L. Muskhelishvili et al., AGE-RELATED-CHANGES IN THE INTRINSIC RATE OF APOPTOSIS IN LIVERS OF DIET-RESTRICTED AND AD LIBITUM-FED B6C3F1 MICE, The American journal of pathology, 147(1), 1995, pp. 20-24
Cancer incidence increases progressively with age. This observation su
ggests that a mechanistic relationship may exist at the cellular level
between these two apparently diverse processes. Indirect evidence for
this fundamental relationship is derived from the fact that intervent
ions that retard the rate of aging simultaneously retard the incidence
of many forms of cancer Dietary restriction of rodents is a noninvasi
ve manipulation that reproducibly retards most physiological indices o
f aging as well as the incidence of spontaneous and chemically induced
tumors. As such, it provides a powerful model in which, to study comm
on mechanistic processes associated with both aging and cancer In a re
cent study, toe established that chronic dietary restriction induces a
n increase in the spontaneous rate of apoptotic cell death in hepatocy
tes of 12-month-old B6C3F1 mice and is associated with a significant r
eduction in the subsequent development of spontaneous hepatoma in this
genetically susceptible strain, The purpose of the present investigat
ion uas to extend and confirm these original observations by determini
ng whether the increased rate of spontaneous apoptosis w,ith chronic d
ietary restriction is maintained throughout the life span itt this str
ain. We quantified the spontaneous apoptotic rate by histological exam
ination of liver sections from diet-restricted and ad libitum-fed B6C3
F1 mice at age intervals of 12, 18, 24, and 30 months. The incidence o
f apoptotic bodies was enumerated in non-tumor-bearing mice bq, scorin
g 50,000 hepatocytes per liver by in situ end-labeling immunohistochem
istry and uas expressed as the mean incidence per 100 cells. The rate
of apoptotic cell death was found to be elevated with age in both diet
groups; however, the rate of apoptosis was significantly and consiste
ntly higher in the diet-restricted mice, relative to the ad libitum-fe
d mice, regardless of age. It has been proposed that apoptosis, or phy
siological cell death, provides a protective mechanism whereby DNA-dam
aged or potentially neoplastic cells are selectively eliminated. Thus,
infertventions that increase cellular sensitivity to apoptotic cell d
eath would tend to protect genotypic and phenotypic stability with age
; on the other hand the failure to initiate or respond to appropriate
signals for apoptosis would tend to accelerate the accumulation of age
-associated genetic lesions and age-related neoplasia, An increase in
the intrinsic rate of apoptotic cell death may contribute, in part, to
decreased tumor incidence and increased life span potential with diet
ary restriction.