Preclinical Review Evaluates Caloric Restriction Impact on Neuropsychiatric Phenotypes

A systematic review of 41 preclinical studies establishes that while mild caloric restriction of less than 40% improves emotionality in rodents, severe restriction of 40% or more triggers anxiety-like behaviors.

Researchers from the University of Ioannina and the Foundation for Research and Technology-Hellas critically reviewed 41 rodent studies examining the impact of caloric restriction (CR) on behavior and neuropsychiatric phenotypes.

The authors reported that mild CR protocols restricted by less than 40% are overall beneficial to rodent emotionality and stress-coping, despite inducing elevated corticosterone levels.

In contrast, severe CR protocols restricting 40% or more of caloric intake were shown to be necessary, though not always sufficient, for producing anxiety-like (anxiogenic) behaviors.

The review identified maternal CR as predominantly anxiogenic for subsequent offspring, indicating transgenerational behavioral risks.

On a molecular level, the review highlighted the proposed involvement of orexigenic hormone and astrocytic ATP signaling pathways in modulating these behavioral outcomes, though preclinical data on these mechanisms remain sparse.

The study demonstrates that the therapeutic index for dietary longevity interventions is highly sensitive to protocol intensity, with a sharp boundary where metabolic benefits transition into neuropsychiatric risks.

By identifying specific variables—such as protocol severity, duration, and parental exposure—the research provides a framework for designing safer metabolic interventions.

The findings highlight a major gap in current preclinical longevity research, specifically the historic omission of female subjects and the lack of testing in models of underlying psychopathology.

Therapeutic developers targeting metabolic longevity pathways must carefully calibrate dosage windows, as severe pathway inhibition may trigger adverse psychiatric side effects like anxiety.

The highlighted connection between astrocytic ATP signaling, orexigenic hormones, and behavioral emotionality points to potential novel targets for safely capturing the benefits of caloric restriction without its behavioral side effects.

The development of future preclinical rodent trials that systematically include both sexes and evaluate caloric restriction regimens within specific psychopathological models to improve translational validity.