Wolf N S, Penn P E, Jiang D, Fei R G, Pendergrass W R
Department of Pathology, University of Washington School of Medicine, Seattle 98195, USA.
Exp Cell Res. 1995 Apr;217(2):317-23. doi: 10.1006/excr.1995.1092.
In male mice of a long-lived hybrid strain (B6D2F1), long-term 40% caloric restriction (CR) extended both mean and maximum life spans by 36 and 20%, respectively, over that of ad libitum fed (AL) controls. Measurements 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 labeling index (L.I.) in all organs studied was lower in young CR mice than in young AL fed mice. In most cases, the L.I. in AL mice fell to the levels of that in the CR mice by 13 months of age, and the two groups then remained so through old age. However, when the L.I. was measured 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 that of similar age AL or CR mice and almost at the level of young AL mice. This was still true, but to a lesser degree, in a repeat study using 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 retention of cellular replication capacity was confirmed by clone size distribution measurements made in several cell types in mice of several age groups. These results indicate that: (1) the rate of cell replication 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 broadly preserves in vivo cellular replicative capacity but often requires the energy levels provided by a switch to AL feeding to demonstrate this late in life; (3) accordingly, the replicative deficit in AL fed mice appears to be cumulative and is significant only in old age. The 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. Correspondingly, 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 damage or physiological alterations which increasingly limit their replicative capacity as the animal ages, and that CR reduces the accrual of this damage.
在一种长寿杂交品系（B6D2F1）的雄性小鼠中，长期40%的热量限制（CR）使平均寿命和最大寿命分别比自由摄食（AL）对照组延长了36%和20%。使用2周的溴脱氧尿苷（BrdU）暴露，在体内对五种不同器官中的六种不同细胞类型进入S期的情况进行了测量。在所有研究的器官中，年轻的CR小鼠的标记指数（L.I.）低于年轻的AL喂养小鼠。在大多数情况下，AL小鼠的L.I.在13个月龄时降至CR小鼠的水平，然后两组在老年期一直保持这种状态。然而，当对已改为AL饮食4周（这被称为再喂养（RF））的老年CR小鼠测量L.I.时，发现其高于同龄的AL或CR小鼠，几乎达到年轻AL小鼠的水平。在一项使用8周RF期的重复研究中，情况仍然如此，但程度较轻。在一项单独但平行的体外研究（本卷中的配套论文）中，通过对几个年龄组小鼠的几种细胞类型进行克隆大小分布测量，证实了CR在保留细胞复制能力方面优于AL。这些结果表明：（1）在所有研究的器官部位，AL饮食小鼠的细胞复制率在中年早期就大幅下降，然后趋于平稳或下降得更缓慢；（2）CR广泛地保留了体内细胞复制能力，但通常需要改为AL喂养所提供的能量水平才能在生命后期证明这一点；（3）因此，AL喂养小鼠的复制缺陷似乎是累积性的，并且仅在老年时才显著。所涉及的机制尚未发现，但可能与延长CR动物寿命的机制相关，甚至相同。相应地，结合我们体外配套研究（W. R. Pendergrass等人，1995年。《实验细胞研究》217，309 - 316）的佐证数据，我们认为细胞群体随着动物年龄增长会积累生化损伤或生理改变，这越来越限制它们的复制能力，而CR减少了这种损伤的积累。
