"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 out this recent post on Linkedin I authored (link provided below) about a compound I think we're all pretty familiar with: Retinoic acid, a compound that is produced as a metabolite of vitamin A, actually reversed DNA damage and corrected nuclear defects in cells taken from Progeria patients. Interestingly, similar to the reversal of aging defects in Progeria cells by methylene blue shown in a study published earlier this month, both methylene blue and retinoic acid activate a central pathway that connects Progeria and HIV-1. Indeed, both methylene blue and a retinoid derivative reactivated dormant HIV-1, making it visible to the immune system and thus facilitating viral eradication. This centralized pathway, governed by the master metabolic regulator AMPK, is activated by an endless array of compounds derived from fruits, herbs, and vegetables (e.g. sulforaphane from broccoli, curcumin from turmeric, EGCG from green tea, etc.). Considering that normal aging humans make the same faulty protein that causes children with Progeria to age rapidly (just at much lower levels that increase with age), the activation of a centralized pathway with naturally-occurring compounds to slow normal aging, accelerated aging, and eradicate viral infections thought to be incurable would be unprecedented.
Vitamin A metabolite reverses aging defects in Progeria cells: Potential connection between AMPK, accelerated aging, and HIV-1 reactivation
Similar to the recent finding that methylene blue restored mitochondrial function and corrected nuclear distortions in fibroblasts derived from patients diagnosed with Hutchinson-Gilford progeria syndrome (HGPS) (see previous post), a recent study published on October 6, 2015, in the Journal Oncotarget also demonstrated that all-trans retinoic acid, a metabolite of vitamin A, combined with rapamycin (an mTOR inhibitor and inducer of autophagy—a process of disposing of unwanted or damaged cellular proteins) rescued cellular dynamics and cellular proliferation through recovery of proteins that are necessary for responding to DNA damage and maintaining nuclear architecture in HGPS patient cells [1,2]. According to the National Cancer Institute, all-trans retinoic acid (ATRA) is a “nutrient that the body needs in small amounts to function and stay healthy. All-trans retinoic acid is made in the body from vitamin A and helps cells to grow and develop, especially in the embryo.” [3].
Interestingly, the Oncotarget study not only showed enhanced recovery of nuclear shape, chromatin structure, and decreased DNA damage with ATRA combined with low-dose rapamycin, but also a down-regulation of progerin mRNA transcript levels leading to an increase in the lamin A to progerin ratio. This increase suggests that ATRA may beneficially alter the splicing of the LMNA gene (the gene that produces both the normal lamin A protein and the deleterious progerin protein), leading to a decrease in the production of progerin mRNA. Furthermore, another study, published on September 1, 2015, in the Journal Methods also showed that treatment of HGPS patient cells with the retinoids isotretinoin (also known as 13-cis retinoic acid) and tazarotene reduced DNA damage markers by approximately 50%, restored nuclear proteins and epigenetic markers negatively affected by progerin, and also lowered the progerin mRNA transcript levels, indicating a potential beneficial effect of retinoic acid or its derivatives on alternative splicing of the LMNA gene [4].
These findings, combined with the recent evidence that methylene blue increases the levels of normal LMNA mRNA and reverses symptoms of HGPS, implies that a central mechanism of action, likely orchestrated by AMPK, may connect compounds as seemingly as distinct as retinoic acid, methylene blue, rapamycin, metformin, etc. that may lead to a correction of aberrant alternative splicing in both normal aging humans and in genetic disorders as well reactivation of T-cells latently (dormant) infected with HIV-1, facilitating recognition and viral destruction by the immune system. Indeed, retinoic acid has been shown to regulate the same gene splicing factors that play a role in both HGPS and latent HIV-1 reactivation and retinoic acid signaling is critical for the activation of T-cells [5-8]. Preliminary data also indicates that the retinoid acitretin may act synergistically with other agents to efficiently reactivate latent HIV-1 viral reservoirs [9]. Additionally, both rapamycin and metformin have been shown to increase the lifespan and healthspan of several organisms as well as enhance the immune response to pathogenic challenges, with metformin facilitating reactivation of latent HIV-1 reservoirs when combined with bryostatin (both of which activate AMPK) [10-14].
Retinoic acid, rapamycin, and metformin have each been shown to activate AMPK in several studies and AMPK activation is essential for T-cell activation and is also a critical component in the life- and healthspan promoting effects of several chemically distinct compounds [15-18]. Considering that normal humans also possess and use the same cryptic splice site in the LMNA gene to make progerin as do HGPS patients (but at much lower levels that increase with age) and that regulation of alternative splicing significantly influences the production of lamin A, progerin, and latent HIV-1 reactivation, it would be an almost inconceivable yet astounding observation that many, if not all, compounds that positively influence accelerated aging, normal aging, and viral eradication (and potentially many other disease states) do so though beneficial activation of AMPK, a master metabolic regulator that is involved in nearly every cellular process in nearly every cell in the body [19].
https://www.linkedin.com/pulse/vitamin-metabolite-reverses-aging-defects-progeria-cells-finley?trk=mp-reader-card
References:
Check out this recent post on Linkedin I authored (link provided below) about a compound I think we're all pretty familiar with: Retinoic acid, a compound that is produced as a metabolite of vitamin A, actually reversed DNA damage and corrected nuclear defects in cells taken from Progeria patients. Interestingly, similar to the reversal of aging defects in Progeria cells by methylene blue shown in a study published earlier this month, both methylene blue and retinoic acid activate a central pathway that connects Progeria and HIV-1. Indeed, both methylene blue and a retinoid derivative reactivated dormant HIV-1, making it visible to the immune system and thus facilitating viral eradication. This centralized pathway, governed by the master metabolic regulator AMPK, is activated by an endless array of compounds derived from fruits, herbs, and vegetables (e.g. sulforaphane from broccoli, curcumin from turmeric, EGCG from green tea, etc.). Considering that normal aging humans make the same faulty protein that causes children with Progeria to age rapidly (just at much lower levels that increase with age), the activation of a centralized pathway with naturally-occurring compounds to slow normal aging, accelerated aging, and eradicate viral infections thought to be incurable would be unprecedented.
Vitamin A metabolite reverses aging defects in Progeria cells: Potential connection between AMPK, accelerated aging, and HIV-1 reactivation
Similar to the recent finding that methylene blue restored mitochondrial function and corrected nuclear distortions in fibroblasts derived from patients diagnosed with Hutchinson-Gilford progeria syndrome (HGPS) (see previous post), a recent study published on October 6, 2015, in the Journal Oncotarget also demonstrated that all-trans retinoic acid, a metabolite of vitamin A, combined with rapamycin (an mTOR inhibitor and inducer of autophagy—a process of disposing of unwanted or damaged cellular proteins) rescued cellular dynamics and cellular proliferation through recovery of proteins that are necessary for responding to DNA damage and maintaining nuclear architecture in HGPS patient cells [1,2]. According to the National Cancer Institute, all-trans retinoic acid (ATRA) is a “nutrient that the body needs in small amounts to function and stay healthy. All-trans retinoic acid is made in the body from vitamin A and helps cells to grow and develop, especially in the embryo.” [3].
Interestingly, the Oncotarget study not only showed enhanced recovery of nuclear shape, chromatin structure, and decreased DNA damage with ATRA combined with low-dose rapamycin, but also a down-regulation of progerin mRNA transcript levels leading to an increase in the lamin A to progerin ratio. This increase suggests that ATRA may beneficially alter the splicing of the LMNA gene (the gene that produces both the normal lamin A protein and the deleterious progerin protein), leading to a decrease in the production of progerin mRNA. Furthermore, another study, published on September 1, 2015, in the Journal Methods also showed that treatment of HGPS patient cells with the retinoids isotretinoin (also known as 13-cis retinoic acid) and tazarotene reduced DNA damage markers by approximately 50%, restored nuclear proteins and epigenetic markers negatively affected by progerin, and also lowered the progerin mRNA transcript levels, indicating a potential beneficial effect of retinoic acid or its derivatives on alternative splicing of the LMNA gene [4].
These findings, combined with the recent evidence that methylene blue increases the levels of normal LMNA mRNA and reverses symptoms of HGPS, implies that a central mechanism of action, likely orchestrated by AMPK, may connect compounds as seemingly as distinct as retinoic acid, methylene blue, rapamycin, metformin, etc. that may lead to a correction of aberrant alternative splicing in both normal aging humans and in genetic disorders as well reactivation of T-cells latently (dormant) infected with HIV-1, facilitating recognition and viral destruction by the immune system. Indeed, retinoic acid has been shown to regulate the same gene splicing factors that play a role in both HGPS and latent HIV-1 reactivation and retinoic acid signaling is critical for the activation of T-cells [5-8]. Preliminary data also indicates that the retinoid acitretin may act synergistically with other agents to efficiently reactivate latent HIV-1 viral reservoirs [9]. Additionally, both rapamycin and metformin have been shown to increase the lifespan and healthspan of several organisms as well as enhance the immune response to pathogenic challenges, with metformin facilitating reactivation of latent HIV-1 reservoirs when combined with bryostatin (both of which activate AMPK) [10-14].
Retinoic acid, rapamycin, and metformin have each been shown to activate AMPK in several studies and AMPK activation is essential for T-cell activation and is also a critical component in the life- and healthspan promoting effects of several chemically distinct compounds [15-18]. Considering that normal humans also possess and use the same cryptic splice site in the LMNA gene to make progerin as do HGPS patients (but at much lower levels that increase with age) and that regulation of alternative splicing significantly influences the production of lamin A, progerin, and latent HIV-1 reactivation, it would be an almost inconceivable yet astounding observation that many, if not all, compounds that positively influence accelerated aging, normal aging, and viral eradication (and potentially many other disease states) do so though beneficial activation of AMPK, a master metabolic regulator that is involved in nearly every cellular process in nearly every cell in the body [19].
https://www.linkedin.com/pulse/vitamin-metabolite-reverses-aging-defects-progeria-cells-finley?trk=mp-reader-card
References:
- 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.
- Pellegrini C, Columbaro M, Capanni C, et al. All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype. Oncotarget. 2015 Oct 6;6(30):29914-28.
- http://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=367465
- Kubben N, Brimacombe KR, Donegan M, Li Z, Misteli T. A high-content imaging-based screening pipeline for the systematic identification of anti-progeroid compounds. Methods. 2015 Sep 1. pii: S1046-2023(15)30070-0.
- Meseguer S, Mudduluru G, Escamilla JM, Allgayer H, Barettino D. MicroRNAs-10a and -10b contribute to retinoic acid-induced differentiation of neuroblastoma cells and target the alternative splicing regulatory factor SFRS1 (SF2/ASF). J Biol Chem. 2011 Feb 11;286(6):4150-64.
- Yin X, Jin N, Gu J, et al. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) modulates serine/arginine-rich protein 55 (SRp55)-promoted Tau exon 10 inclusion. J Biol Chem. 2012 Aug 31;287(36):30497-506.
- Finley J. Reactivation of latently infected HIV-1 viral reservoirs and correction of aberrant alternative splicing in the LMNA gene via AMPK activation: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome. Med Hypotheses. 2015 Sep;85(3):320-32.
- Hall JA, Cannons JL, Grainger JR, et al. Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. Immunity. 2011 Mar 25;34(3):435-47.
- Li, Peilin. Effects of Acitretin on the activation of latent HIV. Northern California Institute Research & Education, San Francisco, CA, United States. http://grantome.com/grant/NIH/R21-AI104445-02, last accessed, December 29, 2015.
- Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5.
- Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013 Jul 31;4:2192.
- Pearce EL, Walsh MC, Cejas PJ, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009 Jul 2;460(7251):103-7.
- Keating R, Hertz T, Wehenkel M, et al. The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat Immunol. 2013 Dec;14(12):1266-76.
- Mehla R, Bivalkar-Mehla S, Zhang R, et al. Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner. PLoS One. 2010 Jun 16;5(6):e11160.
- Kim YM, Kim JH, Park SW, Kim HJ, Chang KC. Retinoic acid inhibits tissue factor and HMGB1 via modulation of AMPK activity in TNF-α activated endothelial cells and LPS-injected mice. Atherosclerosis. 2015 Aug;241(2):615-23.
- Habib SL, Kasinath BS, Arya RR, Vexler S, Velagapudi C. Novel mechanism of reducing tumourigenesis: upregulation of the DNA repair enzyme OGG1 by rapamycin-mediated AMPK activation and mTOR inhibition. Eur J Cancer. 2010 Oct;46(15):2806-20.
- 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.
- 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.
- McClintock D, Ratner D, Lokuge M, et al. The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin. PLoS One. 2007 Dec 5;2(12):e1269.
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