Vitamin D significantly improves accelerated aging defects in cells from Progeria patients: Connection between AMPK, 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.

Ok Blogger family, this is an absolutely HUGE study that makes the proposals in my publications come scarily close to being true:-) My LinkedIn post below describes an astounding study (just indexed on Pubmed yesterday) that shows that none other than our good (and popular) friend vitamin D actually decreased DNA damage, improved the shape of the nucleus, dramatically decreased the levels of the toxic protein progerin, and increased the lifespan of cells taken from Progeria patients. What's really interesting is that vitamin D signaling was also decreased in older cells taken from the Progeria kid's parents. Because normal unaffected people (you and I) make the same toxic protein (progerin) as Progeria kids make, just at a lower level that increases with age, it looks like good doses of vitamin D may also help to slow the aging process in us as well. And, of course, vitamin D is an activator of AMPK, just like metformin, the Nobel Prize-winning drug artemisinin, and all the rest of the compounds that reverse aging defects in Progeria (e.g. rapamycin, sulforaphane, retinoic acid, methylene blue). Vitamin D signaling is also vital for the activation of your T cells and to mount a healthy immune response to bacteria, viruses, and other pathogens. Indeed, vitamin D was shown in a study to enhance the reactivation of dormant HIV-1. If evidence continues to support the notion that diseases such as HIV-1, Progeria, and even cancer are connected by a similar pathway and that many natural compounds/drugs ward off disease and increase lifespan by activating this pathway,.........Man-oh-Man-oh-Man:-)

Vitamin D significantly improves accelerated aging defects in cells from Progeria patients: Connection between AMPK, aging, and HIV-1 reactivation

In line with recent evidence demonstrating that the AMPK activators rapamycin, sulforaphane, retinoic acid, and methylene blue ameliorated or reversed accelerating aging defects in cells derived from Hutchinson-Gilford progeria syndrome (HGPS) patients, a recent study published online in the journal Oncotarget in May of 2016 provided astonishing evidence that 1α,25-dihydroxyvitamin D3 (1,25D), the most potent metabolite of Vitamin D, profoundly improved nuclear morphology, significantly reduced DNA damage, improved cellular proliferation, delayed premature cellular senescence, and dramatically reduced progerin production in HGPS patient cells [1].  Because vitamin D has also been shown to significantly induce AMPK activation in vivo in mice, alter gene splicing, facilitate T cell activation, and enhance reactivation of latent HIV-1 in certain cell types (see below), the Oncotarget study further strengthens the connection between latent HIV-1 reactivation and HGPS, with AMPK activation representing an “indirect yet common mechanism of action” linking chemically distinct compounds.

1,25D, also known as calcitriol, is the hormonally activate metabolite of vitamin D and exerts many of its calcium regulatory activities via binding to the vitamin D receptor (VDR) [2]. The VDR is a member of the nuclear receptor family of transcription factors that also includes the retinoic acid receptor (RAR), the thyroid hormone receptor (THR), and the retinoid X receptor (RXR) [2]. Upon vitamin D binding to the VDR, the vitamin D/VDR complex heterodimerizes (i.e. forms a pair) with the RXR, and the vitamin D/VDR/RXR complex then binds to sections of DNA to promote gene transcription and expression of gene products [2].  Interestingly, the VDR is also expressed in tissues that are not associated with bone or calcium regulation, indicating that vitamin D/VDR signaling exerts pleiotropic effects [1].

Indeed, the authors in the Oncotarget study initially demonstrated that depletion of lamin A/C (the protein adversely affected in HGPS) markedly decreased VDR levels in normal fibroblasts derived from parents of HGPS patients and ectopic expression of progerin (the toxic protein product that causes accelerated aging phenotypes in HGPS) also leads to a down-regulation of VDR in other fibroblast cell types [1].  Interestingly, VDR levels were decreased during proliferation of both HGPS patient fibroblasts and normal fibroblasts isolated from the parent of the patient, implicating decreased VDR expression as a common biomarker in both HGPS and in normal aging [1].

The authors next observed that depletion of VDR in two separate lines of normal fibroblasts isolated from the parents of HGPS patients led to a decrease in the levels of the DNA repair protein BRCA1, accumulation of DNA damage (e.g. elevated γH2AX levels), and eventual growth arrest and senescence (e.g. β-galactosidase positive cells) [1].  VDR loss in HGPS patient fibroblasts of early passage also led to BRCA1 reduction and accumulation of DNA damage, suggesting that VDR signaling is critical for maintaining genomic integrity in both normal and HGPS cells [1].

Most importantly, however, the authors showed that prolonged treatment of HGPS cells with 1,25D, compared to control cells, led to an increase in the levels of VDR, BRCA1, and 53BP1 (another protein essential for DNA repair) [1].  Prolonged treatment of HGPS cells with 1,25D also substantially reduced both progerin transcript and protein levels, indicating that 1,25D may beneficially alter disease pathology in HGPS.  As accumulation of progerin causes hallmark distortions of nuclear shape in HGPS cells, the authors also showed that treatment of HGPS cells with 1,25D led to a profound improvement in nuclear morphology, as evidenced by a marked decrease in the percentage of cells with abnormally shaped nuclei in an analysis of over 500 cells per condition [1].  Lastly, compared to vehicle-treated cells, 1,25D-treated HGPS cells (two separate HGPS cell lines) grew at a higher rate with passage in culture, effectively delaying premature entry into cellular senescence [1].

Similar to the beneficial effects demonstrated by rapamycin, sulforaphane, retinoic acid, and methylene blue in HGPS cells, 1,25D’s ability to reduce DNA damage, improve nuclear morphology, and delay premature senescence strongly suggests that each of these compounds (and likely many others) share a common mechanism of action that likely involves activation of the master metabolic regulator AMPK.  Independent studies have shown that AMPK activation improves lifespan, is critical for T cell activation, and beneficially alters gene splicing in genetic disorders [3-5]. Metformin, an AMPK activator, also beneficially altered splicing of the insulin receptor gene in normal human diabetics that were not affected with a genetic disorder [5].

Indeed, 1,25D has been shown to activate AMPK in vivo in mice as well as alter gene splicing in cancer cells [6,7,13].  Interestingly, 1,25D also plays a critical role in immune system regulation, as evidenced by an increase in activated CD4+ T cells in HIV-1 patients administered 1,25D in a placebo-controlled randomized study [8].  VDR signaling plays an integral role in T cell activation, with T cell receptor triggering inducing an upregulation of PLC-γ1 (a protein critical for T cell activation) that is dependent on 1,25D and expression of the VDR [9,10].  Interestingly, as PMA (a positive control extensively used in latent HIV-1 reactivation studies) has been demonstrated to enhance 1,25D-induced promoter binding activity of the VDR, Kitano et al. demonstrated that 1,25D, PMA/TPA, and tumor necrosis factor (TNF) stimulated HIV-1 proviral activation to similar levels in a cell line latently-infected with a monocytotropic strain of HIV-1JR-FL [10-12].

Collectively, the Oncotarget study combined with the aforementioned studies suggests a compelling yet provocative connection between diseases as seemingly as disparate as HGPS and HIV-1 latency, with AMPK activation by chemically distinct compounds including sulforaphane, methylene blue, rapamycin, and retinoic acid (and likely many others including artemisinin and metformin) orchestrating the beneficial effects observed in each disease state effectuated by each compound (see Figure below). The observation of such a connection is unprecedented and, if continued to be substantiated, would necessitate a paradigm shift in the assessment of disease pathology.

https://www.linkedin.com/pulse/vitamin-d-significantly-improves-accelerated-aging-defects-finley?published=u

References:

1. Kreienkamp R, Croke M, Neumann MA, et al. Vitamin D receptor signaling improves Hutchinson-Gilford progeria syndrome cellular phenotypes. Oncotarget. 2016 Apr 27. doi: 10.18632/oncotarget.9065.
2. Plum LA, DeLuca HF. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov. 2010 Dec;9(12):941-55.
3. Ulgherait M, Rana A, Rera M, Graniel J, Walker DW. AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep. 2014 Sep 25;8(6):1767-80.
4. Tamás P, Hawley SA, Clarke RG, et al. Regulation of the energy sensor AMP activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med 2006;203(7):1665–70.
5. Laustriat D, Gide J, Barrault L, et al. In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin. Mol Ther Nucleic Acids. 2015 Nov 3;4:e262.
6. Jang W, Kim HJ, Li H, et al. 1,25-Dyhydroxyvitamin D attenuates rotenone-induced neurotoxicity in SH-SY5Y cells through induction of autophagy. Biochem Biophys Res Commun. 2014 Aug 15;451(1):142-7.
7. Cristobo I, Larriba MJ, de los Ríos V, García F, Muñoz A, Casal JI. Proteomic analysis of 1α,25-dihydroxyvitamin D3 action on human colon cancer cells reveals a link to splicing regulation. J Proteomics. 2011 Dec 21;75(2):384-97.
8. Bang U, Kolte L, Hitz M, et al. Correlation of increases in 1,25-dihydroxyvitamin D during vitamin D therapy with activation of CD4+ T lymphocytes in HIV-1-infected males. HIV Clin Trials. 2012 May-Jun;13(3):162-70.
9. von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol. 2010 Apr;11(4):344-9.
10. 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.
11. Jiang Y, Fleet JC. Effect of phorbol 12-myristate 13-acetate activated signaling pathways on 1α, 25 dihydroxyvitamin D3 regulated human 25-hydroxyvitamin D3 24-hydroxylase gene expression in differentiated Caco-2 cells. J Cell Biochem. 2012 May;113(5):1599-607.
12. Kitano K, Rivas CI, Baldwin GC, Vera JC, Golde DW. Tumor necrosis factor-dependent production of human immunodeficiency virus 1 in chronically infected HL-60 cells. Blood. 1993 Nov 1;82(9):2742-8.
13. Swami S, Krishnan AV, Williams J, et al. Vitamin D mitigates the adverse effects of obesity on breast cancer in mice. Endocr Relat Cancer. 2016 Jan 27. pii: ERC-15-0557.
     

Popular cancer drug Velcade shares common mechanism of action with AMPK activator Metformin: Connection between AMPK, 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.

Here's another post I just authored on LinkedIn with a surprising finding that a really popular injectable cancer drug called Velcade (made well over a billion dollars for J&J in 2014) and other drugs that are in Velcade's drug class (called proteasome inhibitors) actually activates the same pathway (AMPK) as does metformin derived from the Galega plant, sulforaphane derived from broccoli sprouts, the vitamin A metabolite retinoic acid, rapamycin derived from bacteria, and the Nobel Prize-winning drug Artemisinin derived from the Artemisia plant. Velcade not only reactivated the dormant HIV-1 virus but also inhibited HIV-1 infectivity and viral output in cells that were actively infected, effectively "pulling a double shift". Velcade has also been shown to be a potent AMPK activator and beneficially alter gene splicing in cancer cells. MG132, another drug that works like and is in the same drug class as Velcade, also activates AMPK, reactivated latent HIV-1, alters gene splicing, and enhanced the removal of the toxic protein progerin in cells from children with Progeria when combined with retinoic acid. Considering that AMPK is critical for T cell activation, beneficially alters gene splicing, and extends lifespan, this looks like yet another example of the interconnectedness of diseases including cancer, HIV-1, Progeria, and even normal aging itself. Man, what on earth have I unearthed????? Time will soon tell:-)

Popular cancer drug Velcade shares common mechanism of action with AMPK activator Metformin: Connection between AMPK, aging, and HIV-1 reactivation

A recent study published in the journal Retrovirology in October of 2013 provided unexpected evidence that the commonly-used cancer drug Velcade (an FDA approved drug for the treatment of multiple myelomas, leukemias, and lymphoma) as well as two other members of the proteasome inhibitor drug class (MG132 and clasto-Lactacystin β-lactone) reactivated latent HIV-1 in two primary human CD4+ T cell model systems as well as in several other in vitro model systems [1].  Strikingly, Velcade (also known as bortezomib) not only reactivated the latent virus but also inhibited HIV-1 infectivity, as evidenced by reduced viral output and virion infectivity [1].  Interestingly, Velcade has been shown to beneficially alter gene splicing in cancer, MG132 has been shown to alter gene splicing and reduce progerin production in fibroblasts derived from Hutchinson-Gilford progeria (HGPS) patients, and both Velcade and MG132 have been shown to activate AMPK in separate studies (see below).  Such evidence again suggests (see prior posts) that chemically distinct compounds, including compounds comprising the proteasome inhibitor class, share an “indirect yet common mechanism of action” of AMPK activation that is likely induced by the induction of a cellular stress response.

The proteasome is a protein complex present in all eukaryotes that functions to degrade or remove damaged proteins by adding a consecutive series of tags to these proteins (called a poly-ubiquitin chain), facilitating proteasome binding and protein degradation [2].  Inhibition of the catalytic site of the 26S proteasome, leading to the accumulation of pro-apoptotic (i.e. self-destruct) factors and subsequent cancer cell death is widely accepted as the mechanism of action by which Velcade acts [3].  However, as noted below, other mechanisms are almost undoubtedly involved.

In the Retrovirology study, the authors initially observed that when OM-10.1 cells (a clonal population of HL-60 promyelocytes) that were latently infected with a replication-competent HIV-1 strain were exposed to all three proteasome inhibitors (i.e. Velcade, MG132, and clasto-Lactacystin β-lactone (CLBL)), proteasome inhibition occurred within two hours, along with a significant increase in the induction of HIV-1 RNAs, indicative of the initiation of latent viral transcription [1].  The authors further showed, using a clonal population of HeLa cells and a human CD4+ T cell line, that all three proteasome inhibitors induced the activation of proviral gene expression in both cell lines [1]. Interestingly, all three proteasome inhibitors as well as the HDAC inhibitor vorinostat also induced viral particle production (as evidenced by a significant increase in the HIV-1 p24 antigen) in OM-10.1 cells [1].  To produce the p24 antigen, the splicing of the HIV-1 genome must be inhibited to produce long unspliced HIV-1 mRNA.  Splicing of the viral genome is reduced on latent HIV-1 reactivation through reduction of the activities of the splicing factor SRSF1 by the splicing-associated factor p32.  SRSF1 is also implicated in the faulty splicing mechanism that causes symptoms of accelerated aging in HGPS as well as in aberrant gene splicing in vascular tissues of normal humans [25].

More importantly, however, the authors demonstrated that both Velcade and MG132 significantly induced HIV-1 proviral gene expression in two latent HIV-1 primary human CD4+ T cell models that mimic central and effector memory T cells (two memory T cell subsets that are known reservoirs for latent HIV-1) [1].  Also, Velcade and MG132 did not activate uninfected primary human resting CD4+ T cells, indicating that both proteasome inhibitors selectively activate only CD4+ memory T cells that are latently infected with HIV-1 [1].

Perhaps most startling, however, was the finding that Velcade was able to significantly reduce viral output in activated primary human CD4+ T cells isolated from PBMCs from healthy donors, as evidenced by a 30% increase in HIV-1 p24 antigen in untreated cells compared to Velcade-treated cells [1].  Velcade was also able to decrease the infectivity of viruses produced from infected CD4+ T cells, with viruses from Velcade-treated cells only able to infect one forth the number of HeLaT4 cells compared to viruses collected from untreated primary CD4+ T cells [1]. Hence, Velcade appears to able to selectively reactivate latent HIV-1 without activating uninfected resting CD4+ T cells, but inhibit HIV-1 infectivity and viral output in productively infected cells.

This seemingly perplexing, multi-pronged antiviral mechanism demonstrated by Velcade and other proteasome inhibitors can be explained by the activation of AMPK.  T cell activation (and thus latent HIV-1 reactivation) is critically dependent on the activation of AMPK and both Velcade and MG132 have been independently shown to activate AMPK, possibly via a stress-induced signal generated by the accumulation of ubiquitinated and damaged proteins [4-6].  Indeed, both PMA and ionomycin, a combination positive control for numerous latent HIV-1 reactivation studies, have been shown to activate AMPK and AMPK activation is essential to mount an effective immune response to viral and bacterial challenges [7-11].  Also, vorinostat, an HDAC inhibitor used in the Retrovirology study as a positive control to gauge latent HIV-1 reactivation, also activates AMPK, and bryostatin (PKC activator) and JQ1 (BET bromodomain inhibitor) each have been shown to both activate AMPK and potently induce latent HIV-1 reactivation without global T cell activation in independent studies [12-15].

Furthermore, low dose proteasome inhibition using MG132 has recently been shown to alter gene splicing and induce a protective antioxidative defense response dependent on the transcription factor Nrf2, a master regulator of the cellular antioxidant response [16,17].  Interestingly, AMPK activation has recently been shown to beneficially alter gene splicing in cells derived from patients with the genetic disorder myotonic dystrophy type I (DM1) and metformin (an AMPK activator) has been shown to beneficially alter gene splicing in normal humans and increase the expression of Nrf2 [18,19].  Also, both Velcade and vorinostat have been shown to alter gene splicing in human hepatoma HepG2 and Huh6 cells by altering the splicing of the Bcl-X transcript, thus preferentially increasing the levels of Bcl-xS (the short pro-apoptotic isoform) compared to Bcl-xL (the pro-survival isoform) [20].

Proteasome inhibition has also been shown to play a role in HGPS, a disease characterized by faulty alternative gene splicing leading to an accelerated aging phenotype. Interestingly, MG132, either alone or in combination with the vitamin A metabolite all-trans retinoic acid, led to a decrease in progerin levels in HGPS cells via a proteasome inhibitor-mediated induction of autophagy, implicating both autophagic and proteasomal pathways in progerin reduction [21].  Indeed, both rapamycin (derived from bacteria) and sulforaphane (from broccoli sprouts) have each been shown to activate AMPK in vivo and induce the autophagic degradation of progerin (toxic protein product that causes accelerated aging) in HGPS fibroblasts [21-24].

Cumulatively, the foregoing studies provide convincing evidence that activation of AMPK by chemically distinct compounds (as indicated in the figure below), including the proteasome inhibitors Velcade and MG132, represents an “indirect yet common mechanism of action” that links pathological diseases states associated with gene splicing, viral latency and replication, and likely many others.

https://www.linkedin.com/pulse/popular-cancer-drug-velcade-shares-common-mechanism-action-finley?trk=prof-post

References:

1. Miller LK, Kobayashi Y, Chen CC, Russnak TA, Ron Y, Dougherty JP. Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication. Retrovirology. 2013 Oct 24;10:120.
2. Finley D. Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu Rev Biochem. 2009;78:477-513.
3. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011 Nov;10(11):2034-42.
4. Tamás P, Hawley SA, Clarke RG, et al. Regulation of the energy sensor AMP activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med 2006;203(7):1665–70.
5. Kwak HJ, Choi HE, Jang J, Park SK, Bae YA, Cheon HG. Bortezomib attenuates palmitic acid-induced ER stress, inflammation and insulin resistance in myotubes via AMPK dependent mechanism. Cell Signal. 2016 Apr 2. pii: S0898-6568(16)30067-5.
6. Jiang S, Park DW, Gao Y, et al. Participation of proteasome-ubiquitin protein degradation in autophagy and the activation of AMP-activated protein kinase. Cell Signal. 2015 Feb 26. pii: S0898-6568(15)00070-4.
7. Spina CA, Anderson J, Archin NM, et al. An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog. 2013;9(12):e1003834.
8. Zogovic N, Tovilovic-Kovacevic G, Misirkic-Marjanovic M, et al. Coordinated activation of AMP-activated protein kinase, extracellular signal-regulated kinase, and autophagy regulates phorbol myristate acetate-induced differentiation of SH-SY5Y neuroblastoma cells. J Neurochem. 2015 Apr;133(2):223-32.
9. Lee JY, Choi AY, Oh YT, et al. AMP-activated protein kinase mediates T cell activation-induced expression of FasL and COX-2 via protein kinase C theta-dependent pathway in human Jurkat T leukemia cells. Cell Signal. 2012 Jun;24(6):1195-207.
10. Blagih J, Coulombe F, Vincent EE, et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity. 2015 Jan 20;42(1):41-54.
11. Rolf J, Zarrouk M, Finlay DK, Foretz M, Viollet B, Cantrell DA. AMPKα1: a glucose sensor that controls CD8 T-cell memory. Eur J Immunol. 2013 Apr;43(4):889-96.
12. Sarfstein R, Bruchim I, Fishman A, Werner H. The mechanism of action of the histone deacetylase inhibitor vorinostat involves interaction with the insulin-like growth factor signaling pathway. PLoS One. 2011;6(9):e24468.
13. 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.
14. Wang H, Sharma L, Lu J, Finch P, Fletcher S, Prochownik EV. Structurally diverse c-Myc inhibitors share a common mechanism of action involving ATP depletion. Oncotarget. 2015 Jun 30;6(18):15857-70.
15. Darcis G, Kula A, Bouchat S, et al. An In-Depth Comparison of Latency-Reversing Agent Combinations in Various In Vitro and Ex Vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression. PLoS Pathog. 2015 Jul 30;11(7):e1005063.
16. Bieler S, Hammer E, Gesell-Salazar M, Völker U, Stangl K, Meiners S. Low dose proteasome inhibition affects alternative splicing. J Proteome Res. 2012 Aug 3;11(8):3947-54.
17. Dreger H, Westphal K, Wilck N, et al. Protection of vascular cells from oxidative stress by proteasome inhibition depends on Nrf2. Cardiovasc Res. 2010 Jan 15;85(2):395-403.
18. Laustriat D, Gide J, Barrault L, et al. In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin. Mol Ther Nucleic Acids. 2015 Nov 3;4:e262.
19. Ashabi G1, Khalaj L, Khodagholi F, Goudarzvand M, Sarkaki A. Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia. Metab Brain Dis. 2015 Jun;30(3):747-54.
20. Emanuele S, Lauricella M, Carlisi D, et al. SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib. Apoptosis. 2007 Jul;12(7):1327-38.
21. 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.
22. 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.
23. Chiao YA, Kolwicz SC, Basisty N, et al. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY). 2016 Feb;8(2):314-27.
24. Choi KM, Lee YS, Kim W, et al. Sulforaphane attenuates obesity by inhibiting adipogenesis and activating the AMPK pathway in obese mice. J Nutr Biochem. 2014 Feb;25(2):201-7.
25. 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.