100 replies to this topic

[albedo]

A couple more papers on autophagy and the mechanism of action in this context of vitamin D (normalizing, it was not me voting you down):

 

Autophagy induction by vitamin D inhibits both Mycobacterium tuberculosis and human immunodeficiency virus type 1.

https://www.ncbi.nlm...pubmed/22892387

 

"Low vitamin D levels in human immunodeficiency virus type-1 (HIV) infected persons are associated with more rapid disease progression and increased risk for Mycobacterium tuberculosis infection. We report that physiological concentrations of 1α,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D, inhibits M. tuberculosis and HIV replication in co-infected macrophages through human cathelicidin microbial peptide-dependent autophagy that requires phagosomal maturation. These findings provide a biological explanation for the importance of vitamin D sufficiency in HIV and M. tuberculosis-infected persons, and provide new insights into novel approaches to prevent and treat HIV infection and related opportunistic infections."

 

Impact of vitamin D on immune function: lessons learned from genome-wide analysis.

https://www.ncbi.nlm...pubmed/24795646

 

"Immunomodulatory responses to the active form of vitamin D (1,25-dihydroxyvitamin D, 1,25D) have been recognized for many years, but it is only in the last 5 years that the potential role of this in normal human immune function has been recognized. Genome-wide analyses have played a pivotal role in redefining our perspective on vitamin D and immunity. The description of increased vitamin D receptor (VDR) and 1α-hydroxylase (CYP27B1) expression in macrophages following a pathogen challenge, has underlined the importance of intracrine vitamin D as key mediator of innate immune function. It is now clear that both macrophages and dendritic cells (DCs) are able to respond to 25-hydroxyvitamin D (25D), the major circulating vitamin D metabolite, thereby providing a link between the function of these cells and the variations in vitamin D status common to many humans. The identification of hundreds of primary 1,25D target genes in immune cells has also provided new insight into the role of vitamin D in the adaptive immune system, such as the modulation of antigen-presentation and T cells proliferation and phenotype, with the over-arching effects being to suppress inflammation and promote immune tolerance. In macrophages 1,25D promotes antimicrobial responses through the induction of antibacterial proteins, and stimulation of autophagy and autophagosome activity. In this way variations in 25D levels have the potential to influence both innate and adaptive immune responses. More recent genome-wide analyses have highlighted how cytokine signaling pathways can influence the intracrine vitamin D system and either enhance or abrogate responses to 25D. The current review will discuss the impact of intracrine vitamin D metabolism on both innate and adaptive immunity, whilst introducing the concept of disease-specific corruption of vitamin D metabolism and how this may alter the requirements for vitamin D in maintaining a healthy immune system in humans."

 

(next to the autophagy stimulation, this second paper in particular emphasizes the possible genetic factors in immune response to vitamin D, e.g. see "... However, improved sputum conversion time was observed in a specific subset of TB patients with a Taq1 single nucleotide polymorphism (SNP) within the VDR gene (Martineau et al., 2011), suggesting that genetic factors may influence immune responses to vitamin D supplementation..."

 

Insights into battles between Mycobacterium tuberculosis and macrophages.

https://www.ncbi.nlm...pubmed/24938416

 

"As the first line of immune defense for Mycobacterium tuberculosis (Mtb), macrophages also provide a major habitat for Mtb to reside in the host for years. The battles between Mtb and macrophages have been constant since ancient times. Triggered upon Mtb infection, multiple cellular pathways in macrophages are activated to initiate a tailored immune response toward the invading pathogen and regulate the cellular fates of the host as well. Toll-like receptors (TLRs) expressed on macrophages can recognize pathogen-associated-molecular patterns (PAMPs) on Mtb and mediate the production of immune-regulatory cytokines such as tumor necrosis factor (TNF) and type I Interferons (IFNs). In addition, Vitamin D receptor (VDR) and Vitamin D-1-hydroxylase are up-regulated in Mtb-infected macrophages, by which Vitamin D participates in innate immune responses. The signaling pathways that involve TNF, type I IFNs and Vitamin D are inter-connected, which play critical roles in the regulation of necroptosis, apoptosis, and autophagy of the infected macrophages. This review article summarizes current knowledge about the interactions between Mtb and macrophages, focusing on cellular fates of the Mtb-infected macrophages and the regulatory molecules and cellular pathways involved in those processes."

 

 

 

[Nate-2004]

I do take inositol but I don't take it when fasting. I am looking for other ways to boost or maintain autophagy during fasted periods and so far the only thing I'd heard of is green tea extract. This thread helps for sure. I think autophagy is great for short periods but then you want to rebuild. It's all about timing. Not sure if I should avoid things that promote autophagy during re-feeding days or what.

[albedo]

I do take inositol but I don't take it when fasting. I am looking for other ways to boost or maintain autophagy during fasted periods and so far the only thing I'd heard of is green tea extract. This thread helps for sure. I think autophagy is great for short periods but then you want to rebuild. It's all about timing. Not sure if I should avoid things that promote autophagy during re-feeding days or what.

 When would or you take inositol and/or GTE?

 

[Nate-2004]

 

I do take inositol but I don't take it when fasting. I am looking for other ways to boost or maintain autophagy during fasted periods and so far the only thing I'd heard of is green tea extract. This thread helps for sure. I think autophagy is great for short periods but then you want to rebuild. It's all about timing. Not sure if I should avoid things that promote autophagy during re-feeding days or what.

 When would or you take inositol and/or GTE?

 

 

I would definitely take it while feeding, but that's for anxiety and tremor mainly. I don't think it's worth taking otherwise.

[albedo]

Not sure this recent paper has been citet, it looks a good read in the context of this thread and should possibly include both NR and Sulforaphane. Unfortunately is pay walled, but I logged for my next visit to a library:

 

Georgakopoulos ND, Wells G, Campanella M. The pharmacological regulation of cellular mitophagy. Nat Chem Biol. 2017;13(2):136-146.

https://www.nature.c...embio.2287.html

[albedo]

Lysosomes in iron metabolism, ageing and apoptosis

http://www.ncbi.nlm....les/PMC2668650/

 

MCOLN1 is a ROS sensor in lysosomes that regulates autophagy

http://www.nature.co...comms12109.html

 

A review showing that pharmacologically induced iron depletion activates mitophagy. So I guess we might also look at supplements which are supposed to lower iron as potentially beneficial to the scope:

 

Allen, G.F.G., Toth, R., James, J. & Ganley, I.G. Loss of iron triggers PINK1/ Parkin-independent mitophagy. EMBO Rep. 14, 1127–1135 (2013).
https://www.ncbi.nlm...pubmed/24176932
 

[Advocatus Diaboli]

If done (lowering iron) it probably would need to be done in some cyclical fashion such that iron level didn't drop into deficiency level and stay there for whatever period of time it would take to adversely affect proper iron utilization.

[Benko]

If done (lowering iron) it probably would need to be done in some cyclical fashion such that iron level didn't drop into deficiency level and stay there for whatever period of time it would take to adversely affect proper iron utilization.

 

How about giving blood?

[Advocatus Diaboli]

That would seem to be a possibility, Benko. Kill 2 birds with one stone. Places that accept blood donations generally have a time criterion on the acceptable interval between donations in order to avoid such problems as effectively lowering blood iron, etc.

 

So, unless someone hits up several sites to donate at then iron levels probably won't be diminished to an unsafe level. But, in the case of pharmacologically-induced iron lowering I suspect that, to be on the safe side, regular blood iron levels would have to be monitored at some given frequency by blood draw and analysis--which could get expensive

[albedo]

Not sure this recent paper has been citet, it looks a good read in the context of this thread and should possibly include both NR and Sulforaphane. Unfortunately is pay walled, but I logged for my next visit to a library:

 

Georgakopoulos ND, Wells G, Campanella M. The pharmacological regulation of cellular mitophagy. Nat Chem Biol. 2017;13(2):136-146.

https://www.nature.c...embio.2287.html

 

OK. I gave a quick look to it but did not study it in details (very technical) so please take this cautiously. They list agents inducing cellular mitophagy notably:

• Iron chelators such as Deferiprone (DFP)
• SIRT1 agonists (Resveratrol, Fisetin, SRT1720)
• NAD+ precursors
• PARP1 inhibitors
• Keap1 inhibitors (e.g. PMI=”p62/SQSTM1-mediated mitophagy inducer”).
• Sulphoraphane is reported as indirect (vs PMI which is direct) inhibitor of Keap1-mediated degradation of Nrf2. So they seems more prone to PMI than sulforaphane as therapeutic. Activation of Nrf2, the  master regulator of the antioxidant response, is acknowledged as key for stimulation of mitophagy.

 

[albedo]

 

Cell Cycle. 2014 Apr 25;13(12).

Coffee induces autophagy in vivo.

Pietrocola F1, Malik SA2, Mariño G3, Vacchelli E1, Senovilla L4, Chaba K3, Niso-Santano M3, Maiuri MC3, Madeo F5, Kroemer G6.

Epidemiological studies and clinical trials revealed that chronic consumption coffee is associated with the inhibition of several metabolic diseases as well as reduction in overall and cause-specific mortality. We show that both natural and decaffeinated brands of coffee similarly rapidly trigger autophagy in mice. One to 4 hours after coffee consumption, we observed an increase in autophagic flux in all investigated organs (liver, muscle, heart) in vivo, as indicated by the increased lipidation of LC3B and the reduction of the abundance of the autophagic substrate sequestosome 1 (p62/STQM1). These changes were accompanied by the inhibition of the enzymatic activity of mammalian target of rapamycin complex 1 (mTORC1), leading to the reduced phosphorylation of p70S6K, as well as by the global deacetylation of cellular proteins detectable by immunoblot. Immunohistochemical analyses of transgenic mice expressing a GFP-LC3B fusion protein confirmed the coffee-induced relocation of LC3B to autophagosomes, as well as general protein deacetylation. Altogether, these results indicate that coffee triggers 2 phenomena that are also induced by nutrient depletion, namely a reduction of protein acetylation coupled to an increase in autophagy. We speculate that polyphenols contained in coffee promote health by stimulating autophagy.

PMID: 24769862

 

ACS Chem Neurosci. 2014 Apr 30.

Lithium and Autophagy.

Motoi Y1, Shimada K, Ishiguro K, Hattori N.

Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms, including autophagy regulation, in various neuropsychiatric conditions. In neurodegenerative diseases, lithium enhances degradation of aggregate-prone proteins, including mutated huntingtin, phosphorylated tau, and α-synuclein, and causes damaged mitochondria to degrade, while in a mouse model of cerebral ischemia and Alzheimer's disease autophagy downregulation by lithium is observed. The signaling pathway of lithium as an autophagy enhancer might be associated with the mammalian target of rapamycin (mTOR)-independent pathway, which is involved in myo-inositol-1,4,5-trisphosphate (IP3) in Huntington's disease and Parkinson's disease. However, the mTOR-dependent pathway might be involved in inhibiting glycogen synthase kinase-3β (GSK3β) in other diseases. Lithium's autophagy-enhancing property may contribute to the therapeutic benefit of patients with neuropsychiatric disorders.

PMID: 24738557

 

 

 

Thank you for these two studies! In particular I have been looking for a while to caffeine concomitant with IF (doing both, IF 16-18 hours, need to double check impact on my biomarkers though, but feel great!). Still researching on potential interaction with IP6 but not sure. Take care!