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

[RapAdmin]

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.

CONCLUSION

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:

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

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.

Jed Fahey, Sc.D. on Isothiocyanates, the Nrf2 Pathway, Moringa & Sulforaphane Supplementation

Phytochemical Activates The NRF2 PATHWAY | The Importance Of FOOD MATRIX | Dr Rhonda Patrick Clips

[DeStrider]

I use Moringa powder because you do.

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

[EnrQay]

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]"

[EnrQay]

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.

[RapAdmin]

Yes - related info in this post:

How to Increase Sulforaphane in your Diet, Cancer Prevention, etc

The research looks pretty good on Sulforaphane, and there is a new study out on sprouts that suggests ways to maximize the sulforaphane density in sprouts. See all info below: [Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More] Broccoli SproutingGuideƒ.pdf (3.1 MB)

[Vlasko]

Ashwagandha may also be helpful:

Therapeutic effects of hydro-alcoholic leaf extract of Withania somnifera on...

[RapAdmin]

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
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039579

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013015/

[jnorm]

I’m surprised they didn’t mention 53BP1 as a possible longevity effector of NRF2. It contains multiple antioxidant response elements/AREs in its promoter that mediates its induction by NRF2.

data from Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells fromionizing radiation and also see Oncogenic KRAS drives radioresistance through upregulation of NRF2-53BP1-mediated non-homologous end-joining repair

The longevity implications of 53BP1 revolve around its ability to increase the efficiency and accuracy of DNA double-strand break/DSB repair. Ionizing radiation/IR is a common experimental source of DSBs and FDA-approved Nrf2 activator omaveloxolone promotes IR resistance in hematopoietic system, suggesting that it improves the DSB DNA damage response.

The administration of a brief course of RTA 408 treatment, beginning 24 h after lethal doses of radiation to bone marrow, significantly increased overall survival. Importantly, treatment with RTA 408 led to the full recovery of steady state hematopoiesis with normalization of the frequency of hematopoietic stem and progenitor cells. Moreover, hematopoietic stem cells from RTA 408-mitigated mice showed lineage-balanced, long-term, multilineage potential in serial transplantation assays, indicative of their normal self-renewal activity. [ref]

In further support of this, pretreatment with Nrf2 activator bardoxolone methyl was shown to reduce IR-induced chromosomal aberrations (which represent unrepaired DSBs), irrespective of whether the cell is in G1 or S/G2 phase at the time of IR application. [ref]

53BP1 appears to vastly improve the fidelity of homology-directed repair by promoting homologous recombination (which can perfectly repair DSBs) over single-strand annealing (which can produce massive deletions). See 53BP1 fosters fidelity of homology-directed DNA repair

As homologous recombination is especially important in mitotic cells, this would suggest a potential role for 53BP1 in preserving stemness.

Furthermore, AMPK phosphorylates 53BP1 to promote NHEJ pathway of DSB repair. NHEJ is the primary pathway for repairing DSB in both mitotic and post-mitotic cells, and it’s interesting to consider that some of AMPK’s longevity effects are mediated via this pathway. They only showed AMPK to promote NHEJ efficiency, but I suspect this would also promote fidelity, as it reduces the amount of time that DNA ends are exposed to exonucleases and other enzymes.

One important mediator of NHEJ is the Ku heterodimer and Ku80 protein levels vary dramatically among species and are strongly correlated with longevity, but the bowhead whale and its 200yr+ MLS is probably the best evidence of how important efficient and accurate NHEJ is. Due to high levels of CIRBP and RPA2, bowhead whales have extremely efficient and accurate NHEJ.

Using CRISPR-induced DSBs you can see that shorter-lived mammals are less likely to repair DSB without modifications, and more likely to introduce large deletions. Whereas bowhead appears to prefer 1bp insertions or unmodified repair. The larger the deletion, the higher probability of cutting into exonic or regulatory sequences. Data from DNA repair and anti-cancer mechanisms in the longest-living mammal: the bowhead whale

Further support for the importance of 53BP1 comes from the paper DNA Damage Detection by 53BP1: Relationship to Species Longevity. They find increased 53BP1 foci formation in response to genotoxic chemicals in longer-lived species, which appears to be due to increased DSB-sensing capacity in longer-lived species.

One last and very intriguing paper (Lamins are rapamycin targets that impact human longevity: a study in centenarians) showed that centenarian fibroblasts have more nuclear prelamin A and that this raises steady-state nuclear 53BP1. Because of this the centenarian fibroblasts can more quickly mobilize DNA repair response in response to oxidative stress-mediated DSBs. And guess what? Rapamycin treatment induced a centenarian-mimetic phenotype, by raising nuclear prelamin A in young fibroblasts which in turn raised nuclear 53BP1. They also showed that a similar effect of lovastatin, which was the first FDA-approved statin and makes up about 2-3% dw of the delicious oyster mushroom.

Maybe I’m just having delusions of grandeur, but I’m imagining that some combination of NRF2 activator (technically most of these are KEAP1 inhibitors), rapamycin, and an AMPK activator might have some special synergy when it comes to maintaining genomic integrity. The NRF2 activator would raise 53BP1 protein levels, the rapamycin would increase its nuclear trafficking, and AMPK phosphorylation would allosterically enhance its activity.

[RapAdmin]

@jnorm

NRF2 activator (technically most of these are KEAP1 inhibitors), rapamycin, and an AMPK activator might have some special synergy when it comes to maintaining genomic integrity

Seems like an opportunity for the Wormbot / million molecule competition!

[Acarb]

thank you for mentioning the dna damage/mutation theory of aging. I believe they are the root causes of aging. unfortunately the theory doesn’t seem to get much traction in longevity field. afaik the obstacles are that until recently it’s expensive to measure dna mutation rate and increasing the fidelity of dna repair/error-free dna repair is difficult(just overexpressing single dna repair gene actually worsens dna repair fidelity in most cases).

Somatic mutation rates scale with lifespan across mammals

[Bezesk]

The synthetic triterpenoid bardoxolone methyl and its analogues (e.g., CDDO-Im) are the most potent known activators of the Nrf2 pathway.

If you’ve got 100 bucks lying around, it’d be cool if you could sponsor it.

Sponsor an intervention – Ora Biomedical, Inc.

[JuanDaw]

An old video from the Biochemical Society.

Hot Topic in Biochemistry: Nrf2 signaling by Thomas Kensler

Fast forward to 1:57

Activation of pathway - resistance to electrophilic, oxidativge, proteotoxic, DNA-damage, and metabolic stresses

Damage Prevention: prevent macromolecular damage by electrophiles, ROS (elevated GSH, GSTs, NQO1, etc.)

Damage Contrl: Induction of macromolecular dage repair/removal systems (proteasome, nucleotide excision DNA repair)

Renewal: Activation of tissue repair/regeneration pathwasy (e.g. Notch 1)

Some of the activators listed - oltipraz, chlorophyllin, triterpenoids.

Chlorophyllin is available from vitacost, and life extension.

[JuanDaw]

Earlier video also from Thomas Kensler of the Biochemical Society.

Keap1-Nrf2 signaling: adaptive responses to exogenous and endogenous stress

Rapid (starting at seven days - minute 5:26) excretion of carcinogen (Benzene-mercapturide) after broccoli sprout beverage intake.