Does Nrf2 Play a Role of a Master Regulator of Mammalian Aging?

A new review paper on the NRF2 Pathway.

For a long time Nrf2 transcription factor has been attracting attention of researchers investigating phenomenon of aging. Numerous studies have investigated effects of Nrf2 on aging and cell senescence. Nrf2 is often considered as a key player in aging processes, however this needs to be proven. It should be noted that most studies were carried out on invertebrate model organisms, such as nematodes and fruit flies, but not on mammals. This paper briefly presents main mechanisms of mammalian aging and role of inflammation and oxidative stress in this process. The mechanisms of Nrf2 activity regulation, its involvement in aging and development of the senescence-associated secretory phenotype (SASP) are also discussed. Main part of this review is devoted to critical analysis of available experimental data on the role of Nrf2 in mammalian aging.


Aging in organisms is accompanied by (i) accumulation of oxidative damage and (ii) development of chronic inflammation, “inflammaging”. Activation of the transcription factor Nrf2 may affect both of these factors, slowing down development of the senile changes. An indirect confirmation of this assumption is the fact that the long-lived animals, such as naked mole rat, have an increased level of Nrf2 activation. An important area of research should aim to obtain independent experimental data on the age-related dynamics of Nrf2 activity changes in animals and humans, since there is no data of this kind.

It is tempting to speculate that in order to successfully fight aging, humans must learn how to properly activate Nrf2, like naked mole rats do. However, we should consider that the long-lived organisms have evolved to adapt to high Nrf2 activity and fine-tuned complex systems of interactions of the signaling and metabolic pathways. Therefore, simple pharmacological activation of Nrf2 to prolong life does not seem to be the most promising approach, moreover, it could increase the risks of serious side effects. There is no reliable data in the literature that unequivocally prove that Nrf2 activation actually leads to increase of the lifespan of mammals.

An open access paper:

Hoping a little NRF2 activation is a good thing I use Moringa powder (which tastes terrible) in my frequent morning smoothie with a lot of frozen berries to mask the taste of the moringa.


I use Moringa powder because you do. :wink:

Yes, the NRF2 pathway is also important. Astaxanthin works through this pathway as well, I believe.


Nrf2 activation is the only reason I grow and eat broccoli sprouts, which also aren’t too great tasting, though lime juice helps.
" regardless of the point of view on the causes of aging, a promising direction in anti-aging therapy is targeted regulation of signaling pathways that reduce inflammation and ROS levels. One such approach is activation of the transcription factor Nrf2 ([Fig. 1]"


Although the main target of rapamycin is mTOR, rapamycin is also capable of activating Nrf2 
 metformin can also activate Nrf2 in Caenorhabditis elegans but apparently, in mice metformin has the opposite effect, inhibiting Nrf2 in the brain

So rapamycin can activate Nfr2 intermittently (due to the common rapa dosing schedule), while it is unclear with metformin. Consuming sulforaphane via moringa or broccoli sprouts would provide sustained activation.


Yes - related info in this post:


Ashwagandha may also be helpful:

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The NIA ITP lifespan studies had good results with the Protandim mixture that includes Ashwagandha:

Protandim contains five herbal ingredients, including ashwagandha, bacopa extract, green tea extract, silymarin, and curcumin , and several studies have shown that Protandim is able to potently activate Nrf2-driven gene expression

Protandim (Prot) is a mixture of five botanical extracts, including bacosides, silymarin, withaferin A, epigallocatechin‐3‐gallate, and curcumin. This composition was designed to stimulate Nrf2/ARE activation at low concentrations of each of the compounds, in principle providing strong, synergistic Nrf2 activation with minimized off‐target side effects (Velmurugan et al ., 2009). Previous studies have shown that in healthy humans supplemented orally with Prot over 120 days, superoxide dismutase (SOD) was increased in red blood cells by 30%, and catalase increased by 54% (Nelson et al ., 2006). Furthermore, biochemical and histological studies in mice revealed that feeding a Prot‐supplemented diet suppressed tumor promoter‐induced oxidative stress, cell proliferation, and inflammation (Liu et al ., 2009). Moreover, Prot treatment was reported to protect the heart from oxidative stress and fibrosis in a rodent model of pulmonary hypertension (Bogaard et al ., 2009).

Beginning at 10 months of age, one group of mice was fed chow containing Prot at 600 ppm, to approximate the intake of humans who consume this commercially available nutritional supplement. The dose of Prot was increased from 600 to 1200 ppm when the mice reached 17 months of age, because testing of mice not included in the longevity cohort had indicated that 600 ppm, contrary to expectation, did not modulate levels of liver mRNA for genes involved in xenobiotic responses. As shown in Figure 1 and Table 1, there was a significant effect (P < 0.012) of Prot on survival of male mice in the pooled population, with a 7% increase in median survival.

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

Randy Strong, Richard A. Miller, [
], and David E. Harrison