Here's a quick post I recently put up on LinkedIn (see below) along with a picture I drafted that helps bring to life the interconnectedness of normal aging, Progeria, and HIV-1 reactivation. If you notice, a lot of compounds are converging on the blue circle called AMPK. It's known as the master metabolic regulator and its basically present in every cell in your body, from head to toe. AMPK is significantly activated by activities and compounds that are known to extend your lifespan as well as your healthspan (i.e. lifespan without disease), including exercise and an enormous array of plant-based compounds including metformin (from Galega), sulforaphane (from broccoli sprouts), and resveratrol (from grapes). The activation of AMPK is necessary to activate your T cells in order to mount an effective immune response to viruses, bacteria, and cancer cells. The activation of AMPK has also been shown to beneficially alter gene splicing in inherited diseases as well as in normal humans (metformin beneficially alters gene splicing in diabetics). Interestingly, this picture shows that AMPK can activate T cells infected with HIV-1, thus pushing the virus out of its hiding spot and making it easier to detect and be destroyed by the immune system. AMPK activation can also activate your cytotoxic T cells to help destroy the HIV-1 virus and AMPK also alters the same gene splicing factors that characterize HIV-1 reactivation, normal aging, and Progeria. What other disease states could be ameliorated or even reversed by AMPK activators? Could Alzheimer’s, Parkinson’s, cancer, autoimmune disorders, heart disease, etc. all be connected by a centralized pathway? More to come;-)
A Common Mechanism linking AMPK, Progeria, Aging, & HIV-1 reactivation: A picture is worth a thousand words
Here’s a graphic view that gives a pretty good layout of the overall interconnectedness of Hutchinson-Gilford progeria syndrome (HGPS), HIV-1 latency, and normal aging (pointed arrow = activation; blocked/blunted arrow = inhibition). What follows is sort of a condensed explanation of how these diseases are connected and how one compound that looks completely different from another (say, methylene blue and rapamycin) can exert the same or similar effects in the same disease states by primarily activating a particular pathway. To keep this post relatively short, references can be found by accessing the links below to separate posts I’ve done previously on each compound.
As you can see from the figure, the activation of AMPK is the focal point that is essential for efficient T cell activation that ultimately reactivates the latent HIV-1 virus (leading to either detection and destruction by the immune system or a self-destruct mechanism by the T cell itself) and the beneficial alteration of gene splicing in the LMNA gene, the gene that’s mutated in HGPS.As the figure shows, ASF/SF2 (also known as SRSF1) is involved in both aberrant gene splicing in HGPS and gene splicing in normal T cells and in T cells latently infected with HIV-1. Indeed, excessive splicing of the latent HIV-1 genome by ASF/SF2 prevents the reactivation of the virus. ASF/SF2 also has been shown to both promote aberrant gene splicing of LMNA via excessive use of a cryptic splice site in the LMNA gene in HGPS and promote aberrant splicing of vascular genes in normal humans, promoting endothelial cell senescence (i.e. loss in ability of cells to divide).
Interestingly, normal humans also possess this same cryptic splice site in their LMNA genes and produce the same toxic protein progerin (the protein that is responsible for symptoms of HGPS) in small amounts that increase with age, whereas HGPS patients produce extremely large amounts of the protein early on in life. Not surprisingly, UV radiation (which promotes accelerating aging in various cells) increases the activity of ASF/SF2 in normal cells and increases the production of progerin in HGPS cells, indicating that ASF/SF2 promotes the use of the LMNA cryptic splice site in both normal humans and HGPS patients, generating symptoms of aging and accelerated aging.
Comparatively, when T cells that are latently (i.e. dormant) infected with HIV-1 are reactivated with various compounds, the levels of ASF/SF2 decrease, preventing excessive splicing of the HIV-1 genome and thus potentiating elimination of the virus by the immune system, possibly leading to a cure. When normal T cells are activated, the splicing activities of ASF/SF2 are also decreased, indicating that downregulation of ASF/SF2 is necessary for T cell activation generally.
Incidentally, studies have shown that selective activation of only T cells latently infected with HIV-1 may be the only successful way to reactivate latent HIV-1. Interestingly, the splicing-associated factor p32 is an endogenous and natural inhibitor of ASF/SF2. As such, p32 activity is indeed upregulated on latent HIV-1 reactivation that is induced by T cell activation. Interestingly, p32 is also absolutely critical for mitochondrial biogenesis and functionality, as it serves as a chaperone necessary for the production of mitochondrial proteins that are indispensable for oxidative phosphorylation. Mitochondria are known as the “powerhouses” of the cell and are a vital source of energy in the form of a molecule known as ATP that drives countless cellular processes in nearly every cell in the body.
Indeed, mitochondria are critical for T cell activation and congregate around the connection that forms between a T cell and a cell that presents a piece of a foreign invader in order to activate the T cell. Similarly, ATP levels, mitochondrial functionality, and mitochondrial biogenesis are significantly decreased in HGPS cells, providing a provocative indication that increased p32 activity may inhibit excessive splicing activities of ASF/SF2 and enhance mitochondrial functionality, thus driving efficient latent HIV-1 reactivation. Moreover, increased p32 activity may inhibit excessive splicing activities of ASF/SF2 in HGPS and in normal cells as well as increase mitochondrial biogenesis, thus decreasing the use of the LMNA cryptic splice site and thus ameliorating symptoms of normal and accelerated aging.
Interestingly, p32 has also been shown to be essential for a process known as autophagy, a process in which a cell degrades and recycles worn or dysfunctional intracellular components (i.e. organelles including mitochondria). Again, the similarities are striking between HGPS and HIV-1 latency. On T cell activation, autophagy is significantly increased and inhibition of autophagy prevents efficient T cell activation. The activation of autophagy by rapamycin and sulforaphane in HGPS cells also leads to the elimination of the toxic protein progerin by autophagic degradation. Perhaps most tellingly, however, is that the induction of autophagy by rapamycin has been shown to be dependent on the stabilization of the autophagic inducer ULK1 by the splicing factor p32, the same splicing factor that is indispensable for mitochondrial function and inhibits the excessive splicing activities of ASF/SF2, both of which have been shown to be associated with HIV-1 latency and HGPS.
Mitochondrial biogenesis, autophagy, T cell activation, and gene splicing are all controlled and influenced by cellular metabolism, which implicates the master metabolic regulator AMPK as a key orchestrator in the connection between HGPS, aging, and HIV-1 latency. Indeed, AMPK activation is critical for T cell activation (inhibition of AMPK leads to decreased T cell responses to viral and bacterial challenges), significantly increases mitochondrial biogenesis, beneficially alters gene splicing, and promotes the induction of autophagy by activating ULK1 (the same protein that is stabilized by p32, characterizing autophagy induced by rapamycin).
As such, it would be expected that chemically distinct compounds that have been shown to both enhance the activation of T cells and correct cellular defects associated with accelerated aging in HGPS would activate AMPK. Indeed, the compounds methylene blue, retinoic acid, rapamycin, and sulforaphane have each been shown to enhance T cell activation and/or latent HIV-1 reactivation, reverse cellular aging defects in HGPS cells, and activate AMPK. As metformin (diabetes drug), a prototypical AMPK activator, has been shown to improve lifespan and healthspan, beneficially alter gene splicing in the disease Myotonic Dystrophy type I, and enhance the reactivation of latent HIV-1, metformin will also likely drive mitochondrial biogenesis, beneficially alter gene splicing, and improve accelerating aging defects in HGPS. Curiously, although the Noble Prize-winning drug artemisinin is more commonly known as an anti-malarial drug, it has recently been shown (along with another compound, JQ1, that reactivates latent HIV-1) to activate AMPK in cancer cells (killing them or inducing differentiation), activate AMPK and induce mitochondrial biogenesis in mice (mimicking caloric restriction), induce autophagy, and enhance T cell functionality, indicating that artemisinin will also likely reverse cellular aging defects in HGPS and in normal human cells as well as enhance latent HIV-1 reactivation.
Most importantly, however, was the recent finding that rapamycin, a compound derived from a bacterium, potently activates AMPK in normal elderly mice. The importance of this finding is instrumental, considering that rapamycin has been found to increase maximal lifespan in vivo in normal mice even when administered late in life. Although it is widely thought that the effects of rapamycin stem from the inhibition of a protein called mTOR (mTOR activation drives anabolic processes in the cell and its over-activation is implicated in many disease states), the recent finding that rapamycin potently activated AMPK in vivo in normal elderly mice during the entire 10 week study provides strong and convincing evidence that rapamycin, very much similar to other compounds, indirectly activates AMPK by inhibiting mTOR. Indeed, in that study, autophagy was increased in the first week and mitochondrial biogenesis was increased in the first and second weeks but both fell back to control levels by the 10th week of the study. However, AMPK was significantly activated for the entire duration of the study (all 10 weeks), indicating that AMPK activation preceded and induced the activation of autophagy and mitochondrial biogenesis.
Indeed, as the induction of autophagy and mitochondrial biogenesis leads to the correction of accelerated cellular aging defects in HGPS cells and efficient T cell activation-induced latent HIV-1 reactivation, and because p32 is critical for mitochondrial function and the induction of ULK1-mediated autophagy by rapamycin, AMPK activation by rapamycin likely represents (similar to the other aforementioned compounds) an “indirect yet primary mechanism of action” of rapamycin. The potential clinical implications of AMPK activation representing a common mechanism of action for compounds as seemingly as distinct as artemisinin, rapamycin, metformin, resveratrol, sulforaphane, retinoic acid, methylene blue, and potentially many others is beyond mind-boggling and may represent a truly novel insight into the interconnectedness of disease pathology and cellular metabolism.
https://www.linkedin.com/pulse/common-mechanism-linking-ampk-progeria-aging-hiv-1-latency-finley
References:
- Anti-aging drug Rapamycin shares common mechanism of action with Metformin and Artemisinin: Connection between AMPK, Progeria, and HIV-1 reactivation, https://www.linkedin.com/pulse/anti-aging-drug-rapamycin-shares-common-mechanism-action-finley?trk=prof-post
- Nobel Prize Winning drug Artemisinin shares common mechanism of action with AMPK activator Metformin: Connection between aging and HIV-1 reactivation, https://www.linkedin.com/pulse/nobel-prize-winning-drug-artemisinin-shares-common-mechanism-finley?trk=prof-post
- AMPK activator Metformin alters gene splicing in humans: Potential connection between AMPK, accelerated aging, and HIV-1 reactivation, https://www.linkedin.com/pulse/ampk-activator-metformin-alters-gene-splicing-humans-potential?trk=prof-post
- Broccoli Sprout compound reverses aging defects in Progeria cells: Potential connection between AMPK, accelerated aging, and HIV-1 reactivation, https://www.linkedin.com/pulse/broccoli-sprout-compound-reverses-aging-defects-progeria-finley?trk=mp-reader-card
- Vitamin A metabolite reverses aging defects in Progeria cells: Potential connection between AMPK, accelerated aging, and HIV-1 reactivation, https://www.linkedin.com/pulse/vitamin-metabolite-reverses-aging-defects-progeria-cells-finley?trk=mp-reader-card
- Symptoms of Progeria reversed by safe, inexpensive compound: Connection between AMPK, accelerated aging, and HIV-1 reactivation, https://www.linkedin.com/pulse/symptoms-progeria-reversed-safe-inexpensive-compound-between-finley?trk=mp-reader-card
- Common Mechanism Linking HIV-1 and Progeria, https://www.linkedin.com/pulse/common-mechanism-linking-hiv-1-progeria-jahahreeh-finley?trk=mp-reader-card
- Potential Correction of Gene Splicing in Progeria via Naturally Occurring Compounds, https://www.linkedin.com/pulse/potential-correction-gene-splicing-progeria-via-naturally-finley?trk=mp-reader-card
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