Dietary Restriction-Induced Alterations in Bone Phenotype: Effects of Lifelong Versus Short-Term Caloric Restriction on Femoral and Vertebral Bone in C57BL/6 Mice

Abstract

Caloric restriction (CR) is a well-described dietary intervention that delays the onset of aging-associated biochemical and physiological changes, thereby extending the life span of rodents. The influence of CR on metabolism, strength, and morphology of bone has been controversially discussed in literature. Thus, the present study evaluated whether lifelong CR versus short-term late-onset dietary intervention differentially affects the development of senile osteoporosis in C57BL/6 mice. Two different dietary regimens with 40% food restriction were performed: lifelong CR starting in 4-week-old mice was maintained for 4, 20, or 74 weeks. In contrast, short-term late-onset CR lasting a period of 12 weeks was commenced at 48 or 68 weeks of age. Control mice were fed ad libitum (AL). Bone specimens were assessed using microcomputed tomography (μCT, femur and lumbar vertebral body) and biomechanical testing (femur). Adverse effects of CR, including reduced cortical bone mineral density (Ct.BMD) and thickness (Ct.Th), were detected to some extent in senile mice (68+12w) but in particular in cortical bone of young growing mice (4+4w), associated with reduced femoral failure force (F). However, we observed a profound capacity of bone to compensate these deleterious changes of minor nutrition with increasing age presumably via reorganization of trabecular bone. Especially in lumbar vertebrae, lifelong CR lasting 20 or 74 weeks had beneficial effects on trabecular bone mineral density (Tb.BMD), bone volume fraction (BV/TV), and trabecular number (Tb.N). In parallel, lifelong CR groups showed reduced structure model index values compared to age-matched controls indicating a transformation of vertebral trabecular bone microarchitecture toward a platelike geometry. This effect was not visible in senile mice after short-term 12-week CR. In summary, CR has differential effects on cortical and trabecular bone dependent on bone localization and starting age. Our study underlines that bone compartments possess a lifelong capability to cope with changing nutritional influences.

Keywords: AGING; ANIMAL MODEL; BONE μCT; NUTRITION; OSTEOPOROSIS.