Article DOI: http://dx.doi.org/10.13140/RG.2.2.16033.74084
I created the 13 Zolman Biological Age Marker Criteria (Z-BAM criteria). This is the process I use to VALIDATE biological age markers for 20one Clinic (www.20one.clinic) and teaching clinicians Longevity Escape Velocity Medicine clinical speciality (www.longevity.school)
Summarised checklist of the 13 Z-BAM criteria
- Marker should have a named categorical physical body, organ system, organ, sub-organ, tissue, cell or sub-cellular process as metadata (groups of organ markers can be weighted together to more accurately calculate whole organ biological age for example, e.g. PWV + 1D intima media + 2D intima media + 3D intima media + Augmentation Index + central BP + 24 hour BP + longitudinal strain + diameters + quantitative calcification + plaque characteristics AT 20 DIFFERENT MAJOR ARTERIES will better predict arterial age than any one or subset of these markers alone)
- Should be measured by gold standard methods
- Should have a biological age resolution of 5 years - ideally 2 - years AFTER adjusting for patient, assay and operator variation coefficients
- Should make biogerontological & clinical sense that it is a good biological age marker
- Multiple readings to increase accuracy should be done if possible
- Should not require chronological age to be calculated
- Should only be used to calculate biological age for the biological ages it is relevant to (e.g. Augmentation index only changes for age 18-50 and then caps out, Pulse wave velocity doesn't change until age 30, and then may not cap out at all).
- Biological age reference range graphs must only be used with their matching device
- Reference graphs should be based on a healthy population with good inclusion exclusion criteria, ideally with high longevity level 1 scores
- All graphs should be fitted with the best fitting curves such as linear, exponential, logarithmic, polynomial 2/3/4/5/6 and axes switched to create a biological age equation
- Gender, ethnicity, height and other confounders should be taken into account to customise biological age equations to more specific demoraphics
- Should have some evidence of older ages resulting in worse clinical or in vitro outcomes
- Should not be conflated with accelerated aging markers, for example quantitative shear wave elastography or magnetic resonance elastography of the liver
As per 20one Clinic, we will be measuring biological age markers in ALL 78 organs, as we believe it is non-scientific to attempt to prove cure for ageing (Longevity Escape Velocity over 1 year/year in clients with over 95% confidence) without such data.
There is a lack of consensus on what makes a good organ biological age criteria, and other than a limited number of lung (FEV1/FVC/PEFR/DLCO) or arterial markers (PWV), biological ages are rarely used in clinical practice. Some non-clinical services such as consumer apps may give a 'brain age', or 'skin age' (Visia 7 TruSkin age) or 'hearing age', however these markers are not valid. Likewise, exercise testing services and the American College of Sports Medicine may use 'exercise marker performance age' typically only for VO2 max, despite the ACSM guidelines having age related reference ranges for many other fitness tests.
Through the author's experience creating hundeds of organ specific, sub-organ specific and multi-organ specific biological age markers to use clinically in 20one Clinic and the author's own created medical specialty (Longevity Escape Velocity Medicine - LEVMED), initial quality criteria (Zolman Biological Age Marker (Z-BAM) criteria) were made.
Previous publications were taken into account such as Butler et al. [Butler R.N., 2004], recommendations for ageing biomarkers:
● change with age; --> Butler does not clarify the AMOUNT that they need to change with age to have clinical and statistical significance taking into account intra/inter assay, subject and operator variation and biological age resolution.
● predicting death is better than calendar age --> I note that this is a very outdated view, as death is the least powered marker, other clinical outcomes, high level surrogates and low level surrogate markers are now much more modern views of longevity medicine rather than death (note the paper is in 2004)
● to determine the early stages of a specific pathology, in particular - an age-related
● be minimally invasive - does not require major surgery or painful procedure.
And Moskalev [Moskalev A., 2019] recommendations:
● have a high sensitivity to early signs of aging of the body;
● be predictable over the foreseeable time frame;
● have low analytical variability - be reliable and reproducible.
- Biological age markers can be for a one or a combination of a particular organ e.g. 'lens age', organ system e.g. 'cardiovascular system age', multi-organ system 'e.g. exercise performance age', whole-body e.g. 'PBMC WBC DNAm GrimAge all cause-mortality age', sub-organ region e.g. 'left prefrontal cortex grey matter age' , tissue or cell type 'e.g. liver sinusoidal endothelial cell age', sub-cellular structure e.g. 'mitochondrial age', SENS or Lopez-Otin or similar hallmark of ageing damage type e.g. 'extracellular matrix extracellular crosslinking age'
- Should be measured by gold standard methods, or methods validated with sufficient sensitivity, specificity, inter and intra and inter-operateror variability to the gold standard (e.g. Withings Body Cardio scales are validated against Sphygmocore for Carotid Femoral Pulse Wave Velocity with around 85% accuracy, whereas fingertip PWV measures are not validated as such and should not be used)
- Should have at least a biological age resolution of 5 years after adjusting for intra-day and intra-month variation, ideally 2 years, taking into account individual intra-day and intra-monthly variation. This means the result of the test should be able to distingush people. For example AST is not a biological age marker because data suggests it only raises from 24 to 28 from age 20 to 80. As such the delta is 4 IU/L for 60 years biological age change; 60/4 = resolution of 15 years, taking into account +/=2 IU intra-day or intra-month or intra-assay variation (which is already generous!), the resolution then becomes 60/(4-(2+2) = infinity years resolution... an awful marker.
- Should make biogerontological & clinical sense that it is a good biological age marker. For example, cholesterols, vitamins, minerals, acute phase reactants are hard to prove they are good biological age markers as they are just dietary controlled, and hence are 'damage causing markers' i.e. markers that cause damage when suboptimal for the individual that lead to biological ageing of organs. Another example is creatinine and urea, it is hard to justify them as good biological age markers of kidneys as they are confounded so heavily by creatinine intake, muscle mass, protein intake etc; rather cystatin-C or imaging based markers of kidney trump these.
- Means of multiple readings of the same marker should be used to reduce noise, for example using triplicate measurements of Diagnoptics AGE volar forearm autofluorescence with no confounding factors, rather than single measures; or using 7 or 30 day mean average of whoop 5 min deep sleep RMSSD HRV rather than 1 day.
- Should not require chronological age in the equation to be calculated (e.g. PhenoAge Blood Panel, Visia TruSkin Age, Mobilograph PWV equation (which is likely why mobilograph has not received FDA approval for this marker))
- Should only be used to calculate biological age for the biological ages it is relevant to; for cystatin-C does not rise until after age 33 in healthy people, similarly with PWV; Montreal Cognitive assessment does not fall until after age 60 in healthy people; so these markers must be capped at predicting biological age to the point at which they start changing. On the other hand, creatinine and urea start rising before age 33, relevant to kidney health, augmentation index starts rising before age 33 for arteries, and digit symbol score and other cognitive tests start declining from age 30 rather than 60. The same applies at the top end of the markers change with age, augmentation index stops changing after around age 50-60, whereas PWV keeps rising past age 70. Augmentation index only applies from for example age 18-50, PWV from age 30-80.
- Biological age reference range graphs must only be used with their matching device: E.g. Sphygmocore and other applanation tonometry devices, or ultrasound based PWV measurements, or Withings Body Cardio each have their own 'age graph' with different references ranges for each device, however the shapes of the graphs are normally highly similar, just translated. Each biological age marker should have its data plotted against chronological age on the X axis, and the device and methodology used to measure it recorded as metadata to this graph. ONLY the same device used for the data created in the graph should be used to use that graph to calculate biological age, unless proven sufficiently otherwise.
- Refernce graphs should be based on a healthy population with good inclusion exclusion criteria, ideally with high longevity level 1 scores (150 mins+ weekly moderate or vigorous MET exercise, high AHEI-2010 diet scores, calorie restricted with optimal nutrition, BMI 18.5-22.5, no major conditions, never smoker, alcohol maximum 2 units per day)
- All graphs should be fitted with the best fitting curves such as linear, exponential, logarithmic, polynomial 2/3/4/5/6 and axes switched to create a biological age equation for the specific marker measured with that device with that methodology in each demographic.
- Gender, ethnicity, height and other confounders should be taken into account to customise biological age equations to more specific demoraphics - the GLI project for lung function is a great example of this, as well as the CKD-EPI project for eGFR.
- Should have some evidence of older ages resulting in worse clinical or in vitro outcomes
- Should not be conflated with accelerated aging markers, for example quantitative shear wave elastography or magnetic resonance elastography of the liver shows no increase with age, almost counterintuitively, likewise with liver blood markers, hence NAFLD, NASH and liver fibrosis are not age-related diseases but rather show ACCELERATED AGING and hence can be justifiably mathematically scored to be older than ones chronological age for that organ/system/tissue, but NOT younger and hence cannot prove rejuvenation. On the other hand, liver parenchymal volume, diffusion weighted quantitative MRI markers and senesncent cell loads on biopsy do all increase with age.
Similar to AGREE-II, AMSTAR-II, STROBE and other checklists, this checklist can be used in a similar fashion by journals, funders, investors, researchers and clinicians.
As per 20one Clinic, we will be measuring biological age markers in ALL 78 organs, as we believe it is non-scientific to attempt to prove cure for ageing without such data.
Clincians and researchers should contribute peer-review to this publication and use Z-BAM checklist to create new biological age markers as well as critique others' claims or insinuations that they are doing quality biological age measurements.