Protocol development in integrative medicine is not typically a simple process. Individuals require individualized care, and what works for one patient may not work for another.
To establish these protocols, we first developed a Rating Scale that could be used to discern the rigor of evidence supporting a specific nutrient’s therapeutic effect.
The following protocols were developed using only A through C-quality evidence.
Global life expectancy has been increasing over the last few decades. During this time the rate of age-related diseases has been increasing as well. (15) Improving quality of life and longevity is essential to having a full healthy and vibrant community of aging adults.
Different biomarkers, such as oxidative stress and vitamin D status, may provide insight into risk of developing a chronic disease at an older age. For example, increased levels of oxidative stress are associated with frailty and sarcopenia in geriatric populations. (2) Vitamin D status can act as an indicator for possible ill health when aging. (4) Telomere length and integrity have been found to correlate with all-cause mortality. (17) Therefore, addressing a range of age-associated biomarkers and risk factors is key in increasing life expectancy and improving quality of life in later years.
Due to the nature of this protocol focusing on all-cause mortality, telomere length, and long-term risk reduction, the supportive research selected below primarily focuses on systematic reviews, meta-analyses, and/or observational cohort studies.
Multivitamin formulation, minimum 8 weeks (9)
- Multivitamin use was associated with a 5.1% longer telomere length of leukocyte DNA in women aged 35 to 74 (18)
- Multivitamins containing a combination of minerals and herbs improved ratings of calmness and decreased perceived mental stress in healthy women aged 50-75 years within a few hours after administration (13)
- Multivitamin supplementation in elderly women was associated with an increase in inhibitory neural processes, indicating a possible improvement in neural efficiency during memory retrieval (14)
- Multivitamins were shown to improve alertness, daily functioning, and mood according to overall score on depression, anxiety, and stress scale in men aged 50-69 years old (9)
Omega-3 fatty acids
- Omega-3 PUFAs in middle to late aged adults decreased inflammation as demonstrated by reductions in IL-1β, TNF-α, and IL-6 (16)
- Improved inflammation, immune cell aging, and decreased oxidative stress by 15% in healthy sedentary overweight middle-aged and older adults; Additionally telomere lengths were found to increase when omega 6 to omega-3 ratios decreased (11)
- Meta-analysis of 13 RCTs found marine-sourced omega-3 supplementation was associated with decreased risk of myocardial infarction, coronary heart disease, cardiovascular disease, and related mortality, in a dose-dependent fashion (10)
Green tea (Camellia sinensis)
- Cohort analysis of 313,381 subjects followed for a mean of 17.3 years found that high consumption of green tea (≥ 5 cups/day) decreased all-cause mortality; moderate consumption (3-4 cups per day) decreased respiratory- and cancer-related mortality (1)
- Systematic review and meta-analysis of 39 cohort studies found that for each cup of tea consumed (estimated 338 mg total flavonoids), there was a decreased risk of CVD mortality (4%), CVD events (2%), stroke (4%), and all-cause mortality (1.5%) (6)
- Green tea extract modulated inflammation by improving total antioxidant status, myeloperoxidase and lactoferrin release (12)
Minimum 800-2000 IU/day
- Systematic review and meta-analysis of 52 trials found a decrease in all-cause mortality with vitamin D3 supplementation and a decrease of 16% for risk of cancer death (20)
- Meta-analysis of 159 trials found vitamin D3 to decrease mortality in independently living and institutionalized care elderly (3)
- Systematic review and meta-analysis of 73 cohort studies and 22 randomized controlled trials found an inverse association of vitamin D levels with risk of cardiovascular disease, cancer, and all-cause mortality; supplementation decreased overall mortality in older adults (5)
- Meta-analysis of 42 randomized controlled trials found a decrease in all-cause mortality when supplemented long term (3 years or more) (21)
Variable based on each B vitamin and form
- Systematic review and meta-analysis of 18 articles found supplement decreased stress status in healthy and at-risk populations (those at risk for poor nutrient status or poor mood status) (19)
- Long term supplementation (2 years) of B-complex improved health-related quality of life in older adults with elevated homocysteine (7)
- Total plasma homocysteine was found to be 30% lower than placebo when supplemented long-term (2 years) with B-complex in patients with mild cognitive impairment; cognitive decline also slowed and executive function stabilized (8)
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- Abe, S. K., Saito, E., Sawada, N., Tsugane, S., Ito, H., Lin, Y., Tamakoshi, A., Sado, J., Kitamura, Y., Sugawara, Y., Tsuji, I., Nagata, C., Sadakane, A., Shimazu, T., Mizoue, T., Matsuo, K., Naito, M., Tanaka, K., Inoue, M., & Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan. (2019). Green tea consumption and mortality in Japanese men and women: a pooled analysis of eight population-based cohort studies in Japan. European Journal of Epidemiology, 34(10), 917–926. https://pubmed.ncbi.nlm.nih.gov/31392470/ (C)
- Belenguer-Varea, Á., Tarazona-Santabalbina, F. J., Avellana-Zaragoza, J. A., Martínez-Reig, M., Mas-Bargues, C., & Inglés, M. (2020). Oxidative stress and exceptional human longevity: Systematic review. Free Radical Biology & Medicine, 149, 51–63. https://pubmed.ncbi.nlm.nih.gov/31550529/ (A)
- Bjelakovic, G., Gluud, L. L., Nikolova, D., Whitfield, K., Wetterslev, J., Simonetti, R. G., Bjelakovic, M., & Gluud, C. (2014). Vitamin D supplementation for prevention of mortality in adults. Cochrane Database of Systematic Reviews , 1, CD007470. https://pubmed.ncbi.nlm.nih.gov/24414552/ (A)
- Caristia, S., Filigheddu, N., Barone-Adesi, F., Sarro, A., Testa, T., Magnani, C., Aimaretti, G., Faggiano, F., & Marzullo, P. (2019). Vitamin D as a Biomarker of Ill Health among the Over-50s: A Systematic Review of Cohort Studies. Nutrients, 11(10). https://pubmed.ncbi.nlm.nih.gov/31590434/ (A)
- Chowdhury, R., Kunutsor, S., Vitezova, A., Oliver-Williams, C., Chowdhury, S., Kiefte-de-Jong, J. C., Khan, H., Baena, C. P., Prabhakaran, D., Hoshen, M. B., Feldman, B. S., Pan, A., Johnson, L., Crowe, F., Hu, F. B., & Franco, O. H. (2014). Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ , 348, g1903. https://pubmed.ncbi.nlm.nih.gov/24690623/ (A)
- Chung, M., Zhao, N., Wang, D., Shams-White, M., Karlsen, M., Cassidy, A., Ferruzzi, M., Jacques, P. F., Johnson, E. J., & Wallace, T. C. (2020). Dose-Response Relation between Tea Consumption and Risk of Cardiovascular Disease and All-Cause Mortality: A Systematic Review and Meta-Analysis of Population-Based Studies. Advances in Nutrition , 11(4), 790–814. https://pubmed.ncbi.nlm.nih.gov/32073596/ (A)
- de Koning, E. J., van der Zwaluw, N. L., van Wijngaarden, J. P., Sohl, E., Brouwer-Brolsma, E. M., van Marwijk, H. W. J., Enneman, A. W., Swart, K. M. A., van Dijk, S. C., Ham, A. C., van der Velde, N., Uitterlinden, A. G., Penninx, B. W. J. H., Elders, P. J. M., Lips, P., Dhonukshe-Rutten, R. A. M., van Schoor, N. M., & de Groot, L. C. P. G. M. (2016). Effects of Two-Year Vitamin B12 and Folic Acid Supplementation on Depressive Symptoms and Quality of Life in Older Adults with Elevated Homocysteine Concentrations: Additional Results from the B-PROOF Study, an RCT. Nutrients, 8(11). https://pubmed.ncbi.nlm.nih.gov/27886078/ (C)
- de Jager, C. A., Oulhaj, A., Jacoby, R., Refsum, H., & Smith, A. D. (2012). Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. International Journal of Geriatric Psychiatry, 27(6), 592–600. https://pubmed.ncbi.nlm.nih.gov/21780182/ (B)
- Harris, E., Kirk, J., Rowsell, R., Vitetta, L., Sali, A., Scholey, A. B., & Pipingas, A. (2011a). The effect of multivitamin supplementation on mood and stress in healthy older men. Human Psychopharmacology, 26(8), 560–567. https://pubmed.ncbi.nlm.nih.gov/22095836/ (B)
- Hu, Y., Hu, F. B., & Manson, J. E. (2019). Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants. Journal of the American Heart Association, 8(19), e013543. https://pubmed.ncbi.nlm.nih.gov/31567003/ (A)
- Kiecolt-Glaser, J. K., Epel, E. S., Belury, M. A., Andridge, R., Lin, J., Glaser, R., Malarkey, W. B., Hwang, B. S., & Blackburn, E. (2013). Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain, Behavior, and Immunity, 28, 16–24. https://pubmed.ncbi.nlm.nih.gov/23010452/ (B)
- Lowe, G. M., Gana, K., & Rahman, K. (2015). Dietary supplementation with green tea extract promotes enhanced human leukocyte activity. Journal of Complementary & Integrative Medicine, 12(4), 277–282. https://pubmed.ncbi.nlm.nih.gov/26259232/ (C)
- Macpherson, H., Rowsell, R., Cox, K. H. M., Scholey, A., & Pipingas, A. (2015). Acute mood but not cognitive improvements following administration of a single multivitamin and mineral supplement in healthy women aged 50 and above: a randomised controlled trial. Age , 37(3), 9782. https://pubmed.ncbi.nlm.nih.gov/25903286/ (C)
- Macpherson, H., Silberstein, R., & Pipingas, A. (2012). Neurocognitive effects of multivitamin supplementation on the steady state visually evoked potential (SSVEP) measure of brain activity in elderly women. Physiology & Behavior, 107(3), 346–354. https://pubmed.ncbi.nlm.nih.gov/22939764/ (C)
- Olshansky, S. J., Goldman, D. P., Zheng, Y., & Rowe, J. W. (2009). Aging in America in the twenty-first century: demographic forecasts from the MacArthur Foundation Research Network on an Aging Society. The Milbank Quarterly, 87(4), 842–862. https://pubmed.ncbi.nlm.nih.gov/20021588/ (F)
- Tan, A., Sullenbarger, B., Prakash, R., & McDaniel, J. C. (2018a). Supplementation with eicosapentaenoic acid and docosahexaenoic acid reduces high levels of circulating proinflammatory cytokines in aging adults: A randomized, controlled study. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 132, 23–29. https://pubmed.ncbi.nlm.nih.gov/29735019/ (C)
- Wang, Q., Zhan, Y., Pedersen, N. L., Fang, F., & Hägg, S. (2018). Telomere Length and All-Cause Mortality: A Meta-analysis. Ageing Research Reviews, 48, 11–20. https://pubmed.ncbi.nlm.nih.gov/30254001/ (A)
- Xu, Q., Parks, C. G., DeRoo, L. A., Cawthon, R. M., Sandler, D. P., & Chen, H. (2009). Multivitamin use and telomere length in women. The American Journal of Clinical Nutrition, 89(6), 1857–1863. https://pubmed.ncbi.nlm.nih.gov/19279081/ (C)
- Young, L. M., Pipingas, A., White, D. J., Gauci, S., & Scholey, A. (2019). A Systematic Review and Meta-Analysis of B Vitamin Supplementation on Depressive Symptoms, Anxiety, and Stress: Effects on Healthy and “At-Risk” Individuals. Nutrients, 11(9). https://pubmed.ncbi.nlm.nih.gov/31527485/ (A)
- Zhang, Y., Fang, F., Tang, J., Jia, L., Feng, Y., Xu, P., & Faramand, A. (2019). Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ , 366, l4673. https://pubmed.ncbi.nlm.nih.gov/31405892/ (A)
- Zheng, Y., Zhu, J., Zhou, M., Cui, L., Yao, W., & Liu, Y. (2013). Meta-analysis of long-term vitamin D supplementation on overall mortality. PloS One, 8(12), e82109. https://pubmed.ncbi.nlm.nih.gov/24349197/ (A)
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