Vitamin D Supplementation: Exploring Its Potential in Aging and Longevity
It all begins with an idea.
Introduction
As we age, the quest for maintaining health and extending quality of life becomes increasingly important. In recent years, vitamin D has emerged as a promising nutrient with potential implications for healthy aging and longevity. This blog post delves into the scientific evidence surrounding vitamin D supplementation and its impact on the aging process. Vitamin D has historically been known as the necessary nutrient for maintenance of healthy bone primarily because of its major influence on calcium absorption (chemical required for bone formation, maintain bone structure & health). This molecule is classically defined as a steroid hormone, since it shares with steroids the common progenitor molecule (cyclopentanoperhydrophenanthrene). Vitamin D is one of the few biologically important nutrients made in the human body (described below), the term “vitamin” although imprecise, it can also be supplemented (like other vitamins) from food sources such as fatty fish, i.e., salmon and trout, beef liver, cheese, egg yolk, albeit the latter ones provide small amounts, mushrooms and some vegetables, and is fully identified as an essential micronutrient with critical regulatory functions.
Vitamin D (Sunshine Vitamin) is Naturally Produced in Human Body
Vitamin D synthesis is a complex biological process that begins with sun exposure (highlighting the old saying “the sun is good for you”. When ultraviolet B (UVB) rays from sunlight interact with a cholesterol derivative in our skin called 7-dehydrocholesterol, it triggers a photochemical reaction that converts this compound into previtamin D3. This precursor then undergoes two key transformations:
First Transformation (Liver)
Previtamin D3 is converted to 25-hydroxyvitamin D [25(OH)D] in the liver
This is the primary circulating form of vitamin D used to measure an individual's vitamin D status
Second Transformation (Kidneys)
25(OH)D is converted to the biologically active form, 1,25-dihydroxyvitamin D [1,25(OH)2D]
This active form interacts with vitamin D receptors throughout the body, regulating gene expression and cellular functions
The “Need” for Vitamin D Supplementation
Decades of scientific studies have identified vitamin D deficiency as one of the most common reasons related to reduction in musculoskeletal functions and increased risk of disability in locomotion (i.e. physical movement & activities). According to the NIH Office of Dietary Supplements, the normal circulating vitamin D level for most people is 50 nanomoles per liter (nmol/L) or 20 nanograms per milliliter (ng/mL) or higher. Levels below 30 nmol/L (12 ng/mL) are considered too low, while levels above 125 nmol/L (50 ng/mL) are considered too high. According to this definition, approximately a third of the population in the United States have vitamin D insufficiency (levels below guidelines). There are several factors that can contribute to decrease in vitamin D levels including:
Limited Sun Exposure
Modern indoor lifestyles: Buildings with glass panes that block UV light actually reduces or prevents the ability of skin to generate sufficient quantities of vitamin D precursor molecules
Geographic locations with reduced sunlight (higher latitudes): There is a progressive decrease in the type & intensity of UV light components moving from the equator towards the poles (e.g. North Pole, South Pole). Thus, geographical location has the potential to influence the amount of sun exposure (and UV light) required for sufficient vitamin D production by the body.
Age-Related Factors
Decrease in efficiency of synthesis due to age
Reduced dietary intake
Diminished kidney and liver function that impairs vitamin D conversion
Physiological and Genetic Influences
Darker skin (due to presence of melanin pigment acting as natural sunscreen, excessive use of suncreen) protects the skin from UV light injury, the consequence is the reduction in UV light exposure and lowers the amount of vitamin D formation.
Obesity – vitamin D is a fat soluble chemical and is stored in the adipose (fat) tissues instead of it being freely available for maintenance of health functions.
Certain genetic variations affecting vitamin D metabolism
Conditions such as inflammatory bowel disease (IBD) Crohn’s disease, Ulcerative Colitis, Celiac Disease and others where the body has difficulty absorbing vitamin D from foods can result in vitamin D deficiency
In addition to these, the scientific evidence supports the observations that low levels of vitamin D strongly affects multiple processes the influence aging, including basic cell function, counteracting oxidative stress, inflammation and cellular senescence. Given the complex barriers to natural vitamin D synthesis and the consequences, supplementation becomes crucial for individuals to maintain good health. The goal is to maintain serum 25(OH)D levels above 30 ng/mL, which is considered optimal for most health outcomes.
Evidence Supporting Vitamin D Supplementation in Aging and Longevity
As we age, our ability to produce and utilize vitamin D naturally declines, making supplementation an increasingly important consideration for older adults. Vitamin D has garnered considerable interest for its potential role in healthy aging and longevity. Traditionally recognized for its role in calcium homeostasis and bone health, recent research suggests that adequate vitamin D levels may contribute to a range of biological processes associated with aging.
Scientific Evidence: What Research Tells Us
1. Vitamin D and Bone Health in Aging
One of the most established benefits of vitamin D is its crucial role in bone health. As we age, the body’s ability to absorb calcium diminishes, leading to bone loss, frailty, and conditions such as osteoporosis. Vitamin D facilitates calcium absorption in the intestines and maintains adequate serum calcium and phosphate levels, which are essential for normal bone mineralization.
Several studies have demonstrated that vitamin D supplementation can reduce the risk of fractures in older adults. A meta-analysis of randomized controlled trials (RCTs) found that individuals aged 65 and older who took vitamin D supplements had a 20% lower risk of hip fractures compared to those who did not supplement especially important in preventing frailty, a common issue in aging populations.
2. Immune Function and Inflammation
Aging is associated with a decline in immune function, a phenomenon known as immunosenescence, and an increase in chronic, low-grade inflammation (often termed "inflammaging"). Both of these processes contribute to a higher susceptibility to infections, chronic diseases, and mortality in older adults.
Vitamin D is known to modulate the immune system by enhancing the pathogen-fighting effects of monocytes and macrophages and reducing inflammatory responses. Research suggests that vitamin D deficiency may exacerbate the age-related decline in immune function. Vitamin D supplementation can reduce inflammation and potentially improve immune function in older adults, offering protection against age-related diseases, such as cardiovascular disease and autoimmune disorders.
3. Cognitive Health and Neuroprotection
Cognitive decline and neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are common concerns in aging populations. There is growing evidence to suggest that vitamin D plays a role in brain health. Receptors for vitamin D are present in regions of the brain that are involved in memory and cognition, such as the hippocampus and cortex.
Several observational studies have linked low vitamin D levels to an increased risk of cognitive decline and dementia. A large study found that older adults with severe vitamin D deficiency had a 122% increased risk of developing dementia compared to those with adequate levels. Furthermore, raontrolled trials have shown that vitamin D supplementation may slow cognitive decline in older adults, although more research is needed to establish causality.
4. Cardiovascular Health and Longevity
Cardiovascular disease (CVD) remains one of the leading causes of mortality in older adults. Interestingly, vitamin D deficiency has been associated with an increased risk of cardiovascular events such as heart attacks, strokes, and heart failure.
A meta-analysis of prospective studies found that individuals with low vitamin D levels had a 50% increased risk of cardiovascular disease. While the exact mechanism is still unclear, it is believed that vitamin D’s role in regulating blood pressure, reducing arterial stiffness, and modulating inflammation may contribute to cardiovascular health. Some studies suggest that vitamin D supplementation may reduce the risk of cardiovascular events, but more high-quality clinical trials are needed to confirm these findings.
5. Muscle Strength and Physical Performance
Muscle weakness and a decline in physical performance are common as people age. Sarcopenia, the loss of muscle mass and function, is a significant contributor to frailty, falls, and reduced mobility in the elderly. Research suggests that vitamin D is essential for muscle function, as it regulates muscle protein synthesis and the function of muscle fibers.
Several studies have shown that vitamin D supplementation can improve muscle strength and physical performance in older adults. A systematic review found that vitamin D supplementation in people over 65 was associated with improved muscle strength and a reduced risk of falls by up to 19%. Preventing falls and maintaining health are critical for preserving independence and quality of life as we age.
6. Longevity and All-Cause Mortality
Beyond its effects on specific health outcomes, vitamin D may influence overall longevity. Several large-scale studies have explored the relationship between vitamin D levels and all-cause mortality. A meta-analysis of 32 studies involving over half a million participants found that higher levels of vitamin D were associated with a significant reduction in all-cause mortality, particularly in individuals over the age of 70.
While the exact mechanisms are yet to be elucidated, it is hypothesized that vitamin D's broad effects on immune function, inflammation, cardiovascular health, and cancer prevention may contribute to this reduction in mortality risk.
7. Cancer Prevention
Vitamin D has also been studied for its potential role in reducing the risk of certain cancers, particularly colorectal, breast, and prostate cancers. Some studies suggest that vitamin D helps regulate cell growth, promote cellular differentiation, and induce apoptosis (programmed cell death), all of which are important for preventing the uncontrolled growth of cancerous cells.
In a recent study, it was reported that vitamin D daily supplementation was associated with reduction in cancer mortality, with adults aged 70 and older benefited most from the daily dosing. While the evidence is still emerging, vitamin D's role in cancer prevention could have important implications for longevity, given the increased cancer risk associated with aging.
Practical Considerations
While research is promising, it's essential to approach vitamin D supplementation thoughtfully:
Individual Variation: Factors like age, skin tone, geographic location, and overall health can impact vitamin D requirements.
Form of Supplementation: Vitamin D3 (cholecalciferol) is generally considered more effective than D2.
Always consult with a healthcare professional before starting any new supplementation regimen, as individual needs can vary significantly.
Limitations and Ongoing Research
It's crucial to note that while the evidence is encouraging, research is ongoing. Not all studies show definitive proof, and more long-term research is needed to fully understand vitamin D's role in aging and longevity.
Conclusion
Vitamin D supplementation presents an intriguing avenue for supporting healthy aging. While it's not a magic solution, the growing body of evidence suggests it could be a valuable component of a holistic approach to longevity. In the quest for a longer, healthier life, maintaining optimal vitamin D levels may be one of the simplest and most impactful steps we can take.
References
Vitamin D: Fact Sheet for Health Professionals. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/
Schottker, B., et al. (2013). "Vitamin D and Mortality: Meta-Analysis of Individual Participant Data from a Large Consortium of Cohort Studies from Europe and the United States." BMJ, 347, f6820.
Zarei M, Zarezadeh M, Hamedi Kalajahi F, Javanbakht MH (2021). The Relationship Between Vitamin D and Telomere/Telomerase: A Comprehensive Review. J Frailty Aging. 10(1):2-9. doi: 10.14283/jfa.2020.33. PMID: 33331615.
Zhao SS, Mason A, Gjekmarkaj E et al (2023). Associations between vitamin D and autoimmune diseases: A Mendelian randomization analysis. 62, https://doi.org/10.1016/j.semarthrit.2023.152238.
Gonçalves de Carvalho, C., Ribeiro, S. (2017) Aging, low-grade systemic inflammation and vitamin D: a mini-review. Eur J Clin Nutr 71, 434–440. https://doi.org/10.1038/ejcn.2016.177
Harse JD, Marriott RJ, Zhu K, Murray K, Bucks RS. Vitamin D status and cognitive performance in community-dwelling adults: A dose-response meta-analysis of observational studies. Front Neuroendocrinol. 2023 Jul;70:101080. doi: 10.1016/j.yfrne.2023.101080. Epub 2023 Jun 1. PMID: 37268277.
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Girgis, C. M., et al. (2014). "The Roles of Vitamin D in Skeletal Muscle: Form, Function, and Metabolism." Endocrine Reviews, 35(1), 33-83.
Holick, M. F. (2017). "The Vitamin D Deficiency Pandemic: Approaches for Diagnosis, Treatment and Prevention." Reviews in Endocrine and Metabolic Disorders, 18(2), 153-165.
Bischoff-Ferrari, H. A., et al. (2009). "Prevention of Nonvertebral Fractures with Oral Vitamin D and Dose Dependency: A Meta-Analysis of Randomized Controlled Trials." Archives of Internal Medicine, 169(6), 551-561.
Mogire, Regan M et al. Prevalence of vitamin D deficiency in Africa: a systematic review and meta-analysis. The Lancet Global Health, Volume 8, Issue 1, e134 - e142
Michos, E. D., et al. (2008). "Vitamin D Deficiency and the Risk of Incident Acute Conditions in a General Adult Population." Clinical Endocrinology, 68(2), 258-264.
Littlejohns TJ, Henley WE, Lang IA et al. Vitamin D and the risk of dementia and Alzheimer’s disease. Neurology. 83(10):920-928. https://doi.org/10.1212/WNL.0000000000000755
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Metformin Beyond Diabetes: Mechanisms underlying its health benefits in aging and longevity
It all begins with an idea.
Metformin is a drug currently on the World Health Organization (WHO) model list of essential medicines and is the most widely used medicine globally for the management of non-insulin dependent diabetes mellitus (NIDDM, Type 2 diabetes – T2DM). Guanidine, the parent compound from which metformin was developed, is a plant chemical; the plant commonly known as French Lilac or goat’s rue (Galega officinalis is the scientific name) has a long history of medicinal use in medieval Europe. Metformin was one of the many chemicals that were structurally similar to guanidine that were synthesized and tested for their anti-diabetic effects. Metformin was introduced for clinical use to treat diabetes first in Europe in the 1960’s and was approved by the FDA for use in the United States of America in 1995.
Chemical synthesis of metformin dates back to 1922. Since then, scientific exploration of its medicinal properties have provided unique insights into its mechanistic ability to influence many key biological pathways from glucose lowering effects to its potential use an anti-malarial agent, treatment of influenza infection (the flu) and most recently in COVID19, cancers and as a potential drug for slowing down aging process. The scale of its use in humans over the past sixty plus years, understanding its safety profile and low cost of use makes it a potential wonder drug for the management of metabolic dysfunction, maintenance of good health and overall well-being.
Let’s dive into what makes metformin unique and why it’s capturing the imagination of scientists and the public alike.
How Metformin Works
At its core, metformin is a metabolic regulator. It decreases the liver’s production of glucose, increases the muscle tissue's uptake of glucose, and improves insulin sensitivity. These actions help stabilize blood sugar levels, making metformin a cornerstone in managing type 2 diabetes. Interestingly, its mechanism of action doesn’t involve directly stimulating insulin production, making it less likely to cause hypoglycemia—a common concern with some other diabetes medications.
In recent years, research has shown that glucose lowering effects of metformin goes beyond its effects on the liver and skeletal muscle. Metformin influences cells and tissues of the gut lining to improve glucose handling, a mechanism that appears to be synergistic (additive) to the anti-diabetic mechanism of GLP-1 therapies. Metformin also exerts effect on the gut microbiome, altering the composition to promote an overall beneficial effect.
Many mechanisms have been attributed to metformin’s benefits in human health highlighting continued interest in scientific community and health practitioners to continue leveraging its utility in various health conditions.
Beyond Diabetes: A Potential Fountain of Youth?
What truly sets metformin apart is its emerging role in biology beyond metabolic dysfunction and diabetes. While it may not necessarily be a "magic pill," there is growing evidence that it could slow the onset of many age-related biological changes that lead to organ dysfunctions and diseases.
1. Cardiovascular Health
Studies suggest that metformin reduces cardiovascular risk, even in individuals without diabetes. By lowering inflammation and improving lipid profiles, it may protect against heart disease, a leading cause of death worldwide.
Metformin -
Decreases “AGE” (advanced glycation end products)
Decreases “ROS” (reactive oxygen species)
Improves lipid profiles
Influences energy metabolism in heart muscle cells, reduces overall muscle dysfunction
Protects against vascular endothelial (cells lining the walls of blood vessels) dysfunction
Benefits of metformin has been observed in lowering incidence of coronary artery disease (CAD) and congestive heart failure (CHF), two of the major cardiovascular diseases associated with diabetes and aging.
2. Cancer Prevention
The ability of cancer cells to keep growing unchecked requires access to continuous supply of nutrients, growth factors and energy. The evidence of metformin’s anti-cancer potential was identified from human and animal studies comparing diabetes versus non-diabetes groups. Several studies have reported evidence of metformin’s anti-cancer effects in organs like the breast, brain, endometrium, lung, ovary and kidneys. Metformin has been reported to influence key metabolic and cell cycle signaling pathways in cancer cells to elicit its anti-cancer effect. Some of the important signaling pathways influenced by metformin to elicit its anti-cancer effects include:
Inhibits activity of mitochondrial complex 1
Activation of AMPK – energy metabolism pathway
Inhibitors mTOR (mammalian target of rapamycin)
Modulates proteins regulating cell cycle (process of cell division and growth characteristic of cancer) including cyclins, p21, p27, p53, Akt and others
Inhibition of cell cycle
Although metformin does not appear to have significant single agent anti-cancer activity (i.e. cannot be used for treatment of cancer on its own), it has the potential to add benefits when combined with standard of care anti-cancer treatments for multiple cancers including bladder cancer, lung cancer, colorectal cancer, multiple myeloma, melanoma, thyroid cancer, liver cancer and some rare cancers of the bone. As of December 2024, the clinical trials website lists over 400 clinical trials (www.clinicaltrials.gov) testing metformin in combination with other anti-cancer treatments for various cancers.
3. Cognitive Benefits
Age related cognitive decline (slow progressive impairment in memory functions) is an hallmark of the aging process and associated with onset of mild cognitive impairment, dementia and Alzheimer’s disease. Can metformin help our brains age better? Some studies hint at a reduced risk of dementia and Alzheimer’s disease among metformin users, although the data isn’t conclusive yet. Some evidence of potential mechanisms of metformin with potential to influence and improve brain function include:
Metformin crosses the blood brain barrier (it can get access to the brain cells)
Lowers expression of a-synuclein (protein that forms aggregates or clumps in Parkinson’s Disease, potential benefit for patients with disease)
Effects on dementia observed in non-human model testing
Minimizes risk of cognitive impairment in diabetic patients in clinical studies
Improved metabolic fitness with metformin use, reduced ROS production and influence on key metabolic signaling are potential mechanisms involved in metformin associated improvement in brain function
4. Aging
Most recently, metformin has gained significant attention for its potential to slow down the cellular processes associated with aging. In human studies, a comprehensive review and analysis provides evidence of metformin use was associated with a reduction in all-cause mortality (death due to all causes). Numerous metabolic and growth factor signaling pathways, that incidentally also influenced by metformin, have been subject of active investigations as potential targets for anti-aging therapeutics.
The significant contributions from scientific research supporting the impact of metformin on various biological mechanisms has been critical for recent investments in the clinical investigation of its utility as an anti-aging therapy.
The TAME Trial: Targeting Aging with Metformin
The most ambitious study in this area is the TAME trial, led by Dr. Nir Barzilai. This is a nationwide clinical trial that aims to determine (proof of concept) whether metformin can be used to treat aging by delaying the onset of chronic diseases associated with aging, such as heart disease, diabetes, cancer, and cognitive decline. The study is to be conducted at 14 leading research institutions and is expected to involve an estimated 3000 individuals between the ages of 65 – 79. If successful, it could redefine how we approach aging as a modifiable process.
Should Everyone Take Metformin?
While metformin is generally well-tolerated, it isn’t without side effects. Common complaints include gastrointestinal upset, and in rare cases, lactic acidosis. Moreover, its off-label use for aging is not yet FDA-approved, and the long-term effects in non-diabetic individuals remain uncertain.
For now, metformin is a promising tool in the growing toolkit of longevity science, but it’s not a substitute for a healthy lifestyle. Eating well, exercising regularly, and managing stress remain the gold standards for promoting a long and healthy life.
The Future of Metformin
Metformin’s journey from a plant-derived remedy to a potential anti-aging drug is a testament to the evolving landscape of medicine. As research unfolds, it may pave the way for broader acceptance of therapies targeting the aging process itself.
In the meantime, this modest medication continues to transform lives by doing what it does best—helping millions manage diabetes while quietly opening the door to a healthier, longer future.
Have you heard of or used metformin for non-diabetic purposes? Share your thoughts in the comments below!
Select References
1. Bailey, C.J. Metformin: historical overview. Diabetologia 60, 1566–1576 (2017). https://doi.org/10.1007/s00125-017-4318-z. Provides historical overview of metformin from the investigation of guanidine, its analogs to metformin’s glucose lowering effects.
2. Marshall, S.M. 60 years of metformin use: a glance at the past and a look to the future. Diabetologia (2017) 60, 1561–1565. https://doi.org/10.1007/s00125-017-4343-y. Summary description of metformin from discovery to clinical utility.
3. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):854-65. Erratum in: Lancet 1998 Nov 7;352(9139):1558. PMID: 9742977. Demonstrated the benefits of metformin in reducing complications in type 2 diabetes patients.
4. Dutta S, Shah RB, Singhal S, Dutta SB, Bansal S, Sinha S, Haque M. Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes. Drug Des Devel Ther. (2023) 17:1907-1932. https://doi.org/10.2147/DDDT.S409373. A comprehensive review of mechanisms and use of metformin beyond diabetes.
5. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metab. (2016) Jun 14;23(6):1060-1065. doi:10.1016/j.cmet.2016.05.011. This study explores the rationale behind TAME and its potential to validate aging interventions.
6. Foretz, M., Guigas, B. & Viollet, B. Metformin: update on mechanisms of action and repurposing potential. Nat Rev Endocrinol. 19, 460–476 (2023). https://doi.org/10.1038/s41574-023-00833-4. Updated information on the biochemical mechanisms underlying metformin effects on various signaling pathways and relationship to clinical utility.
7. Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E. Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2018;65(4):1225-1236. doi: 10.3233/JAD-180263. PMID: 30149446; PMCID: PMC6218120. Suggests a link between metformin use and cognitive benefits.
8. Mohammed I, Hollenberg MD, Ding H, Triggle CR. A critical review of the evidence that metformin is a putative anti-aging drug that enhances healthspan and extends lifespan. Front Endocrinol (20221) 12:718942. https://doi.org/10.3389/fendo.2021.718942. A comprehensive review of scientific evidence supporting role for metformin in aging and longevity.