Hey Blogger fam, I’m actually really starting to believe I might
be on to something:-) Check out my recent LinkedIn post below about a new study
published by researchers at the National Institutes of Health (NIH) that
provides yet more evidence that a common pathway connects normal aging, Progeria,
and HIV-1. What's really interesting about this study is that the compound used
(oltipraz) to reverse aging defects in cells taken from Progeria kids works
just like the broccoli sprout compound sulforaphane, which was also shown back
in 2013 to reverse aging defects in Progeria cells. What the researchers don't
realize (and I'm not sure that I should be letting them know) is that oltipraz,
just like vitamin D, methylene blue, sulforaphane, metformin, the Nobel-prize winning
drug artemisinin, and rapamycin also activates the master metabolic regulator
AMPK. As I outlined in my recent
publication, AMPK activation is critical for oocyte activation and the creation
of all human beings alive today and any human being that has ever lived. AMPK
activation is also absolutely essential for the activation of your T cells,
allowing your immune system to fend off foreign invaders (viruses, bacteria,
etc) as well as to target and kill cancer cells. Indeed, oltipraz and sulforaphane (not sure
if I should be telling this either) have both been shown to inhibit HIV-1
replication in actively infected cells.
This is absolutely HUGE in that AMPK activation will not only "wake
up" HIV-1 that's asleep in T cells so that the immune system can kill it,
but AMPK activation will also shut down HIV-1 replication in actively infected
cells, basically doing what many combo HIV-1 medications were designed to do
but without the toxicity. EGCG, a
compound found in green tea, tanshinone (an herb also known as red sage),
resveratrol (from grapes and red wine), and curcumin (from the spice turmeric)
have each been shown to potently inhibit active HIV-1 replication, with resveratrol
also reactivating dormant HIV-1. When
you step back and take a look at the big picture, it almost leaves you
breathless: The activation of a single pathway, AMPK, can reverse accelerated
aging defects in Progeria cells, extend lifespan and healthspan in almost every
organism its been tested in, reactivates dormant viruses to be recognized by
the immune system, activates other cells of the immune system to target and
kill those viruses as well as cancer cells, and is responsible for the creation
of every human being that is alive or that has every lived. Ok, my brain is
throbbing, time for a break:-)
New NIH study shows that the drug Oltipraz,
an AMPK and Nrf2 activator that inhibits HIV replication, reverses nuclear
aging defects in Progeria cells
In line with recent findings (see prior posts) that a vitamin A metabolite (or its derivatives), methylene blue, vitamin D/vitamin D receptor (VDR) signaling, and sulforaphane each significantly ameliorated or reversed accelerated aging defects in cells derived from patients diagnosed with Hutchinson-Gilford progeria syndrome (HGPS), a recent study published in the Journal Cell in June of 2016 strikingly demonstrated that the transcriptional activity of Nrf2, a transcription factor implicated in longevity and a master regulator of the antioxidant response, is impaired in cells derived from HGPS patient cells, leading to an increase in chronic oxidative stress [1]. Interestingly, the reactivation of Nrf2 in HGPS patient cells by the Nrf2 activator oltipraz reversed nuclear aging defects and also restored the in vivo viability of HGPS patient-derived mesenchymal stem cells (MSCs) that were implanted into animal models. As oltipraz has been shown to activate AMPK (similar to metformin) and inhibit HIV-1 replication and AMPK has been shown to activate and increase the transcriptional activity of Nrf2, this study contributes to mounting evidence that further substantiates the novel observation that AMPK activation represents a common mechanism that leads to the amelioration or reversal of accelerated aging defects in HGPS, inhibition of HIV-1 replication in acutely infected cells, and reactivation of HIV-1 in latently infected cells (see below).
HGPS is a rare genetic disorder caused by the faulty splicing of a gene called the LMNA gene, producing large amounts of a mutant protein known as progerin. Progerin accumulation (which also accumulates gradually in normal humans via the same faulty gene splicing mechanism) at a very early age in HGPS patients leads to distortions in the shape of the nucleus, aberrations in the signaling mechanisms that occur in the nucleus, as well as mitochondrial dysfunction (the primary energy-producing organelle of the cell), leading to characteristic symptoms of accelerating aging such as thinning of the hair, wrinkling of the skin, and eventual cardiovascular disease.
Interestingly, in this study, the authors showed that the mutant protein progerin impaired the transcriptional activity (i.e. the ability to induce gene expression) and function of Nrf2 in HGPS fibroblasts, as indicated by a 51% reduction in the antioxidant-responsive element (ARE)-Luc activity [1]. Many of the beneficial effects of increased Nrf2 activity stems from the activation of antioxidant genes by Nrf2 via binding of Nrf2 to AREs located in antioxidant genes. Inhibiting Nrf2 via RNA interference (RNAi) further exacerbated nuclear defects in HGPS cells and the application of hydrogen peroxide to HGPS cells to increase oxidative stress increased the levels of progerin and worsened markers of cellular defects, including 53BP1, LAP2, H3K27m3, γH2AX, and HP1γ [1].
Most importantly, however, the authors showed that oltipraz ameliorated lamin B1 and HP1γ levels in HGPS fibroblasts by 73% and 53%, respectively, and also partially reduced LAP2 and H3K27me3 defects [1]. Moreover, as the ability of mesenchymal stem cells (MSCs) to respond to oxidative stress is inhibited in HGPS, the authors also generated MSCs derived from HGPS cells (i.e. HGPS-iPSC-MSCs) to determine the effects of Nrf2 activation on MSC survival and viability in vivo when implanted into an animal model. Expectedly, the HGPS-iPSC-MSCs expressed progerin which led to stem cell attrition. However, oltipraz-mediated Nrf2 activation rescued HGPS nuclear defects (e.g. increased levels of LAP2 and lamin B1), reduced the number senescence-associated β-galactosidase positive cells (a marker of cellular senescence), and restored the in vivo viability of HGPS-MSCs, indicating that activation of Nrf2 may play a key role in ameliorating or reversing the pathology associated with HGPS [1].
Just as other chemically distinct compounds, including methylene blue, retinoic acid and/or its derivatives, vitamin D/VDR signaling, and the Nrf2 activator sulforaphane have each been shown to ameliorate or reverse accelerated aging defects and activate the master metabolic regulator AMPK, the Nrf2 activator oltipraz would also be expected to activate AMPK. Indeed, several independent studies have shown that oltipraz and/or its metabolites induce activation of AMPK, increase expression of genes that encode proteins involved in mitochondrial fuel oxidation, increase mitochondria DNA content and oxygen consumption rate, reduce cellular reactive oxygen species (ROS) production, activate LKB1 (an upstream activator of AMPK), and increase the AMP/ATP ratio (an indication of cellular stress induction) [2-6]. Interestingly, AMPK has also been shown to increase the transcriptional activity of Nrf2 and a recent study has also demonstrated that AMPK phosphorylates Nrf2, leading to retention of Nrf2 in the nucleus [7,8].
Interestingly, as the Nrf2 activator sulforaphane has been shown to stimulate the immune response by enhancing the cytotoxicity of natural killer cells and dendritic cells, promote the infiltration of T cells in neoplastic regions, and decrease several epigenetic markers that promote the latency/dormancy of memory T cells infected with HIV-1, including EZH2 and SUV39H1 (both of which are also dysregulated in progeria cells), the Nrf2 activator oltipraz would also be expected to possess immune-modulating effects that would impact the life cycle of HIV-1 [9-14]. Indeed, several studies have shown that oltipraz and/or its metabolites inhibit replication of HIV-1 and a recent study demonstrated that sulforaphane inhibited HIV-1 replication in macrophages through Nrf2 mobilization [15-20].
Although, the inhibition of HIV-1 replication and the reactivation of latent HIV-1 via enhancing T cell activation are seemingly at odds, the activation of AMPK as a common mechanism by sulforaphane and oltipraz provides an explanation for this dichotomy. AMPK is critical for the activation of T cells and compounds that have been shown to potently reactivate latent HIV-1 activate AMPK and also induce selective low-level T cell activation during HIV-1 latency reversal [21]. Both AMPK and Nrf2 have also been shown to inhibit HIV-1 replication in productively infected cells (i.e. active), indicating that AMPK activation likely exerts dually beneficial roles via inhibition of active HIV-1 replication and reactivation of latent HIV-1 reservoirs [22,23]. This duality was recently demonstrated in a study in which the proteasome inhibitor Velcade (bortezomib) reactivated latent HIV-1 but also inhibited HIV-1 infectivity, as evidenced by reduced viral output and virion infectivity [24].
In light of the AMPK-activating and HIV-1 inhibitory effects exerted by oltipraz, the Cell study by NIH researchers demonstrating that oltipraz reverses nuclear aging defects and restores the in vivo viability of HGPS patient-derived MSCs is indicative of a common mechanism of AMPK activation that links diseases as seemingly disparate as HGPS, HIV1-1 latency and replication, and potentially many others (see Figure below). As supporting evidence of this connection continues to mount, a paradigm shift recognizing the interconnectedness of disease pathology is inevitable.
https://www.linkedin.com/pulse/new-nih-study-shows-drug-oltipraz-ampk-nrf2-activator-finley?trk=pulse_spock-articles
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