Transcription factor Nrf2 as a Regulator of Mammalian Aging

Relevance. The study of aging processes is a fundamental task of modern science. Gerontologists all over the world have long been paying attention to the transcription factor Nrf2, which is often called the master regulator of aging.

Aim. To analyze data pertaining to the impact of Nrf2 on aging in human and non-human mammals.

Materials and Methods. Analysis of available information from PubMed database with no publication time limit.

Results and conclusions. Many studies have demonstrated the direct involvement of Nrf2 in cellular and organismal aging. The transcription factor Nrf2 controls the expression of genes involved in antioxidant response, redox homeostasis, detoxification of toxic compounds, mitochondrial biogenesis and many other processes. Activation of these genes protects cells from oxidative stress and the development of inflammation. Nrf2 activation increases the expression of hemoxygenase (HO-1), responsible for the degradation of pro-inflammatory free heme and the formation of anti-inflammatory compounds such as CO and bilirubin; NAD(P)H: quinone oxidoreductase (NQO1), which has antioxidant activities; the cytoplasmic form of the antioxidant enzyme superoxide dismutase-1 (SOD-1); and key enzymes of glutathione biosynthesis (Gclc, Gclm), which is a major cellular antioxidant. The absence of Nrf2 in knockout mice causes an uncontrolled inflammatory response: activation of innate immune cells, high production of cytokines, chemokines and reactive oxygen species - all these factors contribute to cell and tissue damage [1-4].

In aging organisms, Nrf2 activity decreases, and oxidative damage to biomolecules gradually accumulates, accompanied by the production of inflammatory cytokines and subchronic inflammation. Activation of the transcription factor Nrf2 can reduce oxidative stress and inflammation in animal models such as Drosophila and nematodes, thereby retarding the development of senescent changes. That said, there are very few data on the effects of Nrf2 activators on human and mammalian aging. It might be expected that stimulation of Nrf2 would also lead to an increase in their lifespan. Indirect evidence for this assumption is the increased level of Nrf2 activation in long-lived animals such as the naked mole rat. Experimental work on the age-related dynamics of changes in Nrf2 activity in animals and humans, as well as on the effect of long-term administration of inducers of the transcription factor Nrf2 on longevity and signs of aging should become an important area of research. At the same time, there is a possibility that long-term pharmacological activation of Nrf2 may lead to the development of serious side effects, because long-lived organisms are finely adapted to the consequences of such activation, while humans and many other mammals do not have such adaptations [4].

The thesis about the key role of Nrf2 in aging processes is extremely controversial. Nrf2 regulates the expression of several hundreds of genes carrying specific sequences in their promoters, called antioxidant response element, ARE. But aging produces complex multidirectional expression changes that are unique to different tissues and species. These changes only correspond to a small extent to the pattern of genes controlled by Nrf2. Thus, it cannot be concluded at this time that Nrf2 is a "master regulator of the aging process" [4-5].

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2. Schmidlin CJ, Dodson MB, Madhavan L, Zhang DD. Redox regulation by NRF2 in aging and disease. Free Radic Biol Med. 2019;134: 702-707. doi: 10.1016/j.freeradbiomed.2019.01.016.

3. Zhou L, Zhang H, Davies KJA, Forman HJ. Agingrelated decline in the induction of Nrf2-regulated antioxidant genes in human bronchial epithelial cells. Redox Biol. 2018 Apr;14: 35-40. doi: 10.1016/j.redox.2017.08.014.

4. Zinovkin RA, Kondratenko ND, Zinovkina LA. Does Nrf2 Play a Role of a Master Regulator of Mammalian Aging? Biochemistry (Mosc). 2022;87(12): 1465-1476. doi: 10.1134/S0006297922120045.

5. Vargas-Mendoza N, Morales-González Á, MadrigalSantillán EO, Madrigal-Bujaidar E, Álvarez-González I, García-Melo LF, Anguiano-Robledo L, Fregoso-Aguilar T, Morales-Gonzalez JA. Antioxidant and Adaptative Response Mediated by Nrf2 during Physical Exercise. Antioxidants (Basel). 2019 25;8(6): 196. doi: 10.3390/antiox8060196.