4.6. Metabolomics

Tens of thousands of metabolites are found in plasma.[133] Since the circulating blood collects metabolites from all organs, metabolomic profiling provides very integral data of human phys- iology and age-related degenerative processes. The metabolome changes constantly over time and in response to myriad fac- tors, complicating the interpretation of results, but at the same time opening a unique opportunity for comprehensive analy- sis. The advantages of metabolomics in aging research over other omics approaches are enhanced sensitivity and predictabil- ity to the physiological state of the body, as well as the po- tential rapid responsiveness to intervention (diet, lifestyle, and drugs).[93] However, similar to proteomics, current metabolomics analytical methods cover only a limited fraction of circulating metabolites in a single experiment.[90]

These and similar biomarkers of physical capability and phys- iological function can be applied as a general assessment of over- all health status for middle-aged and elderly subjects in clinical settings; however, measurable changes in physical function and organ morphology generally occur in the late stage of aging and such biomarkers are less effective at early stages, prior to overt diseases onset.

Earlier studies had analyzed several hundred plasma com- pounds and a large number of them showed statistically signif- icant changes in concentration with age.[134] Advances in high- throughput technologies allow metabolomics profiling on co- horts having a larger size and with enhanced accuracy. In the largest to date metabolomics study (44 168 individuals from 12 cohorts), 14 circulating biomarkers were independently asso- ciated with all-cause mortality, and these associations were simi- lar for men and women and across different ages.[63] The identi- fied biomarkers related to lipoprotein and fatty acids metabolism, glycolysis, fluid balance, and inflammation. Most are well-known risk factors for age-related diseases, such as lipids, glucose, or al- bumin, but their strong independent effect, when combined into one model, was shown for the first time. Importantly, the model based on metabolomic biomarkers and sex had higher predic- tion accuracy of 5- and 10-year mortality than a scoring model composed of conventional risk factors (body-mass index, systolic blood pressure, total cholesterol, etc.). It was therefore confirmed that despite the impermanentnatureof the metabolome, circulat- ing concentrations of particular metabolites measured at a single point in time can predict future clinical outcomes years later.

5.2. Digital Biomarkers

Over the last decade, cheap, portable, and wearable digital devices have emerged as novel tools for monitoring individual health sta- tus inside and outside of the clinic. These advances have spurred the development of so-called digital biomarkers, defined as pa- rameters collected by sensor elements and processed from raw data using the device’s software and hardware. Depending on the method of signal detection, the sensors can be classified into two main groups: physical and biochemical.

Physical sensors are able to measure a number of clinically- relevant physiological characteristics, including the temperature of human skin (by digital thermometer), blood pressure (by digi- tal sphygmomanometer), body motion (by gyroscope, accelerom- eter, and magnetometer), heart rhythms (by wearable electro- cardiograph), heart rate (by photoplethysmography device), and

A particular area of interest is the metabolome of long-lived individuals. Cross-sectional metabolome profiling was carried

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 Molecular & cellular biomarkers~ Genomic instability& mutations- Epigenetic modification- Loss of proteostasis- Mitochondrial dysfunction& oxidative stressSystemic biomarkers- Dysregulated nutrientsensing- Classic blood-based biomarkers- Inflammatory markers- Increased cell senescence- Decreased stemness ~ Hormones- Altered intercellular ~ Metabolic markerscommunication - Organ-specific biomarkers ehetteratePhysical abilityand functionalperformancetesting       eas eenee etsEen rus)   eee an eeu tesCiehiernukes etchishstetes   eres cere tralBeco cicutkelee eresreeitBiomarker-basedmetrics    AGE  Transcriptomics & miRNA omics.Omics-based molecule-pattern biomarkersGenomics & epigenomics Proteomics MetabolomicsreeAging profiles   

Figure 2. The diversity of aging biomarkers in humans. Existing groups of biomarkers show distinct preferences for different stages of aging progression. As people age very differently, the most accurate way to measure degeneration and to predict future outcomes seems to be the use of integrative biomarkers-based metrics able to define personalized trajectories of aging, or aging profiles.

clinical settings is limited due to the labor-intensive and time- consuming modes of detection. Circulating systemic biomark- ers, which are typically used in clinical practice for the diagno- sis of medical conditions and diseases, are more relevant in the later stages of aging progression (Figure 2); moreover, different composite sets of clinical biomarkers are broadly incorporated in current models for biological age assessment and risk predic- tion. Classical anthropometric measurements, physical and cog- nitive functionality measurements, together with rising digital biomarkers, complement discrete molecular biomarkers in the evaluation of health at advanced ages.

blood oxygen levels (by noninvasive pulse oximeter). These mea- surements complement and can even replace traditional physio- logical tests.[141]