Biomarkers

Albumin is the most abundant plasma protein, synthesized exclusively by the liver, and maintains colloid osmotic pressure while transporting hormones, fatty acids, calcium, bilirubin, and many drugs. Serum levels reflect hepatic synthetic capacity, nutritional status, inflammation, and renal or gastrointestinal losses. Lower albumin is a robust marker of biological aging and is consistently associated with sarcopenia, frailty, longer hospital stays, and higher all-cause mortality, which is why it features in many composite aging indices.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are intracellular enzymes released into blood when hepatocytes are injured. ALT is relatively liver-specific, while AST also originates from muscle, heart, and red blood cells. Elevated values most often reflect metabolic-associated steatotic liver disease, alcohol use, viral hepatitis, or drug toxicity, and the AST/ALT ratio helps distinguish causes. Persistently raised liver enzymes are associated with cardiometabolic risk and higher all-cause mortality.

Apolipoprotein B (ApoB) is the structural protein of atherogenic lipoproteins, including LDL, VLDL, IDL, and Lp(a). Because ApoB-100 is typically present as approximately one molecule per atherogenic particle, plasma ApoB serves as a clinical proxy for atherogenic particle number. Multivariable Mendelian randomization (e.g., Richardson et al.) prioritizes ApoB and particle burden as the causal lipid driver of coronary artery disease, making ApoB a more accurate predictor of cardiovascular events and mortality than LDL cholesterol alone. Lower ApoB is associated with reduced atherosclerotic disease.

The coronary artery calcium (CAC) score is a non-contrast cardiac CT measurement reported as an Agatston score that quantifies calcified atherosclerotic plaque as a marker of total atherosclerotic burden; non-calcified (soft) plaque is not detected. A higher CAC score is strongly associated with future myocardial infarction, cardiovascular events, and all-cause mortality, and primary-prevention guidelines (2018 ACC/AHA, 2021 ESC) recommend CAC for risk reclassification in intermediate-risk adults. A score of zero indicates very low short-term event risk but does not fully exclude atherosclerosis, particularly in younger adults or those with elevated Lp(a) or familial hypercholesterolemia.

Creatinine is a breakdown product of muscle creatine, produced at a relatively constant rate and cleared predominantly by glomerular filtration with a small contribution from tubular secretion, making serum creatinine a core marker of renal function. Because absolute values depend on muscle mass, age, sex, dietary meat intake, and creatine supplementation, laboratories report estimated glomerular filtration rate (eGFR) using the 2021 race-free CKD-EPI equation as current standard. Lower eGFR indicates reduced filtration capacity and is robustly associated with cardiovascular events, frailty, and mortality.

Dehydroepiandrosterone sulfate (DHEA-S) is the sulfated, long-circulating form of DHEA, secreted by the adrenal cortex (zona reticularis) and serving as a precursor to androgens and estrogens in peripheral tissues. Although it has minor diurnal variation, serum levels are far more stable than DHEA itself, making DHEA-S the preferred clinical marker of adrenal androgen output. It peaks in early adulthood and declines steeply with age (adrenopause); lower values are observationally associated with frailty, reduced bone density, and impaired immune function, though DHEA supplementation trials have largely been null for hard outcomes.

Estradiol (E2) is the most biologically active estrogen, produced mainly in the ovaries before menopause and in smaller amounts via aromatization of androgens in adipose tissue, brain, bone, liver, breast, and other peripheral tissues. It supports endothelial function, bone turnover, reproductive tissues, and may support cognition. After menopause, levels drop sharply and remaining production occurs via peripheral aromatization, contributing to accelerated bone loss, vasomotor symptoms, and a multifactorial rise in cardiometabolic risk. In men, modest estradiol from aromatization is important for bone health.

Fasting glucose is the plasma blood-sugar concentration after at least eight hours without caloric intake. It reflects baseline glucose homeostasis driven by hepatic glucose output, β-cell insulin secretion, peripheral insulin sensitivity, and counter-regulatory hormones such as glucagon, with renal glucose handling as a further contributor. Persistently elevated values indicate impaired fasting glucose, prediabetes, or type 2 diabetes, and Mendelian randomization supports a causal effect of higher fasting glucose on coronary disease. Even within the upper-normal range, rising fasting glucose tracks with increased risk, so stable lower-normal values are generally favorable.

Fasting insulin measures circulating insulin after an overnight fast and reflects β-cell output, hepatic insulin clearance, and peripheral insulin sensitivity together. Elevated fasting insulin is one of the earliest signs of insulin resistance and often appears before fasting glucose or HbA1c rise, consistent with the natural history seen in cohorts such as Whitehall II and IRAS. Hyperinsulinemia is associated with metabolic syndrome, type 2 diabetes, and a higher risk of cardiovascular disease and all-cause mortality. Lower fasting insulin generally indicates better insulin sensitivity and metabolic flexibility.

Free T3 (fT3) and free T4 (fT4) are the unbound, biologically active fractions of triiodothyronine and thyroxine. T4 is the main thyroid secretion product and is deiodinated peripherally to the more potent T3, which acts on nuclear receptors to regulate metabolism, thermogenesis, and cardiovascular function. Measuring free fractions avoids interference from binding-protein changes and helps distinguish primary thyroid disease, central hypothyroidism, and non-thyroidal illness when interpreted alongside TSH.

Gamma-glutamyl transferase (GGT) is a membrane-bound enzyme that transfers gamma-glutamyl groups and supports glutathione recycling, with highest activity in liver, biliary epithelium, and kidney. Serum GGT rises with cholestasis, alcohol intake, hepatic steatosis, and many enzyme-inducing drugs, making it a sensitive but unspecific liver marker. Beyond hepatology, higher GGT within the reference range is independently associated with insulin resistance, cardiovascular disease, and increased all-cause mortality, marking oxidative stress.

HDL cholesterol (high-density lipoprotein cholesterol) measures the cholesterol carried by HDL particles, which transport cholesterol from tissues back to the liver in reverse cholesterol transport. Population studies historically associated higher HDL-C with lower cardiovascular risk, but Mendelian randomization and HDL-raising drug trials show the relationship is non-causal and U-shaped: very high HDL-C is also linked to increased mortality. HDL functionality matters more than its concentration alone.

Homocysteine is a sulfur-containing amino acid produced during methionine metabolism and cleared via remethylation or transsulfuration pathways that depend on folate, vitamin B12, and vitamin B6. Elevated plasma homocysteine reflects impaired one-carbon metabolism and is associated with vascular endothelial dysfunction, atherosclerosis, and stroke; cognitive decline and dementia are observationally associated, but causality is uncertain. Major randomized trials of B-vitamin lowering (HOPE-2, NORVIT, VISP, SEARCH, VITATOPS) have not consistently reduced cardiovascular events overall, though some meta-analyses suggest a small reduction in stroke risk. Homocysteine is therefore interpreted as a risk and metabolic-health marker.

High-sensitivity C-reactive protein (hs-CRP) is a liver-produced acute-phase protein, induced primarily by IL-6, and measured with an assay sensitive enough to detect low-grade systemic inflammation. Outside acute infection, persistently elevated hs-CRP signals chronic inflammation linked to atherosclerosis, insulin resistance, and metabolic syndrome. hs-CRP is a downstream marker of IL-6–driven inflammation; Mendelian randomization does not support CRP itself as causal for coronary heart disease, while trials targeting upstream inflammation (e.g., CANTOS with canakinumab) reduce cardiovascular events. It remains a useful marker of inflammatory burden associated with cardiovascular and mortality risk.

Insulin-like growth factor 1 (IGF-1) is produced mainly in the liver under growth hormone stimulation and mediates many anabolic GH effects on muscle, bone, and other tissues. As a biomarker it serves as a stable surrogate for GH activity and reflects nutritional status and protein intake. Higher levels in adulthood are linked to greater cancer risk, while very low levels are associated with frailty and reduced lean mass, suggesting a U-shaped relationship with longevity.

LDL cholesterol (low-density lipoprotein cholesterol) reflects the cholesterol carried by LDL particles in the bloodstream. Excess ApoB-containing LDL particles can enter and be retained in the arterial intima, where modification (e.g., oxidation) and inflammation drive atherosclerotic plaque formation. LDL-C is a long-established causal risk factor for atherosclerotic cardiovascular disease, heart attack, and stroke; lifelong genetically lower LDL-C (e.g., PCSK9 loss-of-function variants) reduces ASCVD risk dose-dependently. From a longevity perspective LDL-C is lower-is-better, ideally interpreted alongside ApoB and Lp(a), as LDL-C and ApoB can be discordant.

Lipoprotein(a) is an LDL-like particle in which apolipoprotein(a) is covalently linked to apoB-100 via a disulfide bond. Plasma levels are largely (often cited around 70–90%) genetically determined and usually stable across adulthood, although modest changes can occur with menopause, kidney disease, or inflammation. Mendelian randomization at the LPA locus supports a causal role for elevated Lp(a) in myocardial infarction, ischemic stroke, and calcific aortic valve stenosis. Because diet and lifestyle barely influence it, Lp(a) should be measured at least once to stratify lifetime cardiovascular risk.

Testosterone is the principal androgen, produced mainly by Leydig cells in the testes in men and in smaller amounts by the ovaries and adrenals in women. It supports muscle mass, bone density, libido, mood, and erythropoiesis. Laboratories report total testosterone alongside free or bioavailable testosterone, since roughly 98% circulates bound to SHBG and albumin. Levels typically decline with age in men; lower values are observationally associated with sarcopenia, frailty, metabolic syndrome, and higher all-cause mortality and adverse cardiometabolic outcomes, with confounding by obesity, inflammation, and SHBG changes.

Triglycerides are the main storage form of dietary and endogenous fat, transported in the blood by triglyceride-rich lipoproteins, mainly VLDL, chylomicrons, IDL, and their remnants. Fasting triglyceride levels rise with insulin resistance, excess refined carbohydrates, alcohol intake, and metabolic syndrome. Elevated values reflect higher concentrations of triglyceride-rich remnant lipoproteins, and remnant cholesterol carried by these particles is causally linked to atherosclerotic cardiovascular disease (Mendelian randomization). Lower fasting triglycerides are associated with better insulin sensitivity and reduced cardiovascular risk.

Thyroid-stimulating hormone (TSH) is released by anterior pituitary thyrotrophs and regulates thyroid hormone production via negative feedback from circulating T3 and T4. In primary thyroid disease it is the most sensitive single marker of thyroid status: higher values typically indicate hypothyroidism, while suppressed values suggest hyperthyroidism or exogenous hormone excess. In central (pituitary or hypothalamic) hypothyroidism, TSH may be inappropriately normal or low alongside low fT4, so combined interpretation with free T4 is required. Reference ranges shift slightly upward with age, and subclinical dysfunction is common in older adults.