vitamin D assoc with less telomere shortening

 A recent study found that vitamin D supplementation was associated with less telomere shortening, which could foretell deceasing aging effects and associated severe diseases, in a pre-publication paper (see vit d longer telomeres  AmJClinNut2025 in dropbox, or DOI: 10.1016/j.ajcnut.2025.05.003)

 

Details:

-- this current study was part of the VITAL study (Vitamin D and Omega-3 trial), a large, randomized, double-blind, placebo-controlled trial with a 2x2 factorial design of vitamin D₃ 2000IU/d (equivalent to 50mcg) and/or marine n-3 fatty acids (n-3 FAs) 1 gm/d for 5 years. randomization was from 2011 to 2014, with intervention until the end of 2017

-- the overall study included 25,871 US females aged at least 55yo and males aged at least 50yo

-- the VITAL Telomere study, which included 1054 participants, was designed to assess the effect of these supplements on leukocyte telomere length (LTL)

    -- LTL was assessed by the (excuse the very long name) Absolute Human Telomere Length Quantification Quantitative Polymerase Chain Reaction method...., done at baseline, year 2 and year 4

 

-- mean age 65, 50% female, 85% white/8% Black, BMI 28

-- current smoking 5%; meds for hypertension in 41%, diabetes in 9%; hyperlipidemia in 35%

-- baseline 25(OH)D levels 28 ng/mL; but 84% had levels <20ng/ml

-- baseline n-3 FA% (a measure of omega-3 fatty acids) 3%

-- baseline BP 124/76

-- baseline LTL 8.7 kilobase pairs (kb)

 

-- Three adjusted models were assessed:

    -- model one: adjusted for randomization group for the other supplement (intention-to-treat assessment)

    -- model two: (primary analysis) adjusted for age, sex, race, and BMI in addition to model one

    -- model three: further adjusting for smoking, and taking medications for hypertension, diabetes, and high cholesterol

 

-- prespecified primary outcomes: changes in LTL between baseline, year 2, and year 4

-- median treatment of 5.3 years

 

Results:

-- yearly questionnaire response rates averaged 93% and mortality follow-up rate exceeded 98%

-- 80% of participants reported taking at least two-thirds of their study capsules

-- LTL was measured in a total of 2571 samples from the 1031 participants

-- LTL and vitamin D supplementation as compared to placebo:

    -- vitamin D supplementation at year 4: decreased LTL attrition by 0.14 kilobase pairs (0.01-0.27), p=0.039 (ie, a decrease of 140 base pairs)

    -- overall trend per year, per the adjusted models as noted above:

        -- model one: LTL's were 0.034 kilobase pairs higher with vitamin D, vs placebo (0.002-0.07), p=0.039

        -- model two: LTL's were 0.035 kilobase pairs higher vs placebo (0.002-0.07), p=0.037

        -- model three: LTL's were 0.04 kilobase pairs higher vs placebo (0.005-0.07), p=0.025

 

-- LTL and n-3 FAs supplementation as compared to placebo: none of these models were statistically significant

 

-- subgroup analyses, per the effect on the 4-year change by vitamin D supplementation, by subgroups:

    -- age less than median 64.4yo versus higher: P= 0.038

    -- nonsmokers: P= 0.002

    -- nonobese (BMI<30): P= 0.03

    -- baseline 25(OH)D <20 ng/mL: P=0.03

    -- baseline lower omega-3 index of 2.7%, P=0.005

    -- not being on high cholesterol medication: P=0.003

    -- having diabetes: P=0.025

    -- having hypertension: P= 0.012

   

 -- no significant interaction between vitamin D and n-3 FA supplementation

   

 

Commentary:

-- telomeres are specialized chromatin structures at each end of the chromosome; they protect chromosome integrity and stability, including from inappropriate chromosomal recombinations

    -- telomeres do naturally shorten with every cell cycle; cells with critically short telomeres have replicative senescence, mitochondrial dysfunction and cell death (apoptosis), likely leading to human tissue and organ degeneration and dysfunction, and somatic aging: https://link.springer.com/article/10.1007/s10522-018-9769-1

        -- this telomere shortening is thought to decrease chromosome stability and increase the risks for chronic diseases, including cancer, cardiovascular disease, and cognitive decline, as well as overall mortality (short telomeres are associated with decreased longevity and serve as a marker of aging)

-- leukocyte telomere length (LTL) integrates genetic factors and the cumulative effects of environmental, lifestyle, and nutritional factors through human life

-- of particular note, the telomere regions of the chromosome are particularly sensitive to oxidative stress and are less efficiently repaired when there are single-stranded breaks or ultraviolet -induced damage

-- vitamin D deficiency itself is associated with elevated DNA damage, particularly in patients with hyperglycemia and cancer. And there are some suggestive data in the literature the vitamin D helps protect against DNA damage (references to these studies are noted in the article)

  

-- Prior studies have found that both vitamin D and omega-3 fatty acids provide an array of vital cellular processes, including cellular differentiation, proliferation, and apoptosis and therefore could be helpful in preventing age-related chronic diseases. however, these results are not consistently found in studies

    -- the TwinUK study of 2160 females did find that a higher vitamin D level as assessed by serum 25(OH)D was associated with longer LTL, with that longer LTL being of equivalent magnitude as found in 5 years of chronologic change

    -- the Nurses Health Study of 1424 females also found a positive relationship between LTL and serum 25(OH)D levels

    -- the US NHANES epidemiologic study from 2001-2002 found that a 25(OH)D level higher than 50 nmol/L (equivalent to 20 ng/mL) versus a lower number was associated with a 0.13 kilobase pair longer LTL (P=0.01), 0.13 kb being equivalent to 130 base pairs: https://pubmed.ncbi.nlm.nih.gov/28179486/

    -- a 12-month Chinese study of 183 patients at least 65-year-old with mild cognitive impairment found that vitamin D supplementation increased LTL, associated with clinically improved cognitive function and reduced oxidative stress: https://pubmed.ncbi.nlm.nih.gov/33164936/

-- a secondary analysis of the VITAL trial found that supplemental vitamin D reduced the risk of advanced cancer (metastatic or fatal) by 17%, with the strongest reduction in those with normal weight; there was no benefit from the omega-3 fatty acids  https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2773074 (for my evaluation of the study, see https://gmodestmedblogs.blogspot.com/2020/12/vitamin-d-coffee-decreases-advanced.html )

-- another secondary assessment of the VITAL study found a 22% decreased risk of all incident autoimmune diseases with vitamin D supplementation and a non-statistically significant 15% decrease by omega-3 fatty acids: https://gmodestmedblogs.blogspot.com/2022/02/vitamin-d-and-omega-3-dec-autoimmune.html . LTL is also considered a biomarker of future aging of the immune system (immunosenescence), which may be an important link to autoimmune diseases, cancer, and several other chronic diseases. And telomere length reductions have been found in some other studies to be associated with more rapidly increased development of autoimmune diseases. Shortened  LTL’s have been found in patients with lupus and  rheumatoid arthritis, as well as inflammatory bowel disease, psoriasis, spondyloarthritis and uveitis

-- in this light, this current study was done in a large randomized controlled trial to assess the potential role of vitamin D and omega-3 fatty acids in reducing telomere shortening over a five-year period

-- this study found that supplementation with 2000IU of vitamin D3 was associated with reduced telomere attrition by 0.14 kilobase pairs (ie 140 base pairs) over a 4-year period

-- but there was no association with taking omega-3 fatty acids at either year 2 or year 4, or in the overall trend of change.

-- there was no interaction statistically between vitamin D3 and n-3 fatty acid supplementation on LTL (P=0.527). A prior study found that 510 participants havd an average 460 base pair decrease in LTL over 10 years; this finding would translate in the current study to LTL preservation by vitamin D supplementation of a 3-year decrease in aging by the 140 base pair change that they found (https://doi.org/10.1093/ije/dyp273 )

-- the presumed mechanism for vitamin D benefit has to do with its antiproliferative, anti-inflammatory, and apoptotic properties

    -- a small placebo-controlled trial of 16 weeks of vitamin D supplementation equivalent to 2000 IUs per day in an overweight population found that mononuclear cell telomere activity increased by 19.2% from baseline versus placebo.

        -- another analysis of the VITAL study found that vitamin D was associated with a decrease in the high-sensitive C-reactive protein levels by 19% at year 2

-- of note, taking cholesterol medications was inversely associated with LTL benefit in the current study. There are findings in the medical literature that statins decreases the 25(OH)D levels in those on supplemental vitamin D, with a 21% smaller increase in 25(OH)D levels than non-statin users after 12 months (ie, if repleting vitamin D levels in those on statins, one should check their 25(OH)D levels to make sure they are at goal)

-- and, the issue with vitamin D having a less profound effect in those who had higher adiposity could be related to the fact that vitamin D is a fat-soluble vitamin and may be more sequestered into the more prevalent fat tissue in these individuals, thereby reducing its bioactivity; and meta-analyses have suggested that obesity itself is associated with more aggressive LTL shortening

 

Limitations:

-- this was a pre-publication paper and not peer-reviewed, and it potentially has some uncorrected errors

-- the majority of enrolled people were white, limiting generalizability to others

-- though there was no benefit found from omega-3 fatty acids, this might be related to the fact that 37% of the participants in this group were missing LTL data at year 4 follow-up, decreasing the statistical power for this assessment.

-- the subgroup analyses had limited statistical power and should be considered exploratory and interpreted with caution

-- this study was done as a post hoc analysis of a completed randomized controlled trial, and was not designed specifically to assess telomere changes, reducing it statistical rigor

-- diabetes was considered a binary item (yes/no) which makes it hard to understand fully, since the effects of supplements in patients with hemoglobin A1c of 6.5% may well be different from one of 13%, but not significantly different than 6.4%

-- the information on medication adherence is self-reported and subject to error

 

So how do we put this all together?

-- It is pretty clear by many studies that decreasing telomere length is associated with aging

    -- the effects on health also seem to be rather broad with studies suggesting decreased longevity as well as potentially increased cancer, immunologic diseases, cognitive impairment/Alzheimer’s disease, etc (https://pmc.ncbi.nlm.nih.gov/articles/PMC7029372/ ).

    -- as we know, vitamin D receptors are on essentially every cell in the human body (though not red cells), including several components of the immune system (ie, they are likely present so extensively for some evolutionary reason, or they would likely have decreased over time)

-- and, especially those of us working in the more northern climates in the US and elsewhere with less intense sun exposure, 25(OH)D levels are often quite low (probably 10% of my patients have undetectable levels and the great majority have levels well below 20ng/ml)

-- the risk of vitamin D toxicity is very low unless people take exorbitant amounts of vitamin D, leading to 25(OH)D levels >150 ng/mL (https://www.ncbi.nlm.nih.gov/books/NBK557876/ )

-- given the relationship between statins and decreased 25(OH)D levels in those on vitamin D supplementation, it is especially important for us to assess their 25(OH)D to make sure the supplementation is adequate

-- so, reasonable up-side to having appropriate vitamin D levels, and minimal down-side.....

geoff

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