Video Blog: Discussing Recent Criticisms of Biological Age Clocks
Is it time to add a custom dose of vitamin D to your Younger You protocols? A small Younger You study from the UK and the importance of D more broadly suggest YES. Don’t miss thoughts on dosing (and some new data showing inadequacy of many dosing recommendations) towards the end of this article.
Not too long ago, vitamin D deficiency surpassed iron deficiency as the most common nutritional deficiency in the world. Importantly, our ability to synthesize, metabolize, and utilize vitamin D is altered as we age, making it especially important to investigate vitamin D status during the aging journey.
With age, we can see dysregulated vitamin D function, in part due to reduced sensitivity of vitamin D receptors to active vitamin D (1,25(OH)D3). That reduced sensitivity can result from an age-related decline in vitamin D receptor gene expression and altered gene expression relating to other enzymes in the vitamin D metabolic pathways, as well as impaired synthesis of vitamin D in the skin.
Vitamin D is ALWAYS top of mind with any patient of our clinic and it’s a workhorse Younger You nutrient (p. 214 in the Younger You book). However, we didn’t require vitamin D supplementation as part of our original study protocol, nor in the follow up published case series and there’s reason to rethink this for our future research. (To be clear, we did allow study participants to continue vitamin D supplementation if they were already taking it – other supplements had to be discontinued for a two week washout period and for the duration of the study – but we didn’t specifically include vitamin D in the protocol)
Pertinent to this (and actually what prompted this blog topic) is a small (proof-of-concept) Younger You study write-up by NetMind Life, a company that helps clients find personalized aging solutions including dietary, lifestyle, supplements and testing. We were excited to learn that their esteemed team of scientists had done this!
You can access the NetMind Life Younger You study write-up here
To summarize what you’ll find in the linked report above, NetMind Life independently initiated a study with four participants who enacted the 8-week Younger You study protocol (aka the Younger You Intensive). All four experienced a significant decrease in the Pace of Aging (Dunedin PACE) clock (the one we currently recommend and use in practice – it’s also available here and to patients who work with our clinic). There was also a trend towards a decline in PhenoAge, which we do also recommend in its non-DNA methylation version based on easily-obtained blood biomarkers as an alternative laboratory assessment where it’s difficult to access the Pace of Aging (i.e. internationally, and for cost reasons). Other measures which we have not used in our research did not change significantly in their small sample – telomere length, GlycanAge and OMICmAge (and they note that the OMICmAge is considered less sensitive to acute variations relative to the Pace of Aging clock).
Firstly, it’s nice to have the additional feedback and data points on the Younger You protocol. But how does this relate to vitamin D? Notably, all the participants in the NetMind group developed vitamin D deficiency over the course of the 8 week program. In contrast to our original study, these individuals stopped their vitamin D supplementation during the program. It is well worth noting that even in this short time frame (and in the context of a cold and dark London winter), vitamin D levels appeared to drop alarmingly, without supplementation.
It seems important to explore (and underscore) the relevance of vitamin D in light of this experience.
Pleiotropic Effects of Vitamin D in the Body
Let’s start with a brief recap – We already know that vitamin D has wide ranging impact in the body, including on:
- Bone: Higher levels of circulating vitamin D (as 25-OH-D) are associated with better bone health over time, likely due to vitamin D’s ability to promote osteoblast (bone forming cell) activity and reduce bone turnover.
- Muscle: Mounting evidence indicates that vitamin D supports the energy-producing capacity of mitochondria in muscle cells and plays a role in muscle repair and regeneration. Since the heart is also a muscle, it’s perhaps one reason why vitamin D deficiency has been associated with worse cardiovascular health.
- Immune System: The effects of vitamin D on the immune system include the production of antimicrobial peptides (with subsequent impact on microbiome patterns) and the regulation of inflammation via macrophages and T regulatory cells. Although we normally think of the liver and kidney as the sites of vitamin D activation, immune cells such as macrophages actually also have the capacity to do so, suggesting the essentiality of vitamin D in their activity.
- DNA Integrity: Vitamin D deficiency is a predictor of genomic instability and DNA damage. Vitamin D sufficiency is also (one of the limited known factors) associated with better preservation of DNA telomere length.
- Epigenetics and Gene Regulation: Where would we be without a consideration of the effects of vitamin D on epigenetics and gene regulation? Approximately 3 percent of DNA is thought to be regulated in part by vitamin D. Let’s look a little deeper at vitamin D’s influence on the epigenome…
Vitamin D as Epinutrient – Its Influence on Epigenetic Mechanisms
Vitamin D is known to be a nuclear hormone, meaning it has activity in the cell nucleus, interacting with our DNA/chromatin. One way in which it exerts these effects is in the binding of the active form of vitamin D (1,25-hydroxyvitaminD) with vitamin D receptors (VDRs), which can then join with vitamin D responsive elements (VDREs) on the genome. Often this binding takes place up- or downstream of the transcription start site of target genes and alters gene expression by interacting with transcriptional machinery.
But vitamin D also interacts with other known epigenetic mechanisms including acetylation and methylation. Vitamin D-VDR complexes have been shown to alter histone acetyltransferase (HAT), histone methyltransferase (HMT) and DNA methyltransferase (DNMT) activity. The latter (DNMT) appears to be potentially selectively-inhibitory, similar to the activity of certain phytonutrients, especially polyphenols.
Of course, this begs the question – does vitamin D then have any effect on DNA methylation-based clocks? Early research suggests yes –
Vitamin D and DNA Methylation-based Epigenetic Age
One of the very first studies that looked at interventions that might shift epigenetic (DNA methylation-based) age used vitamin D (Chen et al., 2018). We read this paper with interest as we were in the process of conducting our initial clinical trial when it was published. In their paper, Chen and colleagues described how doses of 4,000 IU per day of vitamin D3 for 16 weeks were associated with an average 1.85 year decrease in the Horvath DNAm (DNA methylation) clock. The population they studied was overweight/obese African Americans with deficient vitamin D status (<50 nmol/L).
In 2020 and 2022, two papers were published by scientists in Europe who looked at correlations in larger cross-sectional population data from the Berlin Aging Study II. In the 2020-published analysis they found that individuals who had vitamin D sufficiency (defined as having 25(OH)D levels above 50 nmol/L) had an average Horvath DNAm-based age 1.4 years below their vitamin D insufficient/deficient counterparts. Several of the same scientists subsequently published a follow up paper in 2022 using longitudinal data 7.4 years after the original cross-sectional data. In this second publication, vitamin D deficient participants in the original cohort who chose to start vitamin D supplementation had an average 1.3 year reduction in Horvath DNAm age.
Vitamin D and Other Hallmarks of Aging
A recently-published review paper summarized the potential impact of vitamin D on the hallmarks of aging, as indicated by clinical evidence. Those hallmarks where vitamin D has been shown in humans (i.e., clinical data) to have an influence are indicated on the right of the graphic below. The thickness of the lines relates to the amount of available evidence. There are also other preclinical data that link vitamin D to other hallmarks such as intercellular communication which are not shown here. The authors then made correlations between the hallmarks of aging and diseases of aging, based on the preclinical data that are so far available, shown on the left of the graphic:
Image Source: Ruggiero et al, 2024.
How Much Vitamin D?
In our practice, we generally target a serum vitamin D (25-OH-D) range of at least 40-60 ng/mL, although we consider 50-70 ng/mL for individuals with certain conditions such as autoimmunity, cardiovascular disease, cognitive decline, and cancer, and where kidney function is normal. As a side note, it’s always important to think of vitamin K too, alongside vitamin D (in particular K2) since it’s essential for the additional calcium absorbed due to vitamin D to be deposited in bone, not soft tissue such as the vascular lining.
Recent scientific publications have underscored what we have seen in practice – that the amount of vitamin D supplementation needed to maintain optimal vitamin D levels varies significantly from one person to the next: In two abstract studies presented at the American Heart Association’s Scientific Sessions in November 2023, researchers reported on their analysis of the Target-D study, in which 316 patients initiated vitamin D supplementation and the dose tailored to raise 25-OH-D levels to at least 40 ng/mL. Of these, 86.5% required more than 2,000 IU of vitamin D daily and 14.6% required more than 10,000 IU daily to achieve target levels. Aside from the need to significantly exceed the 600 – 800 IU RDA in most cases, these findings suggest that dosing in many vitamin D intervention studies (as well as clinical recommendations) is inadequate.
2,000 IU is a commonly-used level of vitamin D dosing in research studies. However, analysis of data from the Target-D study illuminates the need for custom dosing, higher than 2,000 IU for the majority of individuals, to reach target 25-OH-D levels.
The bottom line – testing (and repeat testing) is essential. And vitamin D should always be a consideration within the Younger You program.
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