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:

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