The Effects of Lifelong Glutathione Deficiency on Functional Decline and Redox Signaling




Mock, J. Thomas


Journal Title

Journal ISSN

Volume Title



Purpose: A recent paradigm shift has implicated redox state as a potential key determinant underlying the aging process. Specifically, a pro-oxidizing shift in the ratio of reduced to oxidized glutathione (key substrate in redox status) is hypothesized to disrupt cellular signaling leading to functional impairments and mortality. Chronic glutathione deficiency is achieved by global knockout of glutamate-cysteine ligase modifier (GCLM), an enzyme subunit at the rate-limiting step in glutathione synthesis. Glutathione levels in GCLM-/- mice are 10-30% of those in GCLM+/+ mice. Our hypothesis stated that diminished glutathione synthesis would be sufficient to produce an accelerated, aging-like pattern effect on function, a shortened lifespan, and negative alterations in redox state. Methods: We characterized GCLM+/+ and GCLM-/- male and female mice with a functional battery (n = 15-23 / sex / age / genotype) measuring motor, cognitive and affective function. We also measured redox state, inflammation, metabolism and autophagy markers in central and peripheral tissues (n = 3-6 / group) at 5, 10, or 20 months of age. Lastly, survivorship and body weights were recorded for all animals (n = 455). Results: Overall, age-related declines in function were observed in all functional tests. In young and adult mice glutathione deficiency did not negatively affect function, rather it decreased anxiety-related behavior, improved coordinated running performance in young females and adult males, and delayed general motor decline in both sexes. In old mice, glutathione deficiency improved balance in males and worsened age-related motordecline in females, yet it had no negative effects on cognition in either sex. Lifespan was also extended in male and female GCLM-/- mice (median and maximum). Lastly, GCLM-/- had reduced liver redox state throughout life but only at 5 months in the young, and had increased inflammatory markers in old mice. Discussion: These data imply that (i) motor and cognitive domains appear to be differentially affected by glutathione deficiency and led to benefits in young/adult GCLM-/- mice, (ii) functional and biochemical outcomes were sexually dimorphic, (iii) glutathione deficiency did not decrease lifespan, but rather extended lifespan, and (iv) redox state was impaired in GCLM-/- mice across the lifespan peripherally, but primarily only at 5 months in central tissues. These data do not support the redox stress hypothesis of aging and require further investigation of the beneficial outcomes associated with chronic glutathione deficiency.