Nrf2, a guardian of healthspan and gatekeeper of species longevity

Abstract

Although aging is a ubiquitous process that prevails in all organisms, the mechanisms governing both the rate of decline in functionality and the age of onset remain elusive. A profound constitutively upregulated cytoprotective response is commonly observed in naturally long-lived species and experimental models of extensions to lifespan (e.g., genetically-altered and/or experimentally manipulated organisms), as indicated by enhanced resistance to stress and upregulated downstream components of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2)-signaling pathway. The transcription factor Nrf2 is constitutively expressed in all tissues, although levels may vary among organs, with the key detoxification organs (kidney and liver) exhibiting highest levels. Nrf2 may be further induced by cellular stressors including endogenous reactive-oxygen species or exogenous electrophiles. The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating the transcription of more than 200 genes that are crucial in the metabolism of drugs and toxins, protection against oxidative stress and inflammation, as well as playing an integral role in stability of proteins and in the removal of damaged proteins via proteasomal degradation or autophagy. Nrf2 interacts with other important cell regulators such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-κB) and through their combined interactions is the guardian of healthspan, protecting against many age-related diseases including cancer and neurodegeneration. We hypothesize that this signaling pathway plays a critical role in the determination of species longevity and that this pathway may indeed be the master regulator of the aging process.

Fig. 1

Lifespan is predicted by body size. The natural log (Ln) of body size in mammals and birds has long been known to correlate allometrically with maximum species lifespan (MLSP) as modified from Sacher (1959) and updated with new species longevity data. This relationship may be described by the equation MLSP = 3.34(Mass)^0.193 (from Hulbert et al. 2007). The LQ is the ratio of actual longevity to the expected longevity from this regression of longevity on body size of non-flying, eutherian mammals. Species that live twice as long as expected on the basis of this relationship are considered long-lived and may have evolved mechanisms that resist the aging process. We hypothesize that the cytoprotective Nrf2-signalling pathway is upregulated in long-lived species, conferring enhanced resilience, and resistance to the aging process.

Fig. 2

The Nrf2 cytoprotective signaling pathway. This pathway regulates transcription of a variety of cellular defenses that bolster an organism’s response to stresses normally encountered during metabolism as well as protect against unexpected cellular insults from environmental toxins. Following its biosynthesis in the endoplasmic reticulum, Nrf2 may translocate directly into the nucleus (as indicated by the arrow) where it transactivates its target genes, thereby contributing to their constitutive expression. Steady state levels of Nrf2 are determined primarily through modulation of its continuous proteasomal degradation following ubiquitination by Cullin-3/Rbx1. Under homeostatic conditions Nrf2 is bound in the cytoplasm to Keap1 an E3 ubiquitin ligase substrate adaptor that targets Nrf2 for degradation. Under stressful conditions, conformational changes in Keap1 block the ubiquitylation of Nrf2, increasing both the half-life of Nrf2 and the size of the free Nrf2 pool, allowing more Nrf2 to translocate into the nucleus, bind to the ARE/EpRE and induce expression of a multitude of cytoprotective enzymes, including GSTs and NQO1 and those that increase GSH biosynthesis. Not surprisingly, depletion and deregulation of this pathway and or downstream components is implicated in diverse pathological conditions, many of which show increased incidence with age (e.g., diabetes, cancer, and neurodegeneration). We predict that this pathway is constitutively upregulated in longer-lived species.

Fig. 3

Increased cytoprotection is a key contributor to longevity. We predict that marked differences among species in Nrf2 protein levels and concomitant signaling exist and that they are commensurate with species longevity. In this regard we predict that naturally or genetically-altered long-lived species have more free Nrf2 that is localized in the nucleus, resulting in greater Nrf2 binding to the ARE and thus in an increase in the transcription of cytoprotective target genes such as GST and NQO1, which show greater activity and that this enhanced cellular protection contributes to species longevity. We hypothesize that shorter-lived species, in contrast, show low constitutive levels of Nrf2 with concomitant lower primed defenses against cellular insults and are thus more susceptible to toxins and accumulated damage.