Vitamins, supplements and telomerase – upregulation or downregulation?

It seems like scarcely a day goes by now without new telomerase research news items showing up in the popular press, the latest having to do with fish oil.  I mention this news here but my purpose is to make a few broader points:

1.      Taking a number of popular supplements in the anti-aging firewalls Supplement Regimen like Vitamin E, fish oils, Vitamin D3 and resveratrol can lead to telomeres being longer than they otherwise might be, possibly because they induce the production of telomerase, possibly for other reasons.  As such, these supplements are quite possibly life-extending.

2.     Despite the popular conception, telomere lengths do not uniformly get shorter with advancing age.  Sometimes they get longer over substantial periods of time.  Nobody is quite sure of how or why.

3.     Many of the same supplements that lead to longer telomeres in healthy people seem to have the capacity to turn off telomerase and shorten telomeres in cancer cells and help kill them.

Fish Oil and longer telomeres

Yesterday’s news is based on a January 20 publication in JAMA: Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease.  “Context  Increased dietary intake of marine omega-3 fatty acids is associated with prolonged survival in patients with coronary heart disease. However, the mechanisms underlying this protective effect are poorly understood. ^— Objective  To investigate the association of omega-3 fatty acid blood levels with temporal changes in telomere length, an emerging marker of biological age. ^— Design, Setting, and Participants  Prospective cohort study of 608 ambulatory outpatients in California with stable coronary artery disease recruited from the Heart and Soul Study between September 2000 and December 2002 and followed up to January 2009 (median, 6.0 years; range, 5.0-8.1 years). ^— Main Outcome Measures  We measured leukocyte telomere length at baseline and again after 5 years of follow-up. — Results  Individuals in the lowest quartile of DHA+EPA experienced the fastest rate of telomere shortening (0.13 telomere-to-single-copy gene ratio [T/S] units over 5 years; 95% confidence interval [CI], 0.09-0.17), whereas those in the highest quartile experienced the slowest rate of telomere shortening (0.05 T/S units over 5 years; 95% CI, 0.02-0.08; P < .001 for linear trend across quartiles). –. Each 1-SD increase in DHA+EPA levels was associated with a 32% reduction in the odds of telomere shortening (adjusted odds ratio, 0.68; 95% CI, 0.47-0.98). ^— Conclusion  Among this cohort of patients with coronary artery disease, there was an inverse relationship between baseline blood levels of marine omega-3 fatty acids and the rate of telomere shortening over 5 years.”

The temptation is to conclude that “taking fish oils leads to less telomere length shortening,” but that is not what the study says.  The conclusions of this study are based on levels of DHA and EPA measured at baseline and do not take possible supplementation during the study period into account.  Further, the study population was a very special one, people with coronary artery disease.  Another temptation is to conclude that fish oil leads to the expression of telomerase, but this conclusion is also not directly supported.  The study does not say why the rate of telomere shortening was less in those with higher baseline levels of the fish oils.  Nontheless, the popular press has yielded to these temptations with news story titles like Is Fish Oil the Elixir of Life? And  Stay young by eating fish oil, say scientists. I chalk this up to a general hunger in the population for anti-aging news.  And now, after Blackburn, Greider and Szostak  have received a Nobel prize for work on telomeres and telomerase, it is almost household news that longer telomeres are associated with longevity and are better for health.

Natural telomere lengthening with age

The report on omega-3 fish oils and telomeres was preceded two weeks ago by another PLoS ONE report based on data for the same 608 individuals in the Heart and Soul Study Telomere length trajectory and its determinants in persons with coronary artery disease: longitudinal findings from the heart and soul study.  “METHODOLOGY/PRINCIPAL FINDINGS: In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline, and again after five years of follow-up. We used multivariable linear and logistic regression models to identify the independent predictors of leukocyte telomere trajectory. Baseline and follow-up telomere lengths were normally distributed. Mean telomere length decreased by 42 base pairs per year (p<0.001). Three distinct telomere trajectories were observed: shortening in 45%, maintenance in 32%, and lengthening in 23% of participants. The most powerful predictor of telomere shortening was baseline telomere length (OR per SD increase = 7.6; 95% CI 5.5, 10.6). Other independent predictors of telomere shortening were age (OR per 10 years = 1.6; 95% CI 1.3, 2.1), male sex (OR = 2.4; 95% CI 1.3, 4.7), and waist-to-hip ratio (OR per 0.1 increase = 1.4; 95% CI 1.0, 2.0). CONCLUSIONS/SIGNIFICANCE: Leukocyte telomere length may increase as well as decrease in persons with coronary artery disease. Telomere length trajectory is powerfully influenced by baseline telomere length, possibly suggesting negative feedback regulation. Age, male sex, and abdominal obesity independently predict telomere shortening.”

Note that this is not the first study to show average telomere length increasing for a substantial part of the study population over a substantial period of time. According to a large Swedish study, a third of the population experienced telomere lengthening over 9 to 11 year intervals(ref).

Fish Oil, other supplements and turning off telomerase in cancers

According to the 2005 report Polyunsaturated fatty acids inhibit telomerase activity in DLD-1 human colorectal adenocarcinoma cells: a dual mechanism approach “We investigated the inhibitory effect of various fatty acids on telomerase, with particular emphasis on those with antitumor properties, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).  – In contrast, cis-unsaturated fatty acids significantly inhibited the enzyme, and the inhibitory potency was elevated with an increase in the number of double bonds. Accordingly, polyunsaturated fatty acids (PUFAs), like EPA and DHA, appeared to be powerful telomerase inhibitors. — Culturing DLD-1 cells with either EPA or DHA resulted in a remarkable decrease in telomerase activity. EPA and DHA inhibited telomerase by down-regulating human telomerase reverse transcriptase (hTERT) and c-myc expression via protein kinase C inhibition. These results indicate that PUFAs can directly inhibit the enzymatic activity of telomerase as well as modulate the telomerase at the transcriptional level.” 

So there we have it.  The same DHA and EPA fish oils that seem to be correlated with longer telomeres in the recent population study also clobber telomerase in a cancer cell line.  This property seems to be shared by several other popular supplements as well. 

Alpha-tocopherol (Vitamin E) seems to repress age-related telomere shortening(ref). Yet, the 2007 study Vitamin E suppresses telomerase activity in ovarian cancer cells concludes “Our data suggest that, by suppressing telomerase activity, Vitamin E may be an important protective agent against ovarian cancer cell growth as well as a potentially effective therapeutic adjuvant.”  

Another supplement that is both associated with longer telomere lengths and that inhibits telomerase expression in cancer cells is Vitamin D3.   The 2007 paper Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women reports ”Serum vitamin D concentrations were measured in 2160 women aged 18–79 y (mean age: 49.4)  – Serum vitamin D concentrations were positively associated with LTL (longer telomere length) (r = 0.07, P = 0.0010), and this relation persisted after adjustment for age (r = 0.09, P < 0.0001) and other covariates (age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity; P for trend across tertiles = 0.003). The difference in LTL between the highest and lowest tertiles of vitamin D was 107 base pairs (P = 0.0009), which is equivalent to 5.0 y of telomeric aging.” Yet, D3  is another substance that can help inhibit the expression of telomerase in cancer cells as pointed out in the 2003 publication Combination treatment with 1alpha,25-dihydroxyvitamin D3 and 9-cis-retinoic acid directly inhibits human telomerase reverse transcriptase transcription in prostate cancer cells.  Also, see Induction of Ovarian Cancer Cell Apoptosis by 1,25-Dihydroxyvitamin D3 through the Down-regulation of Telomerase.

Resveratrol is another supplement substance that seems to have a dual personality, on the one hand associated with enhancing telomerase activity in healthy cells(ref)(ref) and on the other hand inhibiting expression of telomerase in cancer cells(ref)(ref).   

The active ingredient in green tea EGCG appears to be yet another dietary substance with the dual personality characteristic.  Drinking ample quantities of green tea appears to slow down age-dependent telomere shortening on the one hand(ref),  and EGCG represses telomerase expression in cancer cells(ref)(ref).  I am sure the same point can be made for other substances in the anti-aging supplement regimen.

Telomerase regulation is in fact a very complex process(ref).   As I have put it in my treatise “These results suggests to me that telomere shortening is a complex process involving a balance of shortening due to cell division, lengthening due to natural telomerase expression and perhaps cell replacement due to differentiation of stem cells. And these in turn are affected by many lifestyle and dietary factors and moderated by cell-signaling feedback loops.” 

Yet, it could well be the case that management of telomere length is our best hope for realizing extraordinary longevity in the nearer future.  The 12^th theory of aging in my treatise Telomere Shortening and Damage forwards the hypothesis that longer telomere lengths are likely to be correlated with longer lifespans and that keeping one’s telomeres as long as possible through expression of telomerase is vital for health and longevity. Telomeres and telomerase are among my favorite subjects for treatment in this blog.  Among the many relevant blog postings are the recent postings Exercise, telomerase and telomeres, Timely telomerase tidbits, Breakthrough telomere research finding, and Telomere and telomerase writings. And, as time proceeds, I expect there will be more.

This entry was posted on 22. January 2010 at 06:16 and is filed under Uncategorized. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response or trackback from your own site.