Magnesium and Aging: Can Low Magnesium Levels Impact Aging?

Magnesium (Mg2+) is one of the most abundant minerals in the human body and an essential nutrient required for the healthy function of every organ in the human body. Magnesium is a cofactor for over 600 enzymes and an activator of an additional 200 enzymes involved in all major biochemical and metabolic processes in cells. Among its many important roles, magnesium is essential for DNA and protein synthesis, cell energy metabolism, cell division and growth, nerve impulse conduction, skeletal and heart muscle contraction, bone growth and mineralization, and immune function [1].

Magnesium Levels in the Body

The U.S. Food and Nutrition Board recommends a daily magnesium intake of 420 mg for men and 320 mg for women [2]. However, the majority of people in Western countries do not get sufficient amounts of magnesium in their diets [1,3,4]. One of the main reasons for the insufficiency of magnesium in the Western diet is the fact that an estimated 80–90% of magnesium is lost during grain refinement, food processing, and even just by cooking foods. Furthermore, the soil used for agriculture is becoming increasingly poor in essential minerals [5], which means that even if you follow a healthy diet rich in vegetables, nuts, legumes, and whole grains, which are good sources of magnesium, you may still be falling short on the daily goals for magnesium intake. 

Figure 1. Dietary sources of magnesium and factors that increase or decrease its bioavailability. Source: Dominguez LJ et al. Nutrients 2024, 16(4):496. License: CC BY 4.0

As a consequence, many people have low magnesium levels in their body and this is particularly frequent among older adults [6,7]. This insufficiency often goes unnoticed because magnesium levels are usually determined by measuring total blood serum levels, which reflect only a very small fraction of the body’s magnesium content. Around 50–60% of the total body magnesium content is stored in bone as part of its mineralized matrix and the rest is stored within cells. Only less than 1% of the body’s magnesium is found in the serum [6,8]. 

Magnesium insufficiency often goes unnoticed because magnesium levels are usually determined by measuring total blood serum levels.

Therefore, serum values often fail to accurately reflect intracellular magnesium status—they may be low even if serum levels are within the adequate range. Furthermore, low levels of magnesium are usually asymptomatic or manifest in non-specific ways that can easily be confused with common signs of aging, for example [6]. 

How Magnesium Levels Change with Aging

With aging, although serum magnesium levels tend to remain constant in healthy people [9], low total body levels of magnesium are believed to be common [7], particularly in older individuals, for whom an age-dependent decrease in cellular magnesium levels has been reported [10]. 

One of the reasons for a progressive decline in magnesium levels with aging is low dietary magnesium intake. Data from the National Health and Nutrition Examination (NHANES), a program of studies of the U.S. Centers for Disease Control and Prevention (CDC) have confirmed that aging is associated with inadequate magnesium consumption [11].

Another factor that contributes to the decline in magnesium levels is the reduction in the intestinal absorption of magnesium with age, along with increased urinary elimination of magnesium due to poorer kidney function and renal reabsorption of magnesium [6]. 

Because of the important functions of magnesium, low magnesium levels can have a great impact on cellular function and general health as we age.

Magnesium and the Hallmarks of Aging

The hallmarks of aging are a set of interconnected cellular and molecular changes that accompany and promote the aging process and that can be influenced by physiological and lifestyle factors. 

Currently, twelve hallmarks of aging have been established [12]:

• Genomic instability
• Telomere attrition
• Epigenetic alterations
• Loss of proteostasis
• Deregulated nutrient sensing
• Loss of mitochondrial function
• Cellular senescence
• Stem cell exhaustion
• Altered intercellular communication
• Disabled autophagy
• Altered immune signaling
• Altered gut microbiota composition

All of these hallmarks involve pathways or processes in which magnesium plays a part and that may therefore be affected by the cellular availability of magnesium. Check out our article The 12 Hallmarks of Aging to learn more about them. 

Figure 2. Magnesium and the hallmarks of aging. Adapted from: Dominguez LJ et al. Nutrients 2024, 16(4):496. License: CC BY 4.0

Genomic Instability

DNA repair and maintenance mechanisms become less efficient as we age, which allows for growing genetic instability and the accumulation of DNA damage in aged cells [13]. Magnesium plays a key part in maintaining genomic stability because it is necessary for the activity of the enzymes that build DNA and RNA molecules and that are involved in DNA repair, DNA replication, RNA transcription, amino acid synthesis, and protein production. Magnesium also binds to DNA and RNA chains and stabilizes their structure [1]. Therefore, magnesium is essential for the whole process of replicating DNA when cells divide and accurately translating the information stored in DNA into the assembly of proteins used for building cellular structures and carrying out cellular processes. Low magnesium levels may therefore promote genetic instability and impair cells' ability to properly divide and maintain healthy function [8]. 

Telomere Attrition

Telomeres are DNA sequences at the ends of chromosomes that get shorter every time a cell divides, and consequently, as we age [14]. When telomeres reach a critical length, cell division stops [15]. Telomeres have protective functions over chromosomes and their shortening induces genomic instability and, ultimately, cellular senescence or cell death. Magnesium plays an important role in regulating telomere structure, integrity, and function [16] and is involved in regulating the activity of telomerase [17], an enzyme that prevents telomere shortening in specific cells (e.g.. stem cells and lymphocytes) by elongating them when cells divide [18,19]. Research has shown that higher dietary magnesium intake is associated with longer telomere length in immune cells [20].

Epigenetic Alterations

Epigenetic alterations are a set of regulatory changes to DNA that influence gene expression based on lifestyle and environment [21]. Patterns of epigenetic alterations change with age and can lead to gene expression changes that affect biological processes and lead to loss of cellular homeostasis, modifications in stem cell behavior, metabolic health decline, and the development and progression of other features of aging [22–25]. In preclinical research, low dietary magnesium levels have been linked to gene expression changes due to epigenetic alterations [26]. In humans, a pilot study that assessed gene-expression profiles after 4-week supplementation with magnesium showed several changes in gene expression, many of which were linked to metabolic and immune signaling pathways [27].

Loss of Proteostasis

Cells have several protein quality control mechanisms to maintain proteostasis (i.e., protein homeostasis) and proper protein structure and function. These mechanisms decline with aging and lead to the accumulation of misfolded or damaged proteins resulting in the formation of aggregates that deposit within cells and compromise cellular and tissue function [28–31]. Although little is known about how magnesium influences proteostasis, low brain levels of magnesium have been reported in conditions that are known to be associated with the accumulation of protein aggregates in the brain [32]. Magnesium administration has been shown to help to promote the elimination of those aggregates and reduce their accumulation [33–35]. These findings suggest that magnesium availability may influence protein quality control as we age.

Deregulated Nutrient Sensing

The nutrient-sensing network is a central regulator of cellular metabolic activity that responds to nutrition, energy availability, and stress. If nutrients and cell energy are available and stress is low, it shifts cellular metabolism to the production of macromolecules; if nutrient and cell energy availability is low and stress is high, it shifts cellular metabolism to the breakdown of macromolecules into small molecules to produce energy and activates adaptive stress responses [44]. With aging, the nutrient-sensing network becomes progressively more deregulated leading to poorer adaptive cellular stress responses [12,44]. Low intracellular magnesium levels may contribute to this process. For example, low magnesium can disrupt insulin signaling and secretion and mitochondrial metabolic pathways, which can compromise metabolic health [45–47]. Accordingly, several studies have shown an association between low dietary magnesium intake or low extracellular and/or intracellular magnesium levels and poor metabolic health [48–53]. On the other hand, higher magnesium intake levels, through foods or supplementation, have been associated with better metabolic parameters and outcomes [54–58]. 

Loss of Mitochondrial Function

With aging, mitochondrial function declines due to multiple linked processes, including an accumulation of mitochondrial DNA mutations, loss of proteostasis, and loss of mitochondrial quality control mechanisms [59,60]. These changes compromise the efficiency of mitochondrial metabolism and cell energy production, enhance the production of reactive oxygen species (ROS), and can trigger signaling pathways that lead to oxidative stress, altered immune signaling, and cell death, all of which can contribute to an acceleration of the aging process [12,61]. 

Over a third of cellular magnesium is found within mitochondria [62]. Magnesium is required for many enzymes involved in mitochondrial cell energy pathways and ATP production [63,64]. Importantly, ATP itself must bind to a magnesium ion to be biologically active, forming an Mg–ATP complex. Consequently, magnesium availability is essential for the maintenance of proper mitochondrial function [1,65]. Low magnesium levels have been linked to loss of mitochondrial function through several mechanisms, including alterations in ATP production, suppression of the antioxidant defense system, increased mitochondrial ROS production, and disruption of calcium homeostasis [66–71]. On the other hand, magnesium supplementation has been shown to support mitochondrial function by balancing ROS production, preserving the mitochondrial membrane potential, balancing calcium levels, reducing pro-apoptotic signaling, and balancing autophagy [66,69,72–75].

Cellular Senescence

Cellular senescence is a protective stress response in which cells stop dividing, but don’t die. In normal conditions, senescent cells are eliminated by the immune system. With aging, several cellular stressors that induce senescence increase, and the immune system becomes less efficient at finding and clearing senescent cells (often called zombie cells), allowing a growing accumulation of senescent cells [76–78]. This accumulation can interfere with tissue repair and regeneration [79–81] and contribute to age-related functional decline [82,83]. Some cellular changes that occur during senescence are similar to those caused by low magnesium levels, including impaired cell cycle progression and reduced defenses against oxidative stress [84]. In vitro research showed that low magnesium conditions could induce senescent features in human endothelial cells and accelerate cellular senescence in human fibroblasts [85,86]. 

Stem Cell Exhaustion

Stem cells are cells that haven’t yet developed into a specific type of cell and that can differentiate into different types of cells. They have the capacity to divide indefinitely to self-renew, thereby maintaining a stem cell pool. Stem cells are found within tissues and organs and play a key role in tissue regeneration and repair and in maintaining tissue homeostasis throughout life [87,88]. With aging, there is a decline in the stem cell pool that contributes to a reduced capacity to renew and repair tissues that is characteristic of the aging process [12,88]. Although it is still unclear how and to what extent magnesium may influence stem cell pools with aging, studies have indicated that magnesium levels can influence stem cell viability and differentiation potential [89–95].

Altered Intercellular Communication

Intercellular communication occurs through three main pathways—neural, endocrine, and immune signaling pathways—along with short-lived extracellular signaling molecules (such as ROS, nitric oxide, and prostaglandins), mediators released from tissues, cell-bound ligands, and receptors, as well as cell-to-cell interactions through tight junctions or gap junctions [12,96]. Aging is associated with progressive changes in intercellular communication processes that can compromise the homeostatic regulation of tissues and organs and change the properties of tissues in ways that may favor the aging process [97,98]. Magnesium plays important parts in many intercellular communication processes, particularly in the main pathways. Magnesium is a cofactor for enzymes that synthesize several neurotransmitters and neurohormones and a regulator of neurotransmitter signaling, thereby influencing neural communication pathways [99–101]; it regulates endocrine signaling pathways, including stress hormone signaling and insulin signaling, for example [45,102]; and it influences immune signaling and the levels of immune mediators [103–105]. 

Disabled Autophagy

Autophagy is a cellular process through which cells degrade and recycle damaged cell organelles (including mitochondria—mitophagy), protein aggregates, or unused proteins and other macromolecules (e.g., DNA, lipid vesicles, and glycogen) [36]. The expression of autophagy-related genes declines with age, which contributes to the accumulation of protein aggregates and damaged cellular structures [12,37,38]. Preclinical studies have shown that magnesium contributes to cellular and tissue health by regulating autophagy [39–41]. Low dietary magnesium levels have been linked to reduced autophagy [42], while magnesium supplementation may support autophagy [43].  

Altered Immune Signaling

With aging, immune signaling changes and becomes progressively more detrimental, a process known as inflammaging [106]. In association with these changes, immune function also declines [107]. Several studies have established links between magnesium levels and the development of inflammaging. In vitro studies showed that low concentrations of magnesium promote detrimental changes in immune markers and magnesium deprivation in experimental animal models led to increased production of detrimental immune mediators [103,108,109]. On the other hand, magnesium supplementation was found to support healthier immune signaling processes [110,111]. In humans, several studies have shown an association between low serum magnesium concentrations and low dietary magnesium intakes with increased levels of detrimental immune mediators [112–115]. Meta-analyses of clinical studies have indicated that magnesium supplementation reduced those immune markers [104,116].

Altered Gut Microbiota Composition

The composition of the gut microbiota changes gradually during aging, leading to a general decrease in ecological diversity. This can result in an imbalance in the composition of the gut microbiota and a disruption of microbial metabolism that changes human-microbiota interactions in ways that can influence physiological processes in the human body and contribute to several age-related features [117,118]. Analyses of the gut microbiome have shown associations between dietary magnesium levels and the composition of the gut microbiota [119]. Magnesium supplementation has been shown to increase the population of bacteria linked to intestinal health and metabolic homeostasis and reduce bacteria associated with detrimental immune signaling [120]. Mice fed a magnesium-deficient diet had reduced concentrations of beneficial gut bacteria and changes indicative of poorer gut barrier function [121]. 

Conclusion

Magnesium is one of our most important essential nutrients. It has crucial roles that help to maintain healthy cellular function and tissue and organ health. Because of these roles, low magnesium levels can help to drive many of the changes that are typical of the aging process and have a great impact on health as we age. Therefore, it’s important to maintain adequate dietary intakes of magnesium throughout life, either through foods or supplements.

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*These statements have not been evaluated by the Food and Drug Administration.  This product is not intended to diagnose, treat, cure, or prevent any disease.

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