Autophagy an alternative to vitamin D supplements? / Getting Stronger

An alternative to vitamin D supplements? /  Getting Stronger

Getting Stronger is a blog about the philosophy of Hormetism, based on the application of progressive, intermittent stress to overcome challenges and grow stronger physically, mentally and emotionally. For additional background, click here for the OVERVIEW and AUTHOR pages. 

My recent post on Why I don’t take vitamin D supplements generated a lot of interest and a few misconceptions.  In that article, I did not suggest any practical alternatives to taking high dose vitamin D supplements.  Here I will suggest a way that may provide the benefits of vitamin D without popping any pills, spending all day in the sun, or ingesting copious amounts of fish.

Some readers got the idea that I believe vitamin D is not beneficial, and that I discount the evidence from studies that show the benefits.  I want to dispel that notion.  I do acknowledge the key role that vitamin D and the vitamin D receptor (VDR) play in bone mineralization and regulation of  innate and adaptive immunity, and among other things.  I further acknowledge that many (but certainly not all) studies support an association between higher vitamin D3 levels and reduced incidence of diseases such as cancer.
As I wrote:

Nobody doubts the important role of vitamin D in the body. But are higher levels of a hormone like vitamin D–whether or not provided as a supplement– always a good thing?

My doubts are focused on several points:

• Under-appreciation of the fact that vitamin D is a hormone with diverse and dose-dependent systemic effects, still not fully understood
• Misleading  claims that vitamin D supplementation is “equivalent”  to vitamin D from sun exposure. While the two forms are chemically identical, levels of vitamin D3 synthesized from sun exposure are self-limiting due to feedback regulation.  What happens when we chronically exceed natural limits?
• Inadequate attention to the possible effects of chronic vitamin D supplementation on homeostatic down-regulation of the VDR receptor. See this discussion bv Dr. David Agus of USC medical school.
• Inadequate study of the possible long term adverse effects of chronic vitamin D supplementation. Few studies look beyond 4 years. Hormone replacement therapy was in favor for 50 years before the risks came to light . Things don’t necessarily look any more promising when synthetic hormones are replaced bioidentical hormones.

My article created a dilemma for several commenters. These people acknowledged the risks, but nevertheless cited  benefits they personally experienced  from supplementing with vitamin D–ranging from fewer colds and flu, to relief of autoimmune symptoms, and even lessening of depression.

For these people, a key question remains:

Is there a way to get the benefits of vitamin D supplementation, while avoiding the dependency and risks of taking vitamin D capsules daily for the rest of your life?  While I don’t have a definitive proven answer to that question, recent research leads me to speculate here that there is a promising approach that is within everyone’s reach.

It lies within a powerful natural biological process called autophagy.

What is autophagy?   This term  derives from the Greek roots for “self eating”.  It refers to a process that normal cells in every organism can use to derive energy by breaking down and recycling unneeded or “damaged” components.  Autophagy typically kicks in when a cell is  temporarily deprived of externally supplied nutrients, or subjected to other stresses such as low oxygen, infection and chemical exposure.  In the most common type of autophagy–known as macroautophagy–the cell constructs a special membrane enclosure, called an autophagosome, that floats around inside the cell.  The autophagosome is a kind of miniature recycling factory that detects, engulfs and digests damaged proteins and larger organelle structures.  After trapping the cellular components, the autophagosome fuses with a packet of degradative enzymes, known as a lysosome.  It then degrades these large molecules down to their component amino acids, sugars and fatty acids, which can be used as fuels and building blocks for repair and growth.  This recycling of damaged parts ensures an uninterrupted supply of energy and structural components need by the cell.



But the benefits of autophagy go far beyond fueling the cell, and ridding the cell of useless “junk”. Autophagy’s cellular housekeeping function actively counteracts many of the degenerative processes of aging!



Damage to cell structures and proteins is cumulative, and if allowed to proceed without correction, it can lead to malfunctioning of cellular processes and the genesis of illness. For example, a diet high in reactive sugars such as sucrose and fructose can glycate proteins, creating cross-linked structures known as advanced glycation end-products (AGEs), Similarly, oxidative stress can damage lipid bilayer membranes. The accumulation of these abnormal molecules has been implicated in the genesis of degenerative diseases such as diabetes, Alzheimers, cardiovascular disease and stroke.

Autophagosomes have also been shown to engulf and remove intracellular pathogens, such as the tuberculosis bacterium. Most intriguing, while autophagy regenerates the viability of normal cells, it has been show trigger the self-destruction (apoptosis) of some cancer cells and other abnormal cells.  In short, regular and recurrent autophagy is a key defense against a range of degenerative diseases.
The vitamin D connection.  What does autophagy have to do with vitamin D, you ask?  In mammals, the vitamin D receptor (VDR) sits at the beginning of a important cascade of biochemical pathways. Vitamin D3 or 25-D, from supplements or cutaneous synthesis, is converted to the active 1,25-D form in the kidneys in response to pituitary hormone (PTH).  Renal 1,25-D plays a key role in the regulation of bone mineralization and waste excretion. But the VDR is also distributed to widely in cells throughout the body.  After the kidney has converted vitamin D3 (25-D) to the active form of vitamin D (1,25-D) it is transported through the circulation to extra=renal sites by a protein known as vitamin D binding protein (VDBP).  Within the cell, the active vitamin D  interacts with the VDR to provide local control of a range of metabolic functions, including cellular immunity, anti-inflammatory, anti-infective, and anticancer responses.

And recent research indicates that one of the key functions of the VDR is to regulate autophagy!
Studies by several research groups have elucidated this signaling pathways that connect the VDR and calcium metabolism to autophagy. According to Shaoping Wu and Jun Sun at the University of Rochester Department of Medicine,

The signaling pathways regulated by vitamin D₃ include Bcl-2, beclin-1, mammalian target of rapamycin (mTOR), the class III phosphatidylinositol 3-kinase complex (PI3KC3), cathelicidin, calcium metabolism, and cyclin-dependent kinase (Table 1). These pathways are critical in host defense and inflammatory responses. Hence, vitamin D₃ and autophagy are associated with innate immunity…Vitamin D₃ is a major regulator of calcium metabolism. Increased circulating vitamin D₃ activates VDR, leading to increased intestinal calcium absorption. In excitable cells such as neurons, calcium is released from the sarcoplasmic or endoplasmic reticulum (ER) to activate calcium-dependent kinases and phosphatases, thereby regulating numerous cellular processes, including autophagy. ER calcium induces autophagy when stimulated by vitamin D₃. This process is inhibited by mTOR, a negative regulator of macroautophagy, and induces massive accumulation of autophagosomes in a beclin-1- and ATG7-dependent manner since they are not fused with lysosomes. Vitamin D₃ can down-regulate the expression of mTOR protein, thus inducing autophagy by inhibiting the mTORC1 complex.

A review by Høyer-Hansen et al., of the Institute of Cancer Biology at the Danish Cancer Society, elucidates the mechanisms by which vitamin D (“VD” here) induced autophagy selectively target cancer cells:

VD analogs are potent inducers of autophagy in different cell types, and autophagy is crucial for their cytotoxic activity towards cancer cells….[T]he signaling pathways connecting VD compounds to autophagy induction are similar in breast cancer cells and monocytes [7,12]. Autophagy induction in both cell types relies on an increase in [Ca2+]cyt, which could result from VDR-mediated changes in the expression levels of calcium-regulating proteins and the subsequent endoplasmic reticulum stress.
…Autophagy usually exerts a cytoprotective function in stressed cells; however, in EB1089-treated breast cancer cells, the enhancement of the autophagic response by ectopic expression of Becn1 increases cell death… Importantly, 1a,25-(OH)2D3-treated primary monocytes do not show any signs of cell death even though their autophagy response is similar to that observed in cancer cells. Thus, it is tempting to speculate that 1a,25- (OH)2D3-induced autophagic cell death could be specific for cancer cells; if true, this would represent a new cancer-specific treatment.

The Danish group has also shown that vitamin D acts to contain and eliminate the tuberculosis bacterium by inducing autophagy, perhaps providing an explanation for the historical use of cod liver oil and vitamin D as early therapies against TB  before the advent of antibiotics:

In tuberculosis, M. tuberculosis resides in phagosomes and evades host antimicrobial mechanisms by blocking phagosome maturation and fusion with the lysosome. Ultimately, the host must overcome this evasion strategy to destroy the pathogen. Accumulating evidence suggests that this occurs via the autophagic degradation of bacteria-containing phagosomes and the subsequent killing of the bacteria in autolysosomes. Interestingly, a recent paper links the 1a,25-(OH)2D3- and autophagy-controlled antimycobacterial defense-pathways.

They conclude:

Recent data link autophagy to two of the beneficial effects of VD: the induction of cancer cell death and the clearance of M. tuberculosis. This opens the possibility that autophagy could be a general mediator of the health-promoting effects of 1a,25-(OH)2D3. Accordingly, there is a striking overlap among the diseases promoted by VD deficiency and defective autophagy. The new data linking the two health-promoting pathways open an interesting research field that could lead to new options for the treatment and prevention of many common diseases.

All very interesting. But if the vitamin D receptor is an activator of cellular autophagy, with its many apparent health benefits is there a way to activate the process without taking vitamin D capsules or spending all day in the sun?

How to activate autophagy without vitamin D.   While vitamin D is one potent way to turn on the autophagy switch, it’s by no means the only way. Autophagy is a phenomenon that occurs throughout the animal kingdom, not just vitamin D utilizing mammals like ourselves. For example, Morselli et al. have shown that autophagy is a requirement for the demonstrated life-extending benefits of caloric restriction in nematodes, mice, flies and worms.

In fact there are several ways you can naturally activate autophagy in your body.  It turns out that all of them involve one form of hormesis or another:

• Calorie restriction and intermittent fasting.  In my post on Calorie restriction and hormesis,  I summarized some of the research on calorie restriction in humans, primates and other animals. including the role played by autophagy and other mechanisms.  This is also described in my talk on Intermittent Fasting for Health and Longevity.
• Brief, strenuous exercise.  A 2012 paper in Nature by Levine et al. in mice found that “Exercise is even faster than starvation” at inducing autophagy… “If you just exercise the mice for 30 minutes on a treadmill, autophagosomes start to form. Thirty minutes of running induces autophagy 40 to 50 percent.”
• Hormetic stress in general.   A wide range of short term, intense but sublethal stressors have been shown to activate autophagy via a common pathway.  Criollo et al.  showed that multiple stressors, including nutrient starvation and numerous chemicals, trigger the activation of the IKK (IκB kinase) complex, inducing the classical autophagy pathway involving p53 depletion, mTOR inhibition, AMPK and JNK1 activation, and release of the pro-autophagic protein Beclin-1.  How many of the other hormetic stressors we’ve discussed in this blog– such as cold showers–might effectively activate autophagy?

 
Why I prefer natural stressors.  So perhaps you might be persuaded you to at least consider trying intermittent fasting and exercise (better yet: fasted workouts) to activate your autophagy. If you are one of those who finds that vitamin D helps reduce colds or asthma symptoms — try skipping meals and snacks, and cut back on carbohydrates and excess protein.  I eat one or two small meals a day, mostly low carb or Paleo, and I can’t remember the last time I had a flu or cold.

But taking vitamin D supplements is so much more convenient, right?  I mean — why go to all the effort to subject yourself to uncomfortable hormetic practices when you can just pop a tiny, inexpensive gel capsule once day?  Or even if you go in for exercise and intermittent fasting, why not hedge your bets and throw in vitamin D supplementation too, just to strengthen the brew?
Ultimately a decision like this is a personal one.  You can read all the studies and science that’s out there, but each of us has a different way of balancing considerations of risks and effort, science and intuition.  I can’t make that decision for you.  But I’ll leave you with one thought:

The human species has existed on earth for about six millions years, mammals for 160 million years. Basic cellular defense and repair mechanisms, including autophagy, have played an essential role in protecting us against degenerative diseases during most of that history.  Real world stressors act broadly and in a varied manner. And we have evolved to experience these stressors in their full variety. As Art DeVany likes to point out, real world stressors have  ”fractal” pattern that keeps our metabolisms guessing. To the extent that vitamin D is protective against these diseases, it is likely because vitamin D activates the autophagy signaling pathways. But as David Agus notes in the video I linked above, vitamin D hits a single node in the signaling pathway. Supplementation protocols provide the same fixed amount of vitamin D, day in and day out.

Our ancestors did not have access to a highly purified, concentrated vitamin D pills to activate their autophagy at a fixed dosage every day.  They did it the old-fashioned way:  they “earned” their autophagy with natural and varied stressors like intense physical activity and more sporadic access to foods (and foods with lower insulin and mTOR activation potential).  And they got their vitamin D from the sun and certain fatty foods — again in a varied pattern.

This old-fashioned way of activating autophagy is a experiment that has been running for millions of years. Chronic, life-long supplementation with high doses of vitamin D is a relatively recent  innovation. Do you want to be so dependent on a single compound you take every day?  What happens if you are away from civilization for a few days without your vitamins?