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VO₂ max – Your Real Biological Age Test

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dr. Karunia Valeriani Japar

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Why VO₂ max Matters for Aging and Longevity

Cardiorespiratory fitness, quantified objectively by maximal oxygen uptake (VO2max), reflects the body’s peak capacity to transport and utilize oxygen during intense exercise. Physiologically, VO₂ max integrates the performance of multiple organ systems like pulmonary ventilation, cardiac output, blood oxygen-carrying capacity, and skeletal muscle mitochondrial function. In other words it captures how efficiently oxygen moves from the atmosphere to the mitochondria, making it one of the most comprehensive indicators of systemic health and energetic capacity.

Emerging evidence positions VO₂ max as a core biomarker of biological age. Large cohort studies, including those from the Cooper Center Longitudinal Study and CARDIA, demonstrate that low VO2max strongly correlates with increased all-cause and cardiovascular mortality, independent of traditional risk factors like BMI, cholesterol, or blood pressure. In contrast, individuals within the highest quintile of VO₂ max have significantly lower mortality risk and better preserved physiological function across aging. Mechanistically, higher aerobic capacity is associated with improved mitochondrial biogenesis, increased insulin sensitivity, enhanced NAD⁺ metabolism, and lower chronic inflammation, all hallmarks of slowed cellular aging.

From a metabolic health perspective, VO₂ max represents more than fitness; it reflects, metabolic flexibility, the ability of cells to efficiently switch between fat and glucose oxidation based on energetic demands. Declines in this flexibility accompany aging, insulin resistance, and mitochondrial dysfunction, forming the foundation of many chronic diseases. Improving VO₂ max thus enhances not only aerobic endurance but also the efficiency of substrate utilization at rest and during stress.

Despite its profound prognostic value, VO₂ max remains largely overlooked in routine clinical assessments. Most healthcare providers track blood pressure, fasting glucose, or lipid profiles, yet few measure aerobic capacity even though VO₂ max predicts survival more accurately than these traditional markers. As a result, a key determinant of vitality, resilience, and aging trajectory often goes unnoticed. Framing VO₂ max as the “sixth vital sign” could shift preventive medicine toward a more dynamic, functional assessment of metabolic and physiological integrity.

The Physiology Behind VO2Max: A Systems Perspective

Maximal oxygen uptake (VO₂ max) emerges from the integrated performance of multiple organ systems along the entire oxygen transport and utilization pathway, making it a powerful window into both cardiorespiratory function and metabolic health. At the central level, VO₂ max is heavily determined by maximal cardiac output, which is the product of heart rate and stroke volume; classic work suggests that 70–85% of the limitation in VO₂ max in healthy individuals resides in the capacity of the cardiovascular system to deliver oxygenated blood to active muscle. With endurance training, structural and functional adaptations such as increased stroke volume, expanded plasma volume, and improved diastolic filling lead to higher maximal cardiac output and proportional increases in VO₂ max [1,2,3].

At the peripheral level, skeletal muscle characteristics critically shape the ability to extract and utilize the delivered oxygen. VO₂ max correlates strongly with indices of mitochondrial volume density and oxidative enzyme activity (e.g., succinate dehydrogenase, citrate synthase), indicating that mitochondrial content and function are key determinants of whole-body oxidative capacity. Experimental data show that in many healthy individuals, muscle mitochondrial respiratory capacity actually exceeds in‑vivo VO₂ max, implying that the circulation and oxygen delivery typically constrain maximal aerobic power more than mitochondrial machinery per se. Hemoglobin mass and concentration are also tightly linked to VO₂ max, as hemoglobin defines the oxygen-carrying capacity of blood; meta-analytic data demonstrate a robust positive association between changes in hemoglobin and changes in VO₂ max across diverse populations [2,4,5,6].

These central and peripheral determinants operate along what is often termed the oxygen cascade, a stepwise process that extends from ambient air to mitochondrial respiration. Oxygen must first be convectively transported through the airways and lungs, where alveolar ventilation and diffusion across the alveolar–capillary membrane govern arterial oxygen loading. It is then convected by the heart and vascular system to skeletal muscle, with cardiac output, blood volume, and vascular conductance determining bulk delivery, while capillary density and red blood cell transit time influence diffusion from blood to myofibers. Finally, within muscle, mitochondrial oxygen affinity, respiratory chain capacity, and the abundance of oxidative enzymes dictate how effectively oxygen is reduced to water to drive ATP synthesis, closing the cascade. Any limitation at one step of this cascade such as ventilation, diffusion, perfusion, or mitochondrial utilization can cap VO₂ max and, by extension, the organism’s maximal sustainable aerobic metabolism [1,5].

The physiology underpinning VO₂ max intersects closely with key markers of metabolic health. Higher VO₂ max is consistently associated with better insulin sensitivity, whereas individuals with type 2 diabetes and insulin resistance exhibit reduced peak VO₂ and slower oxygen uptake kinetics during exercise, reflecting both central and peripheral impairments. At the cellular level, mitochondrial dysfunction is increasingly recognized as a mechanistic bridge between low aerobic capacity, insulin resistance, and ectopic lipid accumulation, with impaired oxidative phosphorylation promoting lipotoxic intermediates that disrupt insulin signalling. Exercise-induced improvements in VO₂ max coincide with enhanced mitochondrial biogenesis, more efficient electron transport, and favourable shifts in redox state and NAD⁺‑dependent signalling, suggesting that raising VO₂ max may modulate pathways fundamental to cellular energy sensing and metabolic resilience. In this systems framework, VO₂ max is not merely a measure of athletic performance but central integrative biomarker linking oxygen transport, mitochondrial health, and whole‑body metabolic flexibility[7,8,9,10].

The epidemiological evidence linking VO₂ max to longevity is among the most robust in preventive medicine. Large-scale cohort studies consistently demonstrate a steep, dose-dependent inverse relationship between cardiorespiratory fitness and all-cause mortality that persists across age, sex, and comorbidity strata. The landmark meta-analysis by Kodama and colleagues, encompassing over 100,000 participants, revealed that each 1-MET increase in VO₂ max (approximately 3.5 mL/kg/min) conferred a 13% reduction in all-cause mortality risk and a 15% reduction in cardiovascular disease events. In a more recent analysis of 122,007 adults undergoing exercise treadmill testing, elite performers defined those achieving VO₂ max ≥2 standard deviations above age- and sex-matched norms exhibited an 80% reduction in mortality risk compared to the lowest fitness quintile, with no observed upper limit of benefit. Strikingly, the mortality risk associated with low cardiorespiratory fitness was comparable to or exceeded that of traditional clinical risk factors such as diabetes, smoking, and coronary artery disease [11,12,13,14,15].

Longitudinal follow-up data underscore that changes in VO₂ max over time carry prognostic weight independent of baseline fitness. In the Kuopio Ischemic Heart Disease Risk Factor Study, each 1 mL/kg/min increase in VO₂ max at 11-year reexamination was associated with a 9% relative risk reduction in all-cause mortality, even after adjusting for baseline fitness and cardiovascular risk factors. Data from the Coronary Artery Risk Development in Young Adults (CARDIA) study further demonstrate that higher early-adulthood VO₂ max and its retention through midlife predict reduced premature death and cardiovascular events decades later, suggesting that early optimization of aerobic capacity builds a protective reserve across the life course [11,16].

The mechanistic link between VO₂ max and cellular aging operates through multiple intersecting pathways. Mitochondrial dysfunction stands as a central mediator: aging is characterized by a progressive decline in skeletal muscle mitochondrial respiratory capacity, oxidative enzyme activity, and mitochondrial content, all of which constrain oxygen utilization and energy production. In sedentary older adults, mitochondrial capacity in skeletal muscle declines by approximately 17%, with this decline independent of oxygen delivery, indicating intrinsic mitochondrial impairment rather than vascular limitation. Importantly, this reduction in mitochondrial function correlates with diminished exercise efficiency, insulin sensitivity, and physical function, hallmarks of metabolic aging. Regular exercise, particularly high-intensity training, counteracts this decline by inducing mitochondrial biogenesis, enhancing TCA cycle activity, and improving electron transport chain efficiency, thereby increasing both mitochondrial content and function [17,18,19,20].

Metabolic inflexibility, the reduced capacity to switch between fat and carbohydrate oxidation in response to metabolic demand emerges as a critical link between low VO₂ max and accelerated aging. Aging and sedentary behaviour lead to impaired substrate utilization, characterized by reduced basal and exercise-induced fat oxidation, accumulation of lipotoxic intermediates, and greater reliance on anaerobic glycolysis. Individuals with higher cardiorespiratory fitness exhibit superior maximal fat oxidation rates and metabolic flexibility, attributable to enhanced mitochondrial density, upregulated fatty acid transport proteins, and more efficient oxidative phosphorylation. This metabolic flexibility is strongly associated with plasma levels of Klotho, a longevity-associated protein, suggesting that substrate oxidation capacity may represent a powerful biomarker of biological aging independent of chronological age [20,21,22].

Age-related sarcopenia, the progressive loss of muscle mass, strength and function is tightly intertwined with declining VO₂ max and mitochondrial health. Sarcopenia is accompanied by reductions in basal metabolic rate, fat oxidation capacity, and daily energy expenditure, creating a vicious cycle that promotes visceral adiposity, insulin resistance, and chronic inflammation. At the cellular level, sarcopenic muscle exhibits increased oxidative damage to lipids, proteins, and mitochondrial DNA, alongside reduced activity of antioxidant enzymes and impaired protein turnover. Physical activity and training that elevate VO₂ max counteract sarcopenia by increasing muscle protein synthesis, capillarization, and mitochondrial respiratory function, thereby preserving muscle quality and metabolic health even into advanced age [17,23,24,25,26,27].

The concept of aerobic fitness reserve, the margin between resting and maximal oxygen consumption represents a critical buffer against age-related metabolic deterioration. This reserve capacity determines an individual’s ability to meet metabolic challenges, from activities of daily living to acute physiological stressors such as infection, surgery, or trauma. Higher VO₂ max confers a larger aerobic reserve, allowing older adults to perform physical tasks at a lower percentage of their maximal capacity, reducing fatigue and preserving functional independence. Prospective data demonstrate that individuals with VO₂ max ≥10 METs maintain significantly lower cardiovascular risk factor burden across all age groups, and the protective effect of high fitness against clustering of metabolic risk factors persists even in the presence of advancing chronological age. This suggests that aerobic fitness acts as a physiological resilience reserve, buffering the cumulative effects of aging and delaying the onset of multimorbidity [28,29,30,31].

Emerging evidence positions VO₂ max as a modifiable determinant of biological age that operates independently of, and often more powerfully than, traditional risk markers. The aggregate effect of enhanced mitochondrial function, preserved metabolic flexibility, resistance to sarcopenia, and expanded aerobic reserve converge to slow cellular aging, reduce chronic disease burden, and extend both lifespan and healthspan. In this framework, VO₂ max is not merely an endpoint of physical fitness but a central integrative biomarker and therapeutic target for metabolic longevity [3,32].

Training Strategies to Elevate VO2Max: Evidence-Based Protocols

Endurance training modalities that target VO₂ max can be broadly grouped into classic moderate-intensity continuous training (MICT), high-intensity interval training (HIIT), and lower-intensity “zone 2” work, each with distinct physiological emphases and practical trade-offs. MICT typically consists of 30–60 minutes of continuous exercise at 60–75% of VO₂ max (or 65–75% of maximal heart rate), producing gradual improvements in stroke volume, capillary density, and mitochondrial content with a favourable safety profile, particularly in deconditioned or older adults. In contrast, HIIT protocols alternate brief bouts of work at 85–95% of maximal heart rate with active recovery, eliciting larger and faster gains in VO₂ max than work-matched MICT in both healthy and clinical populations, primarily via robust central and peripheral cardiovascular adaptations. Zone 2 training, usually defined as steady-state work below lactate threshold but above light activity (roughly 65–75% of HRmax, conversational pace), is especially potent for improving mitochondrial density, fat oxidation, and metabolic flexibility, forming a foundational base that synergizes with higher-intensity sessions for long-term VO₂ max development [33,34].

Among HIIT models, the Norwegian 4×4-minute protocol is one of the most studied and clinically translatable paradigms. In moderately active individuals, 8 weeks of 4×4-minute intervals at 90–95% of HRmax, interspersed with 3 minutes of active recovery at around 70% HRmax, produced significantly greater VO₂ max gains than either training at lactate threshold or traditional MICT, with improvements closely paralleling increases in stroke volume. Similar 4×4 treadmill-based protocols have been shown to increase VO₂ max by roughly 10% in adults with obesity and to outperform work-matched MICT in patients with coronary artery disease, underscoring their utility across cardiometabolic risk strata. Sprint interval training (SIT), characterized by supramaximal efforts of 20–30 seconds “all-out” with 1–3 minutes of recovery, offers an even more time-efficient stimulus: meta-analytic data in athletes indicate that 3 weeks of SIT, with 8–12 sprints per session, can raise VO₂ max by approximately 2–4 mL/kg/min, despite a very low total training volume. Emerging protocols using just 2×20-second supramaximal sprints within a 10-minute session have demonstrated meaningful improvements in VO₂ max and cardiometabolic markers, suggesting that extremely low-volume SIT may be a viable option for highly time-constrained individuals when properly supervised. Polarized training models, which allocate the majority of volume to low-intensity work (zone 1–2) and a small but targeted fraction to very high-intensity intervals (zone 4–5), appear to optimize both VO₂ max and endurance performance in athletes by combining mitochondrial and central cardiovascular adaptations while limiting accumulated fatigue [33,34,35,36].

Despite their efficacy, higher-intensity protocols require careful periodization and safety screening, particularly in sedentary adults, midlife professionals with subclinical disease, and older adults with reduced physiological reserve. For previously inactive or metabolically compromised individuals, initial phases should prioritize low- to moderate-intensity continuous training and zone 2 work 3–4 days per week, focusing on joint tolerance, movement competency, and basic cardiovascular conditioning before progressing to HIIT. In this group, early “intro-HIIT” might consist of short intervals (e.g., 4–6 × 30–60 seconds at 80–85% HRmax with 2–3 minutes of easy recovery) embedded once weekly, with gradual escalation toward classic 4×4 structures only after several weeks of adaptation and medical clearance when indicated. Midlife professionals with some training history but high allostatic load often benefit from a mixed model: 2–3 weekly zone 2 sessions of 45–60 minutes combined with 1 structured HIIT day (e.g., 4×4 or 6–8 × 2–3 minutes at 90–95% HRmax), while avoiding back-to-back high-intensity days to reduce injury and overreaching risk. In older adults, particularly those with multimorbidity or frailty, supervised programs using scaled intervals (e.g., 4×3 minutes at a “hard but sustainable” RPE with longer recoveries) have been shown to be both safe and effective, but require close monitoring of symptoms, blood pressure, and recovery, with an emphasis on progression from duration to intensity rather than the reverse. Across all populations, the integration of progressive loading, adequate recovery, and regular reassessment of VO₂ max or submaximal proxies is essential to harness the powerful benefits of HIIT and SIT while minimizing adverse events, making VO₂ max training a cornerstone, but not a standalone element of comprehensive metabolic and longevity-focused exercise prescriptions [34,37,38,39,40,41,42,43].

Lifestyle and Nutritional modulators of VO2Max

Lifestyle and nutritional factors modulate VO₂ max by shaping recovery, mitochondrial function, and the efficiency of oxygen transport and utilization across organ systems. Sleep and circadian alignment appear to be foundational regulators of cardiorespiratory fitness: observational data in middle‑aged and older adults indicate that poor sleep efficiency, shorter total sleep time, and prolonged wake after sleep onset are associated with lower VO₂ max and impaired energetic efficiency, even after adjustment for physical activity and comorbidities. Experimental work in recreationally active adults suggests that approximately 6 hours of good‑quality sleep with high sleep efficiency can sustain or enhance VO₂ max more effectively than longer but fragmented sleep, highlighting that quality of sleep may be as important as duration for maintaining cardiorespiratory fitness. Disruption of circadian rhythm as seen with social jet lag or shift work exacerbates insulin resistance, alters endocrine responses to exercise, and may blunt training-induced improvements in VO₂ max, whereas aligning training and feeding schedules with the endogenous circadian cycle likely amplifies adaptive responses, though direct interventional data remain limited [44,45].

Micronutrient sufficiency and mitochondrial cofactors are crucial for optimizing the physiological substrate on which VO₂ max training acts. Iron deficiency, especially when accompanied by anemia, reduces hemoglobin concentration and oxygen-carrying capacity, leading to measurable reductions in VO₂ max and endurance capacity; iron repletion over 8 weeks in iron-deficient but otherwise healthy women has been shown to increase VO₂ max and lower blood lactate during submaximal exercise, illustrating the reversibility of this component of aerobic limitation. Beyond iron, nutrients such as carnitine and coenzyme Q10 (CoQ10) support mitochondrial fatty acid transport and electron transport chain function, respectively, and low levels may contribute to diminished exercise tolerance and impaired oxidative phosphorylation, although evidence for routine supplementation in non-deficient individuals remains mixed. Mitochondrial cofactors and antioxidants must also be considered carefully: while chronic deficiencies in compounds involved in redox balance and mitochondrial metabolism can constrain adaptation, high-dose exogenous antioxidant supplementation has been shown in some studies to blunt training-induced mitochondrial biogenesis and improvements in insulin sensitivity, suggesting a narrow window in which physiological reactive oxygen species (ROS) signalling is required for optimal VO₂ max gain [46,47,48,49].

Dietary patterns that support mitochondrial health, vascular function, and metabolic flexibility may synergize with exercise training to enhance VO₂ max. The Mediterranean diet rich in polyphenols, mono- and polyunsaturated fats, and nitrate-containing vegetables is associated with improved endothelial function, reduced systemic inflammation, and better cardiorespiratory fitness profiles, likely through convergent effects on nitric oxide (NO) bioavailability, lipid metabolism, and oxidative stress. Intermittent fasting and time‑restricted eating can enhance metabolic flexibility, increase fat oxidation, and upregulate cellular stress-resistance pathways (e.g., autophagy, sirtuin signalling), potentially augmenting the mitochondrial and cardiometabolic adaptations to endurance and interval training, although direct trials with VO₂ max as the primary endpoint are still emerging. Nitrate-rich foods, particularly beetroot juice have a more direct, short‑term impact: multiple randomized trials show that nitrate supplementation increases plasma nitrite, reduces the oxygen cost of submaximal exercise by approximately 4%, and can improve exercise performance, with the greatest benefits seen in individuals with lower baseline VO₂ max. Meta-analytic evidence further suggests that beetroot juice and other nitrate-rich interventions can modestly but significantly increase VO₂ max and time to exhaustion in various populations, likely via enhanced NO-mediated vasodilation and improved mitochondrial efficiency [44,50].

Effective VO₂ max development also depends on recovery kinetics, redox balance, and inflammation control, which collectively determine the net adaptation to training stimuli. Inadequate recovery due to insufficient sleep, high psychosocial stress, or excessive training volume can elevate basal cortisol, increase sympathetic tone, and promote a pro-inflammatory milieu, all of which impair endothelial function, blunt mitochondrial biogenesis, and slow VO₂ max progression. Conversely, strategies that normalize autonomic balance (e.g., sleep optimization, stress-reduction practices, active recovery sessions) and support a diet rich in anti-inflammatory and antioxidant phytochemicals appear to preserve redox signalling while limiting chronic oxidative damage, thereby facilitating the structural and functional remodelling of the cardiovascular and muscular systems that underlies improvements in VO₂ max. From a systems perspective, the interaction between training load, lifestyle recovery factors, and nutritional status determines whether an exercise program functions as a hormetic stimulus that upgrades aerobic capacity, or as a chronic stressor that accelerates metabolic wear and impairs the very adaptations needed for long-term cardiorespiratory resilience [51,52,53,54,55,56].

Tracking and Quantifying VO2Max in Digital Era

The democratization of VO₂ max assessment represents a paradigm shift from laboratory-based testing to continuous, real-world monitoring via wearable technologies and artificial intelligence-driven algorithms. Until recently, direct measurement of VO₂ max required expensive cardiopulmonary exercise testing (CPET) performed in specialized laboratories, limiting assessments to athletes or patients with specific clinical indications. CPET remains the gold standard, combining indirect calorimetry with exercise physiology to measure oxygen consumption, ventilatory thresholds, cardiac dynamics, and metabolic limitations, providing rich diagnostic information for risk stratification and precise exercise prescription. However, its cost, time requirement, and limited accessibility have rendered it impractical for population-wide screening and longitudinal monitoring, making wearable-based estimation an increasingly valuable complement to clinical testing [57,58,59,60,61].

Contemporary wearable devices estimate VO₂ max using machine learning algorithms trained on heart rate variability, accelerometry, and activity data collected during both structured exercise and free-living conditions. Validation studies reveal variable accuracy across platforms: Garmin devices, leveraging Firstbeat algorithms based on physiological modeling, consistently report mean absolute percentage errors (MAPE) below 10%, demonstrating acceptable validity for tracking fitness trends in recreational users. In contrast, Apple Watch estimates show higher variability, with MAPE ranging from 10–18% and systematic underestimation of VO₂ max by approximately 4–6 mL/kg/min compared to laboratory-measured values, particularly in individuals with higher fitness levels. Recent advances using deep neural networks and long short-term memory (LSTM) models on wearable sensor data have demonstrated promise, with machine learning approaches achieving 82% agreement with laboratory-measured VO₂ max at baseline and 72% at follow-up testing in large prospective cohorts, even when trained exclusively on heart rate and accelerometer data without contextual information such as GPS [57,62,63,64,65,66,67].

A critical distinction exists between population-level trend tracking and individual clinical decision-making: while wearable- derived O₂ max estimates are increasingly reliable for identifying fitness changes and stratifying risk across groups, the individual-level margin of error, typically 5-10mL/kg/min remains substantial relative to clinically meaningful thresholds. This limitation suggests that wearables excel at longitudinal self-monitoring and detecting improvement or decline over weeks to months, yet may not reliably pinpoint absolute fitness status for precise exercise prescription in a single assessment. Given these constraints, a pragmatic framework integrates wearable-derived estimates for real-time engagement and population screening, reserving CPET for individuals requiring precise functional capacity evaluation, risk stratification before starting high-intensity training, or diagnostic assessment of unexplained exercise limitation or dyspnea [57].

Integration of VO₂ max metrics into unified digital health platforms amplifies their preventive and therapeutic value. AI-powered health coaching systems that synthesize continuous VO₂ max data from wearables alongside sleep, heart rate variability, activity, and nutritional data enable real-time, personalized exercise and lifestyle recommendations, with demonstrated capacity to improve adherence and health outcomes in chronic disease management. For metabolic wellness and longevity-focused organizations, scalable aggregation of wearable-derived VO₂ max data across populations permits early identification of individuals at high risk of cardiovascular events or all-cause mortality, creating opportunities for targeted intervention before advanced atherosclerosis or functional decline emerges. Moreover, serial VO₂ max measurements captured via wearables can serve as a biomarker of intervention efficacy whether from training programs, nutritional modifications, or pharmacological therapies offering a dynamic, modifiable metric that reflects whole-body metabolic and physiological responsiveness [58,59,60,61]

The practical transition to continuous VO₂ max monitoring also raises important caveats around algorithm transparency, data privacy, and clinical validation at the individual level. Many proprietary algorithms powering commercial wearables remain undisclosed, making it impossible for users or clinicians to understand the precision, generalizability, or stability of predictions as hardware and software evolve. For organizations deploying VO₂ max data in clinical or occupational health settings, transparent, open-source algorithms with published validation studies and clearly defined error margins are preferable to black-box commercial solutions. Integration of wearable VO₂ max assessments into preventive health screening protocols should thus emphasize serial tracking of trends and relative changes rather than absolute values, combining estimates with periodic formal CPET validation in high-risk or elite performance contexts where precision is critical. In this hybrid model, continuous wearable monitoring coupled with periodic laboratory verification and AI-assisted clinical interpretation, VO₂ max transitions from an occult, rarely-measured biomarker to a transparent, actionable vital sign accessible across diverse healthcare and wellness ecosystems [60,65].

Building a Metabolically Resilient future Through Aerobic Fitness

VO2max emerges as a central, integrative biomarker of biological aging, metabolic resilience, and survival that is at least as important as traditional risk factors yet remains underused in clinical practice. Large cohort and longitudinal studies consistently show a steep, dose-dependent, and apparently “no-upper-limit” inverse relationship between VO2max and all-cause as well as cardiovascular mortality, where even a 1-MET increase confers meaningful risk reduction and elite VO2max levels are associated with up to ~80% lower mortality compared with the least fit. Mechanistically, the article highlights that VO2max reflects the entire oxygen cascade from pulmonary ventilation and cardiac output to hemoglobin mass, muscle capillarity, and mitochondrial function, and that higher aerobic capacity supports insulin sensitivity, metabolic flexibility, mitochondrial biogenesis, favorable redox/NAD+ signaling, and reduced chronic inflammation, thereby slowing features of metabolic and cellular aging.

Clinically and from a public health perspective the key conclusion is that VO2max should be reframed as a “sixth vital sign” and targeted explicitly through structured physical activity, and exercise training across the lifespan, with routine assessment and longitudinal tracking integrated into preventive care to shift both individual trajectories and population risk profiles toward healthier, more resilient aging.

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