines much more slowly; (2) CR b roadly preserves in vive cellular replicative capacity but often requi res the energy levels provided by a switch to AL feeding to demonstrat e this late in life; (3) accordingly, the replicative deficit in AL fe d mice appears to be cumulative and is significant only in old age. Th e mechanism(s) involved is yet to be discovered but may be related to, or even the same as, that which extends life spans in CR animals. Cor respondingly, and with corroborative data from our in vitro companion study, (W. R. Pendergrass et al., 1995. Exp. Cell. Res. 217, 309-316), we suggest that cell populations sustain an accrual of biochemical da mage or physiological alterations which increasingly limit their repli cative capacity as the animal ages, and that CR reduces the accrual of this damage. (C) 1995 Academic Press, Inc.