"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.
Here's another REALLY interesting recent post of mine from LinkedIn (see below) : Sulforaphane, a compound that is found heavily concentrated in cruciferous vegetables, particularly broccoli sprouts, actually reversed many of the symptoms of accelerated aging in cells taken from children diagnosed with the accelerated aging disorder Hutchinson-Gilford progeria syndrome. Interestingly, sulforaphane corrected the shape of the nucleus, increased the growth and proliferation of progeria cells, decreased the levels of the mutant progerin protein, and also increased the levels of ATP produced by the cells. What's really jaw-dropping is that sulforaphane also did the same thing to normal cells (corrected nuclear shape, increased growth and proliferation, decreased mutant progerin levels). Because normal people (you and I) produce the same mutant protein (progerin) that progeria kids produce that causes accelerated aging, just at lower levels that increase as we age, sulforaphane will likely have a positive effect on slowing the aging process in normal humans. And just as methylene blue and retinoic acid reactivate dormant HIV-1 to facilitate removal by the immune system, sulforaphane also boosts the immune response and inhibits factors that keep HIV-1 dormant. Each one of these compounds are likely acting via a common mechanism of AMPK activation that links diseases that most people (including experts) think are completely unrelated (e.g. progeria, HIV-1, fertility, cancer, etc). If this turns out to be true............:-)
Broccoli Sprout compound reverses aging defects in Progeria cells: Potential connection between AMPK, accelerated aging, and HIV-1 reactivation
In line with recent findings (see prior posts) that a vitamin A metabolite (or its derivatives) and the safe, inexpensive compound methylene blue 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 Aging Cell in February of 2015 strikingly demonstrated that sulforaphane, a compound found in broccoli sprouts and other cruciferous vegetables, enhances the disposal of the mutant protein progerin (the protein responsible for accelerated aging) in HGPS cells, leading to a reduction in DNA damage and improved nuclear morphology (i.e. shape) in HGPS fibroblasts [1].
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) 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 researchers showed that in HGPS fibroblasts, both autophagy and proteasome activity, two cellular processes that are essential for the removal of damaged or mutated proteins, were significantly decreased [1]. Surprisingly, sulforaphane treatment increased autophagy and proteasome activity in both HGPS cells and in normal cells, leading to a decrease/clearance of mutant progerin in HGPS cells by nearly 40% by day 9 compared to mock-treated control cells.
Moreover, sulforaphane also significantly increased the growth rate of both HGPS and normal cells by day 3 and ameliorated proliferation (i.e. increase in cell number) defects by day 9 in HGPS cells [1]. Additionally, sulforaphane treatment decreased the levels of reactive oxygen species (reactive molecules that can damage DNA, lipids, and proteins) that were elevated in HGPS cells and also increased intracellular ATP levels (indispensable energy molecule produced by mitochondria) in both normal and HGPS cells, implying a similar mechanism of action in HGPS cells as methylene blue (e.g. enhancing mitochondrial biogenesis/functionality) [1,2].
Sulforaphane administration also improved nuclear morphology in both normal and HGPS cells, as evidenced by a reduction in the frequency of nuclear blebbing after 4 days of treatment that was further enhanced after 9 days. The levels of DNA damage in HGPS cells was also reduced by sulforaphane through improving DNA repair. Perhaps most importantly, however, is that both control and HGPS cells that underwent long-term administration of sulforaphane for several months experienced sustained increases in growth, an increase in the proportions of normal lamin A, and a decrease in the levels of mutant progerin levels during an 85-day period, dramatically demonstrating that sulforaphane is capable of inducing an increase in the levels of normal lamin A but a decrease in mutant progerin levels in both normal and HGPS cells [1].
Because methylene blue was shown to increase lamin A mRNA ratios and retinoic acid or its derivatives was shown to decrease progerin mRNA levels in HGPS cells, it is likely that sulforaphane, methylene blue, and retinoic acid are capable of positively influencing splicing of the LMNA gene in both normal persons and children affected with progeria though activation of the master metabolic regulator AMPK [2-4]. Indeed, normal humans possess the same cryptic splice site in the LMNA gene that is responsible for mutant progerin production in HGPS and normal humans gradually accumulate, over many decades, the same mutant progerin protein that causes accelerated aging in HGPS (see prior posts). Sulforaphane has been shown to alter gene splicing in pre-malignant prostate tissue as well as increase the levels of PGC-1a, the same transcription factor that was induced by methylene blue to facilitate correction of mitochondrial abnormalities in progeria cells [2,5,6].
Additionally, just as methylene blue and retinoic acid have been shown to enhance T cell activation and reactivate latent/dormant HIV-1 infected T cells to facilitate viral destruction and removal by the immune system (see prior posts for references), sulforaphane has also been shown to stimulate the immune response by enhancing the cytotoxicity of natural killer cells and dendritic cells against prostate cancer cells and promote the infiltration of T cells in neoplastic regions [7]. Strikingly, sulforaphane has also been shown to 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 [8-12].
Such pleiotropic effects in seemingly disparate disease states may be explained, provocatively, by a common mechanism of action that methylene blue, retinoic acid, and sulforaphane (and many other compounds) possess: the activation of AMPK. Because AMPK activation has been shown to beneficially alter gene splicing, increase lifespan and healthspan in several organisms, and is essential for activation of T cells (see prior posts for references), a transient induction of cellular stress, leading to a compensatory activation of AMPK, quite possibly explains how such chemically distinct compounds can have similar therapeutic effects in infectious diseases, disorders associated with gene splicing, accelerated aging, and likely many others (cancer, neurodegeneration, etc).
Indeed, the activation of AMPK by sulforaphane was shown to prevent neurotoxicity induced by scrapie prion protein (PrpSc), a misfolded protein that causes the neurological disorder Creutzfeldt-Jakob Disease in humans, scrapie in sheep, and “mad cow disease” in cattle [13]. An unimaginable shift in the practice of medicine would be inevitable if a common mechanism of AMPK activation actually links several distinct compounds with their efficacy in several distinct disease states.
https://www.linkedin.com/pulse/broccoli-sprout-compound-reverses-aging-defects-progeria-finley?trk=mp-reader-card
References:
Here's another REALLY interesting recent post of mine from LinkedIn (see below) : Sulforaphane, a compound that is found heavily concentrated in cruciferous vegetables, particularly broccoli sprouts, actually reversed many of the symptoms of accelerated aging in cells taken from children diagnosed with the accelerated aging disorder Hutchinson-Gilford progeria syndrome. Interestingly, sulforaphane corrected the shape of the nucleus, increased the growth and proliferation of progeria cells, decreased the levels of the mutant progerin protein, and also increased the levels of ATP produced by the cells. What's really jaw-dropping is that sulforaphane also did the same thing to normal cells (corrected nuclear shape, increased growth and proliferation, decreased mutant progerin levels). Because normal people (you and I) produce the same mutant protein (progerin) that progeria kids produce that causes accelerated aging, just at lower levels that increase as we age, sulforaphane will likely have a positive effect on slowing the aging process in normal humans. And just as methylene blue and retinoic acid reactivate dormant HIV-1 to facilitate removal by the immune system, sulforaphane also boosts the immune response and inhibits factors that keep HIV-1 dormant. Each one of these compounds are likely acting via a common mechanism of AMPK activation that links diseases that most people (including experts) think are completely unrelated (e.g. progeria, HIV-1, fertility, cancer, etc). If this turns out to be true............:-)
Broccoli Sprout compound reverses aging defects in Progeria cells: Potential connection between AMPK, accelerated aging, and HIV-1 reactivation
In line with recent findings (see prior posts) that a vitamin A metabolite (or its derivatives) and the safe, inexpensive compound methylene blue 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 Aging Cell in February of 2015 strikingly demonstrated that sulforaphane, a compound found in broccoli sprouts and other cruciferous vegetables, enhances the disposal of the mutant protein progerin (the protein responsible for accelerated aging) in HGPS cells, leading to a reduction in DNA damage and improved nuclear morphology (i.e. shape) in HGPS fibroblasts [1].
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) 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 researchers showed that in HGPS fibroblasts, both autophagy and proteasome activity, two cellular processes that are essential for the removal of damaged or mutated proteins, were significantly decreased [1]. Surprisingly, sulforaphane treatment increased autophagy and proteasome activity in both HGPS cells and in normal cells, leading to a decrease/clearance of mutant progerin in HGPS cells by nearly 40% by day 9 compared to mock-treated control cells.
Moreover, sulforaphane also significantly increased the growth rate of both HGPS and normal cells by day 3 and ameliorated proliferation (i.e. increase in cell number) defects by day 9 in HGPS cells [1]. Additionally, sulforaphane treatment decreased the levels of reactive oxygen species (reactive molecules that can damage DNA, lipids, and proteins) that were elevated in HGPS cells and also increased intracellular ATP levels (indispensable energy molecule produced by mitochondria) in both normal and HGPS cells, implying a similar mechanism of action in HGPS cells as methylene blue (e.g. enhancing mitochondrial biogenesis/functionality) [1,2].
Sulforaphane administration also improved nuclear morphology in both normal and HGPS cells, as evidenced by a reduction in the frequency of nuclear blebbing after 4 days of treatment that was further enhanced after 9 days. The levels of DNA damage in HGPS cells was also reduced by sulforaphane through improving DNA repair. Perhaps most importantly, however, is that both control and HGPS cells that underwent long-term administration of sulforaphane for several months experienced sustained increases in growth, an increase in the proportions of normal lamin A, and a decrease in the levels of mutant progerin levels during an 85-day period, dramatically demonstrating that sulforaphane is capable of inducing an increase in the levels of normal lamin A but a decrease in mutant progerin levels in both normal and HGPS cells [1].
Because methylene blue was shown to increase lamin A mRNA ratios and retinoic acid or its derivatives was shown to decrease progerin mRNA levels in HGPS cells, it is likely that sulforaphane, methylene blue, and retinoic acid are capable of positively influencing splicing of the LMNA gene in both normal persons and children affected with progeria though activation of the master metabolic regulator AMPK [2-4]. Indeed, normal humans possess the same cryptic splice site in the LMNA gene that is responsible for mutant progerin production in HGPS and normal humans gradually accumulate, over many decades, the same mutant progerin protein that causes accelerated aging in HGPS (see prior posts). Sulforaphane has been shown to alter gene splicing in pre-malignant prostate tissue as well as increase the levels of PGC-1a, the same transcription factor that was induced by methylene blue to facilitate correction of mitochondrial abnormalities in progeria cells [2,5,6].
Additionally, just as methylene blue and retinoic acid have been shown to enhance T cell activation and reactivate latent/dormant HIV-1 infected T cells to facilitate viral destruction and removal by the immune system (see prior posts for references), sulforaphane has also been shown to stimulate the immune response by enhancing the cytotoxicity of natural killer cells and dendritic cells against prostate cancer cells and promote the infiltration of T cells in neoplastic regions [7]. Strikingly, sulforaphane has also been shown to 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 [8-12].
Such pleiotropic effects in seemingly disparate disease states may be explained, provocatively, by a common mechanism of action that methylene blue, retinoic acid, and sulforaphane (and many other compounds) possess: the activation of AMPK. Because AMPK activation has been shown to beneficially alter gene splicing, increase lifespan and healthspan in several organisms, and is essential for activation of T cells (see prior posts for references), a transient induction of cellular stress, leading to a compensatory activation of AMPK, quite possibly explains how such chemically distinct compounds can have similar therapeutic effects in infectious diseases, disorders associated with gene splicing, accelerated aging, and likely many others (cancer, neurodegeneration, etc).
Indeed, the activation of AMPK by sulforaphane was shown to prevent neurotoxicity induced by scrapie prion protein (PrpSc), a misfolded protein that causes the neurological disorder Creutzfeldt-Jakob Disease in humans, scrapie in sheep, and “mad cow disease” in cattle [13]. An unimaginable shift in the practice of medicine would be inevitable if a common mechanism of AMPK activation actually links several distinct compounds with their efficacy in several distinct disease states.
https://www.linkedin.com/pulse/broccoli-sprout-compound-reverses-aging-defects-progeria-finley?trk=mp-reader-card
References:
- Gabriel D, Roedl D, Gordon LB, Djabali K. Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts. Aging Cell. 2015 Feb;14(1):78-91.
- 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.
- 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.
- Traka MH, Spinks CA, Doleman JF, et al. The dietary isothiocyanate sulforaphane modulates gene expression and alternative gene splicing in a PTEN null preclinical murine model of prostate cancer. Mol Cancer. 2010 Jul 13;9:189.
- Fernandes RO, Bonetto JH, Baregzay B, et al. Modulation of apoptosis by sulforaphane is associated with PGC-1α stimulation and decreased oxidative stress in cardiac myoblasts.
- Singh SV, Warin R, Xiao D, et al. Sulforaphane inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice in association with increased cytotoxicity of natural killer cells. Cancer Res. 2009 Mar 1;69(5):2117-25.
- Balasubramanian S, Chew YC, Eckert RL. Sulforaphane suppresses polycomb group protein level via a proteasome-dependent mechanism in skin cancer cells. Mol Pharmacol. 2011 Nov;80(5):870-8.
- Watson GW, Wickramasekara S, Palomera-Sanchez Z, et al. SUV39H1/H3K9me3 attenuates sulforaphane-induced apoptotic signaling in PC3 prostate cancer cells. Oncogenesis. 2014 Dec 8;3:e131.
- McCord RP, Nazario-Toole A, Zhang H, et al. Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome. Genome Res. 2013 Feb;23(2):260-9.
- Liu B, Wang Z, Zhang L, Ghosh S, Zheng H, Zhou Z. Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model. Nat Commun. 2013;4:1868.
- Das B, Dobrowolski C, Shahir AM, et al. Short chain fatty acids potently induce latent HIV-1 in T-cells by activating P-TEFb and multiple histone modifications. Virology. 2015 Jan 1;474:65-81.
- Lee JH, Jeong JK, Park SY. Sulforaphane-induced autophagy flux prevents prion protein-mediated neurotoxicity through AMPK pathway. Neuroscience. 2014 Oct 10;278:31-9.
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