Hypervitaminosis D and premature aging

For a great many years the medical establishment warned everyone of dire consequences that could result from taking large doses of vitamin D.  The daily maximum of 400iu was the strict acceptable limit to avoid vitamin D toxicity.  In recent years the consensus of the medical establishment has flipped as a result of many studies showing dire consequences of too little vitamin D and strong benefits of taking it as a supplement.  As I state in my treatise “A recent eight-year study of 3,258 men and women  indicates that the higher the blood level of Vitamin D, the less is the chance of dying from heart disease – and the less the chance of dying from a number of other diseases as well.”  — “Today there are over 80 population and laboratory studies indicating that vitamin D can reduce incidences of and mortality due to multiple kinds of cancer with reductions of 50% or more in some cases.  The biological impact of this substance is far from simple; it activates 200 or more human genes and has differential affects in regulating cancer cells with respect to cell proliferation, apoptosis and differentiation.  It also regulates angiogenesis.  Several studies of nursing home and residential care residents show that people taking vitamin D supplements suffer fewer falls – the reduction being between 23% to 53%.  And I have already mentioned Vitamin D’s role with respect to reducing heart disease fatalities.   Daily doses of 1,000 or 2,000iu are now thought to be harmless and often recommended for older people.“  Advising people to take even larger doses is not unusual now.

There is a possibility the viewpoint may be flipping again, at least for patients with certain genetic defects.  Mouse studies suggest that excess levels of vitamin D under certain situations may lead to premature aging.   The concern is current.  The 2009 publication Vitamin D and aging states “Recent studies using genetically modified mice, such as FGF23-/- and Klotho-/- mice that exhibit altered mineral homeostasis due to a high vitamin D activity showed features of premature aging that include retarded growth, osteoporosis, atherosclerosis, ectopic calcification, immunological deficiency, skin and general organ atrophy, hypogonadism and short lifespan. The phenotype reversed by normalizing vitamin D and/or mineral homeostasis.” 

The story is also summarized in the abstract of the 2006 publication Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice. “The essential role of low levels of vitamin D during aging is well documented. However, possible effects of high levels of vitamin D on the aging process are not yet clear. Recent in vivo genetic-manipulation studies have shown increased serum level of vitamin D and altered mineral-ion homeostasis in mice that lack either fibroblast growth factor 23 (Fgf23) or Klotho (Kl) genes. These mice develop identical phenotypes consistent with premature aging. Elimination or reduction of vitamin-D activity from Fgf23 and Kl mutant mice, either by dietary restriction or genetic manipulation could rescue premature aging-like features and ectopic calcifications, resulting in prolonged survival of both mutants. Such in vivo experimental studies indicated that excessive vitamin-D activity and altered mineral-ion homeostasis could accelerate the aging process.”  

So, these studies have led me to inquire about what is involved and what is the danger of taking 2000 to 4000iu of vitamin D3 a day as I have personally been doing.  My bottom line is that you should be particularly concerned if you are a Klotho-knockout mouse, a FGF23 knockout mouse or a vitamin D receptor knockout mouse.  If you happen to be in one of the first two categories,  you may be able to live longer by immediately ceasing to take vitamin D supplements.  Also, you could have a Hypervitaminosis D problem if your natural FGF23 or Klotho expression is sub-par.

My remarks are based on the fact that the vitamin D research is based on experiments with Klotho knockout and FGF23 knockout (FGF23-/- and Klotho-/-) mice.   Conceivably, similar D hypervitaminosis could happen in people with Klotho or FGF23 deficiencies.  See the recent post Klotho anti-aging gene in the news.  I have reviewed the following papers which describe mouse studies on laboratory animals with the characteristics in parentheses:

The 1997 paper Mutation of the mouse Klotho gene leads to a syndrome resembling ageing (mutated Klotho gene)

The 2002 publication Association of human aging with a functional variant of Klotho (mutated Klotho gene)

The 2004 paper Klotho is a serum factor related to human aging (FGF23 null mice)

The 2006 publication Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process (FGF23 null mice)

The 2006 paper Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals (FGF23 null mice)

The 2006 publication Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice (FGF23 null or Klotho null mice)

The 2007 paper Premature aging in Klotho mutant mice: cause or consequence? (FGF23 null or Klotho null mice)

The 2008 paper FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis (FGF23 null or Klotho null mice)

The 2009 publication Vitamin D and aging (FGF23 null or Klotho null mice) 

All these studies related to Hypervitaminosis D were based on working with mice in which either Klotho or FGF23 or both were knocked out.  It seems that when the transduction pathways initiated by FGF23 and Klotho are working well, apoptosis caused by excessive systemic vitamin D and resulting tissue atrophy is avoided.    

Another  2009 study is of particular interest because the mice were ones with the vitamin D receptor knocked out instead of Klotho or FGF23. The publication Premature aging in vitamin D receptor mutant mice  (vitamin D receptor (VDR) knockout mice)  states “Overall, VDR KO mice showed several aging related phenotypes, including poorer survival, early alopecia, thickened skin, enlarged sebaceous glands and development of epidermal cysts.”  “Since the phenotype of aged VDR knockout mice is similar to mouse models with hypervitaminosis D(3), our study suggests that VDR genetic ablation promotes premature aging in mice, and that vitamin D(3) homeostasis regulates physiological aging.”   

Knocking out VDR seems capable of producing the same pro-aging affect as hypervitaminosis D(3).  I believe the conclusion that “vitamin D(3) homeostasis regulates physiological aging” could be of profound importance if it is born out. 

Since I have normal Klotho and FGF23 expression as far as I know, I am not personally worried about Hypervitaminosis D at the moment.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com. Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.
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5 Responses to Hypervitaminosis D and premature aging

  1. singularityFan says:

    Hi Vince,

    It is unfortunate seeing such a low number of comments on this blog and the low exposure it seems to be getting.

    I have told many of my friends, mostly medical students, about it.

    I don’t think that they have yet the education to appreciate the depth and quality of this research, but hopefully it will help spread the word and maybe get a few of them interested it in biomedical gerontology.

    All the best, and keep up the spectacular work!

  2. admin says:


    Many thanks for the encouraging comment. I too have been concerned about the relatively low level of comments on this blog. It seems there are many readers who don’t comment. The ISP that hosts the blog keeps good daily statistics and it appears that on a typical day 600-1000 different readers go on the blog and visit at least two different pages. Usage is slowly rising month-by-month. Apparently exposure is slowly increasing due to word-of-mouth communication like you have been doing. I do appreciate you telling yopur friends about it.

    For me personally, the work on the blog and treatise and the underlying research has become a passion. If I have to miss a day of working on it because of other things in my life, it is painful.


  3. TH says:

    Don’t worry Vince, I rarely comment just because my education is usually too low to add something valuable on the material you publish, I’m sure many other readers feel the same, but you can be sure there’s a HUGE appreciation of your work on this. It’s a great great blog, I try to spread the word too when I have a chance. Best of luck to you!

  4. Katerina Geronian says:

    I also rarely comment just because of lack of time. But your blog is so well organized and has such an exceptional scientific quality which should be well appreciated by both general and professional targets. Thank you for your efforts and all the best to you!
    Katerina Geronian

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