Methylene Blue reverses aging defects in Progeria cells: Connection between AMPK, accelerated aging, and HIV-1 reactivation

"Hutchinson-Gilford Progeria Syndrome" by The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. Scaffidi P, Gordon L, Misteli T; https://commons.wikimedia.org/wiki/File:HIV-budding-Color.jpg#/media/File:HIV-budding-Color.jpg. "HIV-budding-Color" by Photo Credit: C. Goldsmith. Content Providers: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus.

Check the reprint below of a super-interesting post I authored for LinkedIn recently (a link and references are also provided below). A compound that reverses progeria symptoms also reactivates latent HIV-1 & corrects defects in normal aging cells, indicating a common mechanism of action among HIV-1, Progeria, & normal aging. This compound, methylene blue activates the same pathways as does curcumin from turmeric, resveratrol from red wine, sulforaphane from broccoli sprouts, metformin, etc. Can normal aging, progeria, & HIV-1 be treated by the same compounds? I'm betting so:-)

Methylene Blue reverses aging defects in Progeria cells: Connection between AMPK, accelerated aging, and HIV-1 reactivation

A recent study published online on December 10, 2015, in the Journal Aging Cell demonstrated that methylene blue, a safe and inexpensive chemical that has been used to treat a variety of pathological conditions, not only corrected mitochondrial functioning in fibroblasts derived from patients diagnosed with Hutchinson-Gilford progeria syndrome (HGPS) but also ameliorated the characteristic nuclear distortion and blebbing observed in HGPS [1,2]. HGPS, a rare genetic disease linked to faulty splicing of a gene (the LMNA gene) necessary to main the structural integrity of the nucleus and the signaling mechanisms that occur in the nucleus, is often characterized by symptoms of accelerated aging in affected children, including hair loss, wrinkling of the skin, and bone deformations.  Mitochondria, often described as powerhouses of the cell, are the primary energy-producing organelles of the cell (in the form of ATP) and are absolutely essential for proper cell functioning.

Interestingly, methylene blue also increased the levels of  LMNA mRNA (the product of the LMNA gene), implying that methylene blue beneficially altered the splicing of the LMNA gene [1]. The levels of PGC1a, a transcription factor that is vital for mitochondrial biogenesis (the birth of new mitochondria) was also increased [1]. Even more striking, methylene blue corrected damage to mitochondria in healthy cells that were allowed to age, suggesting that the compound activates pathways that may attenuate or reverse symptoms associated with normal aging [1].
 
According to the University of Maryland’s website, treatment of progeria cells with methylene blue “effectively improved every defect, causing progeria cells to be almost indistinguishable from normal cells” [2]. Kan Cao, senior author of the study, also noted that “it seems that methylene blue rescues every affected structure within the cell. When we looked at the treated cells, it was hard to tell that they were progeria cells at all. It’s like magic” [2].

The results of this study implicate a centralized mechanism, orchestrated by AMPK, that when activated, can correct faulty alternative splicing in a genetic disorder, ameliorate symptoms associated with aging, as well as potentially reactivate dormant T cells infected with HIV-1, allowing the immune system to detect and destroy the infected cell.  AMPK, a master regulator of cell metabolism that has been shown to extend lifespan in several organisms, is a well known activator of PGC1a, mitochondrial biogenesis, and is necessary for efficient T cell activation [3,4].

Interestingly, several studies indicate that methylene blue indeed activates AMPK, delaying what is known as cellular senescence (loss of the capacity for division and growth of a cell associated with aging).  A recently published study online in the Journal Redox Biology on December 6, 2015, shows that methylene blue displays an anti-senescence effect on lung fibroblasts that is mediated by the activation of AMPK, leading to the induction of PGC1a, a significant increase in mitochondrial activity, a decrease in telomere erosion (the caps on the end of chromosomes that shortens as a cell ages), and a decrease in cellular oxidants [5].

Combined with evidence showing that methylene blue enhances the reactivation of latently-infected HIV-1 viral reservoirs through photosensitization and also reverses T-cell suppression, a common mechanism of action appears to connect aging, alternative splicing, T cell activation, as well as other cellular and physiological processes [6,7].  Even more startling is that compounds as seemingly as disparate as methylene blue, metformin, resveratrol, berberine, etc (and possibly many others) likely exert a beneficial effect on each of these cellular processes by sharing a common mechanism of action of activating AMPK.  The possibility of potentially eradicating HIV-1, correcting alternative splicing in genetic disorders, and ameliorating or reversing symptoms of normal aging via a common mechanism of AMPK activation would be unprecedented and would represent a paradigm shift in determining the etiology of many diseases.

https://www.linkedin.com/pulse/symptoms-progeria-reversed-safe-inexpensive-compound-between-finley?trk=mp-reader-card

References:

1. Xiong ZM, Choi JY, Wang K, et al. Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria. Aging Cell. 2015 Dec 14. doi: 10.1111/acel.12434. 
2. https://cmns.umd.edu/news-events/features/3352 
3. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2012 Apr;11(2):230-41.
4. Tamás P, Hawley SA, Clarke RG, et al. Regulation of the energy sensor AMPactivated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med 2006;203(7):1665–70.
5. Atamna H, Atamna W, Al-Eyd G, Shanower G, Dhahbi JM. Combined activation of the energy and cellular-defense pathways may explain the potent anti-senescence activity of methylene blue. Redox Biol. 2015 Dec;6:426-35. doi: 10.1016/j.redox.2015.09.004.
6. Piret B, Legrand-Poels S, Sappey C, Piette J. NF-kappa B transcription factor and human immunodeficiency virus type 1 (HIV-1) activation by methylene blue photosensitization. Eur J Biochem. 1995 Mar 1;228(2):447-55.
7. Bingisser RM, Tilbrook PA, Holt PG, Kees UR. Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway. J Immunol. 1998 Jun 15;160(12):5729-34.