S2.6  Monday, Jan. 4  Xenobiotic metabolism, lifespan and aging LEWIS, K.; MELE, J.; KIM, S.-A.; BUFFENSTEIN, R.*; Barshop Institute for Longevity and Aging Studies, Department of Physiology, University of Texas Health Science Center at San Antonio
; Barshop Institute for Longevity and Aging Studies, Department of Physiology, University of Texas Health Science Center at San Antonio; Barshop Institute for Longevity and Aging Studies, Department of Physiology, University of Texas Health Science Center at San Antonio; Barshop Institute for Longevity and Aging Studies, Department of Physiology and Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio

Mammals that are long-lived for their body size provide powerful tools with which to elucidate molecular mechanisms that may abrogate aging and facilitate prolonged longevity. It is well documented that cells from long-lived species are more resistant to cellular stressors than those of short-lived species. This may be due to enhanced cellular protection and better maintenance of somatic integrity, although the mechanisms facilitating this enhanced resilience are poorly understood. Nuclear factor erythroid 2-related factor 2 [Nrf2] is a versatile regulator of cellular adaptation to stress that transactivates antioxidant response element [ARE]-driven genes under both basal and stress conditions. Nrf2 thus regulates the expression of antioxidants, detoxicants, molecular chaperones, p53, as well as both proteasome and lysosome activity. As such, Nrf2 mediates a complex and coordinated defense against damage accrual and potentially lethal injury, and may be a key factor in longevity. We hypothesized that long-lived species constitutively have higher levels of Nrf2 and and up-regulated Nrf2 transcription activity with augmented detoxicant activity, and that this is due to enhanced Nrf2 stability, and nuclear localization. We tested this in a comparative study in rodents with disparate longevity, including at the extremes laboratory mice (maximum longevity 3.5 years) and naked mole-rats (maximum longevity 30 years). Nrf2 was present in all tissues (liver, kidney, brain, small intestine, large intestine) examined to date. Under non-stressed homeostatic conditions Nrf2 levels vary among the various tissues with the small intestine, and the liver exhibiting the highest levels. Western blot analyses, using antibodies raised against mouse Nrf2, and liver tissues reveal that protein homogenates from NMR livers contain ~-5-fold higher levels of Nrf2 protein than those of mice with an intermediate living rodent (the white footed deer mouse (maximum longevity 8 years) showing an intermediate value. DNA binding activity of Nrf2 to the ARE-oligonucleotide is >20-fold greater in liver nuclear extracts of naked mole-rats than in those from mice and not surprisingly constitutive levels of NAD(P)H:quinone oxidoreductase 1 [NQO1] and glutathione S-Transferase [GST] activity are also significantly higher in the longest-lived rodent species. Furthermore, Nrf2 induction in response to both cellular stressors to fibroblasts and xenobiotics is increased in the longer-lived species.
These findings suggest that compared to shorter-lived species naked mole-rats, not only have higher constitutive levels of Nrf2 and ARE-proteins, but also that these proteins are both constitutively more active and more responsive to induction. This greater chemoprotective efficacy may play a critical role in species longevity.