Metabolism & Nutrient Sensing

Adiponectin is a 30-kDa adipokine secreted predominantly by white adipocytes, with lower expression in brown adipose tissue and trace expression in other tissues such as placenta and cardiac muscle, and is unique among adipokines in being inversely related to fat mass: levels fall with obesity and visceral adiposity and rise with weight loss, caloric restriction, and aerobic exercise. It circulates as trimers, hexamers, and high-molecular-weight multimers; the high-MW form is considered the most biologically active. Adiponectin signals through AdipoR1 and AdipoR2 receptors to activate AMPK and PPAR-α, improving insulin sensitivity, promoting fatty acid oxidation, suppressing hepatic glucose output, and exerting anti-inflammatory and atheroprotective effects. Low adiponectin is an independent predictor of type 2 diabetes, metabolic syndrome, and cardiovascular disease, and is associated with accelerated biological aging; high levels are observed in centenarians and their offspring.

Brown adipose tissue is a thermogenic organ characterized by high mitochondrial density and the expression of uncoupling protein 1 (UCP1), which dissipates the proton gradient across the inner mitochondrial membrane as heat rather than storing it as ATP. In adult humans, metabolically active BAT depots are found primarily in the supraclavicular, paravertebral, and cervical regions and are activated by cold exposure and sympathetic signaling via β3-adrenergic receptors. BAT activity declines with age and increasing adiposity, and lower activity associates with higher BMI, worse insulin sensitivity, and greater cardiometabolic risk in cross-sectional data. Cold exposure, β3-agonists, and candidate compounds such as mirabegron and capsinoids can augment BAT activity, with ongoing investigation into whether sustained augmentation improves metabolic health outcomes in humans.

Caloric restriction is a sustained reduction in energy intake, typically 10–30% below ad libitum, without malnutrition. It activates conserved nutrient-sensing pathways including AMPK and sirtuins while suppressing mTOR and insulin/IGF-1 signaling. In many rodent models it extends lifespan, though effects vary by strain, sex, age at onset, and protocol; non-human primate trials gave divergent results (Wisconsin vs. NIA). In humans, the CALERIE-2 trial (~12% achieved restriction, below the 25% target) improved cardiometabolic markers and reduced inflammation.

A continuous glucose monitor (CGM) is a wearable sensor, typically inserted into subcutaneous tissue, that measures interstitial glucose every few minutes, typically about 7 to 14 days for transcutaneous sensors (system-dependent), and up to a year for implantable devices such as Eversense 365. It generates trend data on fasting, postprandial, and nocturnal glucose, time-in-range, and glycemic variability. CGMs are increasingly used in non-diabetic adults to personalize nutrition and inform longevity-oriented lifestyle adjustments.

CRON is a structured form of caloric restriction in which energy intake is reduced by roughly 20–30% while micronutrient density (vitamins, minerals, essential fatty acids, protein quality) is deliberately maximized. The approach was developed by Roy Walford (with Lisa Walford, and later Brian M. Delaney as a popularizer and CR Society co-founder), with The Anti-Aging Plan (1994) by Roy and Lisa Walford as a key reference. The aim is to capture metabolic benefits—improved insulin sensitivity, lower inflammation, favorable lipids—without inducing nutrient deficiencies.

De novo lipogenesis (DNL) is the pathway by which the liver converts excess carbohydrates — primarily glucose and fructose — into fatty acids, packaged as triglycerides into VLDL or stored as hepatic fat. Two transcription factors drive the process: SREBP-1c, activated by insulin, and ChREBP, activated by intracellular sugar phosphates; both upregulate acetyl-CoA carboxylase and fatty acid synthase. Fructose is a more potent DNL substrate than glucose because it enters glycolysis downstream of the rate-limiting phosphofructokinase step, flooding hepatic acetyl-CoA largely unregulated; chronic surplus drives steatosis and is mechanistically linked to MASLD. Stable-isotope tracer studies (¹³C-acetate or deuterium water) estimate DNL accounts for roughly 15–25 % of hepatic triglycerides in MASLD patients — modest absolutely, yet malonyl-CoA from DNL simultaneously suppresses mitochondrial fatty-acid oxidation via carnitine palmitoyltransferase I, amplifying lipid accumulation. A non-randomized isocaloric controlled feeding study (Schwarz et al., 2017, n = 41 obese children) in which each participant served as their own control showed that replacing dietary sugar with starch for nine days reduced liver fat, DNL flux, and fasting insulin without altering calories — establishing a causal rather than associational role for sugar-derived DNL in pediatric hepatic steatosis. The evidence base remains weighted toward short-term human feeding studies and rodent models; long-term randomized data in adults with established MASLD are lacking.

Ectopic fat is lipid stored within or around organs that normally contain little adipose tissue — liver, skeletal muscle, pancreas, heart, and pericardium — distinct from subcutaneous or visceral depots. When energy intake chronically exceeds subcutaneous storage capacity, fatty acids and triglycerides spill into these organs, generating lipotoxic intermediates (diacylglycerol, DAG; ceramides) that impair insulin signalling. DAG activates PKC-ε in the liver — blunting insulin receptor substrate phosphorylation and driving hepatic glucose overproduction — and PKC-θ in skeletal muscle, reducing glucose uptake; in β-cells, lipid accumulation suppresses first-phase insulin secretion. Roy Taylor formalised the personal fat threshold: each individual has a genetically determined subcutaneous storage limit beyond which ectopic deposition begins, independent of body weight. The 2023 Clinical Science ReTUNE study, in normal-BMI individuals with type 2 diabetes, showed that a median 6.5% weight loss normalised liver fat and restored β-cell function, achieving remission in 70% of participants. Shulman's 2014 NEJM review established the mechanistic framework linking ectopic lipid to insulin resistance in humans via MR spectroscopy; causal direction is supported by intervention and Mendelian randomisation studies, though some observational associations remain confounded. Measurement via MRI, MR spectroscopy, or CT provides cardiometabolic and age-related disease risk information beyond BMI or waist circumference, even at a metabolically normal body weight.

The fasting-mimicking diet is a 5-day low-calorie, low-protein, plant-based regimen developed by Valter Longo's group that reproduces metabolic effects of water-only fasting—reduced IGF-1, glucose, and insulin; elevated ketones—while still providing some food. Pivotal trials used 3 cycles spaced one month apart and reported improvements in cardiometabolic risk markers and abdominal adiposity. Suggested benefits on biological age estimates rest on secondary analyses (Brandhorst et al. 2024, Nature Communications) and should be considered preliminary.

Free fatty acids (NEFA, non-esterified fatty acids) are long-chain fatty acids in plasma bound to albumin, released by lipolysis of adipose triglycerides via hormone-sensitive lipase. Fasting concentrations range from 0.3 to 0.8 mmol/L. Insulin suppresses lipolysis; impaired antilipolytic signalling — as in adipose insulin resistance — causes chronically elevated NEFA flux. In liver, skeletal muscle, myocardium, and pancreatic β-cells, excess NEFA undergo incomplete oxidation, generating ceramides, diacylglycerols, and acylcarnitines that impair mitochondrial function, activate inflammatory kinases (IKKβ, JNK), and blunt insulin signalling — collectively termed lipotoxicity. Karpe, Dickmann, and Frayn (Diabetes, 2011) concluded that physiological postprandial NEFA swings are insufficient to cause insulin resistance per se, but chronic basal NEFA excess in visceral obesity contributes causally to hepatic and muscle insulin resistance. In the Baltimore Longitudinal Study of Aging (Carlson et al., 2007), elevated NEFA were linked to post-challenge dysglycaemia despite normal fasting glucose. Evidence for NEFA as a modifiable longevity biomarker remains associational; exercise and caloric restriction reduce NEFA flux, but long-term trials targeting NEFA specifically are lacking.

Glucagon is a 29-amino-acid peptide hormone secreted by pancreatic alpha-cells in response to hypoglycemia, prolonged fasting, and amino acid ingestion, and suppressed by glucose and insulin. It acts on hepatic glucagon receptors to stimulate glycogenolysis and gluconeogenesis, raising blood glucose, and promotes hepatic ketogenesis during fasting. It is classically viewed as the counter-regulatory hormone to insulin, and the glucagon-to-insulin ratio is an important determinant of hepatic fuel partitioning. In type 2 diabetes, glucagon secretion is paradoxically elevated postprandially and resistant to glucose-mediated suppression, contributing to hyperglycemia; GLP-1 receptor agonists partly correct this by potentiating insulin and suppressing inappropriate glucagon release. Newer dual and triple agonists targeting glucagon, GLP-1, and GIP receptors are in clinical development for obesity and metabolic disease.

Gluconeogenesis is the metabolic process by which the liver — and, during prolonged fasting, the kidney — synthesizes glucose de novo from non-carbohydrate precursors: primarily lactate, glycerol, and glucogenic amino acids such as alanine and glutamine. The pathway runs largely in reverse of glycolysis but bypasses its three irreversible steps via four specific enzymes: pyruvate carboxylase, phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase, and glucose-6-phosphatase. Glucagon and cortisol activate the pathway; insulin suppresses it. In healthy adults fasting overnight, gluconeogenesis accounts for roughly 50% of hepatic glucose output, rising to ~93% after 42 hours as glycogen stores are exhausted (Landau et al., 1996). Blood glucose therefore remains in the normal range during ketogenic diets or prolonged fasting, sustained by adipose-derived glycerol and muscle-derived alanine even without dietary carbohydrate. In aging research, upregulation of PEPCK in *C. elegans* intestinal cells extends lifespan under dietary restriction, and its inhibition abolishes this benefit (Onken et al., 2020, *PLoS Genetics*) — though whether the mechanism translates to mammals remains associational rather than causal.

Glucose variability quantifies the magnitude and frequency of blood glucose fluctuations over hours and days, typically expressed as standard deviation, coefficient of variation, or mean amplitude of glycemic excursions (MAGE). High variability is implicated in oxidative stress, endothelial dysfunction, and diabetic complications independent of mean glucose. In non-diabetic adults, lower variability correlates with better metabolic health, and continuous glucose monitoring increasingly tracks it as a longevity-relevant biomarker.

HbA1c (glycated hemoglobin) reflects the proportion of hemoglobin stably bound to glucose, providing an integrated estimate of average blood glucose over approximately the prior 2 to 3 months, with the most recent ~30 days contributing roughly half of the signal per published kinetic models. It is the primary biomarker for diagnosing and monitoring type 2 diabetes (threshold 6.5%) and prediabetes (5.7 to 6.4%). HbA1c is influenced by erythrocyte lifespan, anemia, and hemoglobin variants.

Hepatic insulin resistance describes the selective failure of the liver to suppress gluconeogenesis and glycogenolysis in response to postprandial insulin, while lipogenesis may paradoxically remain insulin-responsive — a dissociation termed selective hepatic insulin resistance. The result is excessive fasting and postprandial hepatic glucose output, driving compensatory hyperinsulinemia that further promotes de novo lipogenesis and hypertriglyceridemia. Primary drivers include intrahepatic lipid accumulation from excess free fatty acid influx, fructose metabolism, and impaired mitochondrial fat oxidation, converging on serine phosphorylation of the insulin receptor substrate (IRS-1/IRS-2). Hepatic insulin resistance is an early and mechanistically central feature of metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes, and epidemiologically associates with elevated cardiometabolic and all-cause mortality risk.

HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) is a fasting blood index calculated as (fasting insulin in µU/mL × fasting glucose in mmol/L) / 22.5, or equivalently (fasting insulin in µU/mL × fasting glucose in mg/dL) / 405. It estimates whole-body insulin resistance from fasting measures, predominantly reflecting hepatic insulin action, as a low-cost surrogate for clamp methods. Cutoffs are population- and assay-dependent, with no universal threshold; values are commonly cited around 2 to 2.9 in adults.

The incretin effect is the observation that oral glucose ingestion triggers a larger insulin secretory response than an equivalent intravenous glucose infusion — a difference attributed to gut-derived peptides called incretins. The principal incretins are glucagon-like peptide-1 (GLP-1), released by L-cells in the distal small intestine and colon, and glucose-dependent insulinotropic polypeptide (GIP), released by K-cells in the proximal small intestine; together they account for 50–70 % of postprandial insulin output in healthy individuals (Baggio & Drucker, 2007). Both act on G-protein-coupled receptors on pancreatic β-cells to augment insulin release; GLP-1 also suppresses glucagon and slows gastric emptying. In type 2 diabetes the incretin effect is substantially diminished — principally because GIP loses insulinotropic potency at the β-cell level, while GLP-1 secretion is only modestly reduced (Nauck & Meier, 2016). GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists have reduced cardiovascular events and all-cause mortality in high-risk T2D cohorts. Whether endogenous incretin tone predicts aging trajectories in metabolically healthy individuals remains an open question; evidence to date derives primarily from T2D intervention trials (Nauck & Müller, 2023).

Insulin resistance is a state in which target tissues respond poorly to insulin, prompting the pancreas to secrete more to maintain glucose homeostasis. Driven by visceral adiposity, ectopic fat in liver and muscle, chronic inflammation, and inactivity, it underlies prediabetes, type 2 diabetes, metabolic syndrome, and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD). Insulin resistance is also associated with accelerated cardiovascular aging, cognitive decline, and shortened healthspan.

Insulin sensitivity describes how effectively cells, especially in muscle, liver, and adipose tissue, respond to insulin to take up glucose and suppress hepatic glucose output. Higher sensitivity allows lower circulating insulin to maintain normoglycemia, reducing strain on pancreatic beta cells. It is improved by physical activity, sleep, low visceral fat, and dietary fiber. Robust insulin sensitivity is a hallmark of metabolic health and longevity-relevant resilience.

Intermittent fasting is an umbrella term for eating patterns that alternate normal intake with extended fasting windows, including 16:8 time-restricted eating, alternate-day fasting, and 5:2 protocols. Fasting periods lower insulin and glycogen, trigger lipolysis and ketogenesis, and induce autophagy. Clinical trials show modest improvements in body composition, glycemic control, and blood pressure; meta-analyses suggest results are broadly comparable to matched continuous calorie reduction, though some trials report small advantages for visceral fat or insulin sensitivity.

The ketogenic diet is a very-low-carbohydrate (typically <50 g/day), high-fat, moderate-protein eating pattern that drives the body into sustained nutritional ketosis. Originally developed to treat refractory pediatric epilepsy, it is now studied for type 2 diabetes, obesity, and neurodegenerative conditions. Mechanisms include lower insulin, improved metabolic flexibility, and ketone-mediated signaling. Long-term effects on lipid profiles, kidney function, and adherence remain under active investigation.

Ketone bodies are three water-soluble molecules—β-hydroxybutyrate, acetoacetate, and acetone—produced in hepatocyte mitochondria from acetyl-CoA derived from fatty acid β-oxidation when carbohydrate availability is low. Beyond serving as efficient ATP fuel for brain and heart, β-hydroxybutyrate is an endogenous signaling molecule that inhibits class I histone deacetylases, dampens NLRP3 inflammasome activity, and may improve mitochondrial efficiency, mechanisms relevant to fasting biology and longevity research.

Ketosis is a metabolic state in which the liver converts fatty acids into ketone bodies—β-hydroxybutyrate, acetoacetate, and acetone—that serve as alternative fuel for brain, heart, and muscle when glucose is scarce. It is induced by fasting, prolonged exercise, or very-low-carbohydrate diets, with blood β-hydroxybutyrate typically rising above the 0.5 mmol/L nutritional-ketosis threshold described by Volek and Phinney. β-hydroxybutyrate also acts as a signaling molecule, inhibiting class I HDACs and modulating inflammation.

Leptin is a 16-kDa adipokine secreted by white adipose tissue in proportion to fat mass; it acts on hypothalamic receptors, particularly in the arcuate nucleus, to suppress appetite via melanocortin signaling and stimulate energy expenditure, functioning as the primary long-term adiposity signal. Plasma leptin levels follow a diurnal pattern and are acutely influenced by insulin; sustained fasting or weight loss reduces leptin, while weight gain raises it over days to weeks. Leptin resistance is a state in which the brain responds inadequately to circulating leptin despite normal or elevated levels, perpetuating hyperphagia and reduced energy expenditure; proposed mechanisms include impaired leptin transport across the blood-brain barrier, receptor downregulation, and disruption of JAK2/STAT3 signaling by inflammatory mediators such as SOCS3. Leptin resistance is present in most obese individuals and is associated with insulin resistance, metabolic syndrome, and impaired recovery of weight-loss-induced leptin deficiency.

MASLD (metabolic dysfunction-associated steatotic liver disease) is the 2023 reclassification of what was previously called non-alcoholic fatty liver disease (NAFLD), agreed by major hepatology societies including EASL, AASLD, and ALEH. The new nomenclature shifts from exclusion-based (excluding alcohol) to inclusion-based criteria: steatosis on imaging or biopsy must co-occur with at least one of five cardiometabolic risk factors (overweight/obesity, prediabetes or T2D, elevated blood pressure, elevated triglycerides, or low HDL), reflecting the metabolic substrate of the disease. Patients who drink above defined alcohol thresholds but also meet cardiometabolic criteria are classified as MetALD. The histological spectrum progresses from simple steatosis through metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) to fibrosis, cirrhosis, and hepatocellular carcinoma. MASLD affects an estimated 25–32% of adults globally and is a leading cause of liver-transplant waitlisting in the United States and several other high-income countries.

Metabolic flexibility is the capacity of cells and the whole organism to switch efficiently between fuel sources—primarily glucose and fatty acids—in response to feeding, fasting, and physical activity. It depends on intact mitochondrial function, insulin sensitivity, and hormonal signaling. Loss of flexibility, marked by impaired fasting fat oxidation and postprandial glucose handling, is a hallmark of insulin resistance, obesity, and aging, and is a key target of fasting and exercise interventions.

Metabolic syndrome is a cluster of interrelated cardiometabolic risk factors that substantially amplify the risk of type 2 diabetes, cardiovascular disease, and premature mortality. The most widely applied diagnostic criteria are those of the International Diabetes Federation (IDF) and the harmonised joint scientific statement (IDF/AHA/NHLBI, 2009), which require the presence of three or more of five components: elevated waist circumference (with ethnicity-specific thresholds), elevated fasting triglycerides (≥150 mg/dL), reduced HDL-cholesterol (<40 mg/dL in men, <50 mg/dL in women), elevated blood pressure (≥130/85 mmHg), and elevated fasting glucose (≥100 mg/dL). Insulin resistance and abdominal adiposity are considered the central drivers. Prevalence exceeds 30% in Western adult populations and rises with age, making metabolic syndrome a key target of lifestyle and pharmacological longevity interventions.

Postprandial glucose refers to blood glucose levels after a meal, often peaking within 30–90 minutes (typically around 60 minutes for mixed meals) before returning toward fasting baseline; conventional clinical measurement at 2 hours post-meal reflects glucose returning toward baseline rather than the peak. The size and duration of the spike reflect carbohydrate quantity and quality, gastric emptying, insulin response, and tissue uptake. Recurrent large excursions (a value rarely exceeded in non-diabetics is roughly 140 mg/dL) are associated, in a graded fashion, with vascular risk and cardiovascular disease, making postprandial control a key target in metabolic and longevity-oriented nutrition.

Prolonged fasting refers to fasting periods of roughly 48 hours up to several days during which only water, electrolytes, and sometimes minimal calories are consumed. After glycogen depletion, the body shifts to fatty acid oxidation and ketogenesis, suppresses IGF-1 and mTOR, and upregulates autophagy. Stem-cell-based regeneration has been demonstrated in rodents; human translation remains limited. Risks include electrolyte disturbances and refeeding syndrome, so prolonged fasting should be medically supervised.

The respiratory exchange ratio (RER), synonymous with the respiratory quotient (RQ) under resting and moderate aerobic conditions, is the ratio of carbon dioxide produced (VCO₂) to oxygen consumed (VO₂) per unit time, measured non-invasively by indirect calorimetry. Pure fat oxidation yields an RER near 0.70, mixed macronutrient combustion yields ~0.80–0.85, and exclusive carbohydrate oxidation yields 1.00; values above 1.00 during intense exercise reflect bicarbonate buffering of lactate rather than substrate use. A chronically elevated fasting RER (>0.91) signals reduced fat oxidation and prospectively predicts incident metabolic syndrome and type 2 diabetes (Pujia et al. 2019). In the Energy Balance Study, a higher baseline RQ was associated with greater gains in body weight and fat mass over 12 months in adults aged 21–35 years (Shook et al. 2016). Aging elevates fasting RER and blunts fuel-switching range independently of adiposity; sarcopenic older adults (mean age ~81 years) show significantly higher resting RQ than age-matched non-sarcopenic peers, suggesting metabolic inflexibility as both a correlate and a potential accelerant of muscle-function decline (Shoemaker et al. 2022). Whether restoring a lower fasting RER through aerobic training, dietary fat adaptation, or caloric restriction extends healthspan causally requires further randomised trial evidence.

Resting metabolic rate (RMR) — sometimes used interchangeably with basal metabolic rate (BMR), though BMR requires stricter fasting and thermoneutral conditions — is the energy expended at complete rest to maintain core physiology: ion-pump activity, protein turnover, cardiac and respiratory work, and thermoregulation. RMR typically accounts for 60–70% of total daily energy expenditure (TDEE) and is quantified by indirect calorimetry; predictive equations (Harris–Benedict, Mifflin–St Jeor) carry systematic errors of ±10–15%. RMR declines with age primarily because skeletal muscle is lost through sarcopenia; the Baltimore Longitudinal Study of Aging documented longitudinal RMR decreases accelerated by chronic disease (Zampino et al. 2020). A doubly-labelled-water study across 6,421 participants aged 8 days to 95 years found that body-composition-adjusted TDEE is stable from roughly age 20 to 60, then falls ~0.7% per year, attributing the age-related RMR drop largely to fat-free mass loss rather than an intrinsic organ-metabolism slowdown (Pontzer et al. 2021). During caloric restriction, RMR falls beyond what lean-mass loss predicts — a defended adaptation that impedes weight loss; Martin et al. (2022) quantified that ~60% of post-diet RMR suppression reflects tissue loss and ~40% true metabolic adaptation. Epidemiological data consistently link low fat-free mass with higher all-cause mortality risk.

Time-restricted eating (TRE) confines daily food intake to a consistent window of typically 6–10 hours, leaving 14–18 hours of fasting. The concept emerged from Satchin Panda's circadian biology lab at the Salk Institute. Some trials report improved insulin sensitivity, lipids, and blood pressure independent of calorie reduction; others, including Liu et al. (NEJM 2022), found that time-restricted eating combined with caloric restriction was not superior to caloric restriction alone for weight or metabolic outcomes. Early-window TRE may be preferable, but the evidence remains preliminary.

Uncoupling proteins (UCPs) are carrier proteins in the inner mitochondrial membrane that dissipate the proton electrochemical gradient as heat rather than ATP. UCP1, the best-characterized member, is expressed almost exclusively in brown adipose tissue (BAT), enabling non-shivering thermogenesis: activated by long-chain fatty acids from adrenergic stimulation and inhibited by purine nucleotides (GDP, ADP), UCP1 short-circuits the mitochondrial proton motive force (Cannon & Nedergaard 2004), allowing BAT to burn substrates without proportional ATP production. Beyond thermogenesis, mild mitochondrial uncoupling — including the basal proton leak present in all tissues — lowers membrane potential and reduces reactive oxygen species (ROS) formation at respiratory chain complexes I and III. This "uncoupling to survive" hypothesis links modestly reduced coupling efficiency to attenuated oxidative damage, a central driver of cellular aging. In human skeletal muscle, Amara et al. (2007, PNAS) showed that mitochondrial coupling degree — not respiration rate alone — predicts accumulation of age-related mitochondrial defects in vivo. Human BAT activity, detectable by ¹⁸F-FDG PET during cold exposure, declines markedly with age and obesity, prompting interest in pharmacological or cold-conditioning strategies to activate UCP1-mediated thermogenesis; whether such interventions extend healthspan in humans remains open, as most lifespan evidence derives from rodent models and observational human studies.

HOMA-β (Homeostatic Model Assessment of Beta-cell function) is a fasting-state surrogate for pancreatic β-cell insulin-secretory capacity, calculated as (20 × fasting insulin in µU/mL) / (fasting glucose in mmol/L − 3.5). It reflects predominantly basal insulin secretion and correlates modestly with more demanding assessments such as the disposition index from intravenous glucose tolerance tests, though it cannot capture dynamic glucose-stimulated secretion. β-cell mass and secretory function decline progressively with age and are accelerated by insulin resistance, glucolipotoxicity, and chronic low-grade inflammation. Monitoring HOMA-β alongside HOMA-IR provides a paired view of both demand and supply within the glucose-regulation axis, relevant to prediabetes risk stratification and longevity-oriented metabolic assessment.

β-oxidation is the principal mitochondrial pathway for catabolizing fatty acids, sequentially cleaving two-carbon acetyl-CoA units from the acyl chain through cycles of oxidation, hydration, further oxidation, and thiolysis. Each cycle of a saturated even-chain fatty acid also yields one FADH2 and one NADH, which feed the electron transport chain, making fat a highly energy-dense fuel per gram. Very-long-chain and branched-chain fatty acids require prior peroxisomal β-oxidation before mitochondrial entry. During fasting, sustained aerobic exercise, or ketogenic conditions, increased β-oxidation delivers acetyl-CoA for hepatic ketogenesis and supports muscle energy supply. Impaired β-oxidation, which occurs in fatty acid oxidation disorders and accumulates with mitochondrial dysfunction in aging, contributes to ectopic lipid deposition, insulin resistance, and metabolic inflexibility.