Biomarkers of Longevity: A Scientific Review of Key Predictors for Long-Term Health and All-Cause Mortality

Introduction: The Paradigm Shift in Preventive Medicine—From Disease Treatment to Healthspan Optimization

The practice of modern medicine is undergoing a fundamental paradigm shift, moving from a reactive model focused on the diagnosis and treatment of established disease to a proactive, preventative framework centered on the optimization of "healthspan"—the period of life spent in good health, free from chronic disease and disability. This evolution is driven by the recognition that the major causes of morbidity and mortality in developed nations—cardiovascular disease, cancer, neurodegenerative disorders, and metabolic diseases—are not acute events but rather the culmination of decades of slow, subclinical physiological decline. Central to this new paradigm is the use of a panel of sensitive molecular biomarkers. These markers serve as a high-resolution tool to quantify risk, monitor physiological status, and guide personalized interventions long before the manifestation of clinical symptoms. By measuring the underlying processes that drive aging and disease, it becomes possible to move beyond population-level statistics and toward a precision-based approach to extending the years of healthy, functional life.

This report will provide an exhaustive scientific review of the biomarkers most predictive of long-term health risk and all-cause mortality. The analysis is organized around four thematic pillars representing the core biological processes that underpin the majority of age-related chronic diseases. These pillars provide a coherent framework for understanding how seemingly disparate biomarkers are, in fact, deeply interconnected nodes within a complex physiological network.

1. Atherogenesis: The process of atherosclerotic plaque development within the arterial wall is the primary pathophysiological driver of cardiovascular disease, the leading cause of death globally. The analysis will begin with an in-depth examination of Apolipoprotein B (ApoB), the definitive metric for quantifying the burden of atherogenic lipoprotein particles that initiate this process.
2. Systemic Inflammation: Chronic, low-grade, sterile inflammation, a state often termed "inflammaging," has emerged as a common mechanistic pathway for a multitude of age-related conditions, including cardiovascular disease, cancer, and neurodegeneration. High-sensitivity C-reactive protein (hs-CRP) will be examined as the cardinal biomarker of this systemic inflammatory state.
3. Metabolic Dysfunction: Impaired energy metabolism, characterized by insulin resistance, is a foundational driver of systemic disease. This state promotes atherogenesis, fuels inflammation, and is directly linked to the development of type 2 diabetes, obesity, and certain cancers. Key markers of this axis, including uric acid, fasting insulin, and glycated hemoglobin (HbA1c), will be analyzed.
4. Nutritional and Cofactor Status: Optimal cellular function is contingent upon the availability of essential nutrients, minerals, and cofactors that participate in countless enzymatic reactions. Deficiencies or imbalances in these foundational components can cripple metabolic pathways, impair cellular repair, and promote a pro-inflammatory state. The Omega-3 Index and Magnesium status will be reviewed as critical indicators of nutritional adequacy and cellular health.

The report will proceed by examining each primary biomarker in detail, establishing its physiological role, its link to disease pathogenesis, the evidence-based optimal ranges for longevity, and its quantitative association with all-cause mortality. Subsequently, an integrated framework will be presented, illustrating the critical interrelationships between these markers and introducing additional high-impact biomarkers, such as Lipoprotein(a), to build a more complete and actionable picture of long-term health risk.

Section I: Apolipoprotein B (ApoB): The Definitive Metric of Atherogenic Particle Burden

Physiological Function and Pathophysiology

Apolipoprotein B (ApoB) is the primary, obligate structural protein for all lipoproteins considered to be atherogenic.¹ These include very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and Lipoprotein(a) [Lp(a)], all of which originate from the liver. The central and defining characteristic of ApoB in a clinical context is that there is precisely one molecule of ApoB per lipoprotein particle.¹ This immutable 1:1 stoichiometric relationship makes the plasma concentration of ApoB a direct and accurate measure of the total number of circulating atherogenic particles, a quantity often referred to as LDL particle number (LDL-P).³

The pathophysiology of atherosclerosis is fundamentally a particle-driven process. The initiating event is the penetration of an ApoB-containing lipoprotein particle through the endothelial layer of the arterial wall into the subendothelial space, a process known as lipoprotein retention.¹ Once trapped, these particles undergo oxidative and enzymatic modifications, triggering a chronic inflammatory response. This cascade involves the recruitment of monocytes, which differentiate into macrophages and engulf the modified lipoproteins, transforming into "foam cells"—the hallmark of the early atherosclerotic lesion, or fatty streak.¹ Over time, this inflammatory process leads to the development of a complex atherosclerotic plaque, which can narrow the artery and, if it ruptures, cause an acute thrombotic event such as a myocardial infarction or ischemic stroke.⁵ The probability of this initiating event is a direct function of the number of atherogenic particles in circulation and the duration of their exposure to the arterial wall. Therefore, the total particle burden, as measured by ApoB, is the primary driver of atherosclerotic cardiovascular disease (ASCVD).¹

Clinical Significance: The Case for ApoB's Superiority Over LDL-C

For decades, the standard for assessing lipid-related cardiovascular risk has been the measurement of LDL-Cholesterol (LDL-C). However, a significant body of evidence now establishes that ApoB is a more accurate and reliable predictor of cardiovascular risk.⁴ The fundamental limitation of LDL-C is that it measures the mass of cholesterol contained within LDL particles, not the number of particles themselves. This is a critical distinction because the amount of cholesterol per particle can vary substantially, leading to a potential discordance between LDL-C levels and the actual number of atherogenic particles.⁵

This discordance is most pronounced in individuals with metabolic syndrome, insulin resistance, or type 2 diabetes. In these common conditions, patients frequently exhibit a lipid profile characterized by high triglycerides and low HDL-C. This metabolic environment promotes the formation of small, dense LDL (sdLDL) particles, which are cholesterol-depleted.² Consequently, an individual can have a high number of these highly atherogenic sdLDL particles—and thus a high ApoB level and high cardiovascular risk—while simultaneously having a "normal" or even low LDL-C level. In this scenario, an LDL-C measurement would fail to identify the elevated risk, whereas an ApoB test would correctly classify the individual as high-risk.⁵

Large-scale, landmark epidemiological studies have consistently validated the superior predictive power of ApoB. The AMORIS (Apolipoprotein-related Mortality Risk) study and the INTERHEART study both demonstrated that ApoB and the ApoB/ApoA1 ratio (which reflects the balance between atherogenic and anti-atherogenic particles) were significantly stronger predictors of myocardial infarction than LDL-C.¹ More recently, a 2021 analysis of over 389,000 individuals from the UK Biobank confirmed that ApoB was the single strongest lipid-related predictor of myocardial infarction risk.⁵ This evidence supports a fundamental reframing of cardiovascular risk assessment, moving the focus from the quantity of cholesterol being transported to the number of particles responsible for its delivery into the arterial wall.

Optimal and Risk-Stratified Ranges

The standard reference ranges for ApoB provided by many clinical laboratories are often misleadingly high and do not reflect levels associated with minimal long-term risk of ASCVD. For example, ranges defining "normal" as less than 100 mg/dL or even up to 130 mg/dL are common.⁵ However, a consensus among cardiovascular prevention experts, based on extensive epidemiological and clinical trial data, advocates for significantly lower targets for optimal health and risk mitigation. These evidence-based ranges are typically stratified by an individual's overall cardiovascular risk profile ⁵:

• Optimal / Low Risk: <80 mg/dL. Some guidelines suggest <90 mg/dL.⁵ This range is considered ideal for healthy individuals with no major risk factors seeking primary prevention.
• High Risk: <70 mg/dL. This target is appropriate for individuals with established risk factors such as diabetes, metabolic syndrome, or a strong family history of premature ASCVD.⁵
• Very High Risk: <60 mg/dL. This aggressive target is recommended for individuals with established ASCVD, such as a prior myocardial infarction or stroke, for secondary prevention.⁵

Association with Disease and Mortality

The relationship between ApoB concentration and cardiovascular disease is linear, continuous, and causal. Observational data indicate that for every 10 mg/dL increase in ApoB, the risk of coronary heart disease rises by approximately 10-15%.⁵ This is strongly supported by Mendelian randomization studies, which use genetic variants as a proxy for lifelong exposure to a risk factor. A large-scale genetic analysis found that each 1-standard deviation (SD) increase in genetically determined ApoB was associated with a 65% higher risk of coronary artery disease and, critically, a 36% higher risk of cardiovascular mortality.¹⁰ The analysis further revealed that this positive, dose-response relationship holds across the entire natural distribution of ApoB levels, with no evidence of a lower threshold below which risk is eliminated. This finding provides strong genetic support for the clinical paradigm of "lower is better" for cardiovascular health.¹⁰

The association between ApoB and all-cause mortality is more complex and often presents as a U-shaped or J-shaped curve in observational studies.¹¹ The high-risk arm of this curve is driven by the strong link between elevated ApoB and fatal cardiovascular events.¹⁰ However, several large cohort studies have reported a paradoxical increase in all-cause mortality at very low endogenous ApoB levels (e.g., <65 mg/dL).¹² It is crucial to understand that this association does not imply that high ApoB is protective. Instead, this phenomenon is mediated by confounding from severe non-cardiovascular illnesses. ApoB is synthesized in the liver, and its production is dependent on adequate nutritional status and hepatic function. In conditions such as advanced cancer, cachexia, severe liver disease, or malnutrition, the body's synthetic capacity collapses, leading to very low levels of ApoB and other proteins.¹² In this context, a very low ApoB level is not a marker of cardiovascular health but rather a biomarker of systemic frailty and impending mortality from a non-cardiovascular cause.

This distinction is critical when interpreting ApoB levels. While the therapeutic reduction of ApoB is a primary goal for preventing cardiovascular mortality, an endogenously very low ApoB level in an untreated individual should be considered a red flag that warrants investigation for serious underlying pathology. Data from intervention trials reinforces the benefit of lowering ApoB; a meta-regression analysis of 29 randomized controlled trials found that for every 10 mg/dL decrease in ApoB achieved through therapy, the relative risk of all-cause mortality was reduced by 5% (RR=0.95), an effect driven primarily by statin therapy.¹⁴

Section II: High-Sensitivity C-Reactive Protein (hs-CRP): A Barometer of Systemic Inflammation

Physiological Function and Pathophysiology

C-reactive protein (CRP) is a canonical acute-phase reactant protein synthesized predominantly by hepatocytes in the liver. Its production is rapidly and dramatically upregulated in response to pro-inflammatory cytokines, with Interleukin-6 (IL-6) being the principal stimulus.¹⁶ The primary physiological role of CRP is to participate in the innate immune response. It functions as an opsonin, binding to phosphocholine expressed on the surface of dead or dying cells and certain pathogens, thereby activating the classical complement pathway to facilitate the clearance of cellular debris and microbes.¹⁶

While standard CRP assays measure levels in the range of 10 to 1,000 mg/L to detect acute infection, trauma, or significant tissue injury, the development of high-sensitivity CRP (hs-CRP) assays has enabled the precise quantification of much lower concentrations, typically in the 0.5 to 10 mg/L range.¹⁶ This has been a pivotal advance, as it allows for the measurement of chronic, low-grade systemic inflammation—a subclinical state now recognized as a fundamental contributor to the pathogenesis of a wide array of age-related, non-communicable diseases.¹⁸ This persistent, low-level inflammatory state is often referred to as "inflammaging".¹⁹

Mounting evidence indicates that CRP is not merely a passive bystander or marker of inflammation but an active participant in the progression of atherosclerosis. Within the vascular wall, CRP has been shown to induce the expression of adhesion molecules on endothelial cells, promoting the recruitment of monocytes into developing plaques.¹⁹ It can also suppress the production and bioavailability of endothelial nitric oxide (NO), a critical vasodilator and anti-inflammatory molecule, thereby contributing to endothelial dysfunction.¹⁹ Furthermore, by activating the complement system within ischemic cardiac tissue, CRP may exacerbate myocardial damage following an infarction.¹⁹ This dual role as both a marker and a mediator solidifies its position as a central biomarker in cardiovascular risk assessment.

Optimal Levels for Longevity and Risk Stratification

Based on extensive data from large prospective cohort studies, the American Heart Association (AHA) and the U.S. Centers for Disease Control and Prevention (CDC) have established standardized risk categories for hs-CRP that are widely used in clinical practice to stratify cardiovascular risk ¹⁶:

• Low Risk (Optimal): <1.0 mg/L
• Average Risk: 1.0 to 3.0 mg/L
• High Risk: >3.0 mg/L

It is important to note that hs-CRP levels should be measured when an individual is clinically stable, as any acute illness or injury can cause a transient elevation, confounding the interpretation of baseline inflammatory status. Levels between 2 and 10 mg/L, in the absence of an acute condition, are often considered to represent a state of "metabolic inflammation," which is strongly associated with the pathophysiology of atherosclerosis and type 2 diabetes mellitus.¹⁶

Predictive Power for Disease and Mortality

The predictive power of hs-CRP extends far beyond cardiovascular disease, implicating systemic inflammation as a common pathway in multiple age-related pathologies.

• Cardiovascular Disease: Elevated hs-CRP is a robust and independent predictor of future cardiovascular events, including myocardial infarction, ischemic stroke, and sudden cardiac death, in both apparently healthy individuals and patients with established cardiovascular disease.¹⁷ Its predictive value is additive to that of traditional risk factors, including lipid levels. The causal role of the inflammatory pathway in ASCVD has been substantiated by clinical trials such as CANTOS, which demonstrated that targeting the IL-1β to IL-6 to CRP pathway with the monoclonal antibody canakinumab significantly reduced cardiovascular events, an effect that was correlated with the degree of CRP reduction.²⁰ Similarly, low-dose colchicine, another anti-inflammatory agent, has been shown to lower CRP and improve cardiovascular outcomes.²⁰
• Cancer: A strong and consistent association has been observed between elevated hs-CRP levels and both the incidence of and mortality from various cancers.¹⁸ A meta-analysis of data from a large Chinese cohort study found that, compared to individuals with hs-CRP levels<1 mg/L, those with levels of 1-3 mg/L had a 51% increased risk of cancer mortality (HR=1.51), and those with levels >3 mg/L had a 56% increased risk (HR=1.56).¹⁸ The proposed mechanisms involve inflammation-driven carcinogenesis, where a chronic inflammatory microenvironment promotes DNA damage, cell proliferation, angiogenesis, and inhibits apoptosis.¹⁸
• Cognitive Decline and Aging: Chronic systemic inflammation, as quantified by hs-CRP, is increasingly linked to accelerated biological aging and adverse neurological outcomes. Elevated hs-CRP is associated with cognitive impairment, dementia, and an increased risk of Alzheimer's disease.¹⁹ A particularly insightful study demonstrated a synergistic and multiplicative effect between inflammation and metabolic dysfunction on the aging process. It found that adults with both high CRP (>3 mg/L) and diabetes experienced a biological age acceleration of 8.74 years, whereas those with high CRP but without diabetes showed an acceleration of only 1.66 years. The combined presence of high CRP and diabetes more than tripled the risk of all-cause and cardiovascular mortality.¹⁹ This highlights a vicious cycle where metabolic disease fuels inflammation, and inflammation in turn exacerbates metabolic dysfunction and accelerates aging.
• All-Cause Mortality: The association between hs-CRP and all-cause mortality is strong, graded, and independent of a wide range of traditional risk factors. Data from multiple large, multi-ethnic cohorts consistently show a dose-response relationship.¹⁷ The aforementioned meta-analysis provided clear quantitative risk estimates: compared to the optimal group with hs-CRP<1 mg/L, individuals in the average risk group (1-3 mg/L) had a 29% higher risk of all-cause mortality (HR=1.29), while those in the high-risk group (>3 mg/L) had a 53% higher risk (HR=1.53).¹⁸ Another study analyzing a Brazilian cohort found that the risk of death increased steadily across quartiles of hs-CRP, with the highest quartile having a 95% greater risk of all-cause mortality compared to the lowest quartile (HR=1.95).¹⁷ This demonstrates that hs-CRP acts as a powerful, integrative indicator of systemic stress, capturing risk signals from metabolic, infectious, and lifestyle-related sources into a single, highly prognostic measure.

Section III: Homocysteine: A Marker of Methylation Efficiency and Vascular Health

Biochemical Pathways and Physiological Role

Homocysteine is a non-proteinogenic, sulfur-containing amino acid that occupies a critical juncture in cellular metabolism. It is not obtained from the diet but is synthesized endogenously as an intermediate in the metabolism of the essential amino acid methionine.²⁴ Once formed from S-adenosylhomocysteine (SAH), homocysteine has two primary metabolic fates, the balance of which is essential for maintaining cellular homeostasis ²⁴:

1. Remethylation: Homocysteine can be remethylated back to methionine, a reaction that is a cornerstone of the one-carbon metabolism or methylation cycle. This pathway is catalyzed by the enzyme methionine synthase and requires vitamin B12 (as methylcobalamin) as a cofactor and 5-methyltetrahydrofolate (the active form of folate) as the methyl group donor.
2. Transsulfuration: Alternatively, homocysteine can be irreversibly converted into cysteine through a two-step process known as the transsulfuration pathway. This pathway is catalyzed by the enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), both of which require vitamin B6 (as pyridoxal-5'-phosphate) as an essential cofactor. Cysteine is subsequently used for the synthesis of proteins and, most importantly, the master antioxidant glutathione.

Because its clearance is entirely dependent on the efficient functioning of these two pathways, the circulating level of homocysteine serves as a highly sensitive functional biomarker for the status of the methylation cycle and, by extension, the adequacy of three key B-vitamins: folate, vitamin B12, and vitamin B6.²⁴ Elevated homocysteine levels, or hyperhomocysteinemia, signal a bottleneck in one or both of these critical metabolic pathways.

Association with Health Risks

A vast body of observational and epidemiological research has established a strong and consistent association between elevated plasma homocysteine levels and an increased risk for a wide spectrum of chronic diseases. These include cardiovascular and thromboembolic diseases (coronary artery disease, stroke, peripheral vascular disease, deep vein thrombosis), renal dysfunction, osteoporotic fractures, and neurodegenerative conditions, particularly Alzheimer's disease and age-related cognitive decline.²⁴

The proposed pathophysiological mechanisms linking hyperhomocysteinemia to vascular disease are multifactorial. Elevated homocysteine has been shown to impair endothelial function by increasing oxidative stress and reducing the bioavailability of nitric oxide.²⁶ It also promotes a pro-thrombotic state by activating platelets and interfering with anticoagulant pathways, and may contribute directly to the proliferation of vascular smooth muscle cells, a key feature of atherosclerotic lesions.²⁵ In the context of neurodegeneration, high homocysteine levels are associated with increased oxidative stress, neuroinflammation, and hippocampal atrophy.²⁶

The Causality Debate and Clinical Utility

Despite the compelling observational data, the role of homocysteine as a causal agent in disease has been the subject of intense debate. This controversy stems primarily from the results of large-scale randomized controlled trials (RCTs) conducted in the early 2000s. These trials demonstrated that while supplementation with folic acid, B6, and B12 effectively lowered plasma homocysteine levels, this biochemical improvement did not translate into a significant reduction in cardiovascular events or mortality.²⁸

This apparent contradiction has been further reinforced by Mendelian randomization studies. One such analysis utilized the common C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene—a genetic variant that naturally leads to higher homocysteine levels—as an instrumental variable. The study found that while the genetically predicted higher homocysteine levels were associated with increased stroke risk, they were not causally linked to coronary heart disease or all-cause mortality.²⁸

These findings have led to a critical shift in the clinical interpretation of homocysteine. The current consensus is that while homocysteine may not be a direct causal target for therapy in the general population, it remains an extremely valuable and powerful integrative risk marker. An elevated homocysteine level is not the disease itself, but rather a diagnostic clue—a signal that a fundamental metabolic process is impaired. Its elevation should prompt a clinical investigation into the underlying causes, which may include inadequate B-vitamin status, poor dietary habits, impaired renal function, or genetic factors affecting methylation pathways. Addressing these root causes, rather than simply lowering the homocysteine number, is the appropriate clinical response.

Relationship with All-Cause Mortality

The association between homocysteine levels and all-cause mortality in observational studies is remarkably strong, linear, and dose-dependent. A major dose-response meta-analysis of prospective studies provided a clear quantitative estimate of this risk: for every 5 µmol/L increase in plasma homocysteine levels, the risk of all-cause mortality increased by 33.6% (RR=1.336, 95% CI: 1.254–1.422).²⁶ Another meta-analysis, which compared individuals in the highest category of homocysteine to those in the lowest, found a staggering 93% increase in the risk of all-cause mortality (

RR=1.93, 95% CI: 1.54–2.43).³⁰

While there are no universally standardized optimal ranges, functional and preventive medicine practitioners generally aim for levels significantly lower than the typical laboratory cutoff for hyperhomocysteinemia (often defined as >15 µmol/L).²⁴ An optimal level is frequently considered to be below 10 µmol/L, with some experts advocating for a target of less than 7 µmol/L to minimize long-term risk. The power of homocysteine as a biomarker may lie in its ability to reflect the integrity of the methylation cycle, a ubiquitous and fundamental process essential for DNA repair, epigenetic regulation of gene expression, neurotransmitter synthesis, and detoxification. An elevated homocysteine level may therefore be a proxy for impaired cellular maintenance and repair capacity, providing a plausible mechanistic link to the broad range of age-related diseases and the increased mortality risk with which it is associated.

Section IV: Uric Acid: The Paradoxical Regulator of Oxidative Stress

A Dual-Edged Sword: Physiology and Pathophysiology

Uric acid, or serum urate (SUA), is the terminal catabolic product of purine metabolism in humans. Purines are derived from two sources: endogenous turnover of nucleic acids from the body's own cells and exogenous dietary intake, particularly from purine-rich foods such as organ meats, certain seafood, and alcohol.³¹ During primate evolution, a mutation inactivated the gene for the enzyme uricase, which in other mammals degrades uric acid into the more soluble allantoin. This evolutionary event resulted in humans having significantly higher circulating uric acid levels, suggesting a potential survival advantage was conferred by its retention.³¹

This advantage is likely rooted in the paradoxical, dual nature of uric acid. In the extracellular environment, such as the blood plasma, uric acid is one of the most powerful and abundant antioxidants, responsible for neutralizing a significant portion of circulating free radicals.³¹ This antioxidant capacity may have provided benefits related to neuroprotection and protection against systemic oxidative stress. However, this protective role is starkly contrasted by its function once it is transported

inside cells, such as vascular endothelial cells, adipocytes, or hepatocytes. Intracellularly, uric acid acts as a potent pro-oxidant, stimulating the production of reactive oxygen species (ROS) via pathways like NADPH oxidase, which in turn activates pro-inflammatory signaling cascades.³¹

This location-dependent switch from antioxidant to pro-oxidant is central to its pathophysiology. High levels of uric acid directly inactivate nitric oxide (NO), a critical signaling molecule that promotes vasodilation. The resulting endothelial dysfunction contributes to hypertension and impairs blood flow.³¹ Furthermore, intracellular uric acid can directly promote inflammation and worsen insulin resistance, establishing it as a key player in metabolic and cardiovascular disease.³¹

Metabolic Derangement and Disease Risk

Hyperuricemia (high serum uric acid) is a hallmark feature of the metabolic syndrome and is tightly interwoven with its core components: hypertension, visceral obesity, dyslipidemia, and insulin resistance.³³ The relationship is often bidirectional. Insulin resistance, for instance, can impair the kidneys' ability to excrete uric acid, leading to higher serum levels. Conversely, elevated uric acid can exacerbate insulin resistance by inducing oxidative stress and inflammation in target tissues, creating a vicious cycle.³⁴

Dietary factors play a major role in driving uric acid production. The metabolism of fructose, which occurs almost exclusively in the liver, is a particularly potent stimulus for uric acid synthesis. The process of metabolizing fructose depletes intracellular ATP, leading to the degradation of purines and a subsequent surge in uric acid production.³¹ This provides a direct biochemical link between the high consumption of fructose (e.g., from sugar-sweetened beverages and processed foods) and the development of hyperuricemia and its associated metabolic derangements. At very high concentrations, uric acid can exceed its solubility limit and crystallize in joints and soft tissues, causing the intensely painful inflammatory condition known as gout, or in the urinary tract, forming kidney stones.³¹

The J-Shaped Mortality Curve

Consistent with its dual physiological role, the relationship between serum uric acid levels and all-cause mortality follows a distinct J-shaped or U-shaped curve, as demonstrated in multiple large-scale epidemiological studies.³⁶ This indicates that risk is elevated at both high and low extremes of the distribution.

• High Levels: The association between hyperuricemia and increased mortality is well-established and robust. A study of over 350,000 individuals found that, compared to a reference range of 0.30-0.41 mmol/L, those with SUA levels ≥0.66 mmol/L had more than double the risk of all-cause mortality (age- and sex-adjusted HR=2.12).³⁶ Another study noted an 8-11% increase in mortality for every 1 mg/dL (approximately 0.06 mmol/L) increase in SUA above the hyperuricemic threshold of 7 mg/dL.³¹ A recent, comprehensive meta-analysis involving over 2.5 million participants confirmed this, finding that higher SUA levels were associated with a 32% increased risk of all-cause mortality (RR=1.32). This risk was particularly pronounced in women, who experienced a 91% increased risk (RR=1.91), compared to a 16% increase in men (RR=1.16).³⁷
• Low Levels: The other side of the curve shows that very low levels of uric acid are also associated with increased mortality. In the same large Taiwanese cohort, individuals with the lowest SUA levels (≤0.17 mmol/L) had a nearly threefold higher risk of all-cause mortality compared to the reference group (HR=2.79).³⁶ The mechanism for this is less certain but may relate to the loss of uric acid's systemic antioxidant capacity, or it could be that very low levels act as a marker for other conditions such as malnutrition, frailty, or certain malignancies.
• Optimal Range: The nadir of the mortality curve represents the "Goldilocks" zone of lowest risk. The large Taiwanese study identified this optimal range as 0.30-0.41 mmol/L (approximately 5.0-7.0 mg/dL for men and 4.0-6.0 mg/dL for women, though the study used combined data).³⁶ However, given the strong evidence linking even high-normal levels to metabolic dysfunction, more recent research and expert opinion suggest a tighter optimal range for proactive health management, with a recommended upper limit of 5.5 mg/dL (approximately 0.33 mmol/L).³¹ This target aims to maximize the extracellular antioxidant benefits while minimizing the risk of intracellular pro-oxidant damage.

Section V: The Omega-3 Index: A Measure of Cellular Membrane Health and Inflammatory Tone

Defining the Biomarker

The Omega-3 Index (O3I) is a validated nutritional biomarker that quantifies the long-term status of the marine-derived omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). It is specifically defined as the percentage of EPA plus DHA in the total fatty acid composition of red blood cell (RBC) membranes.³⁹ RBCs have a lifespan of approximately 120 days, which means the O3I provides a stable, integrated measure of an individual's omega-3 status over the preceding 3-4 months. This makes it a far more reliable and clinically useful marker than measuring transient plasma levels or relying on often inaccurate dietary recall questionnaires. Furthermore, the fatty acid composition of RBC membranes has been shown to correlate well with the levels in other critical tissues, including the myocardium (heart muscle), making it an excellent surrogate for the body's overall omega-3 tissue status.³⁹

Physiological Roles and Mechanisms

The physiological importance of EPA and DHA stems from their fundamental roles in cellular structure and function. As long-chain polyunsaturated fatty acids, they are preferentially incorporated into the phospholipid bilayers of all cell membranes throughout the body.³⁹ This incorporation directly influences the biophysical properties of the membrane, such as fluidity, flexibility, and thickness, which in turn affects the function of embedded proteins like receptors, ion channels, and transporters.

Beyond their structural role, EPA and DHA are key modulators of the inflammatory response. They serve as precursors for a specialized class of potent anti-inflammatory and pro-resolving lipid mediators, including resolvins, protectins, and maresins. These molecules are critical for actively resolving inflammation and promoting tissue healing. Additionally, EPA and DHA compete with the pro-inflammatory omega-6 fatty acid, arachidonic acid (AA), for the same metabolic enzymes. By displacing AA from cell membranes and competing for enzymatic conversion, a higher omega-3 status shifts the body's eicosanoid balance away from the production of pro-inflammatory prostaglandins and leukotrienes and towards a less inflammatory or anti-inflammatory state.⁴² This modulation of the body's inflammatory tone is a key mechanism underlying many of the health benefits associated with a high O3I.

Optimal Levels and Risk Stratification

Research over the past two decades has led to a strong consensus on clinically meaningful risk thresholds for the Omega-3 Index, which are now widely used for risk stratification and to guide therapeutic interventions ³⁹:

• High Risk: An O3I of <4%. This level is associated with the highest risk for adverse cardiovascular events and other chronic conditions.
• Intermediate Risk: An O3I between 4% and 8%.
• Low Risk (Optimal): An O3I of >8%. This is considered the target zone for optimal health and cardioprotection, with a desirable range often cited as 8-12%.⁴⁶

Evidence for Disease Prevention and Mortality Reduction

A substantial body of observational evidence links a higher Omega-3 Index to a reduced risk of multiple chronic diseases and improved longevity.

• Cardiovascular Disease: The strongest evidence for the O3I relates to cardiovascular health. A higher index is consistently and inversely associated with the risk of cardiovascular events, particularly fatal coronary heart disease and sudden cardiac death.³⁹ A meta-analysis of 10 cohort studies estimated that increasing the O3I from 4% (high risk) to 8% (low risk) would reduce the risk of fatal coronary heart disease by approximately 30%.⁴⁴ Data from the landmark Framingham Heart Study provided powerful confirmation of these findings. Among 2,500 participants followed for a median of 7.3 years, those in the highest quintile of the O3I (>6.8%) had a 39% lower risk of experiencing a first-time cardiovascular event compared to those in the lowest quintile (<4.2%).⁴⁷
• All-Cause Mortality: The protective association of a high O3I extends to mortality from all causes. The same Framingham Heart Study analysis found that individuals in the highest O3I quintile had a 34% lower risk of death from any cause during the follow-up period compared to those in the lowest quintile.⁴⁷ Other prospective studies have independently confirmed this inverse association between blood levels of EPA and DHA and all-cause mortality, particularly in patients with stable coronary heart disease.⁴⁵
• Aging and Other Conditions: The benefits of an optimal omega-3 status are systemic. A higher O3I has been associated with slower biological aging, as measured by epigenetic clocks, and a reduced risk of certain cancers.³⁹ It is also linked to better cognitive function, a lower risk of dementia, and a reduced incidence of major depression, reflecting the critical role of DHA as a structural component of neuronal membranes.⁴⁵

Addressing Inconsistencies in Intervention Trials

While the observational data linking O3I to better health outcomes are remarkably consistent, randomized controlled trials (RCTs) of omega-3 supplementation have produced mixed and often conflicting results, particularly for all-cause mortality.⁴² This apparent discrepancy can be largely explained by critical flaws in the design of many of these trials. A key issue is the failure to measure participants' baseline O3I and to treat to a specific target level. Administering a fixed, one-size-fits-all dose of omega-3s to a heterogeneous population—some of whom may already have an adequate O3I—will inevitably dilute the treatment effect. The therapeutic benefit of supplementation is likely concentrated in those individuals who start with a low O3I (

<4%) and are given a sufficient dose to raise their level into the protective range (>8%).⁴⁰ Furthermore, there is vast inter-individual variability (up to 13-fold) in the absorption and metabolism of omega-3s, meaning the same dose can produce vastly different changes in the O3I in different people.³⁹ This underscores the necessity of a personalized, "treat-to-target" approach, using the O3I not just as a prognostic marker but as a prescriptive tool to guide and verify the efficacy of supplementation.

Section VI: Magnesium Status: The Master Mineral for Cellular Energetics

Clarifying the Measurement

Assessing an individual's true magnesium status is notoriously challenging due to the mineral's distribution in the body. The term "Magnesium Index," as used in the user query, is not a standard clinical term and most closely relates to soil science.⁵² In human health, the most commonly ordered test is serum magnesium. However, this measurement is a notoriously poor and often misleading indicator of total body magnesium stores.⁵³ This is because less than 1% of the body's total magnesium circulates in the bloodstream. The vast majority—approximately 99%—is located intracellularly (primarily in muscle and soft tissues) and within the bone matrix.⁵⁴ The body tightly regulates serum magnesium levels. When circulating levels begin to fall due to inadequate intake or excessive loss, magnesium is actively pulled out of cells and bone to maintain serum concentrations within the normal range.⁵³ Consequently, a normal serum magnesium level can coexist with, and effectively mask, a significant and functionally important intracellular or total body deficiency.

A more accurate and clinically useful method for assessing functional magnesium status is the measurement of Red Blood Cell (RBC) magnesium.⁵³ Because magnesium's primary roles are intracellular, the concentration within RBCs provides a much better reflection of the body's readily available stores in other tissues. Therefore, this analysis will focus on RBC magnesium as the most relevant biomarker for assessing long-term health risk related to magnesium status.

Indispensable Physiological Roles

Magnesium is an essential mineral and one of the most critical cofactors in human physiology. It is required for the proper functioning of over 600 enzymatic reactions, second only to zinc.⁵³ Its roles are ubiquitous and fundamental to life:

• Energy Production: Magnesium is indispensable for energy metabolism. It binds to adenosine triphosphate (ATP), the primary energy currency of the cell, to form the Mg-ATP complex, which is the biologically active form of ATP required for virtually all energy-dependent processes.⁵³
• Synthesis and Repair: It is a critical cofactor for enzymes involved in the synthesis of DNA, RNA, and proteins, as well as for the synthesis of the master antioxidant, glutathione.⁵³
• Neuromuscular Function: Magnesium plays a central role in regulating neuromuscular excitability. It acts as a natural physiological calcium channel blocker, modulating the influx of calcium into nerve and muscle cells. This function is essential for proper nerve conduction, muscle contraction and relaxation, and the maintenance of a normal heart rhythm.⁵³
• Vitamin D Metabolism: Magnesium is an obligatory cofactor for several key enzymes involved in the activation and metabolism of Vitamin D. A deficiency in magnesium can impair the body's ability to convert vitamin D into its active form, 1,25-dihydroxyvitamin D, rendering vitamin D supplementation ineffective.⁵³

Deficiency and Chronic Disease

Despite its critical importance, inadequate magnesium intake is remarkably common. It is estimated that up to half of the adult population in the United States may not consume enough magnesium to meet their needs.⁵⁵ This widespread, often subclinical, deficiency is strongly linked to an increased risk for a broad spectrum of chronic diseases. Associated conditions include cardiovascular diseases (hypertension, atherosclerosis, cardiac arrhythmias), metabolic syndrome, type 2 diabetes, osteoporosis, migraines, asthma, and various neurological and psychiatric disorders such as depression and anxiety.⁵³

The link between magnesium deficiency and these conditions is mechanistically plausible. For example, by impairing insulin signaling and glucose metabolism, magnesium deficiency contributes to insulin resistance.⁵³ By promoting vasoconstriction and sodium retention, it contributes to hypertension. And by failing to counterbalance calcium's excitatory effects, it can lead to cardiac arrhythmias and muscle cramps.

Association with Health Outcomes

While large-scale prospective studies directly linking RBC magnesium levels to all-cause mortality are less prevalent in the literature compared to other biomarkers, the evidence from studies on magnesium intake and serum levels in specific populations is compelling. A meta-analysis of prospective studies found a significant inverse association between dietary magnesium intake and the risk of cardiovascular events, including coronary heart disease and stroke.⁵³ Hypomagnesemia (low serum magnesium) is a very strong predictor of increased mortality in hospitalized and critically ill patients.

The optimal ranges for magnesium are best defined by the more accurate RBC test. While laboratory reference ranges can vary, many functional medicine experts recommend a target RBC magnesium level of >6.0 mg/dL to ensure optimal intracellular status.⁵³ For the less reliable serum test, the normal range is typically 1.82-2.30 mg/dL, but evidence suggests that levels greater than 2.07 mg/dL are more likely to reflect true adequacy.⁵³ Correcting magnesium status may be a foundational and underappreciated strategy for mitigating risk for two of the most prevalent chronic conditions in modern society: hypertension and metabolic syndrome.

Section VII: An Integrated Framework: Key Interrelationships and Additional High-Impact Biomarkers

Connecting the Dots: A Systems-Biology Perspective

The biomarkers analyzed in this report should not be viewed as isolated, independent variables. They are, in fact, deeply interconnected nodes within a complex web of human physiology, and their true predictive power is realized when they are interpreted as part of an integrated system. A systems-biology approach reveals how a primary insult, such as a modern Western dietary pattern, can trigger a cascade of pathological changes reflected across multiple biomarkers.

For example, a diet high in refined carbohydrates and fructose acts as a primary metabolic stressor.³¹ This directly drives an increase in

Uric Acid production. The elevated intracellular uric acid then actively promotes hepatic fat accumulation and worsens Insulin Resistance.³¹ This state of insulin resistance, in turn, signals the liver to increase production of VLDL particles, leading to a higher number of atherogenic particles in circulation, which is directly measured as an elevated

ApoB.¹ The increased ApoB particle burden is the direct cause of

Atherosclerosis. Concurrently, the underlying metabolic dysfunction and associated increase in visceral adiposity create a pro-inflammatory state, stimulating the liver to produce more hs-CRP.¹⁹ The resulting systemic inflammation further accelerates the atherosclerotic process. This integrated view, which traces the pathway from dietary input to molecular changes and eventual pathology, is essential for a comprehensive understanding of health risk. To build upon this framework, it is necessary to include several other high-impact biomarkers that provide critical, complementary information.

Additional High-Impact Biomarker 1: Lipoprotein(a) [Lp(a)]

• Function and Significance: Lipoprotein(a), or Lp(a), is a unique and highly atherogenic lipoprotein particle. It consists of an LDL-like particle, complete with a single molecule of ApoB-100, to which a large glycoprotein called apolipoprotein(a), or apo(a), is covalently attached.⁵⁶ The apo(a) protein has a structural homology to plasminogen, the precursor to the fibrin-dissolving enzyme plasmin. This structure gives Lp(a) not only pro-atherogenic properties (by delivering cholesterol to the artery wall) but also pro-thrombotic and anti-fibrinolytic properties (by interfering with clot breakdown).⁵⁶ A defining feature of Lp(a) is that its plasma concentration is almost entirely determined by genetics—specifically, by polymorphisms in theLPA gene—and remains remarkably stable throughout an individual's lifetime, largely unaffected by diet, exercise, or most lipid-lowering drugs.⁶⁰
• Disease and Mortality Risk: Decades of epidemiological and genetic research, including large-scale Mendelian randomization studies, have unequivocally established elevated Lp(a) as an independent and causal risk factor for atherosclerotic cardiovascular disease, myocardial infarction, stroke, and calcific aortic valve stenosis.⁵⁶ A comprehensive dose-response meta-analysis revealed that for each 50 mg/dL increase in Lp(a) levels, the risk of cardiovascular death increased by 31% in the general population and by 15% in patients with existing CVD.⁶² The association with all-cause mortality is also significant; the same meta-analysis found that individuals in the top tertile of Lp(a) levels had a 9% higher risk of all-cause mortality (HR=1.09) in the general population and an 18% higher risk (HR=1.18) in those with CVD.⁶² Given its strong genetic basis and causal role in ASCVD, major medical bodies, including the European Society of Cardiology, now recommend that Lp(a) be measured at least once in every adult's lifetime to assess their baseline, genetically-determined cardiovascular risk.⁵⁶
• Optimal Levels: There is no "normal" or "safe" level of Lp(a); it represents a continuous risk spectrum. However, clinical consensus guidelines have established thresholds to identify individuals at high risk. Levels greater than 30 mg/dL (approximately 75 nmol/L) are considered to confer increased risk, while levels greater than 50 mg/dL (approximately 125 nmol/L) are widely defined as high risk.⁵⁶

Additional High-Impact Biomarker 2: Fasting Insulin and HOMA-IR

• Function and Significance: Fasting insulin is a direct measure of the amount of insulin the pancreas is secreting in a basal, fasted state. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) is a calculated score based on fasting insulin and fasting glucose that provides a more robust estimate of insulin resistance. Insulin resistance is a foundational metabolic defect in which the body's cells (particularly in the liver, muscle, and adipose tissue) fail to respond efficiently to the signal of insulin. To compensate, the pancreas secretes progressively higher amounts of insulin (hyperinsulinemia) to maintain normal blood glucose levels.⁶⁵ This state of compensated hyperinsulinemia can precede the development of prediabetes and type 2 diabetes by years or even decades, making fasting insulin and HOMA-IR crucial early markers of metabolic dysfunction.
• Disease and Mortality Risk: Chronically elevated insulin levels (hyperinsulinemia) are a central driver of pathology. High insulin is directly linked to the development of hypertension, dyslipidemia (characterized by high triglycerides, low HDL-C, and a high number of small, dense LDL particles, i.e., high ApoB), central obesity, and an increased risk of cardiovascular disease, many types of cancer, and neurodegenerative diseases like Alzheimer's.⁶⁵ A meta-analysis of prospective studies in non-diabetic adults found that individuals with the highest levels of insulin resistance, as measured by HOMA-IR, had a 34% increased risk of all-cause mortality (RR=1.34) and more than double the risk of cardiovascular mortality (RR=2.11) compared to those with the lowest levels.⁶⁷
• Optimal Levels: The conventional laboratory reference range for fasting insulin, often cited as less than 25 μIU/mL, is dangerously permissive and effectively normalizes a state of significant metabolic disease.⁶⁶ Extensive research linking lower insulin levels to improved health outcomes supports the adoption of much more stringent optimal ranges. Evidence-based guidelines from preventive and longevity-focused medicine suggest an optimal fasting insulin level is in the range of2.6-5 μIU/mL.⁶⁵ Levels within this range are associated with significantly lower risks of cardiovascular disease and all-cause mortality, while each unit increase above this optimal zone is associated with a quantifiable increase in long-term risk.⁶⁶

Additional High-Impact Biomarker 3: Glycated Hemoglobin (HbA1c)

• Function and Significance: Glycated hemoglobin, or HbA1c, is a measure of long-term glycemic control. It is formed through a non-enzymatic reaction in which glucose in the bloodstream attaches to hemoglobin within red blood cells. Because RBCs have a lifespan of about 120 days, the HbA1c percentage reflects the average blood glucose concentration over the preceding 2-3 months. It is the international standard for diagnosing prediabetes and diabetes and for monitoring glycemic management in diabetic patients.⁶⁹
• Mortality Risk: The relationship between HbA1c and all-cause mortality is consistently shown to be J-shaped or U-shaped in both diabetic and non-diabetic populations.⁷² This means that risk is elevated at both high and low levels.
• High Levels: The risk associated with hyperglycemia is well-documented. A meta-analysis found that in non-diabetic individuals, HbA1c levels above 6.0% were associated with a 74% higher risk of all-cause mortality (HR=1.74) compared to levels in the 5.0-5.5% range.⁷² In diabetic populations, the risk climbs steadily with increasing HbA1c, with levels above 9.0% conferring a 69% increased risk (HR=1.69).⁷²
• Low Levels: The other side of the curve is equally important. Multiple studies, including the landmark ACCORD trial, have observed increased mortality at very low HbA1c levels, particularly in diabetic patients.⁷³ This increased risk may be due to the dangers of severe hypoglycemia induced by aggressive glucose-lowering therapy, or it may be that in certain contexts, a very low HbA1c can be a non-glycemic marker of frailty, malnutrition, or other severe underlying illness.
• Optimal Levels: The nadir of the J-shaped mortality curve indicates the range of lowest risk. Based on meta-analyses of large observational studies, the optimal HbA1c level for minimizing all-cause and cardiovascular mortality appears to be in the range of 5.0% to 5.5% for non-diabetic individuals. For people with diabetes, the optimal range is wider and subject to individualization, but generally falls between 6.0% and 7.5%, a range that balances the risks of hyperglycemia against the dangers of iatrogenic hypoglycemia.⁷²

Conclusion: A Multi-Marker Strategy for Quantifying Risk and Guiding Healthspan

This comprehensive review has synthesized the extensive evidence supporting a panel of key biomarkers as powerful predictors of long-term health, disease risk, and all-cause mortality. The analysis underscores a critical shift away from single-marker assessments and traditional reference ranges towards a more nuanced, integrated, and proactive approach to preventive medicine.

The evidence strongly supports the primacy of Apolipoprotein B over LDL-C as the definitive metric of atherogenic risk, directly quantifying the particle burden that drives cardiovascular disease. High-sensitivity C-reactive protein has emerged as an indispensable barometer of systemic inflammation, a common pathway linking metabolic dysfunction to a wide spectrum of age-related diseases, including cardiovascular disease and cancer. The measurement of fasting insulin provides the earliest and most sensitive indication of underlying insulin resistance, a foundational metabolic defect that precedes overt disease by decades. Biomarkers of nutritional status, such as the Omega-3 Index and RBC Magnesium, reflect the integrity of cellular membranes and the efficiency of enzymatic machinery, respectively, highlighting the foundational role of nutrition in long-term health. Finally, markers like Uric Acid, Homocysteine, Lipoprotein(a), and HbA1c provide complementary and crucial information about specific metabolic pathways, genetic predispositions, and the long-term consequences of glycemic dysregulation. For each of these, evidence-based optimal ranges, which are often significantly tighter than standard laboratory norms, have been established as targets for healthspan optimization.

The ultimate conclusion of this analysis is that a single biomarker, viewed in isolation, is insufficient for a comprehensive assessment of an individual's long-term health trajectory. True insight is derived from interpreting a panel of these key markers within the integrated framework of atherogenesis, inflammation, and metabolic health. The interplay between these markers is profoundly synergistic. An individual with a high ApoB and a concurrently high hs-CRP, for example, faces a dramatically elevated risk compared to someone with a high ApoB but low hs-CRP, as the former represents a state of both high atherogenic particle burden and the inflammatory fire to accelerate plaque progression. By employing a multi-marker strategy, it becomes possible to construct a high-fidelity map of an individual's unique physiological landscape. This data-driven approach allows for the identification of specific areas of vulnerability and the deployment of precise, targeted interventions—be they dietary, lifestyle, or pharmacological—to mitigate risk. Ultimately, the intelligent and integrated use of these biomarkers facilitates the fundamental goal of modern preventive medicine: to shift the focus from merely extending lifespan to actively managing and extending healthspan, thereby adding not just years to life, but life to years.

References

A comprehensive list of all sources cited in this report can be compiled from the research materials provided, identified by their unique source IDs.³¹

Works cited

1. Apolipoprotein B - Wikipedia, accessed August 21, 2025, https://en.wikipedia.org/wiki/Apolipoprotein_B
2. Rationale for using apolipoprotein B and apolipoprotein A-I as ..., accessed August 21, 2025, https://academic.oup.com/eurheartj/article/26/3/210/487180
3. Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target - PMC - PubMed Central, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8540246/
4. Apolipoprotein B and cardiovascular disease risk: position statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/19168552/
5. What are normal ApoB levels and why do they matter? - SiPhox Health, accessed August 21, 2025, https://siphoxhealth.com/articles/what-are-normal-apob-levels-and-why-do-they-matter
6. Using Apolipoprotein B Levels to Assess Cardiac Risk - AAFP, accessed August 21, 2025, https://www.aafp.org/pubs/afp/issues/2003/0315/p1386.html
7. Apolipoprotein B (APOB) Test - Cleveland Clinic, accessed August 21, 2025, https://my.clevelandclinic.org/health/diagnostics/24992-apolipoprotein-b-test
8. Apolipoprotein B-100 - Content - Health Encyclopedia - University of Rochester Medical Center, accessed August 21, 2025, https://www.urmc.rochester.edu/encyclopedia/content?contenttypeid=167&contentid=apolipoprotein_b100
9. ApoB Test: The Critical Heart Health Biomarker That Outranks LDL Cholesterol, accessed August 21, 2025, https://mitohealth.com/blog/apob-biomarker-health-heart-longevity
10. Even Low Levels of ApoB and LDL Linked With CAD, Mortality: UK ..., accessed August 21, 2025, https://www.tctmd.com/news/even-low-levels-apob-and-ldl-linked-cad-mortality-uk-biobank
11. Association of apolipoprotein B with all-cause and cardiovascular mortality among adults: Results from the National Health and Nutrition Examination Surveys - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/37611866/
12. Paradoxical Association Between Baseline Apolipoprotein B and Prognosis in Coronary Artery Disease - Frontiers, accessed August 21, 2025, https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.822626/full
13. Full article: Low apolipoprotein B and LDL-cholesterol are associated with the risk of cardiovascular and all-cause mortality: a prospective cohort, accessed August 21, 2025, https://www.tandfonline.com/doi/full/10.1080/07853890.2025.2529565
14. Association of lowering apolipoprotein B with cardiovascular outcomes across various lipid-lowering therapies: Systematic review and meta-analysis of trials - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7489462/
15. Association of lowering apolipoprotein B with cardiovascular outcomes across various lipid-lowering therapies: Systematic review and meta-analysis of trials - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/31475865/
16. C-reactive protein - Wikipedia, accessed August 21, 2025, https://en.wikipedia.org/wiki/C-reactive_protein
17. Association between C reactive protein and all-cause mortality in the ELSA-Brasil cohort, accessed August 21, 2025, https://jech.bmj.com/content/74/5/421
18. Prognostic value of C-reactive protein predicting all-cause and ..., accessed August 21, 2025, https://bmjopen.bmj.com/content/15/8/e101532
19. Biological Age BioMarkers Part 3: C-Reactive Protein (CRP) - OptimalDX, accessed August 21, 2025, https://www.optimaldx.com/research-blog/functional-age-biomarkers-part-3-c-reactive-protein-crp
20. Elevated C-reactive protein and cardiovascular risk - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/40014057/
21. The role of C-reactive protein in cardiovascular disease risk - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/10980827/
22. Association between C reactive protein and all-cause mortality in the ELSA-Brasil cohort, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7307658/
23. C-Reactive Protein and the Risk of Cancer: A Mendelian Randomization Study | JNCI, accessed August 21, 2025, https://academic.oup.com/jnci/article/102/3/202/894790
24. What Do Homocysteine Test Results Tell Us? - Rupa Health, accessed August 21, 2025, https://www.rupahealth.com/post/what-do-homocysteine-test-results-tell-us
25. Homocysteine and risk of cardiovascular disease - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/10590184/
26. (PDF) Association between Homocysteine Levels and All-cause ..., accessed August 21, 2025, https://www.researchgate.net/publication/318250522_Association_between_Homocysteine_Levels_and_All-cause_Mortality_A_Dose-Response_Meta-Analysis_of_Prospective_Studies
27. Effect of aging on homocysteine metabolism and possible mechanisms of hyperhomocysteinemia-associated aging diseases. - ResearchGate, accessed August 21, 2025, https://www.researchgate.net/figure/Effect-of-aging-on-homocysteine-metabolism-and-possible-mechanisms-of_fig1_352306156
28. High homocysteine causes cardiovascular disease - The BMJ, accessed August 21, 2025, https://www.bmj.com/content/325/7374/0.2
29. Association Between Plasma Homocysteine Level and Mortality: A Mendelian Randomization Study - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10625855/
30. Elevated homocysteine levels and risk of cardiovascular and all-cause mortality: a meta-analysis of prospective studies - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4288948/
31. The 2023 Levels Guide to uric acid, accessed August 21, 2025, https://www.levels.com/blog/what-is-uric-acid-and-why-should-we-measure-it
32. Uric Acid Variability and All-Cause Mortality: A Prospective Cohort Study in Northern China, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12275564/
33. Uric acid: A marker of increased cardiovascular risk - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/18585721/
34. Chronic Hyperuricemia, Uric Acid Deposit and Cardiovascular Risk - PMC - PubMed Central, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3606968/
35. Hyperuricemia in older age: symptoms and treatment - NORMS, accessed August 21, 2025, https://www.norms.in/blog/hyperuricemia-in-older-age-symptoms-and-treatment/
36. Significance of serum uric acid levels on the risk of all-cause and cardiovascular mortality - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/22923756/
37. Higher serum uric acid levels and risk of all-cause mortality in general population: a systematic review and meta-analysis - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/40491671/
38. Higher serum uric acid levels and risk of all-cause mortality in general population: a systematic review and meta-analysis, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12148453/
39. What is the Omega-3 Index? | Nutriterra, accessed August 21, 2025, https://www.nutriterraomega3.com/blog/what-is-the-omega-3-index
40. Omega-3 index and cardiovascular health - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/24566438/
41. Omega-3 fatty acids in heart disease—why accurately measured levels matter - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10602979/
42. Omega-3 meta-analysis shows mortality benefit - Heart - BMJ Blogs, accessed August 21, 2025, https://blogs.bmj.com/heart/2009/04/14/omega-3-meta-analysis-shows-mortality-benefit/
43. Effect of omega-3 fatty acids on all-cause mortality among studies with... - ResearchGate, accessed August 21, 2025, https://www.researchgate.net/figure/Effect-of-omega-3-fatty-acids-on-all-cause-mortality-among-studies-with-follow-up-12_fig2_44651203
44. The Omega-3 Index and relative risk for coronary heart disease mortality: Estimation from 10 cohort studies - ResearchGate, accessed August 21, 2025, https://www.researchgate.net/publication/316784951_The_Omega-3_Index_and_relative_risk_for_coronary_heart_disease_mortality_Estimation_from_10_cohort_studies
45. Cardiovascular Biomarkers: The Omega-3 Index - OptimalDX, accessed August 21, 2025, https://www.optimaldx.com/research-blog/biomarkers-of-cardiovascular-health-the-omega-3-index
46. Omega-3 Index FAQs - Food for the Brain, accessed August 21, 2025, https://foodforthebrain.org/omega-3-index-faqs/
47. The Omega-3 Index can serve as a marker of overall health in older Americans. Erythrocyte Long-Chain Omega-3 Fatty Acid Levels are Inversely Associated with Mortality and with Incident Cardiovascular Disease: the Framingham Heart Study - ResearchGate, accessed August 21, 2025, https://www.researchgate.net/publication/323513957_The_Omega-3_Index_can_serve_as_a_marker_of_overall_health_in_older_Americans_Erythrocyte_Long-Chain_Omega-3_Fatty_Acid_Levels_are_Inversely_Associated_with_Mortality_and_with_Incident_Cardiovascular_D
48. Erythrocyte long-chain omega-3 fatty acid levels are inversely associated with mortality and with incident cardiovascular disease: The Framingham Heart Study - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6034629/
49. Blood EPA and DHA Independently Predict All-Cause Mortality in Patients with Stable Coronary Heart Disease. The Heart and Soul Study - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3058601/
50. Can omega-3s slow down the aging process? - Responsible Seafood Advocate, accessed August 21, 2025, https://www.globalseafood.org/advocate/can-omega-3s-slow-down-the-aging-process/
51. Omega-3 Index and Cardiovascular Health - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3942733/
52. Soil Analysis Results and Interpretation, accessed August 21, 2025, https://www.reaseheath.ac.uk/wp-content/uploads/2018/04/Soil-analysis-and-interpretationUPDATED.pdf
53. Magnesium: Are We Consuming Enough? - MDPI, accessed August 21, 2025, https://www.mdpi.com/2072-6643/10/12/1863
54. Magnesium basics - PMC - PubMed Central, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4455825/
55. Magnesium | Linus Pauling Institute | Oregon State University, accessed August 21, 2025, https://lpi.oregonstate.edu/mic/minerals/magnesium
56. Lipoprotein A - StatPearls - NCBI Bookshelf, accessed August 21, 2025, https://www.ncbi.nlm.nih.gov/books/NBK570621/
57. Circulating lipoprotein (a) and all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis - PubMed Central, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10164031/
58. Lipoprotein(a) and its linear association with all-cause and cardiovascular mortality in patients with acute coronary syndrome - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12148871/
59. Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/37754581/
60. Lipoprotein(a): What to know about elevated levels | NHLBI, NIH, accessed August 21, 2025, https://www.nhlbi.nih.gov/news/2024/lipoproteina-what-know-about-elevated-levels
61. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5087876/
62. Circulating lipoprotein (a) and all-cause and cause-specific mortality : A systematic review and dose-response meta-analysis - ResearchGate, accessed August 21, 2025, https://www.researchgate.net/publication/367510725_Circulating_lipoprotein_a_and_all-cause_and_cause-specific_mortality_a_systematic_review_and_dose-response_meta-analysis
63. Circulating lipoprotein (a) and all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis - PubMed, accessed August 21, 2025, https://pubmed.ncbi.nlm.nih.gov/36708412/
64. About Lipoprotein (a) | Heart Disease, Family Health History, and Familial Hypercholesterolemia | CDC, accessed August 21, 2025, https://www.cdc.gov/heart-disease-family-history/about/about-lipoprotein-a.html
65. Insulin Levels: A Comprehensive Guide for Working Adults | Mito Health, accessed August 21, 2025, https://mitohealth.com/blog/why-working-adults-should-be-testing-their-insulin-levels-a-comprehensive-guide
66. Optimal Fasting Insulin: Science-backed Optimal Range for Metabolic Health and Longevity, accessed August 21, 2025, https://superpower.com/editorial/optimal-fasting-insulin
67. (PDF) Fasting insulin, insulin resistance and risk of cardiovascular or ..., accessed August 21, 2025, https://www.researchgate.net/publication/319139585_Fasting_insulin_insulin_resistance_and_risk_of_cardiovascular_or_all-cause_mortality_in_non-diabetic_adults_a_meta-analysis
68. Fasting insulin, insulin resistance, and risk of cardiovascular or all-cause mortality in non-diabetic adults: a meta-analysis - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6448479/
69. A1C Test for Diabetes and Prediabetes - CDC, accessed August 21, 2025, https://www.cdc.gov/diabetes/diabetes-testing/prediabetes-a1c-test.html
70. Understanding A1C Test | ADA - American Diabetes Association, accessed August 21, 2025, https://diabetes.org/about-diabetes/a1c
71. Diabetes - Diagnosis and treatment - Mayo Clinic, accessed August 21, 2025, https://www.mayoclinic.org/diseases-conditions/diabetes/diagnosis-treatment/drc-20371451
72. Glycated haemoglobin A1c as a risk factor of cardiovascular ..., accessed August 21, 2025, https://bmjopen.bmj.com/content/7/7/e015949
73. The HbA1c and All-Cause Mortality Relationship in Patients with Type 2 Diabetes is J-Shaped: A Meta-Analysis of Observational Studies - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4310064/
74. Relationship of Glycated Hemoglobin A1c with All-Cause and Cardiovascular Mortality among Patients with Hypertension - PMC, accessed August 21, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10095266/
75. accessed December 31, 1969, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608825/