The Fitness Decline You Won’t See Coming (Even With “Good” Labs)
In a Nutshell
Normal labs miss the real health gap: V2 max (a measure of cardiorespiratory fitness) is one of the strongest predictors of longevity and resilience, yet it is rarely measured because medicine focuses on disease detection rather than functional capacity. Each 1 MET increase in fitness cuts all-cause mortality risk by 11-13%, with the largest gains coming from moving out of the bottom fitness quintile. While most people lack access to gold-standard V2 max testing, the data show that simple, consistent high-intensity efforts—like brisk hill walking—can meaningfully raise fitness and build the physiological reserve that keeps people functional into old age.
These notes were generated by AI and may contain inaccuracies.
Normal labs represent a low bar for health assessment. Individuals can have glucose levels within range, flat glucose curves, and good blood pressure while still losing their physiological reserve. This reserve represents the capacity to handle physical challenges such as climbing stairs, undergoing surgery, fighting infections, or managing difficult periods. Medicine rarely measures this capacity directly.
V2 max serves as one of the strongest available measures of this reserve. However, obtaining an accurate measurement requires specialized equipment including a mask, metabolic cart, and maximal effort testing that most people never undergo.
Traditional diagnostic tests from Quest, LabCorp, and even longevity clinics were designed primarily to detect disease rather than define what constitutes health. These tests can determine whether someone has a disease or falls within normal parameters, but they cannot distinguish between different levels of health or functional longevity.
An A1C value in an elite athlete might appear similar to someone three months away from prediabetes, yet these individuals have vastly different capacities for sustained functional longevity. The fundamental limitation is that traditional labs lack the tools to measure true health rather than merely the absence of disease.
Resilience refers to the buffer capacity that determines how much stress or challenge an individual can absorb before experiencing breakdown. This concept aligns with the academic framework of hormesis - the ability to handle stressors, adapt to them, and potentially become stronger as a result rather than being impaired.
Resilience is not merely bouncing back to a previous state, but rather responding to stress and potentially achieving improved function because of the challenge. Exercise represents a controlled stressor that challenges the body within healthy parameters without causing injury.
Data from the FRIEND dataset, one of the largest collections compiled by the Mayo Clinic, demonstrates that average V2 max across the population has been trending downward over the past 30 years. This dataset is designed to be population-representative, indicating a genuine decline in cardiorespiratory fitness at the societal level.
Modern medicine lacks good reference data for normal physiology because clinical focus remains disease-centric rather than health-centric. The concept of healthy stress response has largely been overlooked in medical thinking.
Sedentary behavior represents a primary driver of population fitness decline, particularly since the industrial revolution when white-collar jobs reduced the physical demands of daily work. Urban planning factors also contribute significantly, including walkability of cities, proximity to parks, and neighborhood safety for physical activity.
The American Fitness Index, developed by the American College of Sports Medicine, tracks factors that influence everyday physical activity levels. Cultural factors also play a role, as evidenced by comparisons with Switzerland where outdoor activity culture persists even in challenging weather, combined with altitude exposure that provides additional hormetic stress through reduced oxygen availability.
The American Heart Association advocated in 2016 that cardiorespiratory fitness should be treated as a clinical vital sign equivalent to resting heart rate or blood pressure. This recommendation was reinforced in their 2024 update. Despite cardiologists being among the earliest medical professionals to recognize this importance, regular measurement of cardiorespiratory fitness remains absent from primary care settings.
Robert Ross, who has spent 30 years advocating for body composition and cardiorespiratory fitness inclusion in annual examinations, identified clinician adoption as a major barrier. The scientific evidence and economic case for implementation exist, yet translation into clinical practice has not occurred.
Cardiorespiratory fitness and body composition function as upstream indicators for the majority of chronic diseases. These metrics characterize heart, lung, blood, muscle, mitochondrial, and brain function before clinical disease manifests. Maximal exercise testing provides one of the best methods for characterizing functional capacity before decline occurs.
Blood tests drive approximately 70% of medical decisions, making integration of fitness assessment into existing blood work panels a practical solution for clinical adoption without requiring additional time or effort from clinicians.
While stress tests are available through cardiologists' offices, they require significant logistical coordination including staff availability and time allocation. These tests are typically used to detect ischemia or atherosclerotic disease, but their sensitivity is limited to identifying only severe cases. The technology exists for earlier preventive assessment but is not utilized for this purpose.
V2 max measurement captures maximum oxygen consumption during peak exercise. This process requires oxygen transfer from the environment through multiple physiological systems to reach active skeletal muscle mitochondria, where oxygen serves as the final electron acceptor in the electron transport chain.
The pathway involves oxygen binding to red blood cells in the lungs, cardiac pumping through blood vessels, delivery to working skeletal muscle, and extraction into mitochondria. Brain activation of muscles is also required. This oxygen cascade integrates function across lungs, heart, blood, muscles, mitochondria, and brain into a single metric.
Meta-analyses demonstrate that each one MET increase in fitness level associates with approximately 11-13% lower all-cause mortality risk. Improvements correlate with better cardiovascular health and reduced cancer risk.
A VA dataset of approximately 760,000 individuals aged 18-100 years revealed consistent patterns across age groups. Moving from the bottom 20th fitness percentile to the 20-40th percentile reduces all-cause mortality risk by 47%. Each subsequent quintile provides additional risk reduction of approximately 15%, then 10%, continuing through the top percentiles. This pattern persists even in the 80-100 year age group.
Higher V2 max creates greater physiological reserve, meaning daily activities represent a smaller fraction of maximum capacity. This reserve explains why higher fitness levels correlate with maintained function into late life, as the test itself requires functional joints, muscles, and the ability to exert complex effort.
Significant V2 max improvements are achievable through intensive training. Cardiologist Ben Levine has demonstrated that heart failure patients and those at risk can progress to marathon running capability through structured training programs.
The Hixon protocol from John Holloszy's research group at Washington University in St. Louis achieved a 44% V2 max improvement in 10 weeks across 10 participants. The protocol involved six sessions per week of maximum-effort interval training (three running, three cycling) with weekly V2 max testing.
V2 max calculation uses milliliters of oxygen per minute per kilogram of body weight. Weight loss alone can improve V2 max values by reducing the denominator, though this improvement depends on maintaining functional muscle mass and mitochondrial capacity. Loss of muscle mass would prevent V2 max improvement despite weight reduction.
The metric appears to reward fat loss specifically while maintaining the functional components necessary for oxygen utilization. Population-level data supports including body weight in the calculation as a helpful screening indicator.
Analysis of the VA dataset shows consistent protective patterns across both sexes and all racial/ethnic categories, including Native American populations as a distinct group. Sex-based differences exist in training responsiveness, with men requiring approximately twice the exercise volume as women to achieve equivalent cardiac benefits.
When comparing V2 max values across sexes, a woman with V2 max of 30 may have similar or slightly better longevity outcomes than a man of the same age and race with V2 max of 38-40, accounting for known sex differences in average lifespan.
A metabolic equivalent represents basal metabolic rate - the energy expenditure required for basic life functions while at rest. METs express fitness as multiples of resting energy expenditure, with 3.5 mL/kg/min commonly used as the standard resting value for population research. This standardization theoretically allows comparison relative to individual resting metabolic rates.
METs remain primarily an epidemiological tool rather than practical for individual assessment, as translating population-level MET values into personal meaning proves difficult for most people.
Zone training attempts to define exercise intensities to drive specific adaptations, with lower zones primarily aerobic and higher zones tapping into anaerobic metabolism. Zones form the basis of Orange Theory Fitness and appear on treadmills, podcasts, and cycling programs. However, numerous ways exist to calculate zones, and academics often coin new terms that generate careers for themselves, creating confusion when different zone systems use different anchors and recommendations.
The core goal of zone training is driving aerobic adaptations where most energy expenditure comes from fats at low intensity. The theoretical difference between zone one and two involves driving more fat oxidation at slightly higher intensities before shifting to mostly carbohydrate oxidation in zones three through five. Zone four and five involve almost all carbohydrate oxidation and possibly lactate oxidation, with lactate increasingly understood as a fuel source rather than just a byproduct.
The practical problem is that multiple zone systems make it challenging to know the actual point of zone 2 training. Even triathlon coaches struggle with this complexity and often recommend aiming for specific heart rates from maximal exercise tests rather than relying on zone systems.
Techno Gym treadmills offer a feature pairing with wearables like Apple Watch to maintain zone 2 automatically. Users can set the treadmill and forget it while listening to podcasts or watching TV during an hour-long walk. This removes the mental burden of programming intensity from the individual.
Iron Man training involves 9 to 14 hours of super aerobic exercise including a full marathon run, yet involves minimal V02 max training. A V02 max test lasts 8 to 12 minutes by design, so activities allowing performance at that duration represent ideal V02 max training. Endurance training differs fundamentally from V02 max training because Iron Man performance requires sustaining high percentages of maximum for extended periods rather than going as hard as possible for 8 minutes.
V02 max optimization involves 3 to 5 minute intervals such as the Norwegian 4x4 protocol, accumulating work that trains for 8 to 10 minute maximal aerobic bouts. A 2,000 meter row represents a highly V02 max dependent competition event because it matches the V02 max test timeframe. Longer activities require different energy system training than V02 max training demands.
CrossFit and hybrid athlete testing reveals that strength is not captured in V02 max measurements. Highest V02 max individuals typically have extremely skinny arms and are mostly cyclists and triathletes. Grip strength represents an independent longevity measure with separate implications for functional capacity.
The approach involves using tools with demonstrated data for best outcomes as starting points, then narrowing in on associated features. Features feeding into high V02 max and lifestyle behaviors supporting high grip strength serve as benchmarks due to existing evidence. V02 max remains popular because it has the strongest evidence and provides concrete objective numbers.
Japanese women represent a long-lived population whose longevity may not stem from V02 max but rather from functional agility and mobility. Longevity involves too many factors for any single measurement to explain everything. Master's athletes who continue exercising longer than peers eventually become number one in their age groups, suggesting the key may be avoiding fitness decline for longer rather than achieving peak values.
Heat exposure through hot water immersion and passive heating shows emerging evidence for increasing blood volume and red blood cell mass. Head positioning during sleep may trick the body into increasing blood volume through related mechanisms. Altitude training and living at altitude increase blood volume through similar pathways.
Peptides and exogenous compounds generally cannot generate sufficient stressful stimulus to drive fitness adaptations except for mitochondrial uncouplers. DNP was effective for body weight loss but caused deaths and was banned by the FDA approximately 100 years ago. Modified versions are being developed with liver targeting or controlled release.
Mitochondrial uncouplers work by poking holes in mitochondrial membranes, driving mitochondria to release energy as heat rather than generating ATP. This challenges mitochondria to work harder and become stronger over time. Beta-3 agonists studied at NIH for overactive bladder can increase energy expenditure and improve insulin sensitivity at higher doses, though they increase heart rate and blood pressure.
GLP-1 drugs appear promising as longevity interventions but act as positive chronotropes, making hearts beat faster and lowering HRV. This creates uncertainty about long-term effects since exercise works effectively as a hormetic intervention because it is intermittent with recovery periods between sessions.
Epet Therapeutics developed a tattoo inhibitor targeting 10-11 translocation proteins as DNA demethylases. The concept involves removing methyl groups, though this approach lacks the selectivity needed. Genome-wide methylation tests lack fine enough resolution to identify which specific genes should be turned on or off.
Selective epigenetic reprogramming represents a systems biology question that becomes increasingly tractable with large language models analyzing simultaneous tweaks to 20 genes and their effects on RNA expression. Transcriptomics at full genome level may enable hypothesizing which genes should receive demethylation or methylation.
PCSK9 inhibitors represent a potential free lunch in medicine, with epigenetic and soon genetic interventions available. Natural genetic variants lowering PCSK9 are associated with long, healthy lives without apparent negatives.
Vio Health focuses on the Omics revolution to create blood tests measuring hundreds to thousands of molecules simultaneously for higher resolution pictures of body function. A molecular fingerprint across molecules becomes possible without reductionist filtering to disease associations.
Existing labs cannot estimate V02 max because biomarkers follow J-shaped curves that do not align cleanly with the dose-response protective effects of fitness. The approach involves profiling approximately 1,000 proteins and narrowing to the subset accurately predicting V02 max. Starting with V02 max as an anchor point, filtering to 50 highly related proteins might reveal even more protective combinations.
Validation occurs through academic collaborations with stored blood and V02 max data, plus IRB-approved prospective clinical studies with resting blood draws and V02 max tests performed within one to two days. Proteins include CRP, insulin, IGF binding proteins, and fatty acid binding proteins. Seven institutions have contributed data: two groups at Yale, Brigham and Women's, University of Connecticut, and University of New Mexico.
Over 1,100 V02 max versus full proteome comparisons have been completed, with plans to reach 3,500 by year's end. UK Biobank provides V02 max estimates from 5-minute submaximal tests with approximately 30% error, while true V02 max tests minimize estimation error.
Composite scores of approximately 50 proteins provide robustness against individual variation. IGF and growth hormones associated with fitness change with feeding and sleep, but having 50 proteins allows aggregation of stable trait proteins and variable state proteins.
Trait proteins remain relatively stable day-to-day and associate with muscle mass, appearing in blood from adipose tissue. State proteins reflect recent exercise intensity and duration, including acid-base buffering proteins that help tolerate high-intensity exercise. These proteins decrease after two weeks without exercise.
Continuous multi-analyte protein monitoring could enable behavior modification similar to heart rate wearables, though technology for 10+ simultaneous proteins in wearables is not yet ready.
Blood tests explain 89.7% of variance in true V02 max. When blood tests show lower fitness than actual V02 max measurements, behaviors like alcohol use and sleep may cause the model to underestimate fitness. Blood may provide more accurate fitness reflection than effort-based maximal exercise tests.
What's in the blood represents a more accurate reflection because it is not effort-based, unlike maximal exercise tests influenced by daily variables affecting effort.
The reproducibility of the gold standard V2 max when looking at the literature is 4 to 8% even in the best testing conditions.
A test participant who had prefaced that they were not a runner was surprised to go much longer than anticipated during a V2 max test. The individual concluded that this was not truly their cardiovascular buffer or resilience, but rather they were afraid to fail and wanted to keep going.
One morning a 10K row was completed on a home rower. A stationary bike and rower are used due to having a new baby. Being an avid CrossFitter allowed for a pretty good V2 max, but no aerobic base was developed. A switch was made from pure CrossFit to more longer-term aerobic exercise.
CrossFit is suspected to be very good training for competition TV shows, as CrossFitters always win. Physical 100 was watched with the observation that CrossFitters always win.
The simplest recommendation for those getting started requires no equipment and can be done mostly anywhere while capturing many fitness levels. The approach is to find the steepest hill around the neighborhood and walk up it as fast as possible. The pace might be very slow or really fast, and some might be running. This stimulus challenges the aerobic system and allows repeated improvement that yields gains for CRF.
The blue zones concept is highly debated regarding whether the correlations mean anything. A documentary showed confusion about why Italian nuns were living so long despite eating bread and drinking alcohol. The observation was made about the stairs in Italian cities. Cars should not get lost in San Francisco due to the insane inclines.
A recent conference experience involved forgetting something in a hotel room and having to run straight uphill very fast.
Dogs in Peru are all very fit due to altitude and hills. The dogs look very different than most American dogs - they are leaner, have muscle definition, and bounce around effortlessly. Peruvians as humans are likely similar in fitness levels.
The discussion was described as deeply interesting and scientific. Future collaboration was hoped for with expressed excitement.
Keep Hillary Lin, MD in your library
Save the videos and channels worth coming back to, and find them again in one place.
