The 5 Biomarkers That Actually Matter for Healthspan (and the 3 That Don't)
By Akash S. Chauhan | First Principles Healthspan, Issue 01
Your annual physical is measuring the wrong things. If your goal is healthspan rather than just "not currently sick," roughly half of the standard panel is decorative, and the markers with the strongest causal evidence rarely make it onto the printout.
Why this matters
The cost of optimizing the wrong markers is not just wasted time. It is years of false reassurance. A "normal" LDL-C, a "normal" fasting glucose, and a "normal" total cholesterol can all coexist with a body quietly accumulating atherosclerotic plaque, insulin resistance, and sarcopenic decline. The markers below were chosen on a single criterion: strength of causal or prospective evidence linking them to all-cause mortality, cardiovascular events, or functional decline. Everything else is noise dressed up as signal.
The goal is not a "perfect" lab panel. The goal is to measure the variables that, when moved, actually move your trajectory.
The 5 Biomarkers That Matter
1. ApoB (Apolipoprotein B)
What it is. ApoB is the structural protein on every atherogenic lipoprotein particle (LDL, VLDL, IDL, Lp(a), chylomicron remnants). One ApoB equals one potentially artery-penetrating particle. LDL-C measures the cholesterol cargo; ApoB counts the trucks.
Standard "normal" range: typically reported as <130 mg/dL for general population, <90 mg/dL for higher risk. Healthspan-optimal range suggested by the evidence: <80 mg/dL for primary prevention; <60 mg/dL for individuals with established atherosclerosis or strong family history.
Why it predicts healthspan. Mendelian randomization and large prospective analyses consistently show ApoB outperforms LDL-C and non-HDL-C as a predictor of myocardial infarction. Sniderman et al. (2019) in JAMA Cardiology demonstrated that when ApoB and LDL-C diverge (which they do in roughly 1 in 5 adults, especially those with metabolic syndrome), ApoB is the marker that tracks event risk (PMID: 31389986). The 2017 EAS consensus statement reached the same conclusion (PMID: 28444290).
How to test it. ApoB is a cheap, standardized immunoassay. It is not in most "annual physical" panels but is included in advanced lipid panels through Function Health and SiPhox Health, or can be ordered directly through Quest or LabCorp.
What the evidence suggests if it is elevated. Diet and exercise reduce ApoB modestly (typically 5-15%). Statins, ezetimibe, bempedoic acid, and PCSK9 inhibitors are the pharmacologic levers with the strongest outcome data. This is a discussion to have with a lipidologist or preventive cardiologist, not a supplement aisle.
2. Lp(a) (Lipoprotein little-a)
What it is. Lp(a) is an LDL-like particle with an additional apolipoprotein(a) tail that makes it both atherogenic and pro-thrombotic. Its level is roughly 80-90% genetically determined and stable across your lifetime.
Standard threshold: <50 mg/dL (or <125 nmol/L) is generally considered low risk. **Healthspan-relevant interpretation:** Risk rises continuously above ~30 mg/dL; levels >180 mg/dL confer cardiovascular risk comparable to heterozygous familial hypercholesterolemia.
Why it predicts healthspan. Mendelian randomization studies (Kamstrup et al., JAMA 2009; PMID: 19531786) established Lp(a) as a causal risk factor for myocardial infarction and aortic stenosis, not merely a correlate. Roughly 20% of the population sits above the high-risk threshold and has no idea.
How to test it. A one-time test is sufficient for most people. Available through Function Health, SiPhox Health, and standard lab orders. Insist on nmol/L units when possible since mass-based assays are less standardized.
What the evidence suggests if it is elevated. No approved drug specifically lowers Lp(a) yet, though several (pelacarsen, olpasiran) are in late-stage trials. Current standard of care: aggressively manage every other modifiable cardiovascular risk factor, particularly ApoB.
3. Fasting Insulin (with HbA1c as confirmation)
What it is. Fasting insulin reflects how hard your pancreas is working to keep glucose in range. It rises years before fasting glucose or HbA1c budge.
Standard "normal" range: typically <25 uIU/mL on most lab printouts. Healthspan-optimal range suggested by the evidence: <7 uIU/mL fasting; HbA1c in the 4.8-5.4% range.
Why it predicts healthspan. Hyperinsulinemia precedes type 2 diabetes by 10-20 years and is independently associated with cardiovascular mortality, cognitive decline, and several cancers. Crofts et al. (2016) reviewed the historical Kraft data showing insulin dynamics predict diabetes long before glucose becomes abnormal. HbA1c above ~5.7% correlates with progressively higher all-cause mortality even within the "non-diabetic" range (Selvin et al., NEJM 2010; PMID: 20200383).
How to test it. Both markers are inexpensive and broadly available through Function Health, SiPhox Health, or any standard lab. Pair with fasting glucose to compute HOMA-IR if you want a single insulin-resistance score.
What the evidence suggests if it is off. Caloric balance, resistance training, sleep duration, and reducing refined carbohydrate intake have the strongest evidence base. Continuous glucose monitoring can be useful diagnostically but is not itself a treatment.
4. VO2max (Cardiorespiratory Fitness)
What it is. The maximal volume of oxygen your body can use per kilogram per minute during peak exertion. It is not technically a blood biomarker, but it is arguably the single most predictive longevity measurement available.
"Average" benchmarks: vary by age and sex; a 40-year-old male average is roughly 35-40 mL/kg/min. Healthspan-relevant target suggested by the evidence: "Elite" or "high" category for your age and sex decile, typically >48 mL/kg/min for men 40-49 and >40 mL/kg/min for women 40-49.
Why it predicts healthspan. The Mandsager et al. (2018) analysis of 122,007 patients in JAMA Network Open found that the difference in all-cause mortality between "low" and "elite" cardiorespiratory fitness was larger than the difference between being a smoker and a nonsmoker, and that there was no observed upper limit of benefit (PMID: 30646252). It is the rare modifiable variable with that magnitude of effect.
How to test it. Gold standard is a CPET (cardiopulmonary exercise test) at a sports medicine or cardiology lab. Reasonable proxies: graded treadmill test, Garmin/Apple Watch estimates (less accurate but trend-useful), or the Cooper 12-minute run test.
What the evidence suggests if it is low. Zone 2 aerobic training 3-4 hours per week plus 1-2 weekly high-intensity intervals (the classic 4x4 protocol from the Wisloff lab has the strongest VO2max-improvement data) is the protocol with the most outcome support. VO2max is highly trainable at any age.
5. Grip Strength (and/or DEXA Appendicular Lean Mass Index)
What it is. Grip strength is a remarkably robust proxy for total-body strength and neuromuscular health. ALMI from a DEXA scan quantifies muscle mass in arms and legs normalized to height.
"Normal" reference: age- and sex-adjusted norms exist but are anchored to a sedentary population. Healthspan-relevant target suggested by the evidence: grip strength above the 75th percentile for your age and sex; ALMI above 7.0 kg/m^2 (men) or 5.5 kg/m^2 (women) at minimum, with higher being protective.
Why it predicts healthspan. The PURE study across 17 countries (Leong et al., Lancet 2015; PMID: 25982160) found each 5 kg decrease in grip strength was associated with a 16% increase in all-cause mortality. Sarcopenia is the silent driver of frailty, falls, and loss of independence in late life, and the muscle you are carrying at 50 strongly conditions what you have at 75.
How to test it. A $30 hand dynamometer at home for grip; a DEXA scan ($50-150 cash pay at most imaging centers) for body composition. Neither is on a typical lab panel.
What the evidence suggests if it is low. Progressive resistance training 2-4 sessions per week, with adequate protein intake (the literature converges on roughly 1.6 g/kg/day for active adults), has the strongest base of evidence for both maintaining and rebuilding muscle.
The 3 Biomarkers That Get Attention but Don't Matter Much
1. Total Cholesterol (in isolation)
A single number that smashes together atherogenic particles (LDL, VLDL, Lp(a)) and protective ones (HDL) and reports their cholesterol cargo. It is the lipid equivalent of judging a city by its average building height. ApoB renders it largely obsolete for risk stratification. Useful as a screening cost-saver in resource-limited settings, not as a decision-making input for someone willing to order ApoB.
2. LDL-C (when ApoB is available)
LDL-C is a calculated (or, less often, directly measured) estimate of the cholesterol content of LDL particles. In roughly 20% of adults, particularly those with insulin resistance, hypertriglyceridemia, or small dense LDL phenotypes, LDL-C systematically underestimates particle number and therefore risk. If you can get ApoB, ApoB wins on every comparative head-to-head. LDL-C is not "wrong," it is just lower-resolution.
3. The Generic Annual CBC (in an asymptomatic, healthy adult)
A complete blood count is essential when you have symptoms, a known condition, or are on certain medications. As an annual screening tool in an otherwise healthy 35-year-old it has very low pre-test probability of changing any decision. It persists in physicals largely by tradition and billing convenience. Skipping it in favor of ApoB, Lp(a), fasting insulin, and hs-CRP is a meaningfully better use of the same blood draw and the same dollar.
This Week's One Thing to Do
Order an ApoB test. If you have never had one, this is the highest-leverage single data point you can add to your file this month. It is roughly $20-40 a la carte through Function Health or SiPhox Health, or as part of a broader panel. Whatever your LDL-C has been telling you, ApoB will tell you something more accurate.
If you already know your ApoB, add Lp(a) once. It is genetic, stable, and you only need to do it a single time in your life.
Sign-off
This is Issue 01 of First Principles Healthspan. The plan: a short, citation-anchored briefing every week on a single high-leverage healthspan question. No supplements to sell, no protocol to join, no 47-step morning routine.
If there is a marker, intervention, or claim you want me to take apart in a future issue, just reply to this email. I read every response.
Until next week, Akash S. Chauhan
Education only. Not medical advice. Always consult a licensed clinician for individual decisions.