When you think of dietary supplements with healthspan-boosting potential, which ingredients come to mind first (or show up in your patient protocols regularly)? Is it resveratrol? Creatine? Collagen? Nicotinamide mononucleotide (NMN)? Or something more niche, like spermidine or ergothioneine? Your personal selection probably depends on which aspects of aging concern patients most, and possibly your own experience taking it.
But where in your longevity treatment list would you place magnesium or berberine? If you work with dietary supplements in your practice, you undoubtedly have recommended magnesium for its well-established importance in muscle contraction and nervous system function, and berberine for blood sugar regulation and metabolic health. But do you ever consider them as ingredients with anti-aging potential?
NMN may dominate the longevity conversation, but magnesium and berberine also influence fundamental mechanisms of aging, from mitochondrial function and cellular energy metabolism to inflammation and metabolic regulation. How strong is the evidence that these three ingredients support healthy aging? Let’s look at what the science actually shows.
Why Magnesium Matters for Healthy Aging and Longevity
In a review of dietary supplements that carry the strongest backing of clinical research supporting their importance for longevity and healthy aging, magnesium rises to the top. As an essential mineral, it has broadly been researched in human trials investigating the impact of deficiency, dietary intake, and dietary supplementation. It also has no shortage of mechanistic and animal studies that also inform our understanding of this nutrient.
In addition to its essentiality for muscular contraction and relaxation and nervous system balance, magnesium is crucially important for cellular energy production and mitochondrial function.[1] In the cell, ATP is primarily utilized as Mg-ATP complex, while magnesium also stabilizes mitochondrial performance by limiting calcium overload and associated oxidative stress. Magnesium also plays an important role in cardiovascular health and vascular relaxation, and is essential for glutathione synthesis, supporting antioxidant defenses and glutathione-dependent Phase II detoxification pathways.[2]
NMN may dominate the longevity conversation, but magnesium and berberine also influence fundamental mechanisms of aging, from mitochondrial function and cellular energy metabolism to inflammation and metabolic regulation.
It has even been proposed that age‐associated drift in mitochondrial magnesium may be a factor associated with cellular senescence;[3] this hypothesis has been supported in vitro.[4] Markers of accelerated aging with magnesium deficiency have also been shown in animal studies, including findings of shorter liver telomeres,[5] reduced cardiac and aortic tissue telomerase activity and increased DNA damage,[6] cardiovascular and blood vessel remodeling and a related increase in mortality,[7] and increased inflammaging.[8]
Magnesium, DNA Damage, Inflammation, and Cellular Aging
So where does the data stand for magnesium in human studies related to aging? Similar to some of these parameters with preclinical data, clinical research has found lower magnesium concentration to be associated with markers of greater DNA damage, particularly among individuals with elevated homocysteine.[9] Magnesium supplementation has been shown to impact DNA methylation, showing its epigenetic influence.[10] Additional research in younger individuals found magnesium supplementation reduced markers of DNA damage in both sedentary individuals and athletes.[11] A large meta-analysis of 17 randomized controlled trials including nearly 900 people found magnesium supplementation significantly decreased CRP, a marker of systemic inflammation associated with biological aging,[12],[13] also increasing nitric oxide, which is important for healthy vascular function especially with aging.[14],[15]
Magnesium for Healthy Aging: Frailty, Blood Pressure, Metabolic Health, and Mortality
Research also connects low magnesium status or intake with functional markers related to aging or mortality, which for many may be of greater relevance. In a large population of over 80,000 women aged 60 years and older, those in the highest versus lowest quintile of dietary magnesium intake had a 32% lower risk of experiencing frailty (defined by having 3 of 5 parameters related to frailty).[16] A 2021 meta-analysis of 1.7 million people found that higher dietary magnesium intake was associated with lower all-cause mortality; assessment of dose-response found that each incremental increase of 100 mg of dietary magnesium daily was associated with a 6% reduced risk of all-cause mortality.[17]
In a large population of over 80,000 women aged 60 years and older, those in the highest versus lowest quintile of dietary magnesium intake had a 32% lower risk of experiencing frailty
Interestingly, in the 2021 meta-analysis, cardiovascular disease-related mortality was not associated with magnesium intake. That said, a different meta-analysis of clinical trials investigating the impact of magnesium supplementation on blood pressure found magnesium had both a systolic and diastolic blood pressure lowering effect, with greater reductions being shown in individuals with hypomagnesemia or those with hypertension already taking blood pressure lowering medications.[18] Although magnesium is typically not thought of as having blood glucose or triglyceride-modifying effects, supplementation for ~4 months has been shown to significantly improve these parameters (as well as systolic and diastolic blood pressure) in individuals with metabolic syndrome, suggesting its benefits extend beyond blood pressure for individuals experiencing these common overlapping challenges with age.[19]
This is not a comprehensive review of magnesium’s impact on all conditions that become increasingly common with age; however, it is worthy to mention that magnesium insufficiency or low dietary magnesium intake have also been associated with Alzheimer’s disease,[20] osteoporosis,[21] and stroke.[22]
Magnesium Deficiency: Common, but Easy to Miss
Despite the broad array of data for this essential mineral, deficient dietary intake is not uncommon with approximately half the U.S. population consuming less than the estimated average requirement.[23] A 2026 publication assessing the 2021-2023 NHANES data found nearly two-thirds of adults experience chronic latent magnesium deficiency.[24] Serum magnesium does not reflect intracellular levels or tissue adequacy, and subclinical magnesium deficiency has been suggested to be one of the most underdiagnosed electrolyte disturbances. Discussion of alternate methods of assessing for magnesium deficiency is beyond the scope of this review, however, can be found elsewhere.[25],[26]
Berberine and Metformin: Shared Mechanisms of Supporting Healthy Aging
Although metformin has been recognized for some time as having anti-aging potential, berberine has not risen to the same fame, despite its very similar mechanisms of action and greater accessibility. A 2026 study published in Nature Metabolism even highlights some of their similarities, detailing experimental evidence showing that both inhibit intestine-specific mitochondrial complex I, which has downstream effects that include improved glucose regulation, increased production of metabolic signaling molecules involved in appetite and energy balance, and potential activation of adaptive pathways involved in mitochondrial stress responses and AMPK activation – all of which may have healthy aging implications.[27],[28],[29] Interestingly, inhibition of intestine-specific mitochondrial complex I leads to metformin-induced citrulline depletion, which is likely a factor in the impaired muscle hypertrophy response to exercise that can be seen with metformin use – and potentially resolved with citrulline supplementation.
Other preclinical research demonstrates berberine, similar to metformin, activates AMPK, indirectly inhibits mTOR signaling, promotes autophagy, attenuates experimentally induced cellular senescence, increases intracellular NAD+ levels, and suppresses NLRP3 inflammasome activation as well as other anti-inflammatory effects.[30],[31],[32],[33],[34]
Inhibition of intestine-specific mitochondrial complex I leads to metformin-induced citrulline depletion, which is likely a factor in the impaired muscle hypertrophy response to exercise that can be seen with metformin use – and potentially resolved with citrulline supplementation.
Beyond Blood Sugar: Berberine’s Broader Clinical Benefits
Beyond these potential anti-aging mechanisms, numerous clinical trials have shown supplementation with berberine improves markers of metabolic dysfunction including hyperglycemia and dyslipidemia.[35] Berberine also has been shown in meta-analyses of randomized controlled trials to support weight loss and a reduced waist circumference[36] and reduce liver enzymes in MAFLD,[37] also lowering hepatic fat content in one of the studies included.[38] A more recent 2026 publication also found that supplementation with berberine to women aged 20 to 65 years significantly improved markers of cardiovascular disease risk, including lipoprotein(a) and apolipoprotein B (ApoB).[39] Interestingly, the improvements in cardiovascular disease risk markers were greater in women than those shown in men in a similar clinical trial.[40] Multiple clinical trials suggest that berberine may reduce inflammatory markers, including CRP, IL-6, and TNF-α, although findings across meta-analyses have been inconsistent and much of the evidence comes from studies evaluating berberine alongside conventional therapies.[41],[42],[43]
Berberine Dosing and Potential Drug Interactions
In most of these clinical trials, berberine is taken in divided doses of 1,000 to 1,500 mg per day. One important consideration for berberine supplementation is the potential for interactions with other medications, as it has been shown in human research to inhibit cytochrome P450 3A4 (CYP3A4), CYP2D6, and CYP2C9,[44],[45] which may alter the metabolism and potentially the circulating concentrations of certain antihypertensive medications and other commonly prescribed drugs, including venlafaxine and sildenafil. However, direct clinical interaction data for these particular drugs are limited.
Berberine Bioavailability: From Gut Activity to Systemic Benefits
Of note, many nutraceuticals have intrinsically low bioavailability, unless they are combined with other substances that facilitate absorption of the active ingredient(s). Berberine’s chemical structure creates additional barriers to absorption, including limited permeability across intestinal cell membranes, while P-glycoprotein-mediated efflux and extensive first-pass metabolism further contribute to its low systemic bioavailability.[46],[47] As is clear from both mechanistic and clinical trials, berberine’s low systemic bioavailability does not necessarily undermine its therapeutic activity. That said, broader systemic effects may be desirable, and can be achieved with phytosome preparations, which have been shown to increase berberine absorption by nearly a factor of 10.[48]
Nicotinamide Mononucleotide and NAD+: The Cellular Energy Connection
Nicotinamide mononucleotide (NMN) has been a popular supplement amongst longevity seekers and individuals looking to enhance cellular energy production and athletic performance for some time, although until recently, much of its use was based on its key mechanism of boosting cellular levels of oxidized nicotinamide adenine dinucleotide (NAD+), which many studies have shown decline with age.[49] NAD+ is necessary for cellular energy production, as it serves as an essential electron acceptor in glycolysis and the tricarboxylic acid (TCA) cycle, generating NADH (reduced NAD) that supplies electrons to the mitochondrial electron transport chain for ATP production.[50] NMN has been shown in a 2025 meta-analysis of clinical trials to have a significant effect of increasing NAD+ levels, supporting this biological effect.[51]
What Human Clinical Trials Show About NMN and Healthy Aging
Prior to 2020, human clinical evidence for NMN was extremely limited, consisting primarily of a small, uncontrolled safety study,[52] while its proposed health benefits were largely supported by preclinical research. Randomized controlled trials investigating its effects on NAD⁺ levels and functional health outcomes began to emerge in 2021.
As of October 2026, the benefits that have been shown in randomized controlled trials with NMN supplementation include improved skeletal muscle insulin sensitivity in prediabetic postmenopausal women,[53] potential improvements in gait speed and left-hand grip strength in men aged 65 years and older,[54] improved sleep quality and maintenance of walking speed over a period of 3 months in men and women aged 65 to 75 years,[55] and potential improvements in lower limb function (as evaluated by 5 repetitions of going from sit-to-stand) and reduced drowsiness in adults aged 65 years and older when taken in the afternoon.[56] A 2026 meta-analysis of 10 eligible randomized controlled trials also found NMN supplementation had a significant effect of reducing diastolic blood pressure by approximately 2.2 mmHg, with significant reductions in systolic blood pressure observed only among adults aged 60 years and older.[57]
NMN Dosage and Safety in Clinical Trials
Most of these clinical trials used NMN at a dose of 250 mg/day, although higher doses have been shown to potentially be more efficacious in studies looking at its effect on aerobic performance in younger individuals.[58] NMN supplementation has generally been shown to be safe in these populations, with doses as high as 1,250 mg/day being safely taken in individuals age 65 and older for up to 24 weeks.[59]
Beyond “Anti-Aging”: Supporting the Foundations of Healthspan
Ultimately, healthy aging may be less about finding the next “anti-aging” compound and more about supporting the fundamental processes that keep us functioning well as we age. Magnesium, berberine, and NMN each have evidence supporting a role in healthy aging, but from different angles: magnesium through its essential roles in cellular function and associations with frailty, metabolic health, and mortality; berberine through substantial clinical evidence for improving metabolic and cardiovascular risk factors; and NMN through emerging trials suggesting benefits for cellular health and physical function. Together, the research summarized above illustrates how supporting healthspan may be less about finding a single “anti-aging” compound and more about targeting the fundamental processes that help maintain metabolic health and physical function throughout life.
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